Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Chiral oxazolines in asymmetric synthesis and studies on the development of organosilicon reagents Hoy, Kevin 1987

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1987_A1 H65.pdf [ 16.42MB ]
Metadata
JSON: 831-1.0060457.json
JSON-LD: 831-1.0060457-ld.json
RDF/XML (Pretty): 831-1.0060457-rdf.xml
RDF/JSON: 831-1.0060457-rdf.json
Turtle: 831-1.0060457-turtle.txt
N-Triples: 831-1.0060457-rdf-ntriples.txt
Original Record: 831-1.0060457-source.json
Full Text
831-1.0060457-fulltext.txt
Citation
831-1.0060457.ris

Full Text

CHIRAL OXAZOLINES IN ASYMMETRIC SYNTHESIS AND STUDIES ON THE DEVELOPMENT OF ORGANOSILI CON REAGENTS by KEVIN HOY B . S c , U n i v e r s i t y of B r i t i s h C o l u m b i a , 1981 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (Department of C h e m i s t r y ) We accept t h i s t h e s i s as conforming to the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA June 1987 © Kev in Hoy, 1987 In p resen t i ng this thesis in part ial fu l f i lment o f the requ i remen ts for an a d v a n c e d d e g r e e at the Univers i ty o f Br i t ish C o l u m b i a , I agree that the Library shal l m a k e it f reely avai lable for re fe rence and s tudy . I fur ther agree that pe rm iss ion for ex tens i ve c o p y i n g o f th is thesis for scho la r l y p u r p o s e s may be g ran ted by the h e a d o f m y depa r tmen t o r by his o r he r representa t ives . It is u n d e r s t o o d that c o p y i n g o r pub l i ca t i on of this thesis fo r f inanc ia l ga in shal l not b e a l l o w e d w i t hou t m y wr i t ten p e r m i s s i o n . D e p a r t m e n t o f T h e Un ivers i ty o f Brit ish C o l u m b i a 1956 M a i n M a l l V a n c o u v e r , C a n a d a V 6 T 1Y3 Da te DE-6 (3 /81 ) i i ABSTRACT T h i s t h e s i s i s d i v i d e d I n t o two c h a p t e r s . C h a p t e r I d e s c r i b e s t h e s y n t h e s i s o f s e v e r a l n o v e l c h i r a l o x a z o l i n e s and i n v e s t i g a t i o n s o f t h e i r u t i l i t y i n a s y m m e t r i c s y n t h e s i s . O x a z o l i n e 33, p r e p a r e d f r o m L - P h e n y I a I an I n e , a n d o x a z o l i n e s 7 5 . 7 6 . 7 7 . a n d £3_, p r e p a r e d f r o m L - t y r o s l n e , w e r e s u b j e c t e d t o a d e p r o t o n a t I o n - a I k y I a t I on s e q u e n c e . The d i a s t e r e o m e r i c e x c e s s o f t h e a l k y l a t e d o x a z o l i n e p o s s e s s i n g t h e S_-conf i g u r a t i on a t t h e a - c h i r a l c a r b o n was o n l y m o d e s t ( 2 0 - 2 3 % ) a s d e t e r m i n e d by 1 H nmr s p e c t r o s c o p y . The e x p e c t e d i n c r e a s e In d l a s t e r e o -s e l e c t i v i t y , d u e t o s t e r i c a n d c h e l a t i o n e f f e c t s , w i t h t h e m o d i f i e d o x a z o l i n e s 23, 23, 12., a n d £3_ was n o t o b s e r v e d . The s e c o n d c h a p t e r d e a l s w i t h v a r i o u s a s p e c t s o f t h e c h e m i s t r y o f o r g a n o s i I I c o n c o m p o u n d s . Ou r a t t e m p t s t o d e v e l o p a s i l i c o n - b a s e d p r o t e c t i n g g r o u p f o r a l c o h o l s a n d a m i n e s met w i t h o n l y l i m i t e d s u c c e s s . Su I f o n y I c h l o r i d e 23, p r e p a r e d f r o m 4 - c h I o r o t o I u e n e , was c o n v e r t e d t o s e v e r a l s u l f o n a t e s 22. a n d s u l f o n a m i d e s 1 0 0 . The p r o p o s e d d e p r o t e c t l o n by a f l u o r i d e -I n d u c e d f r a g m e n t a t i o n p r o c e s s d o e s a p p e a r t o p r o c e e d t h r o u g h a s u l f e n e I n t e r m e d i a t e . H o w e v e r , t h e s u c c e s s o f t h e d e p r o t e c t i o n a p p e a r s t o be d e p e n d e n t on an a n h y d r o u s s o u r c e o f f l u o r i d e i o n , t h e a b s e n c e o f I n t e r n a l p r o t o n s o u r c e s , a n d s t a b i l i z e d l e a v i n g g r o u p s . A p r o p o s e d d e o x y g e n a t i o n m e t h o d i n v o l v i n g f I u o r I d e - i n d u c e d f r a g m e n t a t i o n o f s I I a n e c a r b o x y I Ic e s t e r s was n o t s u c c e s s f u l . T r e a t m e n t o f e s t e r s 148 a n d 157 d i d n o t g i v e a n y o f t h e d e s i r e d d e o x y g e n a t I on p r o d u c t s o c t a n e a n d p.-n I t r o t o I u e n e , r e s p e c t i v e l y , i I I but I n s t e a d gave q u a n t i t a t i v e y i e l d s o f 1 - o c t a n o l and D _ - n i t r o -b e n z y l a l c o h o l . A g e n e r a l and c o n v e n i e n t method o f p r e p a r i n g sI I a n e c a r b o x y I Ic a c i d s has been d e v e l o p e d . O z o n o l y s i s o f b i s -s i I y I a c e t y I e n e s 139 i n d i c h I o r o m e t h a n e a t - 2 4 ° C g i v e s e i t h e r t h e s y m m e t r i c s l l y l sI I a n e c a r b o x y I a t e s 140 o r s i I a n e c a r b o x y I Ic a c i d s 132 d i r e c t l y i n c a s e s where t h e s l l y l g r o u p Is not s t e r l c a l l y h i n d e r e d . S l l y l sI I a n e c a r b o x y I a t e s 140 a r e t h e n r e a d i l y c o n v e r t e d by a c i d - c a t a l y z e d h y d r o l y s i s o r m e t h a n o l y s l s t o sI I a n e c a r b o x y I i c a c i d s . The k i n e t i c s o f t h e t h e r m a l r e a r r a n g e m e n t o f s e v e r a l s I I a n e c a r b o x y I I c e s t e r s In o_-d i c h I o r o b e n z e n e t o g i v e t h e c o r r e s p o n d i n g s l l o x a n e s were s t u d i e d by m o n i t o r i n g t h e p r o g r e s s o f t h e r e a c t i o n s by 1H nmr s p e c t r o s c o p y . T h e s e f i r s t - o r d e r r e a r r a n g e m e n t s a r e c h a r a c t e r i z e d by l a r g e f r e e e n e r g i e s o f a c t i v a t i o n o f a b o u t 32 k c a l / m o l e a t 120°C. The t h e r m o l y s i s o f sI I a n e c a r b o x y I Ic a c i d s has been d e t e r m i n e d t o p r o c e e d by a d i f f e r e n t pathway t o g i v e o n l y t h e c o r r e s p o n d i n g s l l y l f o r m a t e s . A c i d - c a t a l y z e d a l c o h o l y s i s o f s l l y l sI I a n e c a r b o x y I a t e s and s l l y l c a r b o x y l a t e s has been f o u n d t o p r o c e e d by a s i l y I - o x y g e n c l e a v a g e mechanism. K i n e t i c s t u d i e s showed t h a t t h e a c i d -c a t a l y z e d h y d r o l y s i s o f i - b u t y I d I m e t h y I s i IyI phenyI a c e t a t e i s an o v e r a l l t h i r d - o r d e r r e a c t i o n . O n l y t h e A^|_2 mechanism i s c o n s i s t e n t w i t h t h e r e s u l t s of" b o t h t h e c h e m i c a l and k i n e t i c s t u d i e s . T h i s r e s u l t r e p r e s e n t s t h e f i r s t d e m o n s t r a t I on o f c a r b o x y l l c e s t e r h y d r o l y s i s p r o c e e d i n g by t h e A ^ L 2 mechanism. I V o CH 3CH 2-^ J [ I ^ d Z-S^Q-CH.SiMea O £8. R=H ZI R=OMEM 9 8 7 _ r , 25. R=OMe &3_ R=OCH2Ph 77 i'™ 23. R=OMOM ^ Z = R ? o im Z = R1R2N C H 3 0 I II D 2 r,2 t-Bu-Si—C-OR ^ R R 1-Si-CsC-Si-R 1 R3 R3  139 R2 O R2 . I II I R1-Si—C-OSi-R1 R3 R3  140 R^  R1-Si-C02H 122. V TABLE OF CONTENTS P a g e ABSTRACT • ' TABLE OF CONTENTS V L I S T OF TABLES ix L I S T OF FIGURES x i L I S T OF ABBREVIATIONS x i i i COMPOUND INDEX xv ACKNOWLEDGEMENTS x v i i CHAPTER I: ASYMMETRIC SYNTHESIS USING NOVEL CHIRAL OXAZOLINES 1 1 . 1 I n t r o d u c t I on 2 1.1.1 A s y m m e t r i c S y n t h e s i s 2 1.1.2 C h i r a l O x a z o l i n e s . 9 1.1.3 P r o p o s e d Use o f Some New C h i r a l O x a z o l i n e s i n A s y m m e t r i c S y n t h e s i s 16 1.2 D i s c u s s I on 20 1.2.1 P r e p a r a t i o n o f 2 - S u b s t I t u t e d 4 (S_) -Benzy I -o x a z o I i nes 20 1.2.2 4(S_)-Benzy l o x a z o l I nes as a C a r b o x y l i c A c i d P r o t e c t i n g Group 28 1.2.3 C h i r a l A l k y l a t i o n o f ( - ) - 2 - E t h y l -4 (S_) - b e n z y I -o x a z o II ne 35 1.2.4 P r e p a r a t i o n o f 2 - E t h y l D e r i v a t i v e s o f 4 ( S J -(4- M e t h o x y b e n z y I ) o x a z o I i ne, 4 ( S _ ) - [ 4 - ( 2 - O x a -p r o p y I oxy) benzy I ] o x a z o l i n e , and 4( S_)-[4-( 2 ,5-D i o x a h e x y I o x y ) b e n z y I ] o x a z o I Ine 48 1.2.5. C h i r a l A l k y l a t i o n o f Some T y r o s I n e - d e r i v e d C h i r a l O x a z o l i n e s 55 1.2.6 C o n c l u s i o n 62 v i Page CHAPTER I I : SOME CHEMISTRY OF ORGANOSILI CON COMPOUNDS . . 63 PART A. STUDIES ON THE DEVELOPMENT OF A NOVEL SILICON-BASED PROTECTING GROUP 2A.1 I n t r o d u c t Ion 64 2A.1.1 S i l i c o n - b a s e d P r o t e c t i n g G r o u p s and F l u o r i d e C l e a v a g e s 64 2A.1.2 P r o p o s e d P r o t e c t i n g Group 70 2A.2 D i s c u s s Ion 74 2A.2.1 P r e p a r a t i o n o f 4 - [ ( T r I m e t h y I s I I y I ) m e t h y I ] -b e n z e n e s u I f o n a m I d e s and - s u l f o n a t e s 74 2A.2.2 F l u o r I d e C l e a v a g e s o f 4 - [ ( T r I m e t h y I s I I y I ) -m e t h y I ] b e n z e n e s u I f o n a m I d e s and - s u l f o n a t e s . . 78 2A.2.3 C o n c l u s i o n 87 PART B. STUDIES ON THE DEVELOPMENT OF A DEOXYGENATI ON METHOD 2B.1 I n t r o d u c t Ion 88 2B.1.1 E x i s t i n g D e o x y g e n a t I o n Methods 88 2B.1.2 P r o p o s e d D e o x y g e n a t i o n Method 90 2B.2 D i s c u s s i o n 94 2B.2 . 1 P r e p a r a t i o n o f 3 - ( T r i m e t h y I s I I y I ) p r o p a n o i c E s t e r s and A t t e m p t e d F l u o r i d e C l e a v a g e s . . . . 94 2B.2.2 A t t e m p t e d P r e p a r a t i o n s o f SI I a n e c a r b o x y I Ic A c i d s 97 2B.2.3 S i I a n e c a r b o x y I i c A c i d s from B i s - s i I y I a c e t y I e n e s 102 2B.2.4 P r e p a r a t i o n o f SI I a n e c a r b o x y I Ic E s t e r s and F l u o r i d e C l e a v a g e s 114 2B.2.5 C o n c l u s i o n 126 PART C. THERMAL REARRANGEMENT OF SILANECARBOXYLIC ACIDS AND ESTERS 2C.1 I n t r o d u c t i o n 127 V l I P a g e 2 C . 1 . 1 I n i t i a l O b s e r v a t i o n s a n d P r e v i o u s Work . . . . 127 2 C . 1 . 2 K i n e t i c T h e o r y 130 2 C . 2 DI s c u s s I on 136 2 C . 2 . 1 R e a r r a n g e m e n t o f S i I a n e c a r b o x y I I c A c i d s a n d E s t e r s : D e t e r m i n a t i o n o f A c t i v a t i o n P a r a m e t e r s 136 2 C . 2 . 2 R e a r r a n g e m e n t o f SI I a n e c a r b o x y I i c A c i d s . -F o r m a t i o n o f F o r m a t e s 150 2 C . 2 . 3 C o n c l u s i o n 160 PART D. A C I D - C A T A L Y Z E D H Y D R O L Y S I S OF S I L Y L E S T E R S : E V I D E N C E FOR THE A A L 2 MECHANISM 2 D . 1 I n t r o d u c t I on 161 2 D . 1 . 1 A c i d - a n d B a s e - c a t a l y z e d H y d r o l y s i s o f E s t e r s . 161 2 D . 1 .2 The A A L 2 M e c h a n i s m - . P r e v i o u s Work 167 2 D . 1 . 3 P r o p o s e d I n v e s t i g a t i o n 170 2 D . 2 D i s c u s s i on 172 2 D . 2 . 1 A c i d - c a t a l y z e d M e t h a n o l y s i s o f S i l y l S i l a n e -c a r b o x y I a t e s - . C h e m i c a l E v i d e n c e f o r t h e A A j_2 M e c h a n i s m 172 2 D . 2 . 2 A c i d - c a t a l y z e d A l c o h o l y s i s o f S i l y l C a r b o x y l a t e s 177 2 D . 2 . 3 K i n e t i c s o f t h e A c i d - c a t a l y z e d H y d r o l y s i s o f S i l y l C a r b o x y l a t e s : K i n e t i c E v i d e n c e f o r t h e A A L 2 M e c h a n i s m 182 2 D . 2 . 4 C o n c l u s i o n 194 E X P E R I M E N T A L 195 G e n e r a l 196 C h a p t e r I 2 0 0 C h a p t e r I I , P a r t A 227 C h a p t e r I I , P a r t B 243 C h a p t e r I I , P a r t C 272 C h a p t e r I I , P a r t D 278 v l l l P a g e B I B L I O G R A P H Y 282 A P P E N D I X A : K I N E T I C D A T A F O R T H E R M A L R E A R R A N G E M E N T O F S I L A N E C A R B O X Y L I C A C I D S A N D E S T E R S 292 A P P E N D I X B : K I N E T I C D A T A F O R A C I D - C A T A L Y Z E D H Y D R O L Y S I S O F S I L Y L C A R B O X Y L A T E S 305 A P P E N D I X C : 1 H N M R A N D I R S P E C T R A 312 i x L I S T OF T A B L E S Tab Ie T i t l e P a g e I E f f e c t o f O x a z o l i n e S u b s t i t u e n t s on A s y m m e t r i c I n d u c t i o n 13 II E f f e c t o f S u b s t i t u e n t s on E n o l a t e F o r m a t i o n u s i n g 3 - M e t h y I - 3 - s u b s t I t u t e d C y c I o p e n t a n o n e s 16 I I I D e t e r m i n a t i o n o f D i a s t e r e o m e r I c E x c e s s i n A l k y l a t i o n o f O x a z o l i n e 5_£ a t - 7 8 ° C 44 IV A s y m m e t r i c S y n t h e s i s u s i n g N o v e l C h i r a l O x a z o l i n e s 60 V B o n d D i s s o c i a t i o n E n e r g i e s f o r S I - X a n d C - X . . . 65 VI R e l a t i v e E l e c t r o n e g a t i v i t y 66 V I I P r e p a r a t i o n o f 4 - [ ( T r i m e t h y I s i I y I ) m e t h y I ] b e n z e n e -s u I f o n a t e s a n d - s u l f o n a m i d e s 77 V I I I D e p r o t e c t i o n s w i t h BTAF 79 IX D e p r o t e c t I o n s w i t h D 2 0 - t r e a t e d BTAF 82 X P r e p a r a t i o n o f 3 - ( T r i m e t h y I s I I y I ) p r o p a n o i c E s t e r s 95 XI A t t e m p t e d F l u o r i d e C l e a v a g e s o f E s t e r 129a . . . 96 X I I A t t e m p t e d S y n t h e s i s o f T r i m e t h y I s I I a n e c a r b o x y I i c A c i d v I a S l l y l A n i o n s 99 X I I I O x i d a t i o n o f T r i m e t h y I s I I y I m e t h a n o I 101 X I V P r e p a r a t i o n o f B I s - s I I y I a c e t y I e n e s 103 XV O z o n o l y s i s o f B I s - s i I y I a c e t y I e n e s 108 XVI A t t e m p t e d A c t i v a t i o n o f i - B u t y I d i m e t h y I s I I a n e -c a r b o x y l i c A c i d 114 X V I I P r e p a r a t i o n o f S i I a n e c a r b o x y I i c E s t e r s 1 4 8 . 1 5 5 - 1 5 7 121 X V I I I A t t e m p t e d D e o x y g e n a t I on o f E s t e r 148 122 X I X T h e r m a l R e a r r a n g e m e n t o f S i I a n e c a r b o x y I i c A c i d s a n d E s t e r s i n o_-D I c h I o r o b e n z e n e 137 XX R a t e C o n s t a n t s f o r R e a r r a n g e m e n t o f S i l a n e -c a r b o x y l i c A c i d s a n d E s t e r s a t 120°C 147 X T a b l e T i t l e Page XXI A c t i v a t i o n P a r a m e t e r s f o r R earrangement o f S l l a n e -c a r b o x y l i c A c i d s and E s t e r s In o_-D I ch I o r o b e n z e n e 148 XXII D e t e r m i n a t i o n o f C a r b o n M onoxide by Gas C h r o m a t o g r a p h y 158 X X I I I C l a s s i f i c a t i o n o f E s t e r H y d r o l y s i s Mechanisms . . 162 XXIV A c i d - c a t a l y z e d M e t h a n o l y s i s o f S i I a n e c a r b o x y I i c E s t e r s 174 XXV A c i d - c a t a l y z e d E s t e r I f I c a t i o n o f P h e n y l a c e t i c A c i d 178 XXVI A c i d - c a t a l y z e d A l c o h o l y s i s o f i - B u t y I d I m e t h y I -s i l y l Pheny I a c e t a t e 179 XXVII A c i d - c a t a l y z e d A l c o h o l y s i s o f i - B u t y I d i p h e n y I -s i l y l Pheny I a c e t a t e 180 X i LIST OF FIGURES F i g u r e T i t l e Page 1 Energy d i f f e r e n c e between d i a s t e r e o m e r i c t r a n s i t i o n s t a t e s to g i v e enantiomeric products 3 2 P a r t i a l 1H nmr (100 MHz) s p e c t r a of 2 - d e u t e r i o -2-methy I butano I c a c i d (33) In CDC I 3 30 3 Representation of p a r t i a l mass s p e c t r a of a-deuterated a c i d £S and o v e r a l l deuterium i n c o r p o r a t i o n l e v e l 31 4 P a r t i a l 400 MHz ''H nmr spectrum of o x a z o l i n e s 67a and 67b in CDC 13 39 5 P a r t i a l 400 MHz 1H nmr spectrum of o x a z o l i n e s 84a and 84b in CDC 13 prepared by a l k y l a t i o n of o x a z o l i n e 7J5_ at -78°C 56 6 P a r t i a l 400 MHz H^ nmr spectrum of o x a z o l i n e s 85a and 85b In CDC 13 prepared by a l k y l a t i o n of o x a z o l i n e 23 at -78°C 57 7 P a r t i a l 400 MHz 1H nmr spectrum of o x a z o l i n e s 86a and 86b In CDC 13 prepared by a l k y l a t i o n of o x a z o l i n e 22 at -78°C 58 8 P a r t i a l 400 MHz 1H nmr spectrum of o x a z o l i n e s 87a and 87b In CDC 13 prepared by a l k y l a t i o n of o x a z o l i n e 33. at -78 °C 59 9 ORTEP diagram of e s t e r 140d 106 10 P a r t i a l 60 MHz H^ nmr s p e c t r a of rearrangement of e s t e r 140d In g.-d I ch I orobenzene at 140°C . . 139 11 Rate of rearrangement of e s t e r 140d 140 12 E y r i n g p l o t for rearrangement of e s t e r 140d . . 140 13 Rate of rearrangement of e s t e r 156 141 14 E y r i n g p l o t for rearrangement of e s t e r 156 . . . 141 15 Rate of rearrangement of e s t e r 161 142 16 E y r i n g p l o t f o r rearrangement of e s t e r 161 . . . 142 17 Rate of rearrangement of e s t e r 162 143 18 E y r i n g p l o t for rearrangement of e s t e r 162 . . . 143 X i I F i q u r e T i t l e Page 19 R a t e o f r e a r r a n g e m e n t o f e s t e r 155 144 20 E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 155 . . . 144 21 R a t e o f r e a r r a n g e m e n t o f a c i d 132d 145 22 E y r i n g p l o t f o r r e a r r a n g e m e n t o f a c i d 132d . . . 145 23 P a r t i a l 60 MHz 1H nmr s p e c t r a o f r e a r r a n g e m e n t o f a c i d I32d i n d e c a n e a t 125°C 151 24 R a t e o f r e a r r a n g e m e n t o f a c i d 132d i n d e c a n e a t 125°C 152 25 R a t e o f r e a r r a n g e m e n t o f a c i d 132d In t o l u e n e - d 8 a t 100°C 152 26 Gas c h r o m a t o g r a m o f h e a d s p a c e gas In r e a r r a n g e -ment o f e s t e r 140d 155 27 Gas c h r o m a t o g r a m o f h e a d s p a c e gas In r e a r r a n g e -ment o f a c i d 132d 156 28 Gas c h r o m a t o g r a m o f h e a d s p a c e gas In r e a r r a n g e -ment o f a c i d 132e 157 29 T y p i c a l g a s c h r o m a t o g r a m s o f a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I d i m e t h y I s i I y I p h e n y l -a c e t a t e (1521 183 30 R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f w a t e r c o n c e n t r a t i o n 184 31 H y d r o l y s i s o f e s t e r 152: Dependence o f on [ H 2 0 ] . 185 32 H y d r o l y s i s o f e s t e r 152: In k^ v e r s u s In [ H 2 0 ] . 185 33 R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f e s t e r , w a t e r , and a c i d c o n c e n t r a t i o n s 189 34 D e t e r m i n a t i o n o f d e p e n d e n c e on c-TsOH and H 20 . 189 35 R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f t e m p e r a t u r e 191 36 E y r i n g p l o t f o r a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 152 191 X I I I LI S T OF ABBREVIATIONS BTAF = benz y I t r I m e t h y I a m m o n i um f l u o r i d e Bu = b u t y l CDI = 1,1 ' - c a r b o n y I d I ImIdazoIe DBU = 1,8-dIazabI e y e I o [ 5 . 4 . 0 ] u n d e c - 7 - e n e DCC = £i,N.'-dicyclohexylcarbodi i m l d e de = d i a s t e r e o m e r i c e x c e s s DEAD = d i e t h y l a z o d i c a r b o x y I a t e DMAP = 4-dimethy I am I n o p y r I d I n e DME = 1 , 2 - d i m e t h o x y e t h a n e DMF = £J, N.-d Imethy I f o r mam I de DMSO = d i m e t h y l s u l f o x i d e ee = e n a n t i o m e r i c e x c e s s E t = e t h y l e t h e r = d i e t h y l e t h e r h = h o u r ( s ) HMPA = hexamethyI p h o s p h o r i c t r i a m i d e 1H nmr = p r o t o n n u c l e a r m a g n e t i c r e s o n a n c e i r = i n f r a r e d LDA = l i t h i u m dI i s o p r o p y I amide Me = m e t h y l MEM = met h o x y e t h o x y m e t h y I min = m l n u t e ( s ) MOM = methoxymethyI Ms = m e t h a n e s u I f o n y I X I V NBS = N , - b r o m o s u c c i n i m I de Ph = p h e n y l r t = room t e m p e r a t u r e TBAF = t e t r a - n - b u t y I a m m o n I urn f l u o r i d e THF = t e t r a h y d r o f u r a n t i c = t h i n - l a y e r c h r o m a t o g r a p h y Ts = p_-to I u e n e s u I f o n y I F o r s e e a b b r e v i a t i o n s u s e d i n t h e d e s c r i p t i o n o f 1 H nmr s i g n a l s g e n e r a l p a r t o f E x p e r i m e n t a l s e c t i o n . X V COMPOUND INDEX The f o l l o w i n g i s a l i s t o f t h e c o m p o u n d s p r e p a r e d a n d d i s c u s s e d In t h i s t h e s i s . The number o f e a c h c o m p o u n d Is f o l l o w e d by a s e t o f t h r e e n u m b e r s . The f i r s t number r e f e r s t o t h e p a g e w h e r e t h e s t r u c t u r e o f t h e c o m p o u n d a p p e a r s f o r t h e f i r s t t i m e , t h e s e c o n d number r e f e r s t o t h e p a g e w h e r e t h e p r e p a r a t i o n o f t h e c o m p o u n d Is d i s c u s s e d , a n d t h e l a s t number r e f e r s t o t h e p a g e i n A p p e n d i x C w h e r e t h e 1 H nmr a n d i n f r a r e d s p e c t r a o f t h e compound a r e p r o v i d e d . 52 (21 , 2 0 0 , 313) 8 6 * ( 5 8 , 2 2 5 , 321 ) 5.1 (21 , 201 , 313) £ Z * ( 5 9 , 223 , 321 ) 5_a ( 2 3 , 206 , 314) 9 8 * (71 , 229 , 322) 33 ( 2 6 , 2 1 0 , 314) 9 9 a * ( 7 7 , 2 3 0 , 323) 64a ( 3 8 , 2 0 3 , 315) 99b* ( 7 7 , 231 , 323) £ 7 ( 3 4 , 208 , 319) 9_2c_* ( 7 7 , 232 , 324) 33 ( 3 5 , 2 0 8 , 315) 9 9 d * ( 7 7 , 236 , 324) 7 4 * ( 4 9 , 216 , 317) 100a* ( 7 7 , 232 , 325) 7 5 * ( 4 9 , 217 , 318) 100b* ( 7 7 , 233 , 325) 7 6 * (49 , 2 1 8 , 318) .100c* ( 7 7 , 2 3 4 , 326) 7 7 * ( 4 9 , 2 1 9 , 319) 1 0 0 d * ( 7 7 , 2 3 5 , 326) 8 0 * ( 5 0 , 2 1 3 , 316) 100e* ( 7 7 , 2 3 6 , 327) 8_2_* (51 , 2 1 4 , 316) 100f* ( 7 7 , 2 3 7 , 327) 8 3 * ( 5 2 , 2 1 5 , 317) 113. ( 7 5 , 227 , 322) 8 4 * ( 5 6 , 2 2 3 , 320) 1 2 9 a * ( 9 5 , 2 4 5 , 328) 8 5 * ( 5 7 , 2 2 4 , 320) 129b* ( 9 5 , 2 4 6 , 329) XV I 129s* (95, 247, 329) 141d (107, 257, 335) 1 29d* (95, 247, 330) 1 4 § * (112, 255, 333) 13J. (94, 244, 328) 146* (112, 264, 336) 132a* (94, 258, 336) 147* (112, 256, 334) 132b* (98, 259, 337) 148* ( 114, 269, 340) 132C* ( 110, 262, 337) 152 ( 119, 267, 339) 132d* (112, 263, 338) 154 ( 119, 267, 339) 133ft* (97, 261 , 338) 155* ( 121 , 272 , 341 ) 134* (95, 248, 330) 156* ( 121 , 272 , 341 ) 139a (103, 253, 331 ) 157* (121 , 270, 340) 139b (103, 253, 331 ) 161 * (137, 273, 342) 139c (103, 253 , 332) 162* (137, 274, 342) 139d (103, 254, 332) 163a (137, 274, 343) 13?e (103, 255, 333) 13Z (137, 275, 343) 1 4 0 C * (108, 260, 334) 179* (175, 278, 344) 1 40d* (107, 260, 335) 183 ( 181 , 278, 344) An a s t e r i s k i n d i c a t e s new compounds or compounds prepared by a d i f f e r e n t r o u t e from the o r i g i n a l l i t e r a t u r e . X V I i ACKNOWLEDGEMENT I w o u l d l i k e t o e x p r e s s my s i n c e r e t h a n k s t o my s u p e r v i s o r , P r o f e s s o r G o r d o n B a t e s , f o r t h e g u i d a n c e , s u p p o r t , a n d e n c o u r a g e m e n t he p r o v i d e d d u r i n g t h e c o u r s e o f t h i s w o r k . I am e x t r e m e l y g r a t e f u l t o P r o f e s s o r L a r r y W e l l e r f o r t a k i n g t h e t i m e t o r e a d t h e m a n u s c r i p t a n d f o r m a k i n g i n v a l u a b l e s u g g e s t i o n s a n d t o P r o f e s s o r R o s s S t e w a r t f o r h e l p f u l d i s c u s s i o n s i n t h e a r e a o f k i n e t i c s . The c a r e f u l p r o o f r e a d i n g o f t h i s t h e s i s by D r . S . Ramaswamy a n d M r . A u s t i n B a i l e y i s g r e a t l y a p p r e c i a t e d . Many t h a n k s a r e e x t e n d e d t o members o f t h e d e p a r t m e n t a l m a s s s p e c t r o s c o p y , m i c r o a n a l y s i s , x - r a y c r y s t a l l o g r a p h y , a n d nmr l a b s f o r t h e i r c o o p e r a t i o n a n d t e c h n i c a l e x p e r t i s e . F i n a l l y , I w o u l d l i k e t o e x p r e s s my g r a t i t u d e t o my w i f e , B r e n d a , n o t o n l y f o r t h e s k i l l a n d p a t i e n c e s h e e x h i b i t e d l n t y p i n g t h i s m a n u s c r i p t b u t a l s o f o r h e r u n e n d i n g s u p p o r t a n d u n d e r s t a n d i n g t h r o u g h o u t t h e c o u r s e o f t h i s s t u d y . x v i i i To the Loving Memory of My Father 1 CHAPTER I: ASYMMETRIC S Y N T H E S I S US ING NOVEL CHIRAL OXAZOLINES 2 1 . 1 I n t r o d u c t i o n 1.1.1 A s y m m e t r i c S y n t h e s i s T h i s s e c t i o n on a s y m m e t r i c s y n t h e s i s i s n o t i n t e n d e d t o be c o m p r e h e n s i v e b u t r a t h e r t o p r e s e n t g e n e r a l c o n s i d e r a t i o n s w i t h e m p h a s i s on t h e s t r a t e g i e s i n v o l v e d in p e r f o r m i n g a s y m m e t r i c s y n t h e s i s . In a d d i t i o n we s h a l l o n l y be c o n c e r n e d w i t h t h e a s y m m e t r i c s y n t h e s i s o f c h i r a l c e n t e r s . F o r a m o r e c o m p r e h e n -s i v e t r e a t m e n t o f t h i s s u b j e c t , t h e r e a r e many r e v i e w s t o w h i c h r e f e r e n c e 1 " ^ may be m a d e . M o s t o f t h e e a r l y s t e r e o s e l e c t i v e s y n t h e s e s o f n a t u r a l p r o d u c t s w e r e a c h i e v e d in t h e r a c e m i c s e r i e s f o l l o w e d by an o p t i c a l r e s o l u t i o n p e r f o r m e d a t t h e e n d o f t h e s y n t h e t i c s e q u e n c e . T h i s c o u l d be a w a s t e f u l p r o c e d u r e p r e p a r a t i v e I y , s i n c e o n l y o n e o p t i c a l a n t i p o d e was c o n v e r t e d I n t o t h e n a t u r a l p r o d u c t . In a d d i t i o n , r e s o l u t i o n i s u s u a l l y a t e d i o u s and l a b o r i o u s p r o c e s s . T h u s , i t became e c o n o m i c a l l y and e s t h e t i c a l l y a p p e a l i n g t o e x c l u d e u n d e s i r e d o p t i c a l i s o m e r s a t t h e e a r l i e s t p o s s i b l e s t a g e by a s y m m e t r i c f o r m a t i o n o f c h i r a l c e n t e r s . M o s t n a t u r a l p r o d u c t s s y n t h e s e s t o d a y a r e a c c o m -p l i s h e d vI a a s y m m e t r i c " s y n t h e s i s t o g i v e t h e r e q u i r e d a b s o l u t e c o n f i g u r a t i o n s a t c h i r a l c e n t e r s . A s y m m e t r i c s y n t h e s i s Is d e f i n e d a s "a r e a c t i o n In w h i c h an a c h i r a l u n i t i n an e n s e m b l e o f s u b s t r a t e m o l e c u l e s i s c o n v e r t e d by a r e a c t a n t i n t o a c h i r a l u n i t In s u c h a manner t h a t t h e s t e r e o I s o m e r I c p r o d u c t s ( e n a n t i o m e r i c o r d l a s t e r e o m e r l c ) a r e p r o d u c e d i n u n e q u a l a m o u n t s " . 1 T h i s Is t o s a y , an a s y m m e t r i c 3 s y n t h e s i s Is a p r o c e s s w h i c h c o n v e r t s a p r o c h l r a l u n i t i n t o a c h i r a l u n i t s o t h a t u n e q u a l a m o u n t s o f s t e r e o i s o m e r I c p r o d u c t s r e s u l t . T h e r e a c t a n t I n v o l v e d c a n be a s t o i c h i o m e t r i c r e a g e n t , s o l v e n t , o r c a t a l y s t . A s y m m e t r i c s y n t h e s i s Is t h e d e s i r e d m e t h o d f o r o b t a i n i n g c h i r a l m o l e c u l e s s i n c e It p e r m i t s t h e c o n v e r s i o n o f a s much a s 100% o f a p r o c h l r a l compound t o a c h i r a l p r o d u c t d e p e n d i n g on t h e d e g r e e o f a s y m m e t r i c i n d u c t i o n . The g e n e r a l p r o c e s s o f a s y m m e t r i c s y n t h e s i s i n v o l v e s t h e r e a c t i o n o f s u b s t r a t e and r e a g e n t , o n e o f w h i c h must h a v e o n e o r m o r e c h i r a l c e n t e r s t o I n d u c e a s y m m e t r y a t t h e r e a c t i o n s i t e , t o f o r m d i a s t e r e o m e r i c t r a n s i t i o n s t a t e s w h i c h d i f f e r in e n e r g y ( F i g u r e 1 ) . 6 It i s t h e m a g n i t u d e o f t h i s d i f f e r e n c e In f r e e e n e r g y o f a c t i v a t i o n , A A G * , t h a t e v e n t u a l l y d e t e r m i n e s t h e e x c e s s o f one e n a n t i o m e r o v e r t h e o t h e r and h e n c e It Is d e s i r a b l e t o F r e e e n e r g y G A A G * R e a c t i o n c o o r d i n a t e F i g u r e 1. E n e r g y d i f f e r e n c e b e t w e e n d i a s t e r e o m e r i c t r a n s i t i o n s t a t e s t o g i v e e n a n t i o m e r i c p r o d u c t s . 4 m a x i m i z e A AG*. T h i s c a n be a c h i e v e d e i t h e r by l o w e r i n g t h e e n e r g y o f t h e d e s i r e d d i a s t e r e o m e r i c t r a n s i t i o n s t a t e by " f a v o r a b l e i n t e r a c t i o n s " o r by r a i s i n g t h e e n e r g y o f t h e u n d e s i r e d t r a n s i t i o n s t a t e by " u n f a v o r a b l e i n t e r a c t i o n s " . In g e n e r a l , t h e r e a c t i o n o f c h i r a l compound J_ w i t h p r o -c h i r a l compound 2. t o f o r m a new c h i r a l c e n t e r may g i v e two d I a s t e r e o m e r s 3_a and 3_b. T h e d e g r e e o f a s y m m e t r i c I n d u c t i o n d c d c 4a ! k o r t h e d i a s t e r e o s e I e c t I v I t y o f t h i s r e a c t i o n Is g i v e n by t h e v a l u e o f t h e d i a s t e r e o m e r i c e x c e s s ( d e ) ( e q u a t i o n 1) w h e r e r3a1 a n d I2h.l r e p r e s e n t c o n c e n t r a t i o n s o f t h e d I a s t e r e o m e r s . 8 DI a s t e r e o m e r s 3_& and 3_b may s u b s e q u e n t l y be c l e a v e d w i t h t h e f o r m a t i o n o f e n a n t i o m e r s 4a and 4 b . [3ja.]-[3_b_] de(%) = x 100 (1) [3_a.l + r.3_bJ A l t e r n a t i v e l y , c h i r a l compound 1 may r e a c t w i t h p r o c h i r a l compound £ t o g i v e new e n a n t i o m e r s 4a. and 4b d i r e c t l y v I a d i a s t e r e o m e r i c t r a n s i t i o n s t a t e s . T h e e n a n t i o s e I e c t I v i t y o f s u c h a r e a c t i o n i s g i v e n by t h e e n a n t i o m e r i c e x c e s s ( e e ) 5 [4a.]-[4fe] ee(%) = x 100 (2 ) [ a ] 0P(%) = x 100 (3 ) ( e q u a t i o n 2) w h e r e and [4b.] r e p r e s e n t c o n c e n t r a t i o n s o f t h e e n a n t i o m e r s . T h e o p t i c a l p u r i t y (OP) ( e q u a t i o n 3) i s n o r m a l l y I d e n t i c a l t o t h e ee and i t Is d e t e r m i n e d by d i v i d i n g t h e s p e c i f i c r o t a t i o n o f t h e p r o d u c t m i x t u r e by t h a t o f t h e p u r e e n a n t i o m e r . H o w e v e r , o p t i c a l r o t a t i o n m e a s u r e m e n t s a r e a f f e c t e d by i m p u r i t i e s and e x p e r i m e n t a l c o n d i t i o n s s u c h a s t e m p e r a t u r e , c o n c e n t r a t i o n , and s o l v e n t . In a d d i t i o n , t h e maximum o p t i c a l r o t a t i o n o f t h e p u r e e n a n t i o m e r must be known w i t h c e r t a i n t y and f o r new c o m p o u n d s [ a ] m a x Is n o t known and m u s t be d e t e r m i n e d by some m e a n s . T h u s , i t Is b e s t t o d e t e r m i n e t h e e e by a l t e r n a t e m e t h o d s . 1 0 T h e e n e r g y d i f f e r e n c e s i n v o l v e d in d e t e r m i n i n g t h e e x c e s s o f o n e e n a n t i o m e r o r d l a s t e r e o m e r o v e r t h e o t h e r i s a c t u a l l y q u i t e s m a l l b e i n g on t h e o r d e r o f 2 - 3 k c a l / m o l e . A A A G * v a l u e o f a p p r o x i m a t e l y 2 k c a l / m o l e a t 0 ° C i s n e c e s s a r y t o p r o v i d e o n e o f t h e e n a n t i o m e r i c o r d I a s t e r e o m e r I c p r o d u c t s in a t l e a s t an 80% e x c e s s ( 9 0 : 1 0 m i x t u r e ) . 1 1 A s y m m e t r i c r e a c t i o n s c a n be d i v i d e d i n t o two g e n e r a l c l a s s e s a c c o r d i n g t o t h e s t r a t e g y u s e d . T h e f i r s t c l a s s i n v o l v e s t h e r e a c t i o n o f an a c h i r a I compound w i t h a c h i r a l r e a g e n t o r w i t h an a c h l r a l r e a g e n t in a c h i r a l s o l v e n t . In t h e s e c o n d c l a s s , an a c h l r a l compound Is I n i t i a l l y r e a c t e d w i t h a 6 c h i r a l a u x i l i a r y r e a g e n t t o g i v e a c h i r a l I n t e r m e d i a t e c o n t a i n i n g o n e o r more a s y m m e t r i c c e n t e r s . A f t e r p e r f o r m i n g i t s f u n c t i o n o f a s y m m e t r i c i n d u c t i o n , t h e c h i r a l a u x i l i a r y g r o u p Is l a t e r removed f r o m t h e s y s t e m . The c l e a v a g e p r o c e s s s h o u l d t a k e p l a c e w i t h o u t a n y r a c e m l z a t l o n a t t h e n e w l y g e n e r a t e d c h i r a l c e n t e r . W i t h i n t h e two c l a s s e s , a s y m m e t r i c c e n t e r s c a n be c r e a t e d by c o n v e r s i o n o f t r i g o n a l c a r b o n a t o m s t o t e t r a h e d r a l o n e s a t t h e s i t e o f t h e f u n c t i o n a l i t y I n v o l v i n g g r o u p s s u c h a s a c a r b o n y l o r a l k e n e . T h i s a p p r o a c h I n v o l v e s b a s i c a l l y a c h a n g e o f o n e f u n c t i o n a l g r o u p i n t o a n o t h e r w i t h o r w i t h o u t f o r m a t i o n o f a new c a r b o n - c a r b o n b o n d . A l t e r n a t i v e l y , a s y m m e t r i c c e n t e r s c a n be f o r m e d a t a t e t r a h e d r a l c a r b o n f o r e x a m p l e vI a a d e p r o t o n a t I o n - a I k y I a t I on s e q u e n c e . T h e f o l l o w i n g e x a m p l e s a r e r e p r e s e n t a t i v e o f t h e many a s y m m e t r i c s y n t h e s e s w h i c h h a v e b e e n r e p o r t e d . An e x a m p l e o f t h e f i r s t c l a s s o f a s y m m e t r i c r e a c t i o n s Is t h e a s y m m e t r i c a d d i t i o n o f o r g a n o m e t a I I Ic c o m p o u n d s t o c a r b o n y l c o m p o u n d s in t h e p r e s e n c e o f a c h i r a l l i g a n d . 8 ' 1 2 T h e r e a c t i o n o f b e n z a l d e h y d e w i t h n - b u t y I I I t h I urn g a v e a 77% y i e l d o f a l c o h o l £_ in 95% e e when an e x c e s s o f t h e (S_ ) -pro I I ne d e r i v a t i v e 5_ was i n c l u d e d . T h e two n i t r o g e n a t o m s and t h e h y d r o x y l g r o u p o f 5_ a r e n e c e s s a r y f o r t i g h t c o o r d i n a t i o n t o n - b u t y I I I th I urn and t h e PhCHO + n-BuU + 5. 7 r e s u l t i n g c o m p l e x p r o v i d e s an e n v i r o n m e n t f o r g o o d a s y m m e t r i c i n d u c t I o n . 8 T h e a s y m m e t r i c s y n t h e s i s o f p r o s t a g l a n d i n I n t e r m e d i a t e 1Q. d e m o n s t r a t e s t h e u s e o f a s y m m e t r i c h y d r o b o r a t I on t o g i v e c h i r a l a I c o h o I s . 7 ' 1 3 H y d r o b o r a t I o n o f d I e n e 2 w i t h ( + ) - d i I s o p i n o -c a m p h e n y I b o r a n e (fi) f o l l o w e d by a l k a l i n e h y d r o g e n p e r o x i d e o x i -d a t i o n o f o r g a n o b o r a n e 3 g a v e t h e h y d r o x y e s t e r _LQ_ i n 92% e e . T h e a l k y l a t i o n o f k e t o n e s vI a c h i r a l h y d r a z o n e s i s an e x a m p l e o f t h e s e c o n d c l a s s o f a s y m m e t r i c r e a c t i o n s . T h i s m e t h o d i s i l l u s t r a t e d by t h e a s y m m e t r i c s y n t h e s i s o f ( + ) - 4 ( S ) -m e t h y I - 3 - h e p t a n o n e (15. ) , t h e a l a r m p h e r o m o n e o f t h e w i t h t h e c h i r a l a u x i l i a r y r e a g e n t , 1 -am I n o - 2 (£ . ) - m e t h o x y m e t h y I -p y r r o l i d i n e ( IE . ) , t o g i v e t h e c o r r e s p o n d i n g h v d r a z o n e 13 w h i c h was m e t a l a t e d w i t h l i t h i u m dI I s o p r o p y I am Ide (LDA) f o l l o w e d by t r e a t m e n t w i t h 1 - i o d o p r o p a n e . T h e r e s u l t i n g a l k y l a t e d h y d r a z o n e 14. was s u b j e c t e d t o a c i d c l e a v a g e t o a f f o r d J_5_ in an o v e r a l l c h e m i c a l y i e l d o f 60% and In 99 .5% e e . j lO] C H 2 C 0 2 M e 10. l e a f - c u t t l n g a n t A t t a t e x a n a . 1 4 3 - P e n t a n o n e (J_L) r e a c t e d 8 o N CH3 OMe CH 3 , C H 3 11 12. CH3 1) L D A , E t 2 0 2) n-Prl,-11 0° O \ OMe 2) 3-6M HCl, pentane 1) Mel C H 3 P H C H 3 15. 99.5% ee (S) CH3 O t h e r m e t h o d s o f f o r m i n g a s y m m e t r i c c a r b o n a t o m s w h i c h e m p l o y c h i r a l a u x i l i a r y r e a g e n t s i n v o l v e t h e a l k y l a t i o n o f a n i o n s d e r i v e d f r o m d e p r o t o n a t I on o f c h i r a l e n a m l n e s 1 ^ , c h i r a l i m i n e s 1 5 a • 1 6 , c h i r a l o x a z o I i n e s 1 1 » 1 7 , and c h i r a l f o r m a m i d i n e s . 1 8 F u r t h e r e x a m p l e s o f a s y m m e t r i c r e a c t i o n s 1 9 I n c l u d e a s y m m e t r i c h y d r o g e n a t i o n s o f a I k e n e s w i t h c h i r a l c a t a l y s t s 8 , a s y m m e t r i c a I do I r e a c t i o n s 2 0 , a s y m m e t r i c e y e Ioadd111 on r e a c t i o n s 2 1 , and a s y m m e t r i c e p o x i d a t i o n s o f a l l y l i e a l c o h o l s . 2 2 9 1 . 1 . 2 C h i r a l O x a z o l i n e s The s y n t h e t i c u t i l i t y o f t h e h e t e r o c y c l i c 2 - o x a z o l l n e s J_6_ i s w e l l d o c u m e n t e d . 2 3 - 3 0 The a c i d i t y o f t h e p r o t o n s on t h e o - c a r b o n o f 2 - s u b s t I t u t e d 2 - o x a z o l l n e s s u c h a s 2 , 4 , 4 - t r i m e t h y I -2 - o x a z o l l n e (12) h a s a l l o w e d t h e s y s t e m t o be t r a n s f o r m e d i n t o a v a r i e t y o f m o r e c o m p l e x c a r b o x y l i c a c i d d e r i v a t i v e s . 2 4 M e t a l a t i o n o f o x a z o l I n e 1 2 w i t h n - b u t y l I i t h i u m and t h e n t r e a t m e n t w i t h a l k y l h a i I d e s g i v e s t h e a l k y l a t e d o x a z o l i n e 18. N ^ > / ^ 3 |sj. 12 R^CHCOaR2 2_L R2OH H+ 13. 1) n-BuLi 2) R1X 2Z H3C R2OH,H+ H , 0 + RCH2CO2H 19_ RCHgCOgR2 2SL R^ CHCOgH 22. A c i d h y d r o l y s i s p r o v i d e s t h e h o m o l o g a t e d a c e t i c a c i d IS w h e r e a s a l c o h o l y s i s l e a d s t o t h e h o m o l o g a t e d e s t e r 20_. D i a I ky I a t i o n s a r e p o s s i b l e by m e t a l a t i o n o f t h e o x a z o l i n e _1_& f o l l o w e d by a d d i t i o n o f a s e c o n d e q u i v a l e n t o f an a l k y l ha I Ide t o a f f o r d t h e o x a z o l i n e £ 2 . . A c i d h y d r o l y s i s o r a l c o h o l y s i s a g a i n 1 0 p r o v i d e s a c i d £3_ o r e s t e r 21 . T h e 2 - o x a z o l i n e s y s t e m i s a l s o r e p o r t e d t o be a u s e f u l p r o t e c t i n g g r o u p f o r c a r b o x y l i c a c i d s . 2 5 The o x a z o l i n e r i n g s y s t e m i s s t a b l e t o v a r i o u s r e a g e n t s s u c h a s G r i g n a r d r e a g e n t s , l i t h i u m a l u m i n u m h y d r i d e , c h r o m i u m t r l o x i d e , and m i l d b a s e . T h l l r a n e s h a v e b e e n p r e p a r e d vI a t h e i n t e r m e d i a c y o f o x a z o l i n e s . M e t a l a t i o n o f t h e t h l o o x a z o l I n e 24 w i t h n - b u t y l -l i t h i u m in t e t r a h y d r o f u r a n (THF) f o l l o w e d by t r e a t m e n t w i t h a l d e h y d e s o r k e t o n e s p r o v i d e s t h l I r a n e 2j5_ w h i c h c a n t h e n be c o n v e r t e d I n t o a Ikene 2 6 . 2 8 23 23. T h e m e t a l a t i o n o f o x a z o l i n e J_7_ f o l l o w e d by r e a c t i o n w i t h e p o x i d e s r e s u l t s In n u c l e o p h i l i c r i n g o p e n i n g t o g i v e t h e o x a z o l i n e 2JZ.. H y d r o l y s i s In a q u e o u s s o l u t i o n p r o v i d e s t h e b u t y r o I a c t o n e 23-27 O t h e r m a n i p u l a t i o n s o f t h e o x a z o l i n e r i n g h a v e l e d t o t h e f o r m a t i o n o f a l d e h y d e s 2 8 , k e t o n e s 2 9 , and f u n c t i o n a I i z e d a r o m a t i c c a r b o x y l i c a c i d s . 3 0 T h e s y n t h e t i c u t i l i t y o f c h i r a l o x a z o l i n e s h a s a l s o been r e v i e w e d . 1 1 ' 1 7 M o s t o f t h e work in t h i s a r e a h a s b e e n p e r f o r m e d by M e y e r s and h i s g r o u p , and h a s I n v o l v e d t h e u s e o f 11 CH3 •CH3 THF,-78°-n-BuLi LiCH2 CH3 •CH3 IZ R HWR3 0 R H30+ CH3 *CH3 2Z 2 - e t h y I -4 (S_) - m e t h o x y m e t hy l - 5 ( S _ ) - p h e n y l o x a z o l i n e (2S1) • M e y e r s d e m o n s t r a t e d t h a t c h i r a l c a r b o x y l l c a c i d s c a n be p r e p a r e d in good c h e m i c a l y i e l d s (65-88%) and in 60-83% ee f r o m by t h e s e q u e n c e shown on t h e f o l l o w i n g p a g e . 3 1 O x a z o l i n e 3J2 was p r e p a r e d by t h e c o n d e n s a t i o n o f ( + ) - 1 - p h e n y I - 2 - a m i n o - 1 , 3 -p r o p a n e d i o l (£9_) w i t h t h e e t h y l i m i d a t e o f p r o p i on I t r i I e w i t h s u b s e q u e n t f o r m a t i o n o f t h e m e t h y l e t h e r by t r e a t m e n t w i t h s o d I urn h y d r i d e and m e t h y l i o d i d e . One o f t h e d i a s t e r e o t o p i c p r o t o n s o f 2& was s e l e c t i v e l y a b s t r a c t e d w i t h LDA a f f o r d i n g t h e I I t h I o - c h e I a t e d a n i o n s 31 a and 31b w h i c h w e r e a l k y l a t e d a t low t e m p e r a t u r e . T h e a l k y l a t e d o x a z o l i n e was t h e n h y d r o l y z e d t o g i v e t h e 2 - m e t h y I a I k a n o I c a c i d 22. w i t h p r e d o m i n a n t l y t h e S_-c o n f i g u r a t i o n a t t h e a - c h i r a l c e n t e r . S t u d i e s w e r e p e r f o r m e d t o I n v e s t i g a t e t h e f e a t u r e s o f t h i s o x a z o l i n e s y s t e m t h a t w e r e r e s p o n s i b l e f o r t h e a s y m m e t r i c i n d u c t i o n . A s e r i e s o f c h i r a l o x a z o l i n e s , i n w h i c h t h e C - 4 and C - 5 s u b s t l t u e n t s w e r e v a r i e d , w e r e p r e p a r e d and s u b j e c t e d t o 12 t h e meta I a t I o n - a I k y I a t I o n - h y d r o I y s I s s e q u e n c e shown a b o v e ( T a b l e | ) . 3 2 , 3 3 M e y e r s f o u n d t h a t d e c r e a s i n g t h e s t e r i c b u l k o f t h e C - 5 s u b s t i t u e n t f r o m Ph t o Me t o H r e s u l t e d In a s i g n i f i c a n t d e c r e a s e In t h e ee o f c h i r a l a c i d 22- T h i s s u g g e s t e d t h a t t h e l a r g e p h e n y l g r o u p i n h i b i t s t o p s i d e a l k y l a t l o n by b l o c k i n g t h e a p p r o a c h o f t h e a l k y l h a l i d e s o t h a t b o t t o m s Ide e n t r y i s f a v o r e d . R e p l a c e m e n t o f t h e l i t h l u m -c h e l a t i n g C - 4 m e t h o x y m e t h y I g r o u p by m e t h y l a l s o r e s u l t e d in a d r a m a t i c d e c r e a s e in t h e e e o f c h i r a l a c i d 22., i n d i c a t i n g t h a t 13 Tab Ie I . E f f e c t o f O x a z o l i n e S u b s t l t u e n t s on A s y m m e t r i c I n d u c t i on B Ft 3) H 3 0 + ' 3 22. E n t r y A B RX ee(%) 1 Ph C H 2 O M e n - B u I 7 8 . 0 2 Ph C H 2 O M e E t I 78 3 Me C H 2 O M e n - B u I 7 . 2 4 H C H 2 O M e n - B u I 3 . 5 5 Ph Me n - B u i 18 t h e o x y g e n Is I m p o r t a n t . T h u s , t h e d e g r e e o f a s y m m e t r i c i n d u c t i o n i s d e p e n d e n t on a b u l k y s u b s t i t u e n t t o b l o c k t o p s i d e a l k y l a t l o n a n d on o x y g e n - I I th I urn c h e l a t i o n . T h e a b o v e a s y m m e t r i c a l k y l a t l o n t o f o r m c h i r a l c a r b o x y l i c a c i d s h a s b e e n e x t e n d e d t o t h e s y n t h e s i s o f c h i r a l b u t y r o -l a c t o n e s a n d v a I e r o I a c t o n e s . 3 4 D e p r o t o n a t i o n o f o x a z o l i n e 23. w i t h n - b u t y I I i t h l u r n f o l l o w e d by a l k y l a t l o n w i t h e t h y l e n e o x i d e and c h I o r o t r I m e t h y I s I Iane a f f o r d e d o x a z o l i n e 2A- - T h e c h i r a l c e n t e r was i n t r o d u c e d by a s e c o n d meta I a t I o n - a I k y I a t i o n s e q u e n c e a n d h y d r o l y s i s o f o x a z o l i n e 3_5_ a f f o r d e d 2 - s u b s t i t u t e d b u t y r o I a c t o n e 23. w i t h t h e B - c o n f I g u r a t I on in 64 -73% e e . 3 4 a T h e c o r r e s p o n d i n g S _ - b u t y r o I a c t o n e 23 was o b t a i n e d by r e v e r s i n g t h e o r d e r o f i n t r o d u c t i o n o f t h e s u b s t l t u e n t s . T h u s , a c i d h y d r o l y s i s o f o x a z o l i n e 22. p r o v i d e d b u t y r o I a c t o n e 23 w i t h t h e S - c o n f I g u r a t i o n In 70 -86% e e . 3 4 b O t h e r o p e r a t i o n s on c h i r a l o x a z o l l n e s h a v e r e s u l t e d in t h e f o r m a t i o n o f c h i r a l g - h y d r o x y -14 Me3SiO Me3SiO and g - m e t h o x y a I k a n o i c a c i d s (18-25% e e ) 3 5 and c h i r a l 2 - m e t h o x y a I k a n o I c a c i d s (12-42% e e ) . 3 6 T h e a b o v e e x a m p l e s h a v e b e e n c o n c e r n e d w i t h t h e u s e o f c h i r a l o x a z o l i n e s a s n u c l e o p h l l e s in a s y m m e t r i c c a r b o n - c a r b o n b o n d f o r m a t i o n s . C h i r a l o x a z o l i n e s h a v e a l s o b e e n u s e d t o m o d i f y m e t a l h y d r i d e s t o e f f e c t a s y m m e t r i c r e d u c t i o n s o f 15 k e t o n e s . 3 7 In a d d i t i o n , c h i r a l o x a z o l i n e s h a v e b e e n e m p l o y e d a s c h i r a l e l e c t r o p h i I e s . E x a m p l e s o f t h e s e I n c l u d e t h e p r e p a r a t i o n o f c h i r a l 3 - s u b s t I t u t e d v a I e r o I a c t o n e s 40. f r o m o x a z o l i n e 3_9_ (76 -95% e e ) 3 8 and t h e p r e p a r a t i o n o f c h i r a l b i n a p h t h y l s £2 . f r o m o x a z o l i n e 4 1 (87 -96% e e ) . 3 9 0 1) HCI,EtOH,H 20 2) LiAIH 4 16 1 . 1 . 3 P r o p o s e d U s e o f Some New C h i r a l O x a z o l i n e s In A s y m m e t r i c S y n t h e s i s A t t h e t i m e t h i s work was I n i t i a t e d , s u p p o r t f o r l i t h i u m c o m p l e x a t i o n w i t h t h e b a s i c TT e l e c t r o n s o f a r o m a t i c g r o u p s and e v i d e n c e f o r I I t h I u m - a r e n e ir c o o r d i n a t i o n had r e c e n t l y been d e s c r i b e d . 4 0 T h i s e v i d e n c e came f r o m s t u d i e s o f r e a c t i o n s o f 3 - m e t h y I - 3 - s u b s t i t u t e d e y e I o p e n t a n o n e s 4J2. w i t h LDA t o f o r m t h e c o r r e s p o n d i n g e n o l a t e s w h i c h w e r e i s o l a t e d a s t h e i r s i l y l e n o l e t h e r s 44 and 45_. T a b l e II s u m m a r i z e s some o f t h e s e r e s u l t s . W i t h an a r y l g r o u p o n t h e B - c a r b o n a t o m , r e s o n a n c e s t a b i l i z a -t i o n o f t h e e n o l a t e a n i o n w o u l d n o t be p o s s i b l e b u t I n d u c t i v e s t a b i l i z a t i o n o f t h e e n o l a t e may e x i s t and w o u l d be r e l a t e d t o t h e e l e c t r o n - w i t h d r a w i n g a b i l i t y o f p a r a - s u b s t I t u t e d p h e n y l g r o u p s (o_-n I t r o p h e n y I >pheny I >D_-methoxypheny I ) . H o w e v e r , Tab Ie I I . E f f e c t o f S u b s t l t u e n t s on E n o l a t e F o r m a t i o n u s i n g 3 - M e t h y I - 3 - s u b s t I t u t e d C y c I o p e n t a n o n e s 43_ CH3 4 ! CH3 45. CH3 r n-Bu Ph P h C H 2 P h C H 2 C H 2 P h C H 2 C H 2 C H 2 n-MeOPh n-MePh D_-N02Ph 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 0 . 3 3 . 3 6 . 9 2 . 6 1 .7 7 . 4 4 . 3 0 . 9 1 7 e n o l i z a t i o n o c c u r r e d p r e f e r e n t i a l l y toward the a r y l group for p_-subst I tu ted phenyl groups in the r e v e r s e o r d e r . The r e g i o -s e l e c t i v i t y in e n o l a t e fo rmat ion was thus a t t r i b u t e d to the a b i l i t y of the TT e l e c t r o n s of the a r y l group to c o o r d i n a t e wi th and s t a b i l i z e the l i t h i u m Ion c h e l a t e d w i th the e n o l a t e , and t h i s r e g i o s e l e c t i v i t y p a r a l l e l e d the TT e l e c t r o n d o n a t i n g a b i l i t y of the a r y l group (p_-methoxypheny I >pheny I >p_-n I t r o -p h e n y l ) . The i n c r e a s e d d i r e c t i n g e f f e c t on v a r y i n g the s u b s t i t u e n t from n-Bu to Ph to PhCH 2 i s e a s i l y r a t i o n a l i z e d . In the absence of an a r y l group ( R = J Q . - B U ) , s i l y l enol e ther 44 would be f a v o r e d due to fo rmat ion of the l e s s h i n d e r e d e n o l a t e I n t e r m e d i a t e . The phenyl group Is p r o b a b l y b e t t e r p o s i t i o n e d fo r TT bonding to the l i t h i u m ion when the g - s u b s t i t u e n t is benzy l i n s t e a d of p h e n y l . F u r t h e r m o r e , the o b s e r v a t i o n that the d i r e c t i n g e f f e c t d e c r e a s e d as the phenyl group was removed f u r t h e r from the eye Iopentanone r i n g sugges ted tha t l i t h i u m -arene TT c o o r d i n a t i o n o c c u r r e d I ntramo I ecu I ar I y r a t h e r than i ntermoI ecu Ia r Iy . The s y n t h e s i s of 2 - s u b s t I t u t e d 4 (S.)-benzy I oxazo I i nes 4_6_ was r e p o r t e d from our l a b o r a t o r y at about the t ime of the above o b s e r v a t i o n s . 4 1 The s i m i l a r i t i e s in s t r u c t u r e between the e n o l a t e 4_& of a 2 - s u b s t I t u t e d 4 ( £ ) - b e n z y I oxazo I I ne 46. and the e n o l a t e 43. of 3 -benzy I -3 -methy I eye I opentanone (4J7_) a re r e a d i l y a p p a r e n t . Both 4J£ and £9_ c o n t a i n a f I ve-membered r i n g w i th a benzyl group at the same r e l a t i v e p o s i t i o n , and the n e g a t i v e charge of the a n i o n i s d e l o c a l i z e d over t h r e e c e n t e r s In both c a s e s . Due to t h e s e s i m i l a r i t i e s , l i t h i u m c h e l a t i o n w i th the TT e l e c t r o n s on the phenyl r i n g of 4S. Is l i k e l y t o o c c u r , and 18 t h i s I I th i um-arene TT coordination may be likened to the oxygen-1 ithI urn chelate required for asymmetric synthesis using oxazoI i ne 30. The success of asymmetric induction In a l k y l a t l o n s using oxazoline 3_Q also depended on the presence of the phenyl s u b s t i t u t e n t . 3 2 We postulated that a benzyl group alone at the C-4 position, in addition to providing the necessary chelation, may be s u f f i c i e n t l y bulky to block a l k y l a t i o n from the coordinating face so that any a l k y l a t i o n would occur p r e f e r e n t i a l l y from the less hindered opposite face. Thus, we propose to combine the features of s t e r l c bulk and chelation into one functional group. The above observations and results prompted the preparation of several novel c h i r a l oxazolines and the investigation of the use of these c h i r a l oxazolines as c h i r a l a u x i l i a r y reagents in the asymmetric synthesis of c h i r a l a-substItuted carboxylic acids. The s t a b i l i t y of the simplest one of these, 19 2-subst i tuted 4 (S.)-benzy I oxazo I I nes 46_, with respect to potential racemization at the a-carbon was studied f i r s t and then Its use In possible asymmetric carbon-carbon bond formations was Investigated. 20 1.2 D l s c u s s I on 1.2.1 P r e p a r a t i o n o f 2-Subst I t u t e d 4 (S.)-Benzy I o x a z o I i nes The s y n t h e s i s o f 2 - s u b s t I t u t e d 4(S_)-benzy I o x a z o I I nes 46. was a c c o m p l i s h e d a s o u t l i n e d on t h e f o l l o w i n g page. 2 (S_) -Benzy I -a z i r i d l n e was p r e p a r e d from c o m m e r c i a l l y a v a i l a b l e L-Pheny I a I an I ne (5J2) a c c o r d i n g t o t h e p r e v i o u s l y r e p o r t e d p r o c e d u r e . 4 1 L-Pheny I a I an i ne (5J2) was e s t e r l f i e d w i t h t h i o n y l c h l o r i d e and a b s o l u t e e t h a n o l . The I s o l a t e d c r u d e L-pheny I a I an I ne e t h y l e s t e r h y d r o c h l o r i d e (5JL) was s u b s e q u e n t l y r e d u c e d w i t h s o d ium b o r o h y d r i d e i n r e f l u x i n g 50% aqueous e t h a n o l t o g i v e 2 (S_)-am i no - 3-pheny I propan- 1-o I (.£2.) In 69% r e c r y s t a l l i z e d y i e l d . The r e c r y s t a l l i z e d p r o d u c t e x h i b i t e d a m e l t i n g p o i n t o f 91 -93°C and a s p e c i f i c r o t a t i o n o f - 2 6 . 0 ° in c h l o r o f o r m s o l u t i o n . T h e s e v a l u e s compare f a v o r a b l y w i t h t h o s e r e p o r t e d i n t h e l i t e r a t u r e 4 2 (mp 91-93°C, [ a ] D 2 4 - 2 5 . 6 ° i n e t h a n o l ) . A s h a r p 0-H s t r e t c h o f no n - h y d r o g e n bonded h y d r o x y l a t 3640 c m - 1 a s we I I a s an N-H s t r e t c h a t 3380 c m - 1 were e v i d e n t i n t h e i n f r a r e d ( i r ) s p e c t r u m o f t h e p r o d u c t . In a d d i t i o n , a b r o a d band c e n t e r e d a t 3200 c m - 1 was a s s i g n e d t o t h e O-H s t r e t c h o f h y d r o g e n bonded h y d r o x y l . In t h e p r o t o n n u c l e a r m a g n e t i c r e s o n a n c e ( 1 H nmr) s p e c t r u m , m u l t i p l e t s a t 67 . 1 5-7 . 3 5 and 6 3 . 0 6 - 3 . 2 0 c o u l d be a t t r i b u t e d r e s p e c t i v e l y t o t h e p h e n y l p r o t o n s and t h e m e t h l n e p r o t o n . The b r o a d s i n g l e t a t 61 .80 w h i c h d i s a p p e a r e d In t h e p r e s e n c e o f d e u t e r i u m o x i d e c o u l d be r e a d i l y a s s i g n e d t o t h e h y d r o x y ! p r o t o n and t h e two amine p r o t o n s . F u r t h e r m o r e , two d o u b l e t s o f d o u b l e t s a t 6 2.50 21 and 6 2 . 7 9 w e r e a s s i g n e d t o t h e b e n z y l I c p r o t o n s . The two lower f i e l d d o u b l e t s o f d o u b l e t s a t 6 3 . 3 6 and 6 3 . 6 4 w e r e due t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e h y d r o x y l g r o u p . 55. A c o n v e n t i o n a l Wenker e y e I I z a t i o n 4 1 » 4 2 was u t i l i z e d in t h e s y n t h e s i s o f 2 ( £ ) - b e n z y I a z l r i d I n e ( £ 4 ) . T h i s r e a c t i o n 22 I n v o l v e d t h e r e a c t i o n o f a m i n o a l c o h o l 52 w i t h s u l f u r i c a c i d t o g i v e t h e h y d r o g e n s u l f a t e e s t e r 52. w h i c h was t h e n e y e I i z e d by t r e a t m e n t w i t h s o d I urn h y d r o x i d e t o y i e l d a z l r i d i n e 5_4 in an 82% d i s t i l l e d y i e l d . T h i s a c i d s e n s i t i v e compound was f o u n d t o be u n s t a b l e a t room t e m p e r a t u r e and had t o be s t o r e d a t low t e m p e r a t u r e In t h e p r e s e n c e o f p o t a s s i u m h y d r o x i d e . 4 1 The i r s p e c t r u m o f a z i r i d l n e 5_4 e x h i b i t e d an N-H s t r e t c h i n g b a n d a t 3330 c m - 1 . A b r o a d s i n g l e t a t 6 0 . 6 0 In t h e 1 H nmr s p e c t r u m c o u l d be a t t r i b u t e d t o t h e a m i n e h y d r o g e n . M u l t i p l e t s a t 6 2 . 1 6 - 2 . 2 5 and 6 7 . 1 4 - 7 . 3 6 w e r e due t o t h e m e t h i n e p r o t o n and t h e p h e n y l p r o t o n s , r e s p e c t i v e l y . T h e r e s o n a n c e s o f t h e m e t h y l e n e p r o t o n s In t h e a z i r i d i n e r i n g a p p e a r e d a s d o u b l e t s a t 6 1 . 4 4 and 6 1 . 8 0 . T h e two d o u b l e t s o f d o u b l e t s a t 6 2 . 6 5 and 6 2 . 8 0 w e r e a s s i g n e d t o t h e b e n z y l i c p r o t o n s . 2 (S_) - B e n z y I a z i r I d i ne (5A) was t h e n u t i l i z e d in t h e p r e p a r a t i o n o f 2 - s u b s t I t u t e d 4 ( £ . ) - b e n z y I o x a z o I I n e s 4 6 . . 4 1 C a r b o x y l i e a c i d s J_9_ w e r e r e a c t e d w i t h 1 , 1 ' - c a r b o n y I d I im I d a z o I e (CD I ) t o g i v e a c y I I m i d a z o l l d e s 5_£. w h i c h w e r e s u b s e q u e n t l y r e a c t e d w i t h a z l r i d i n e 5_4 t o a f f o r d t h e c o r r e s p o n d i n g £ i - a c y I 2 ( 3 . ) - b e n z y I a z i r I d I n e s 5_5.. T h e s e c o m p o u n d s w e r e i m m e d i a t e l y r e a r r a n g e d t o t h e o x a z o l i n e s by r e f l u x l n g s o l u t i o n s o f 5_5. c o n t a i n i n g a c a t a l y t i c amount o f t e t r a - n - b u t y I a m m o n i u r n i o d i d e in T H F . 0 5_6. T h e p r o p o s e d m e c h a n i s m f o r t h e I o d i d e i o n c a t a l y z e d 23 r e a r r a n g e m e n t o f N . -acy I 2 ( S _ ) - b e n z y l a z i r i d I n e s 5_5_ i s o u t l i n e d b e l o w . T h i s t y p e o f r e a r r a n g e m e n t h a s b e e n p o s t u l a t e d 4 3 t o o c c u r by a t t a c k o f t h e I o d i d e i o n o n t h e l e s s h i n d e r e d c a r b o n a t o m o f t h e a z i r i d l n e r i n g t o p r o d u c e an I n t e r m e d i a t e a n i o n w h i c h s u b s e q u e n t l y e y e I I z e s t o t h e o x a z o l Ine 4 6 . 4JL The s i m p l e s t o x a z o l i n e r e q u i r e d f o r c h i r a l a l k y l a t i o n s t u d i e s w o u l d be o x a z o l i n e 53 w h e r e an e t h y l g r o u p i s a t t h e 2 - p o s i t i o n o f t h e o x a z o l i n e r i n g . T h u s , u s i n g t h e s e q u e n c e o u t l i n e d b e l o w , a y i e l d o f 72% was o b t a i n e d i n t h e p r e p a r a t i o n o f ( - ) - 2 - e t h y I-4 ( S _ ) - b e n z y I o x a z o I I ne (53.) f r o m p r o p a n o i c a c i d (52.)- O x a z o l i n e 53 s h o w e d a C=N s t r e t c h i n g b a n d a t 1665 c m - 1 3) n-Bu4NI 24 In t h e Ir s p e c t r u m , and It had a s p e c i f i c r o t a t i o n o f - 3 6 . 5° in c h l o r o f o r m w h i c h a g r e e s f a v o r a b l y w i t h t h e p r e v i o u s l y r e p o r t e d 4 1 v a l u e o f - 3 7 . 0 ° . The t r i p l e t a t 61.18 and t h e q u a r t e t a t 62.29 In t h e 1H nmr s p e c t r u m were a t t r i b u t e d r e s p e c t i v e l y t o t h e m e t h y l p r o t o n s and t h e m e t h y l e n e p r o t o n s o f t h e e t h y l g r o u p . The m e t h y l e n e p r o t o n s a r e in f a c t d l a s t e r e o -t o p i c and a more complex s i g n a l t h a n a s i m p l e q u a r t e t was e x p e c t e d b u t t h i s was n o t o b s e r v e d due t o c o i n c i d e n t a l c h e m i c a l s h i f t e q u i v a l e n c e o f t h e m e t h y l e n e p r o t o n s . The two d o u b l e t s o f d o u b l e t s a t 62.64 and 63.13 were a s s i g n e d t o t h e b e n z y l i c p r o t o n s . The r e s o n a n c e s o f t h e m e t h y l e n e p r o t o n s in t h e o x a z o l i n e r i n g a p p e a r e d as two t r i p l e t s a t 63.96 and 64.14. F u r t h e r m o r e , t h e two m u l t i p l e t s a t 64.28-4.45 and 67.14-7.37 were a t t r i b u t e d t o t h e m e t h l n e p r o t o n and t h e p h e n y l p r o t o n s , r e s p e c t I v e I y . The i n i t i a l method o f p r e p a r i n g a z l r i d i n e 5_4 by t h e Wenker method r e q u i r e s s e v e r a l s t e p s and a r e l a t i v e l y l o n g p e r i o d o f t i m e . An a t t e m p t was made t o f i n d a more c o n v e n i e n t and l e s s t i m e c o n s u m i n g method o f s y n t h e s i s o f t h i s a z l r i d i n e . Okada e_t a j _ . 4 4 r e p o r t e d t h e u s e o f t r I pheny I phosph I ne dI b r o m i d e i n a o n e - s t e p method o f c o n v e r t i n g g-amlno a l c o h o l s t o t h e c o r r e s p o n d i n g a z i r i d i n e s . The r e a c t i o n o f £ 4 - s u b s t i t u t e d g-am i no a l c o h o l s 5_9_ w i t h t r I pheny l p h osph I ne d i b r o m i d e In t h e Ph3P=0 Et3N«HBr 5_9_ 6_Q_ 25 p r e s e n c e o f t r i e t h y I amine gave t h e c o r r e s p o n d i n g 1 , 2 - d i s u b -s t l t u t e d a z l r l d i n e d e r i v a t i v e s £Q_ In y i e l d s r a n g i n g from 50-74%. We a t t e m p t e d t o use t h i s p r o c e d u r e f o r t h e p r e p a r a t i o n o f 2 ( £ ) - b e n z y I a z i r i d i n e (££) from 2 (S_)-am I no-3-pheny I p r o p a n - 1 - o I (5J2J . The r e a c t i o n was t r i e d I n i t i a l l y w i t h a r e a c t i o n t i m e o f t w e n t y h o u r s , and s u b s e q u e n t l y w i t h a r e a c t i o n t i m e o f two h o u r s . In e a c h a t t e m p t a c r u d e y i e l d o f o n l y a p p r o x i m a t e l y 4% was o b t a i n e d . A c o m p a r i s o n o f t h e 1H nmr s p e c t r u m o f t h e c r u d e p r o d u c t w i t h t h a t o f 54. o b t a i n e d from t h e t w o - s t e p Wenker s y n t h e s i s i n d i c a t e d t h a t t h e r e were c o n s i d e r a b l e i m p u r i t i e s In t h e r e a c t i o n m i x t u r e . The v e r y poor y i e l d s o b t a i n e d made t h i s method o f s y n t h e s i z i n g a z l r l d i n e 5_£ u n f e a s i b l e . C a r l o c k and M a c k 4 5 r e p o r t e d t h e use o f a m i x t u r e o f d i e t h y l a z o d i c a r b o x y I a t e (DEAD) and t r I p h e n y I p h o s p h i n e i n t h e c o n v e r s i o n o f 2-am I no-2-methy I propan-1 -o I (£1) t o 2 , 2-d imethy I -a z l r l d i n e (6J>) . The r e a c t i o n was c a r r i e d o u t a t room t e m p e r a t u r e In t e t r a l l n a s s o l v e n t and a y i e l d o f 100% was o b t a i n e d as d e t e r m i n e d by gas c h r o m a t o g r a p h y . C H 3 \ J DEAD C H \ Ph3P=0 CH 3 -T Ph3P C H 3 " V + Et02C-N-N-C02Et NH2 fj H H £ 1 £2 . The u s e o f DEAD and t r I p h e n y I p h o s p h I n e was t h e n a p p l i e d t o t h e s y n t h e s i s o f a z l r l d i n e £4_. Amino a l c o h o l £ £ was t r e a t e d w i t h 1.5 e q u i v a l e n t s e a c h o f DEAD and t r I p h e n y I p h o s p h i n e in THF a t room t e m p e r a t u r e f o r t e n h o u r s t o a f f o r d t h e d e s i r e d 26 OH THF DEAD,Ph3P 52. H 54. a z i r l d l n e in a p p r o x i m a t e l y 15% y i e l d . T h e p o o r y i e l d o f a z l r l d i n e £4. may be due in p a r t t o t h e d i f f i c u l t y in i t s i s o l a t i o n f r o m t h e b y - p r o d u c t s a s w e l l a s t h e I n h e r e n t i n s t a b i l i t y o f a z i r i d i n e s t o c h r o m a t o g r a p h i c s e p a r a t i o n s , and t h u s i t was d e c i d e d t o a t t e m p t t r a p p i n g t h e f o r m e d a z i r i d i n e as i t s N - a c y I d e r i v a t i v e . A f t e r v a r i a t i o n o f r e a c t i o n c o n d i t i o n s , i t was f o u n d t h a t a g o o d y i e l d o f a c y I a z i r i d i n e £ £ c o u l d be o b t a i n e d . T h e f o r m a t i o n o f t h e a z l r l d i n e was c a r r i e d o u t w i t h e q u i m o l a r q u a n t i t i e s o f a m i n o a l c o h o l 5_2_, t r I p h e n y I p h o s p h I n e , and DEAD in r e f l u x i n g THF f o r o n e h o u r . A s o l u t i o n o f p r o p a n o y l I m i d a z o -l i d e , f o r m e d f r o m p r o p a n o i c a c i d and CD I In T H F , was a d d e d and a l l o w e d t o r e a c t a t room t e m p e r a t u r e f o r 1 .5 h o u r s t o a f f o r d a 76% p u r i f i e d y i e l d o f a c y I a z i r i d i n e £2.. A c y I a z l r l d i n e £3 . was t h e n r e a r r a n g e d w i t h a c a t a l y t i c amount o f t e t r a - n - b u t y I -ammonium i o d i d e t o a f f o r d o x a z o l i n e £ £ In 92% y i e l d . 52. 2) CDI CKjCI-^ COgH THF C=0 CH2CH3 £3. 53. 27 T h e a l t e r n a t i v e r o u t e t o o x a z o l I ne 5_8_ v I a t h e o n e - p o t c o n v e r s i o n o f a m i n o a l c o h o l 5_2_ t o a c y l a z l r i d i n e Q2. w i t h s u b s e q u e n t r e a r r a n g e m e n t h a s an o v e r a l l y i e l d o f 70%. T h i s r o u t e i s s h o r t e r and a l s o h i g h e r y i e l d i n g t h a n t h e i n i t i a l r o u t e I n v o l v i n g t h e t w o - s t e p Wenker e y e I I z a t i o n o f a m i n o a l c o h o l £2 . t o a z l r i d i n e 5_1 f o l l o w e d by t h e o n e - p o t c o n v e r s i o n o f £4_ t o o x a z o l I ne 5_£ w h i c h h a s an o v e r a l I y i e l d o f 59%. 28 1 . 2 . 2 4 ( S _ ) - B e n z y l o x a z o M n e s a s a C a r b o x y l i c A c i d P r o t e c t i n g G r o u p H a v i n g c o n f i r m e d t h a t t h e p r e p a r a t i o n o f 2 - s u b s t I t u t e d 4 ( S _ ) - b e n z y I o x a z o I i n e s 4jg. f r o m c a r b o x y l i c a c i d s and 2(S_)-am i n o - 3 - p h e n y I p r o p a n -1 - o I (52.) p r o c e e d s In g o o d y i e l d s , we t h e n i n v e s t i g a t e d w h e t h e r t h i s o x a z o l i n e s y s t e m c o u l d f u n c t i o n a s a g o o d p r o t e c t i n g g r o u p f o r a - c h l r a l c a r b o x y l i c a c i d s 22 R1 I R—C—CQpH I H 23. b e f o r e i n v e s t i g a t i n g i t s u s e in a s y m m e t r i c s y n t h e s i s . In o r d e r t o f u n c t i o n a s a p r o t e c t i n g g r o u p f o r a - c h i r a l c a r b o x y l i c a c i d s , no s c r a m b l i n g a t t h e c h i r a l c e n t e r must o c c u r d u r i n g f o r m a t i o n o f t h e o x a z o l i n e and s u b s e q u e n t h y d r o l y s i s o f t h e o x a z o l i n e t o r e g e n e r a t e t h e c a r b o x y l i c a c i d . T h e s e two r e q u i r e m e n t s w e r e i n v e s t i g a t e d u s i n g d e u t e r i u m l a b e l l i n g s t u d i e s . Any e p I m e r i z a t I on o f t h e a - c e n t e r w o u l d l i k e l y i n v o l v e t h e f o r m a t i o n o f an I n t e r m e d i a t e e n o l o r e n o l a t e a n i o n w h i c h w o u l d l e a d t o l o s s o f some d e u t e r i u m in an a - d e u t e r i u m l a b e l l e d c a r b o x y l i c a c i d . T h u s , t h e u s e o f an a c h l r a l a - d e u t e r i u m l a b e l l e d c a r b o x y l i c a c i d w o u l d be s a t i s f a c t o r y t o s t u d y t h e p o t e n t i a l r a c e m l z a t i o n o f t h e c h i r a l c e n t e r s i n c e l o s s o f d e u t e r i u m a t any s t e p w o u l d I n d i c a t e t h a t e p I m e r 1 z a t i o n i s I i k e I y t o o c c u r . In t h i s r e s p e c t , a s t u d y on t h e d e g r e e o f p o t e n t i a l r a c e m i -z a t l o n o f t h e c h i r a l c e n t e r upon f o r m a t i o n o f t h e o x a z o l i n e was 29 p e r f o r m e d . R a c e m i c 2 - d e u t e r I o - 2 - m e t h y I b u t a n o I c a c i d ( £ 5 . ) was p r e p a r e d by t h e t r e a t m e n t o f 2 - m e t h y I b u t a n o I c a c i d ( £ 4 J w i t h two e q u i v a l e n t s o f LDA in THF a t 0 ° C t o g e n e r a t e t h e c o r r e s p o n d i n g d i a n i o n w h i c h was t h e n q u e n c h e d w i t h D 2 S O 4 in D 2 O . Two a d d i t i o n a l t r e a t m e n t s g a v e t h e a - d e u t e r a t e d a c i d ,6_5_ w i t h a d e u t e r i u m i n c o r p o r a t i o n l e v e l o f 7 2 . 3 % a s d e t e r m i n e d by m a s s s p e c t r a l a n a l y s i s . The r e s u l t s o f t h i s d e u t e r a t i o n s t u d y a r e s u m m a r i z e d In F i g u r e s 2 and 3 . In t h e 'H nmr s p e c t r u m o f 2 - m e t h y I b u t a n o I c a c i d ( £ 4 ) , t h e t r i p l e t a t 6 0 . 9 5 c o r r e s p o n d e d t o t h e m e t h y l p r o t o n s a d j a c e n t t o t h e m e t h y l e n e g r o u p and t h e d o u b l e t a t 6 1 .18 c o u l d be a t t r i b u t e d t o t h e m e t h y l p r o t o n s a d j a c e n t t o t h e a - c a r b o n . M u l t i p l e t s a t 6 1 . 3 - 1 . 9 and 6 2 . 3 - 2 . 6 c o u l d be a s s i g n e d r e s p e c -t i v e l y t o t h e m e t h y l e n e p r o t o n s and t h e m e t h l n e p r o t o n . T h e r e was a l s o a v e r y b r o a d s i n g l e t a t 6 9 . 8 w h i c h was d u e t o t h e c a r b o x y l p r o t o n . A s c a n be s e e n In F i g u r e 2 , t h e s i n g l e t w h i c h i s s i t u a t e d a t t h e m i d p o i n t o f t h e d o u b l e t i n c r e a s e s i n I n t e n s i t y w i t h I n c r e a s i n g p e r c e n t a g e o f d e u t e r i u m I n c o r p o r a t e d w h e r e a s t h e d o u b l e t d e c r e a s e s i n s i z e . T h e s e o b s e r v a t i o n s c a n be r a t i o n a l i z e d o n t h e b a s i s o f c o u p l i n g b e t w e e n p r o t o n s on a d j a c e n t c a r b o n a t o m s . In t h e u n d e u t e r a t e d a c i d , c o u p l i n g o f t h e p r o t o n on t h e a - c a r b o n t o t h e t h r e e e q u i v a l e n t m e t h y l p r o t o n s r e s u l t s In a d o u b l e t f o r t h e m e t h y l s i g n a l . W i t h £ 1 £ 5 . 30 (C) (d) F I a u r e 2 . P a r t i a l nmr (100 MHz) s p e c t r a o f 2 - d e u t e r I o - 2 -m e t h y I b u t a n o I c a c i d (fL5J In CDC I 3 ( a ) 2 - m e t h y l -b u t a n o i c a c i d ( £ 4 J , (b ) 1 s t d e u t e r a t i o n , ( c ) 2nd d e u t e r a t i o n , (d) 3 r d d e u t e r a t i o n . 31 5 8 5 7 (a) m Iz 5 8 5 7 (b) m/z 5 8 5 7 ( C ) m/ z 5 8 5 7 m/z (d) Figure 3. Representation of p a r t i a l mass spectra of a-deuterated acid 6_5_ and overall deuterium Incorporation level (a) 2-methyIbutanoIc acid (64). (b) 1st deuteratlon:35.9%, (c) 2nd deuteratI on:57.9%, (d) 3rd deuteration:72.3%. 32 d e u t e r i u m a t t h e a - p o s i t i o n , a s i n g l e t i s s e e n f o r t h e m e t h y l p r o t o n s a s c o u p l i n g w i t h d e u t e r i u m Is v e r y s m a l l . T h u s , a s t h e amount o f d e u t e r i u m a t t h e a - p o s i t i o n I n c r e a s e s , t h e r e i s a d e c r e a s e in t h e d o u b l e t I n t e n s i t y w i t h a c o r r e s p o n d i n g I n c r e a s e in t h e s i n g l e t i n t e n s i t y . T h e d e c r e a s e In t h e a r e a o f t h e m u l t i p l e t a t 6 2 . 2 - 2 . 6 and t h e s i m p l i f i c a t i o n o f t h e c o u p l i n g p a t t e r n o f t h e m u l t i p l e t a t 6 1 . 4 - 1 . 9 a r e a l s o i n d i c a t i v e o f a - d e u t e r i u m I n c o r p o r a t i o n . Due t o t h e p o o r s e p a r a t i o n o f p e a k s , 1 H nmr s p e c t r a l a n a l y s i s was n o t u s e d f o r t h e a c t u a l d e t e r m i n a t i o n o f t h e d e u t e r i u m i n c o r p o r a t i o n l e v e l . M a s s s p e c t r a l a n a l y s i s was u t i l i z e d i n s t e a d . Two p r o b l e m s a r o s e f r o m t h e u s e o f t h e p a r e n t peak a t m / z 102 and t h e M+1 peak a t m / z 103 o f t h e a - d e u t e r a t e d a c i d . A r e l a t i v e l y l a r g e M-1 peak (45% o f p a r e n t p e a k ) d u e t o t h e i o n c o r r e s p o n d i n g t o l o s s o f t h e c a r b o x y l p r o t o n was o b s e r v e d , and t h e M+1 peak may be p a r t i a l l y due t o t h e p r e s e n c e o f t h e C 4 H g C 0 2 D + i o n . T h e s e p r o b l e m s w o u l d make a c c u r a t e d e t e r m i n a t i o n o f t h e d e u t e r i u m i n c o r p o r a -t i o n l e v e l v e r y d i f f i c u l t and t h u s o t h e r p e a k s must be u s e d . A common f r a g m e n t a t i o n o f c a r b o x y l i c a c i d s Is t h e c l e a v a g e o f t h e b o n d a t o t h e c a r b o n y l . T h e peak a t m / z 57 (M-45 ) i s d u e t o t h i s t y p e o f f r a g m e n t a t i o n and c o r r e s p o n d s t o t h e C4 f r a g m e n t . T h e d e u t e r i u m l e v e l was t h u s d e t e r m i n e d by a c o m p a r i s o n o f t h e i n t e n s i t i e s o f t h e p e a k s a t m / z 58 a n d m/z 57 f o r t h e u n d e u t e r a t e d a c i d and t h e d e u t e r a t e d a c i d s . F i g u r e 3 shows t h e v a r i a t i o n in t h e peak i n t e n s i t i e s upon t h e d e u t e r a -t i o n s and t h e v a l u e s o f t h e d e u t e r i u m i n c o r p o r a t i o n l e v e l a s c a l c u l a t e d f r o m t h e peak I n t e n s i t i e s a t m / z 58 and m / z 57 33 corrected for 1 3C. After three treatments, a 72.3% deuterium incorporation level was achieved. The labelled acid 615. containing an a-deuterlum content of 72.3% was then converted to oxazoline 6_6_ using the Imidazollde route. A comparison of the 1H nmr spectrum of oxazoline C H 3 / \ £5. 1) CPI 2) 3) n-Bu4NI N 5A H with that of the undeuterated oxazoline Ql, to be discussed in more d e t a i l later, showed a s i g n i f i c a n t amount of deuterium incorporation. Mass spectral analysis using the peaks at m/z 217 (parent mass) and m/z 218 (M+1 peak) Indicated a deuterium incorporation level of 72.8%. The two values, 72.3% and 72.8%, are e s s e n t i a l l y the same and the small difference can be attributed to errors in the measurement of peak heights. Since there was no loss of deuterium in th i s experiment, there is unlikely to be any epimerIzatI on of the c h i r a l center a to the carbonyl of the M-acy I derivatives of 2 (3.)-benzy I az i r I d I ne during the formation and subsequent rearrangement to oxazolInes. Therefore, carboxylic acids containing a c h i r a l center at the a-posltlon can be safely transformed into the c h i r a l oxazoline without any loss of c h i r a l i t y . The degree of potential racemlzation of the c h i r a l center upon hydrolysis of the oxazoline was then studied. (-)-2-(2'-Buty I )-4( S_)-benzy I oxazo I i ne (6_Z) was prepared from 2-methyl-34 2) H 2 0 1) DCI/D 2 0 C H 3 ^ Y C H 3 £ 1 CO2H £ Z b u t a n o l c a c i d ( £ 4 ) u s i n g t h e i m l d a z o l l d e r o u t e . O x a z o l i n e £7 was h y d r o l y z e d by r e f l u x i n g In 6 M DCI i n D 2 0 f o r f o u r h o u r s . D e u t e r i u m c h l o r i d e was u s e d i n s t e a d o f h y d r o c h l o r i c a c i d in o r d e r t o d e t e c t any r a c e m i z a t l o n o f t h e e p l m e r l z a b l e c e n t e r d u r i n g t h e h y d r o l y s i s s i n c e a n y r a c e m i z a t l o n w o u l d r e s u l t In I n c o r p o r a t i o n o f d e u t e r i u m a t t h e a - c a r b o n . A d l s t i I l e d y i e l d o f 95% o f a c i d £4. was a f f o r d e d f r o m t h e h y d r o l y s i s o f o x a z o l i n e £2. M a s s s p e c t r a l a n a l y s i s u s i n g t h e C4 f r a g m e n t i n d i c a t e d t h a t t h e d e u t e r i u m I n c o r p o r a t i o n l e v e l was n e g l i g i b l e ( 0 . 2 % ) . T h i s h y d r o l y s i s e x p e r i m e n t i n d i c a t e d t h a t e s s e n t i a l l y no d e u t e r i u m was I n c o r p o r a t e d a t t h e a - p o s i t i o n . T h e r e f o r e , a - c h l r a l c a r b o x y l i c a c i d s w h i c h h a v e b e e n c o n v e r t e d i n t o 2 - s u b s t I t u t e d 4 ( £ ) - b e n z y I o x a z o I i n e s s h o u l d be r e c o v e r a b l e w i t h o u t any l o s s o f c h i r a l i t y by a c i d h y d r o l y s i s o f t h e o x a z o l i n e . S i n c e t h e o x a z o l i n e f o r m a t i o n p r o c e e d e d in g o o d y i e l d s and no d e u t e r i u m I n c o r p o r a t i o n a t t h e c h i r a l c e n t e r o f t h e a c i d o c c u r r e d In t h e p r o t e c t i o n and d e p r o t e c t l o n s t e p s and a c h r o m o -p h o r e Is I n c o r p o r a t e d f o r u s e a s a c h r o m a t o g r a p h i c m a r k e r , t h e 4 ( £ ) - b e n z y I o x a z o I Ine s y s t e m a p p e a r s t o be a u s e f u l p r o t e c t i n g g r o u p f o r c a r b o x y l i c a c i d s . We c a n now p r o c e e d w i t h c h i r a l i n d u c t i o n s t u d i e s w i t h r e a s o n a b l e c o n f i d e n c e t h a t no I n f o r m a -t i o n w i l l be l o s t d u r i n g a n y o f t h e c h e m i c a l m o d i f i c a t i o n s . 35 1 . 2 . 3 C h i r a l A l k y l a t i o n o f ( - ) - 2 - E t h y I - 4 ( S J - b e n z y I o x a z o I i n e B e f o r e c o n s i d e r i n g c h i r a l a l k y l a t i o n r e a c t i o n s , It was n e c e s s a r y t o c o n f i r m t h a t a l k y l a t i o n o f t h e l l t h l o a n i o n o f ( - ) - 2 - e t h y I - 4 (S_) - b e n z y I o x a z o I I ne (5J1) c o u l d be a c h i e v e d . T h e r e f o r e , t h e f o l l o w i n g e x p e r i m e n t was c a r r i e d o u t . O x a z o l i n e 5JL was a d d e d t o an LDA s o l u t i o n a t - 7 8 ° C a n d s t i r r e d f o r o n e h o u r t o c o m p l e t e f o r m a t i o n o f t h e a n i o n . A l k y l a t i o n was a c h i e v e d by t h e a d d i t i o n o f m e t h y l i o d i d e a t - 7 8 ° C and t h e n 5_8_ OA a l l o w i n g t h e s o l u t i o n t o warm t o room t e m p e r a t u r e w h i l e s t i r r i n g was c o n t i n u e d f o r f i v e h o u r s . ( - ) - 2 - ( 2 ' - P r o p y I ) - 4 ( S_) -b e n z y I o x a z o I I ne (fLBJ was o b t a i n e d In a d i s t i l l e d y i e l d o f 83%. O x a z o l i n e fifi. p r e p a r e d In t h i s manner was I d e n t i c a l in a l l r e s p e c t s t o 6_8_ p r e p a r e d f r o m 2 - m e t h y I p r o p a n o i c a c i d ( £ 9 . ) u s i n g t h e i m i d a z o l i d e r o u t e . O x a z o l i n e 6J£, p r e p a r e d by t h e a l k y l a t i o n r o u t e , had a s p e c i f i c o p t i c a l r o t a t i o n o f - 3 4 . 5 ° in c h l o r o f o r m s o l u t i o n w h i c h a g r e e s w e l l w i t h t h e l i t e r a t u r e v a l u e 4 1 o f - 3 4 . 2 ° . H 3) n-Bu 4NI 36 H a v i n g shown t h a t t h e a l k y l a t i o n o f t h e l l t h i o a n i o n o f ( - ) - 2 - e t h y I - 4 ( £ . ) - b e n z y I o x a z o I I ne (.33) p r o c e e d s in g o o d y i e l d s , t h e m e t a l a t i o n and c h i r a l a l k y l a t i o n o f 33 c o u l d now be i n v e s t i g a t e d . B u t b e f o r e t h i s i s d o n e , some o f t h e m e t h o d s of d e t e r m i n i n g t h e d e g r e e o f c h i r a l I n d u c t i o n w i l l be e x a m i n e d . T h e r e a r e many m e t h o d s a v a i l a b l e f o r t h e d e t e r m i n a t i o n o f t h e m a j o r d i a s t e r e o m e r f o r m e d In an a s y m m e t r i c s y n t h e s i s . 1 0 T h e s e m e t h o d s a r e b a s e d on d i f f e r e n c e s in t h e p r o p e r t i e s o f d I a s t e r e o m e r s . D I a s t e r e o m e r s p o s s e s s d i f f e r e n t c h e m i c a l and p h y s i c a l p r o p e r t i e s . T h e r e f o r e , t h e s e p a r a t i o n o f two d i a s t e r e o m e r s o f t e n c a n be a c c o m p l i s h e d by u s e o f a c h r o m a t o -g r a p h i c t e c h n i q u e s u c h a s p r e p a r a t i v e g a s c h r o m a t o g r a p h y . P r e p a r a t i v e g a s c h r o m a t o g r a p h y was c o n s i d e r e d I n i t i a l l y a s a p o s s i b l e s e p a r a t i o n t e c h n i q u e b u t b a s e d on e a r l i e r r e s u l t s o b t a i n e d i n o u r l a b o r a t o r y , t h i s t e c h n i q u e was n o t a t t e m p t e d . a - D e u t e r a t e d 2 - m e t h y I p r o p a n o I c a c i d was c o n v e r t e d I n t o i t s c h i r a l o x a z o l i n e u s i n g t h e i m i d a z o l l d e r o u t e . M a s s s p e c t r a l a n a l y s i s o f t h e a - d e u t e r a t e d c h i r a l o x a z o l i n e had shown a c o n s i d e r a b l e l o s s o f t h e d e u t e r i u m l a b e l a f t e r i n t r o d u c t i o n of t h e c o m p o u n d I n t o t h e p r e p a r a t i v e g a s c h r o m a t o g r a p h . 4 6 The l o s s o f d e u t e r i u m i n d i c a t e d t h a t e p I m e r I z a t I on o f t h e c h i r a l c e n t e r g e n e r a t e d a t t h e a - p o s l t i o n o f t h e c h i r a l o x a z o l i n e w o u l d l i k e l y o c c u r d u r i n g any a t t e m p t e d s e p a r a t i o n u s i n g p r e p a r a t i v e g a s c h r o m a t o g r a p h y . A s d e s c r i b e d a b o v e , a c i d h y d r o l y s i s o f t h e a l k y l a t e d c h i r a l o x a z o l i n e t o t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d o c c u r s w i t h o u t a n y l o s s i n c h i r a l i t y . T h u s , a c o m p a r i s o n o f t h e s p e c i f i c r o t a t i o n o f t h i s a c i d m i x t u r e w i t h t h a t o f t h e o p t i c a l l y p u r e 37 a c i d o f e i t h e r e n a n t i o m e r w o u l d I n d i c a t e t h e p r e d o m i n a n t e n a n t l o m e r a s w e l l a s o p t i c a l p u r i t y and e e . H o w e v e r , a s m e n t i o n e d e a r l i e r , o p t i c a l r o t a t i o n m e a s u r e m e n t s a r e v e r y s e n s i t i v e t o e x p e r i m e n t a l c o n d i t i o n s and a r e a f f e c t e d by i m p u r I t l e s . 1 0 a A l t e r n a t i v e l y , t h e e e c o u l d be d e t e r m i n e d by 1 H nmr s p e c t r o s c o p y by c o n v e r s i o n o f e n a n t i o m e r s i n t o d I a s t e r e o m e r s by r e a c t i o n w i t h an o p t i c a l l y a c t i v e r e a g e n t , by u s e o f an o p t i c a l l y a c t i v e s o l v e n t , o r by m o d i f i c a t i o n w i t h an o p t i c a l l y a c t i v e s h i f t r e a g e n t . 1 0 H o w e v e r , s i n c e t h e a l k y l a t e d c h i r a l o x a z o l i n e Is c o m p r i s e d o f a m i x t u r e o f d I a s t e r e o m e r s , a n a l y s i s by 1 H nmr s p e c t r o s c o p y d I r e c t I v c a n g i v e t h e de and t h i s g i v e s p o t e n t i a l l y t h e e e . T h e 1 H nmr s p e c t r u m o f a m i x t u r e o f d I a s t e r e o m e r s may be c h a r a c t e r i z e d by a " t w i n n i n g " o f some o f t h e s i g n a l s d u e t o s l i g h t d i f f e r e n c e s In t h e e n v i r o n m e n t o f t h e p r o t o n s l e a d i n g t o d i f f e r e n t c h e m i c a l s h i f t s . T h e de c a n t h u s be d e t e r m i n e d f r o m t h e 1 H nmr s p e c t r u m by c o m p a r i s o n o f t h e r e l a t i v e i n t e g r a l s o f t h e s e t w i n n e d p e a k s . We t h u s p r o c e e d e d t o p r e p a r e p u r e d l a s t e r e o m e r 67a f r o m o p t i c a l l y a c t i v e a c i d 64a and t h e d i a s t e r e o m e r i c m i x t u r e o f o x a z o l i n e s 67a a n d 67b f r o m r a c e m i c a c i d £4 . u s i n g t h e I m i d a z o l i d e r o u t e . An e x a m i n a t i o n o f t h e 1 H nmr s p e c t r a o f t h e s e o x a z o l i n e s w o u l d t h e n i n d i c a t e t h e f e a s i b i l i t y o f u s i n g 1 H nmr s p e c t r o s c o p y a s a m e t h o d f o r t h e d e t e r m i n a t i o n o f t h e de o f t h e m a j o r d l a s t e r e o m e r f o r m e d by m e t a l a t i o n and c h i r a l a l k y l a t i o n o f o x a z o l i n e s . ( + ) - 2 (£ . ) - M e t h y I b u t a n o I c a c i d (64a ) was p r e p a r e d by t h e o x i d a t i o n o f ( - ) - 2 (S_) - m e t h y I b u t an -1 - o I ( 70a ) w i t h a b a s i c 38 KMnQ4 CQ>H 1) GDI , ^ " V ^ / ^ V ^ I C 3 H^CH 3 ^ ° CH3 O^SA CH3°T7a Z"* 3) n-Bu4NI s o l u t i o n o f p o t a s s i u m p e r m a n g a n a t e 4 7 a t room t e m p e r a t u r e in 69% d i s t i l l e d y i e l d . The d i s t i l l e d a c i d had a s p e c i f i c r o t a t i o n o f + 1 6 . 7 ° in c h l o r o f o r m s o l u t i o n . T h i s v a l u e c o m p a r e s f a v o r a b l y w i t h t h e l i t e r a t u r e 4 8 v a l u e o f + 1 6 . 8 4 ° . A c i d 64a was t h e n c o n v e r t e d t o ( - ) - 2 - ( 2 ' ( S ) - b u t y l ) - 4 (S_) - b e n z y I o x a z o l i n e (67a ) u s i n g t h e I m i d a z o l i d e r o u t e in a d i s t i l l e d y i e l d o f 62%. In t h e Ir s p e c t r u m o f o x a z o l i n e 6 7 a . t h e C=N s t r e t c h o c c u r r e d a t 1665 c m - 1 . A d o u b l e t p r e s e n t a t 6 1 . 1 6 in t h e 1 H nmr s p e c t r u m c o u l d be a t t r i b u t e d t o t h e m e t h y l p r o t o n s a d j a c e n t t o t h e m e t h i n e g r o u p . T h e t r i p l e t a t 60 .91 was d u e t o t h e m e t h y l p r o t o n s n e x t t o t h e m e t h y l e n e g r o u p , and t h e two o t h e r t r i p l e t s a t 6 3 . 9 5 and 6 4 . 1 4 w e r e a s s i g n e d t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e o x y g e n a t o m . T h e p h e n y l p r o t o n s a p p e a r e d a s a m u l t i p l e t a t 6 7 . 2 - 7 . 4 and t h e m e t h i n e p r o t o n a d j a c e n t t o t h e n i t r o g e n a tom was s e e n a s a m u l t i p l e t a t 6 4 . 3 - 4 . 5 . M u l t l p l e t s a t 6 1 . 4 - 1 . 5 5 and 6 1 . 6 - 1 . 7 w e r e d u e t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e m e t h y l g r o u p . Two d o u b l e t s o f d o u b l e t s s i t u a t e d a t 6 2 . 6 5 a n d 6 3 . 1 2 w e r e a t t r i b u t a b l e t o t h e b e n z y l I c p r o t o n s a n d t h e m u l t i p l e t a t 6 2 . 3 - 2 . 5 c o u l d be a s s i g n e d t o t h e m e t h i n e p r o t o n a t t a c h e d t o t h e c a r b o n a t o t h e o x a z o l i n e r i n g . It was e x p e c t e d t h a t t h e r e w o u l d be no s e p a r a t i o n o f s i g n a l s f o r o x a z o l i n e 67a s i n c e i t was p r e p a r e d f r o m t h e " o p t i c a l l y p u r e " c h i r a l a c i d . H o w e v e r , t h e 400 MHz 1 H nmr s p e c t r u m d i d FIaure 4. P a r t i a l 400 MHz 1H nmr spectra of oxazolines 67a and 67b In CDC 13 (a) prepared from (+)-2(S)-methyIbutanolc acid, (b) prepared from racemic 2-methyIbutanoIc acid, (c) prepared by alkylation of oxazoline 5_fi at -78°C. 40 r e v e a l a s e p a r a t i o n o f some o f t h e s i g n a l s w i t h a r e l a t i v e l y weak s e t o f p e a k s a t h i g h e r f i e l d ( F i g u r e 4 ( a ) ) i n d i c a t i n g t h a t o x a z o l Ine 67a was c o n t a m i n a t e d w i t h a smaI I amount o f d l a s t e r e o m e r 6 7 b . It was shown e a r l i e r t h a t no e p i m e r I z a t i o n o f t h e c h i r a l c e n t e r a d j a c e n t t o t h e c a r b o x y l f u n c t i o n a l i t y o c c u r r e d i n t r a n s f o r m i n g t h e a c i d t o t h e o x a z o l i n e . H e n c e , t h e s t a r t i n g a c i d was n o t o p t i c a l l y p u r e and t h e s m a l l q u a n t i t y o f t h e o t h e r e n a n t i o m e r p r o b a b l y r e s u l t e d f r o m r a c e m i z a t l o n o f t h e a - c h l r a l c e n t e r u n d e r t h e r e a c t i o n c o n d i t i o n s o f t h e o x i d a t i o n o f a l c o h o l 70a t o a c i d 6 4 a . O x a z o I Ine £ 2 was p r e p a r e d In 72% d I s t i I Ied y i e l d f r o m r a c e m i c 2 - m e t h y I b u t a n o I c a c i d ( £ 4 . ) u s i n g t h e I m i d a z o l i d e r o u t e . T h e 1 H nmr s p e c t r u m o f t h e m i x t u r e o f 67a and 67b d i d £Za 67b r e v e a l t h e e x p e c t e d " t w i n n i n g " f o r s e v e r a l s i g n a l s . T r i p l e t s l o c a t e d a t 6 0 . 9 0 5 and 6 0 . 9 1 0 w e r e due t o t h e m e t h y l p r o t o n s n e x t t o t h e m e t h y l e n e g r o u p . D o u b l e t s a t 6 1 . 1 5 2 a n d 6 1 .156 w e r e a t t r i b u t a b l e t o t h e m e t h y l p r o t o n s a t t a c h e d t o t h e a - c a r b o n . T h e s i g n a l s a t 6 3 . 9 5 a n d 6 4 . 1 3 w h i c h a p p e a r e d a s o v e r l a p p i n g d o u b l e t s o f t r i p l e t s w e r e a s s i g n e d t o t h e m e t h y l e n e p r o t o n s in t h e o x a z o l i n e r i n g , and t h e o v e r l a p p i n g d o u b l e t s o f d o u b l e t s a t 6 2 . 6 2 and 63 .11 w e r e a s s i g n a b l e t o t h e b e n z y l i c p r o t o n s . T h e h i g h e r f i e l d r e g i o n o f t h e 400 MHz 1 H nmr 41 spectrum containing the overlapping t r i p l e t s and overlapping doublets Is shown In Figure 4(b). The Intensities of these twinned peaks were equal which reflected the presence of equal amounts of oxazolines 67a and 67b. By a comparison of Figures 4(a) and 4(b), the overlapping signals In the 1:1 mixture of diastereomers could be assigned. The lower f i e l d sets of peaks were due to oxazoline 67a. which had the 3,-conf i gurat i on at the a - c h l r a l center, and the higher f i e l d sets were at t r i b u t a b l e to oxazoline 67b. which had the B-con fIguratI on at the a-carbon. The above results Indicated that the amounts of the two dIastereomers could be determined by using 1H nmr spectro-scopy. We could now proceed with the metalation and c h i r a l a l k y l a t i o n of 5Ji. Oxazol I ne 5J£ was deprotonated with LDA in THF and the resulting l i t h i o anion was alkylated with ethyl iodide at -78°C. S t i r r i n g was continued for f i v e hours at -78°C. The alkylated oxazoline was obtained In 83% d i s t i l l e d y i e l d . The higher f i e l d region of the 400 MHz 1H nmr spectrum of the diastereomeric mixture of alkylated oxazolines Is shown in Figure 4(c). The lower f i e l d sets of peaks for each signal had a greater Intensity Indicating that the major dlastereomer formed was oxazoline 67a with the S_-conf i gurat I on at the a-carbon. 2) Etl,-78° CHg 53. 67b CH3' H 42 L o w e r i n g t h e t e m p e r a t u r e o f a l k y l a t i o n s h o u l d I n c r e a s e t h e d e g r e e o f a s y m m e t r i c I n d u c t i o n . 3 1 3 M e y e r s f o u n d t h a t t h e ee o f t h e a c i d r e c o v e r e d a f t e r h y d r o l y s i s o f an o x a z o l i n e m i x t u r e , p r e p a r e d by a l k y l a t l o n o f t h e l i t h l o s a l t o f o x a z o l i n e 2Q_ ( p a g e 12) w i t h e t h y l I o d i d e , I n c r e a s e d 12% when t h e a l k y l a t l o n t e m p e r a t u r e was d e c r e a s e d f r o m - 7 8 ° C t o - 1 0 5 ° C . T h u s , t h e a l k y l a t l o n o f t h e I I t h i o s a l t o f o x a z o l i ne 5JB. was p e r f o r m e d a t - 1 0 5 ° C f o r f o u r h o u r s in t h e h o p e s o f a c h i e v i n g a g r e a t e r a s y m m e t r i c i n d u c t i o n . A 69% d i s t i l l e d y i e l d o f t h e m i x t u r e o f o x a z o l I n e s 67a and 67b was o b t a i n e d b u t t h e r a t i o o f 67a t o 67b In t h i s m i x t u r e was o n l y s l i g h t l y g r e a t e r t h a n t h a t o b t a i n e d f r o m t h e r e a c t i o n c a r r i e d o u t a t - 7 8 ° C . S i n c e t h e de s h o u l d p r e d i c t t h e e e , an a d d i t i o n a l h y d r o l y s i s e x p e r i m e n t was p e r f o r m e d t o c h e c k t h e a g r e e m e n t b e t w e e n t h e de and ee v a l u e s . T h e d I a s t e r e o m e r I c o x a z o l I n e s 67a and 67b o b t a i n e d by a l k y l a t i o n o f 5JB. a t - 7 8 ° C w e r e s u b j e c t e d t o a c i d h y d r o l y s i s In d e u t e r a t e d medium and a d i s t l I l e d y i e l d o f 45% o f a c i d s 64a and 64b was o b t a i n e d . The m i x t u r e o f e n a n t i o m e r i c a c i d s had a s p e c i f i c r o t a t i o n o f + 4 . 3 8 ° I n d i c a t i n g an ee o f 26%. T h i s v a l u e c o r r e s p o n d e d w e l l w i t h t h e de o f 23% a s d e t e r m i n e d by 1 H nmr s p e c t r a l a n a l y s i s o f t h e 1) DCI /D 20 64a 67a 2) H20 67b 64b 43 o x a z o l i n e m i x t u r e . In a d d i t i o n , m a s s s p e c t r a l a n a l y s i s o f t h e C4 f r a g m e n t showed o n l y 0 .2% d e u t e r i u m i n c o r p o r a t i o n i n d i c a t i n g t h a t t h e r e Is m i n i m a l r a c e m i z a t i o n o f t h e c h i r a l c e n t e r In t h e h y d r o l y s i s . A s e v i d e n t In F i g u r e A, n o n e o f t h e " t w i n n l n g s " o f t h e 1 H nmr s i g n a l s u s e d In a s s i g n i n g t h e amount o f I n d u c t i o n w e r e b a s e l i n e r e s o l v e d . T h e r e f o r e , t h e de o b t a i n e d f r o m a l k y l a t l o n o f o x a z o l I ne 5J£ w i t h e t h y l I o d i d e c o u l d n o t be d e t e r m i n e d by d i r e c t I n t e g r a t i o n . In o u r c a l c u l a t i o n s , i t was a s s u m e d t h a t t h e l i n e - s h a p e o f p e a k s w e r e t h e same and t h a t peak i n t e n s i t y was p r o p o r t i o n a l t o t h e number o f p r o t o n s . The o v e r l a p p i n g d o u b l e t s and o v e r l a p p i n g t r i p l e t s in t h e h i g h f i e l d p o r t i o n of t h e s p e c t r u m w e r e u s e d In t h e c a l c u l a t i o n s s i n c e t h e s e w e r e m o r e I n t e n s e and l e s s c o m p l e x t h a n some o t h e r s i g n a l s w h i c h showed d I a s t e r e o m e r I c s e p a r a t i o n . T h e de o f o x a z o l i n e 67a was d e t e r m i n e d s e p a r a t e l y f o r e a c h p a i r o f p e a k s , c o n s i s t i n g o f a lower f i e l d peak d u e t o o x a z o l i n e 67a w i t h t h e 3 - c o n f I g u r a t i o n a t t h e a - c h i r a l c e n t e r and a h i g h e r f i e l d peak d u e t o o x a z o l i n e 67b w i t h t h e fi-confIguratI o n , and t h e n t h e a v e r a g e o f t h e s e v a l u e s was t a k e n t o be t h e d e . T h e s e r e s u l t s a r e s u m m a r i z e d in T a b l e I I I . A s e v i d e n t in t h i s t a b l e , l a r g e e r r o r s a r e a s s o c i a t e d w i t h t h i s t y p e o f a n a l y s i s r e s u l t i n g f r o m t h e f a c t t h a t t h e p e a k s a r e n o t b a s e -l i n e r e s o l v e d . T h u s , 400 MHz 1 H nmr s p e c t r a l a n a l y s i s I n d i c a t e d t h a t t h e de o f o x a z o l i n e 67a w i t h t h e 3 - c o n f I g u r a t I o n a t t h e a - c h l r a l c e n t e r was 23% when t h e a l k y l a t l o n t e m p e r a t u r e was - 7 8 ° C . A s i m i l a r t y p e o f a n a l y s i s a p p l i e d t o t h e o x a z o l i n e m i x t u r e f o r m e d by a l k y l a t i o n a t - 1 0 5 ° C I n d i c a t e d t h a t t h e de 44 Tab I e I I I . D e t e r m i n a t i o n of , D i a s t e r e o m e r i c E x c e s s i n A l k y l a t i o n o f O x a z o l i n e 53 a t - 7 8 ° C P e a k a 6 (ppm) I n t e n s I t y ( c m ) de(%) o f 6 7 a b 1 1 . 165 2 8 . ,2 1 8 . 7 2 1.161 19. ,3 3 1 . 147 27 . ,8 2 5 . 6 4 1 . 143 16. ,4 5 0 . 9 2 8 12 . , 7 1 9 . 9 6 0 . 922 8. .5 7 0 . 9 0 9 24 . .4 22 . 7 8 0 . 904 15, ,4 9 0 .891 10, .5 26 .6 10 0 . 8 8 5 6, . 1 a P e a k n o s b a v e r a g e . c o r r e s p o n d de = 23%. t o t h o s e In F i g u r e 4 ( c ) ( p a g e was 25%. T h e l o w e r i n g o f t h e a l k y l a t i o n t e m p e r a t u r e f r o m - 7 8 ° C t o - 1 0 5 ° C r e s u l t e d In o n l y a s m a l l i n c r e a s e , i f a n y a t a l l , in t h e d e g r e e o f a s y m m e t r i c I n d u c t i o n f o r t h e 2 - s u b s t i t u t e d 4 ( 3 ) -b e n z y I o x a z o I Ine s y s t e m . * T h e r e s u l t s o f t h e s e low t e m p e r a t u r e m e t a l a t i o n and c h i r a l a l k y l a t i o n e x p e r i m e n t s may be r a t i o n a l i z e d In t e r m s o f t h e p r o p o s e d m e c h a n i s m o u t l i n e d on t h e f o l l o w i n g p a g e . D e p r o t o n a -t i o n o f o x a z o l I n e 53 w i t h LDA g i v e s two p o s s i b l e I I t h i o a n i o n s 72a a n d 72b f r o m t h e c o r r e s p o n d i n g p s e u d o - s I x - m e m b e r e d * A p o r t i o n o f t h e a b o v e work was p e r f o r m e d a s p a r t o f B . S c . d e g r e e r e q u i r e m e n t s In 1981 . 45 46 t r a n s i t i o n s t a t e s 71 a and 7 1 b . A l k y l a t i o n o f 72a w i t h e t h y l i o d i d e f r o m t h e b o t t o m f a c e o r 72b f r o m t h e t o p f a c e w o u l d g i v e o x a z o l i n e 6 7 a . w h e r e a s a l k y l a t i o n o f 72a f r o m t h e t o p f a c e o r 72b f r o m t h e b o t t o m f a c e w o u l d g i v e o x a z o l i n e 6 7 b . We o b t a i n e d an e x c e s s o f o x a z o l i n e 67a w i t h t h e S_-conf I g u r a t I on a t t h e a - c h l r a l c e n t e r w h i c h I n d i c a t e s t h a t t h e r e Is p r e f e r e n t i a l b o t t o m s l d e a l k y l a t i o n o f 72a o r t o p s i d e a l k y l a t i o n o f 7 2 b . On t h e b a s i s o f p r e v i o u s r e s u l t s 3 3 , t h e r e Is l i k e l y t o be s t e r e o s e l e c t i v e d e p r o t o n a t I on o f o x a z o l i n e 5J£. Due t o t h e d e v e l o p m e n t o f a 1 , 3 - d l a x l a l i n t e r a c t i o n b e t w e e n t h e a x i a l m e t h y l and a x i a l I s o p r o p y l g r o u p s In 7 1 b . t r a n s i t i o n s t a t e 71 a i s f a v o r e d g i v i n g r i s e t o s i g n i f i c a n t l y m o r e l i t h i o a n i o n 72a t h a n 7 2 b . T h i s s t e r e o s e l e c t i v e d e p r o t o n a t I on a l o n g w i t h t h e a s s u m p t i o n s t h a t t h e r e Is no e q u i l i b r a t i o n b e t w e e n 72a and 72b and t h a t t h e r a t e o f a l k y l a t i o n o f 72a and 72b i s t h e s a m e 3 3 , t h e n r u l e s o u t a n y s i g n i f i c a n t c o n t r i b u t i o n f r o m t o p s i d e a l k y l a t i o n o f 7 2 b . T h e r e f o r e , o x a z o l i n e 67a i s m o s t l i k e l y f o r m e d f r o m I i t h i o a n i o n 72a vI a b o t t o m s l d e e n t r y o f e t h y l Iod i d e . A c c o r d i n g t o t h e s e r e s u l t s , o u r p o s t u l a t e o f b l o c k i n g e n t r y o f t h e a l k y l ha I Ide f r o m t h e b o t t o m f a c e by t h e C - 4 b e n z y l g r o u p d i d n o t a p p e a r t o w o r k . If a n y t h i n g , a r e n e rr c o o r d i -n a t i o n t o t h e l i t h i u m i o n seems t o a s s i s t in d e l i v e r i n g t h e a l k y l h a l i d e t o t h e c o o r d i n a t i n g b o t t o m f a c e o f t h e o x a z o l i n e . A s d i s c u s s e d e a r l i e r , o x y g e n - 1 I thI urn c h e l a t i o n a n d a b u l k y g r o u p t o b l o c k t o p s i d e a l k y l a t i o n a r e r e q u i r e d f o r g o o d a s y m m e t r i c I n d u c t i o n ( T a b l e I, p a g e 1 3 ) . 3 2 A l k y l a t i o n o f o x a z o l i n e 30a w h i c h l a c k s t h e p h e n y l g r o u p w i t h e t h y l I o d i d e 47 CH 3 CH 2 -^ N CH 3 CH 2 -^ 5 1 1 1) LDA 2) Etl ca. 5% de 20-25% de 1) LDA 2) Etl w o u l d be e x p e c t e d t o g i v e a b o u t 5% d e * o f t h e a l k y l a t e d o x a z o l i n e . We h a v e f o u n d t h a t a l k y l a t l o n o f o x a z o l i n e 58 w i t h e t h y l i o d i d e g i v e s a d i a s t e r e o s e I e c t I v I t y o f 23%, w h i c h Is a s i g n i f i c a n t i n c r e a s e f r o m a b o u t 5%. T h u s , i t a p p e a r s t h a t t h e o x a z o l i n e s y s t e m w i t h t h e C - 4 b e n z y l g r o u p i s a b e t t e r c h e l a t o r t h a n t h a t w i t h t h e C - 4 m e t h o x y m e t h y I g r o u p . A s y s t e m i n v o l v i n g b o t h I I t h I u m - a r e n e TT c o o r d i n a t i o n and t o p s i d e b l o c k i n g by a b u l k y g r o u p w o u l d be e x p e c t e d t o show s e I e c t I v I t i e s c o m p a r a b l e t o o r e v e n h i g h e r t h a n t h a t e x h i b i t e d by o x a z o l i n e 3 0 . • T h i s v a l u e i s an e s t i m a t e b a s e d on t h e 3 .5% e e o f t h e a - c h i r a l c a r b o x y l i c a c i d o b t a i n e d In t h e a l k y l a t i o n o f o x a z o l i n e 30a w i t h n - b u t y l i o d i d e and s u b s e q u e n t h y d r o l y s i s . 3 2 It w o u l d be e x p e c t e d t h a t a l k y l a t i o n w i t h e t h y l i o d i d e p r o c e e d s s i m i l a r l y s i n c e t h e a l k y l a t i o n s o f o x a z o l i n e 2J2. w i t h n - b u t y l i o d i d e and e t h y l i o d i d e and s u b s e q u e n t h y d r o l y s e s b o t h g a v e 78% e e . 48 1 . 2 . 4 P r e p a r a t i o n o f 2 - E t h y l Der I v a t I v e s o f 4 ( S _ ) - ( 4 - M e t h o x y -b e n z y I ) o x a z o l I n e , 4 ( 2 ) - [ 4 - ( 2 - 0 x a p r o p y I o x y ) b e n z y I ] o x a z o -I I n e , and 4 ( 3 ) - [ 4 - ( 2 , 5 - D I o x a h e x y I o x y ) b e n z y I ] o x a z o I I n e T h e a b o v e I n v e s t i g a t i o n on t h e c h i r a l a l k y l a t i o n o f ( - ) - 2 -e t h y I - 4 ( S J - b e n z y I o x a z o I Ine (53) d e m o n s t r a t e d t h a t c h i r a l i n d u c t i o n i s p o s s i b l e u s i n g t h e 4 ( 3 ) - b e n z y I o x a z o I Ine s y s t e m . A l t h o u g h t h e de o b t a i n e d was o n l y m o d e s t , t h e u s e o f t h e 4 ( 3 ) - b e n z y I o x a z o I Ine s y s t e m a s a r e a g e n t f o r a s y m m e t r i c s y n t h e s i s l o o k e d p r o m i s i n g a t t h i s s t a g e w i t h c e r t a i n m o d i f i c a t i o n s t o t h e s y s t e m . P e r h a p s e n t r y o f t h e a l k y l h a l i d e f r o m t h e c o o r d i n a t i n g f a c e o f t h e o x a z o l i n e c a n be e n h a n c e d w i t h g r e a t e r c h e l a t i o n . A s m e n t i o n e d e a r l i e r , t h e r a t i o o f c o m p o u n d s 45 t o 44 f o r m e d by t r a p p i n g t h e e n o l a t e o f 42. a s t h e s i l y l e n o l e t h e r i n c r e a s e d s i g n i f i c a n t l y ( T a b l e I I , p a g e 16) by u s i n g a B_-methoxypheny I g r o u p i n s t e a d o f a p h e n y l g r o u p a t t h e g - p o s l t l o n and t h i s i n c r e a s e in t h e d i r e c t i n g e f f e c t o f e n o l a t e f o r m a t i o n was a t t r i b u t e d t o t h e g r e a t e r e l e c t r o n d o n a t i n g a b i l i t y o f t h e D _ -methoxypheny I g r o u p w h i c h r e s u l t e d in an I n c r e a s e d d e g r e e o f c o o r d i n a t i o n t o t h e l i t h i u m e n o l a t e . 4 0 A l t h o u g h t h i s t y p e o f s u b s t i t u t i o n s t u d y was n o t p e r f o r m e d f o r t h e c a s e o f £3 w i t h a b e n z y l g r o u p a s t h e g - s u b s t i t u e n t , t h e same e f f e c t ( i e . I n c r e a s e d TT c o o r d i n a t i o n t o l i t h i u m upon C - s u b s t i t u t Ion w i t h m e t h o x y ) m i g h t be e x p e c t e d t o be o b s e r v e d . A n o t h e r p o s s i b l e m e t h o d o f I n c r e a s i n g t h e d e g r e e o f c h i r a l i n d u c t i o n w o u l d be t o i n c r e a s e t h e amount o f c h e l a t i o n t o t h e l i t h i u m I o n . 3 1 T h i s c o u l d be a c c o m p l i s h e d by i n c r e a s i n g t h e number o f o x y g e n a t o m s in t h e o x a z o l i n e s o t h a t in a d d i t i o n t o 49 I I t h I u m - a r e n e u c o o r d i n a t i o n , o x y g e n - I I t h I u m c h e l a t e s c a n a l s o f o r m t h e r e b y I n c r e a s i n g t h e s t r e n g t h o f c h e l a t i o n . C o n c u r r e n t l y w i t h t h e c h i r a l a l k y l a t i o n s t u d i e s u s i n g o x a z o l i n e 33, t h e p r e p a r a t i o n s o f 2 - e t h y I - 4 ( S _ ) - ( 4 - m e t h o x y b e n -z y I ) o x a z o I I ne ( 2 5 . ) , 2 - e t h y I - 4 ( 3 . ) - [ 4 - ( 2 - o x a p r o p y I o x y ) b e n z y I ] -o x a z o l i n e ( 2 3 ) , a n d 2 - e t h y I - 4 ( 3 ) - [ 4 - ( 2 , 5 - d i o x a h e x y I o x y ) b e n z y I ] -o x a z o l i n e (22.) w e r e u n d e r t a k e n . The a s y m m e t r i c i n d u c t i o n a b i l i t y o f t h e s e o x a z o l I n e s w a s t h e n i n v e s t i g a t e d . O u r s t r a t e g y f o r t h e s y n t h e s i s o f o x a z o l i n e s 23, 23., a n d 77 w a s t o t r a n s f o r m t h e r e a d i l y a v a i l a b l e a m i n o a c i d L - t y r o s i n e (73.) i n t o o x a z o l I ne 2A w h i c h i s a common i n t e r m e d i a t e f r o m w h i c h o x a z o l i n e s 23, 23, a n d 22 c a n be m a d e . T h i s w o u l d be m o r e e f f i c i e n t t h a n an i n d e p e n d e n t s y n t h e s i s o f e a c h f r o m L - t y r o s i n e . T h e f i r s t s t e p In t h e s y n t h e s i s I n v o l v e d t h e p r o t e c t i o n o f t h e p h e n o l i c h y d r o x y l g r o u p o f L - t y r o s i n e a s i t s b e n z y l e t h e r . L - T y r o s i n e ( 2 3 . ) i n a q u e o u s s o d i u m h y d r o x i d e w a s t r e a t e d w i t h c o p p e r ( l l ) s u l f a t e p e n t a h y d r a t e f o l l o w e d by m e t h a n o l a n d b e n z y l 50 . ^ s A / ^ 1)NaOH,H20 ^ v v ^ V ^ C C ^ H ( T T CuSCy5H20 Jf J T MOT^S NH2 2) PhCH2Br,MeOH * PhCH 20T^ NH2 ^ 3) HCI,H20 m b r o m i d e . 4 9 T h e b l u e c o p p e r c o m p l e x w h i c h r e s u l t e d a f t e r a few h o u r s was I s o l a t e d and t h e n h y d r o l y z e d u s i n g warm a q u e o u s h y d r o c h l o r i c a c i d t o a f f o r d Q - b e n z y I - L - t y r o s i ne (23.) i n 73% y i e l d . Q - B e n z y I - L - t y r o s I n e (23) was e s t e r i f l e d u s i n g t h i o n y l c h l o r i d e a n d a b s o l u t e e t h a n o l t o g i v e e t h y l e s t e r h y d r o c h l o r i d e 7_9_ In 88% r e c r y s t a l l i z e d y i e l d w h i c h was t h e n r e d u c e d w i t h l i t h i u m a I urn Inum h y d r i d e in r e f l u x i n g THF t o a f f o r d an 88% SOCIa t fY\ L J A I H 4 . EtOH PhCH 2 CT^ NH2-HCI THF P h C H 2 13. r e c r y s t a l l i z e d y i e l d o f 2(3.) -am I n o - 3 - ( 4 - b e n z y I o x y p h e n y I ) -p r o p a n - 1 - o l (30.) • The Ir s p e c t r u m o f a m i n o a l c o h o l 3Q. showed a b s o r b a n c e s a t 3610 and 3380 c m - 1 d u e t o t h e O - H s t r e t c h and N-H s t r e t c h , r e s p e c t i v e l y . In t h e 1 H nmr s p e c t r u m , t h e b r o a d s i n g l e t a t 6 1 . 8 9 c o u l d be a s s i g n e d t o t h e h y d r o x y l and a m i n e p r o t o n s a n d t h e m u l t i p l e t a t 6 3 . 0 3 - 3 . 1 4 was d u e t o t h e m e t h i n e p r o t o n . T h e b e n z y l i c p r o t o n s a d j a c e n t t o t h e m e t h i n e g r o u p a p p e a r e d a s two d o u b l e t s o f d o u b l e t s a t 6 2 . 4 8 a n d 6 2 . 7 3 , and t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e h y d r o x y l g r o u p a l s o a p p e a r e d a s d o u b l e t s o f d o u b l e t s a t 6 3 . 3 7 and 6 3 . 6 3 . T h e s i n g l e t a t 6 5 . 0 4 was a s s i g n e d t o t h e m e t h y l e n e p r o t o n s o f t h e 51 benzyl group. Furthermore, the doublets at <S6.92 and 6 7 . 1 0 were a t t r i b u t a b l e to the four protons on the para-substItuted aromatic ring and the multiplet at 6 7 . 3 0 - 7 . 4 7 was due to the f i v e phenyl protons. We I n i t i a l l y planned to prepare a z l r i d i n e 8_L from amino alcohol QQ. by a Wenker eye I ization. However, when the Wenker eye I ization was ca r r i e d out, none of the desired a z l r i d i n e £1 could be Isolated by d i s t i l l a t i o n or by subsequent extraction. 1) H 2 S 0 4 , A 0 PhCH2Cr^ 8_L P h C H 2 c r ^ N H 2 2)NaOH,H20 PhCH2C The a l t e r n a t i v e one-pot method of reacting amino alcohol J1Q with DEAD and trIphenyIphosphIne 4 5 followed by conversion of the a z l r i d i n e 8J_ to acyI a z l r i d i n e QZ was then attempted. Identical reaction conditions as for the preparation of acyI 1) DEAD,Ph3P PhCH3 PhCH2( PhCH 2 Cf^^' NH 2 2) CDI C=0 CHgCI-^ CC^H CH2CH3 a z l r i d i n e Q3. from amino alcohol QZ (page 26) were applied i n i t i a l l y to the preparation of acyI a z l r i d i n e QZ but a y i e l d of only 3 4 % was obtained. After some experimentation It was found that the y i e l d of QZ could be Improved to 55% by performing the reaction In toluene Instead of THF. The ir 52 s p e c t r u m o f ( +)-1 - p r o p a n o y I -2 (S_)-(4 -benzy I o x y b e n z y I ) a z i r I d I ne (82) showed a c a r b o n y l s t r e t c h a t 1685 c m - 1 . In t h e 1 H nmr s p e c t r u m , t h e t r i p l e t a t 61.08 and t h e m u l t i p l e t a t 62.16-2.33 w e r e d u e t o t h e m e t h y l p r o t o n s and t h e m e t h y l e n e p r o t o n s o f t h e e t h y l g r o u p , r e s p e c t i v e l y . D o u b l e t s a t 62.03 and 62.37 w e r e a s s i g n e d t o t h e m e t h y l e n e p r o t o n s In t h e a z l r i d i n e r i n g , and t h e m e t h i n e p r o t o n a p p e a r e d a s a m u l t i p l e t a t 62.55-2.62. The two b e n z y l I c p r o t o n s a d j a c e n t t o t h e m e t h i n e g r o u p a p p e a r e d a s d o u b l e t s o f d o u b l e t s a t 62.73 and 62.83. A c y I a z l r i d i n e 32. was r e a r r a n g e d by t r e a t m e n t w i t h a c a t a l y t i c amount o f t e t r a-n - b u t y I a m m o n I urn I o d i d e In r e f l u x i n g THF t o a f f o r d a 90% y i e l d o f o x a z o l i n e £3_. T h e i r s p e c t r u m o f CH2CH3 £3_ £2. o x a z o l i n e 33 showed t h e C=N s t r e t c h a t 1660 c m - 1 . T h e m e t h y l p r o t o n s a n d m e t h y l e n e p r o t o n s o f t h e e t h y l g r o u p now a p p e a r e d r e s p e c t i v e l y a s a t r i p l e t a t 61.16 a n d a q u a r t e t a t 62.24 in t h e 1 H nmr s p e c t r u m . T h e d o u b l e t s o f d o u b l e t s a t 62.57 and 63.00 w e r e d u e t o t h e b e n z y l i c p r o t o n s a d j a c e n t t o t h e m e t h i n e g r o u p , a n d t h e t r i p l e t s a t 63.90 and 64.12 c o r r e s p o n d e d t o t h e m e t h y l e n e p r o t o n s in t h e o x a z o l i n e r i n g . T h e m e t h i n e p r o t o n a p p e a r e d a s a m u l t i p l e t a t 64.22-4.36. T h e b e n z y l g r o u p o f o x a z o l i n e 33 was r e a d i l y r e m o v e d by c a t a l y t i c h y d r o g e n o I y s i s u s i n g 10% p a l l a d i u m on c h a r c o a l In 53 CH3CH2' m e t h a n o l t o a f f o r d a q u a n t i t a t i v e y i e l d o f o x a z o l i n e 2 4 - 1 n t h e i r s p e c t r u m o f o x a z o l i n e 2 4 , a b s o r p t i o n s o b s e r v e d a t 3100 and 1650 c m - 1 w e r e due t o t h e 0 - H s t r e t c h and C=N s t r e t c h , r e s p e c t i v e l y . T h e l o s s o f t h e b e n z y l g r o u p was c o n f i r m e d by t h e 1 H nmr s p e c t r u m w h i c h showed an a b s e n c e o f t h e r e s o n a n c e s d u e t o t h e m e t h y l e n e p r o t o n s and t h e f i v e p h e n y l p r o t o n s . T h e p h e n o l i c h y d r o x y l g r o u p o f o x a z o l i n e Z 4 was t h e n c o n v e r t e d t o v a r i o u s e t h e r s by r e a c t i o n w i t h a l k y l a t i n g a g e n t s . O x a z o l i n e 25. was p r e p a r e d In 90% y i e l d by r e a c t i o n o f o x a z o l i n e 2 4 w i t h t e t r a - n - b u t y I a m m o n I urn h y d r o x i d e and m e t h y l i o d i d e in w a t e r and d I c h I o r o m e t h a n e . The m e t h y l p r o t o n s o f t h e m e t h o x y g r o u p a p p e a r e d a s a s i n g l e t a t 6 3 . 7 8 In t h e 1 H nmr s p e c t r u m . n-Bu4N0H Mel - CH3CH2 ^ Q M e CH2CI2,H20 Z5. IA Zfi. 1 ) NaH, THF 2) MEMCI CH3CH2 'OMEM IZ 54 O x a z o l i n e JA r e a c t e d w i t h s o d i u m h y d r i d e In THF t o g i v e t h e p h e n o l a t e a n i o n w h i c h was t h e n a l k y l a t e d w i t h c h l o r o m e t h y l m e t h y l e t h e r t o g i v e a 41% y i e l d o f o x a z o l i n e 76_. In t h e 1 H nmr s p e c t r u m , t h e m e t h y l a n d m e t h y l e n e p r o t o n s o f t h e m e t h o x y m e t h y I (MOM) g r o u p a p p e a r e d a s s i n g l e t s a t 6 3 . 4 7 a n d 6 5 . 1 4 , r e s p e c t i v e l y . O x a z o I I ne 21 w a s s ImI I a r I y p r e p a r e d i n 55% y i e l d f r o m o x a z o l i n e JA, s o d I urn h y d r i d e , a n d 3 - m e t h o x y e t h o x y m e t h y I (MEM) c h l o r i d e i n T H F . The m e t h y l p r o t o n s a n d t h e two m e t h y l e n e p r o t o n s f l a n k e d by two o x y g e n s a p p e a r e d a s s i n g l e t s a t 6 3 . 3 8 a n d 6 5 . 2 4 i n t h e 1 H nmr s p e c t r u m . The f o u r m e t h y l e n e p r o t o n s o f t h e e t h y l e n e b r i d g e s h o w e d up a s t w o m u l t i p l e t s a t 6 3 . 5 6 a n d 6 3 . 8 2 . 55 1 . 2 . 5 C h i r a l A l k y l a t i o n o f Some T y r o s I n e - d e r i v e d C h i r a l O x a z o I Ines W i t h t h e p r e p a r a t i o n o f t h e d e s i r e d o x a z o l I n e s , t h e i r u s e i n a s y m m e t r i c s y n t h e s i s was I n v e s t i g a t e d . T h e m e t a l a t i o n and c h i r a l a l k y l a t i o n o f o x a z o I i n e s 25., 26:, 2 2 , and £ 2 w e r e c a r r i ed o u t u n d e r I d e n t i c a l e x p e r i m e n t a l c o n d i t i o n s a s f o r o x a z o l i n e 58_. T h u s , o x a z o l i n e s 2 5 , 26_, 2 2 , and 8_3_ w e r e e a c h d e p r o t o n a t e d w i t h LDA in THF a t - 7 8 ° C f o r o n e h o u r and t h e r e s u l t i n g l l t h i o a n i o n s w e r e a l k y l a t e d w i t h e t h y l i o d i d e a t - 7 8 ° C . S t i r r i n g was c o n t i n u e d f o r f i v e h o u r s a t - 7 8 ° C , and t h e a l k y l a t e d o x a z o l i n e s w e r e o b t a i n e d In p u r i f i e d y i e l d s o f 7 1 - 8 4 % . T h e 400 MHz 1 H nmr s p e c t r a o f t h e a l k y l a t e d o x a z o l I n e s e x h i b i t e d t h e e x p e c t e d " t w l n n l n g s " f o r some o f t h e s i g n a l s . By a n a l o g y t o t h e e a r l i e r r e s u l t s f o r t h e c h i r a l a l k y l a t i o n o f o x a z o l i n e 55., t h e lower f i e l d s e t s o f p e a k s w e r e a s s i g n e d t o t h e d i a s t e r e o m e r w i t h t h e S_-conf I g u r a t i on a t t h e c a r b o n a t o t h e o x a z o l i n e r i n g and t h e h i g h e r f i e l d s e t s o f p e a k s w e r e a s s i g n e d t o t h e d i a s t e r e o m e r w i t h t h e fi-confIguratIon. The h i g h e r f i e l d p o r t i o n s o f t h e s p e c t r a a r e shown in F i g u r e s 5 t o 8 . In e a c h c a s e t h e lower f i e l d s e t s o f p e a k s p r e d o m i n a t e I n d i c a t i n g t h a t t h e d i a s t e r e o m e r w i t h t h e 3 , - c o n f i g u r a t I on a t t h e a - c h i r a l c e n t e r i s a g a i n f o r m e d In e x c e s s . T h e d e g r e e o f a s y m m e t r i c I n d u c t i o n was d e t e r m i n e d by 1 H nmr s p e c t r o s c o p y by a s i m i l a r m e t h o d a s f o r o x a z o l i n e 5JB. ( T a b l e I I I , p a g e 4 4 ) . T h e peak i n t e n s i t i e s o f t h e o v e r l a p p i n g d o u b l e t s ( d u e t o t h e m e t h y l p r o t o n s a t t a c h e d t o t h e a - c a r b o n ) and t h e o v e r l a p p i n g t r i p l e t s ( d u e t o t h e m e t h y l p r o t o n s a d j a c e n t t o t h e m e t h y l e n e g r o u p ) in t h e h i g h f i e l d p o r t i o n o f 5 6 F i g u r e 5. P a r t i a l 400 MHz 'H nmr spectrum of oxazol ines 84a and 84b in CDC 13 prepared by a l k y l a t i o n of oxazoline 7Jj at -78°C. 57 F i gure 6. P a r t i a l 400 MHz 1H nmr spectrum of oxazol ines 85a and 85P in CDC 13 prepared by a l k y l a t l o n of oxazoline 26: at -78°C. F i a u r e 7 . P a r t i a l 400 MHz 1 H nmr s p e c t r u m o f o x a z o l i n e s 86a a n d 86b In CDC 13 p r e p a r e d by a l k y l a t i o n o f o x a z o l i n e 22 a t - 7 8 ° C . 59 FIaure 8. P a r t i a l 400 MHz 1H nmr spectrum of oxazol ines 87a and 87b In CDC 13 prepared by a l k y l a t i o n of oxazol I ne 8_3_ at -78°C. 60 t h e s p e c t r u m w e r e u s e d In t h e c a l c u l a t i o n s . T h e de o f t h e d l a s t e r e o m e r w i t h t h e S - c o n f i g u r a t i o n a t t h e a - c h l r a l c e n t e r was d e t e r m i n e d f o r e a c h p a i r o f p e a k s , and t h e n t h e a v e r a g e o f t h e s e v a l u e s was t a k e n t o be t h e d e . T h e r e s u l t s o f o u r s t u d y on a s y m m e t r i c s y n t h e s i s u s i n g t h e s e c h i r a l o x a z o l i n e s a r e s u m m a r i z e d In T a b l e IV. It was d i s a p p o i n t i n g t h a t no I n c r e a s e In d I a s t e r e o s e I e c t I v I t y w i t h t h e s e m o d i f i e d o x a z o l i n e s was o b s e r v e d . T h e de o f t h e T a b l e IV. A s y m m e t r i c S y n t h e s i s U s i n g N o v e l C h i r a l O x a z o l i n e s CHgCHa-^ Ar 2) Etl,-78° 1) LDA,-78° CH3 CH3 Ar O x a z o I Ine Y l e l d ( X ) % de ( c o n f i g u r a t i o n ) 83 23 (S_) 84 22 (S_) 71 22 (SJ 81 21 (S_) 77 20 (3 ) 61 a l k y l a t e d o x a z o l i n e p o s s e s s i n g t h e S_-conf I g u r a t I on a t t h e a - c h i r a l c e n t e r was e s s e n t i a l l y t h e same f o r t h e s e m o d i f i e d o x a z o l i n e s y s t e m s s t u d i e d , r a n g i n g f r o m 2 0 - 2 3 % , a s i t was f o r t h e p a r e n t s t r u c t u r e 5_&. T h e a b s e n c e o f a n y e f f e c t by t h e e x t r a a r o m a t i c r i n g and t h e o x y g e n a t o m s may be d u e t o t h e f a c t t h a t t h e s e g r o u p s w e r e t o o f a r r e m o v e d f r o m t h e s i t e o f c h e l a t i o n o f l i t h i u m i o n t o t h e a n i o n t o h a v e a s i g n i f i c a n t i n f l u e n c e o n t h e s t a b i l i z a t i o n o f t h e t r a n s i t i o n s t a t e . 62 1 . 2 . 6 C o n e I u s I on In t h e s e s t u d i e s , t h e 4 (S_ ) -benzy I o x a z o I I ne s y s t e m h a s been shown t o be a g o o d c a r b o x y l i c a c i d p r o t e c t i n g g r o u p . H i g h y i e l d s a r e o b t a i n e d d u r i n g t h e p r o t e c t i o n and d e p r o t e c t l o n s t e p s a n d a c h r o m o p h o r e i s i n c o r p o r a t e d f o r u s e a s a c h r o m a t o -g r a p h i c m a r k e r . T h i s s y s t e m c a n be u s e d f o r t h e p r o t e c t i o n o f a - c h i r a l c a r b o x y l i c a c i d s s i n c e no e p I m e r i z a t I o n o f t h e c h i r a l c e n t e r o c c u r s d u r i n g b o t h t h e t r a n s f o r m a t i o n i n t o t h e o x a z o l i n e and t h e h y d r o l y s i s o f t h e o x a z o l i n e t o r e g e n e r a t e t h e c h i r a l a c i d a s shown by d e u t e r i u m l a b e l l i n g s t u d i e s . T h e s y n t h e s e s o f 2 - e t h y I - 4 ( 3 ) - b e n z y I o x a z o I Ine (53.) , 2 - e t h y I-4 (3.) - ( 4 - b e n z y I o x y b e n z y I ) o x a z o l Ine (33), 2 - e t h y I - 4 ( 3 ) -( 4 - m e t h o x y b e n z y I ) o x a z o I I ne (25.), 2 - e t h y I - 4 ( 3 ) - [ 4 - ( 2 - o x a p r o p y I -o x y ) b e n z y I ] o x a z o I Ine ( 2 3 ) , and 2 - e t h y I - 4 ( 3 ) - [ 4 - ( 2 , 5 - d I o x a h e x y I -o x y ) b e n z y I ] o x a z o I i n e (22) w e r e a c c o m p l i s h e d . T h e i r u t i l i t y in a s y m m e t r i c s y n t h e s i s was I n v e s t i g a t e d by t h e d e p r o t o n a t I on and a l k y l a t i o n o f t h e s e o x a z o l i n e s a s a m e t h o d f o r m a k i n g a - c h l r a l c a r b o x y l i c a c i d s . H o w e v e r , t h e d i a s t e r e o m e r i c e x c e s s o f t h e o x a z o l i n e w i t h t h e 3 - c o n f I g u r a t I on a t t h e a - c h l r a l c a r b o n was o n l y m o d e s t (20-23%) a s d e t e r m i n e d by 1 H nmr s p e c t r o s c o p y . R 53. R=H 13 R=0Me 13 R=0M0M 7_7_ R=0MEM £J3_ R=0CH2Ph 63 CHAPTER I I : SOME CHEMISTRY OF ORGANOSILI CON COMPOUNDS 64 PART A . S T U D I E S ON THE DEVELOPMENT OF A NOVEL S I L I C O N - B A S E D PROTECTING GROUP 2 A . 1 I n t r o d u c t I o n 2 A . 1 . 1 S i l i c o n - b a s e d P r o t e c t i n g G r o u p s and F l u o r i d e C l e a v a g e s T h i s s e c t i o n ( P a r t A) d e a l s s p e c i f i c a l l y w i t h t h e u s e o f o r g a n o s i I I con c o m p o u n d s a s p r o t e c t i n g g r o u p s and o u r s t u d i e s d i r e c t e d t o w a r d t h e d e v e l o p m e n t o f a new s i l i c o n - b a s e d p r o t e c t i n g g r o u p . S e v e r a l b o o k s and r e v i e w a r t i c l e s h a v e a p p e a r e d r e c e n t l y w h i c h p r o v i d e a d e t a i l e d d e s c r i p t i o n o f a p p l i c a t i o n s o f o r g a n o s I I I c o n c h e m i s t r y t o o r g a n i c s y n t h e s i s a s w e l l a s g e n e r a l a c c o u n t s o f t h e c h e m i s t r y o f o r g a n o s i I I c o n c o m p o u n d s . 5 0 - 5 6 O r g a n o s I I i c o n c o m p o u n d s a r e d e f i n e d a s t h o s e s p e c i e s w h i c h c o n t a i n c a r b o n - s i l i c o n b o n d s . 5 0 T h e p a s t t w e n t y y e a r s h a v e w i t n e s s e d an e x p l o s i v e g r o w t h in o r g a n o s i I I c o n c h e m i s t r y . By f o r m a l l y s u b s t i t u t i n g a s i l i c o n m o i e t y f o r a h y d r o g e n a tom o f an o r g a n i c s u b s t r a t e o r r e a g e n t , o n e c a n a c t i v a t e t h e s u b -s t r a t e , d i r e c t t h e c o u r s e o f t h e r e a c t i o n , o r p r o t e c t t h e s u b s t r a t e f r o m u n w a n t e d r e a c t i o n s . S i l i c o n l i e s d i r e c t l y b e l o w c a r b o n In t h e P e r i o d i c T a b l e ( G r o u p IVA e l e m e n t s ) , and t h u s t h e same number o f v a l e n c e s h e l I e l e c t r o n s a r e a v a i l a b l e In e a c h c a s e . T h e m a j o r i t y o f o r g a n o -s i l l c o n c o m p o u n d s e x i s t a s t e t r a c o o r d I n a t e s p e c i e s in w h i c h t h e s i l i c o n o c c u p i e s t h e c e n t r a l p o s i t i o n In an e s s e n t i a l l y t e t r a -h e d r a l c o n f i g u r a t i o n . H o w e v e r , u n l i k e t h e c a r b o n a n a l o g u e , t h e r e a d i l y a c c e s s i b l e empty d o r b i t a l s o f s i l i c o n c a n p r o v i d e 65 e x t r a c o o r d i n a t i o n s i t e s . 5 1 T h e r e a c t i v i t y o f o r g a n o s I I I c o n c o m p o u n d s h a s b e e n m a i n l y a t t r i b u t e d t o t h e r e l a t i v e bond s t r e n g t h s o f s i l i c o n t o o t h e r e l e m e n t s a s w e l l a s I t s e l e c t r o n e g a t i v i t y . 5 0 ' 5 2 T h e a p p r o x i m a t e b o n d d i s s o c i a t i o n e n e r g i e s o f v a r i o u s b o n d s t o s i I i c o n a r e , shown in T a b l e V a l o n g w i t h v a l u e s o f t h e c o r r e s p o n d i n g b o n d s t o c a r b o n . The e n e r g i e s a r e t h o s e r e q u i r e d f o r h o m o l y t i c f i s s i o n o f t h e b o n d , and t h u s do n o t g i v e an a c c u r a t e p i c t u r e o f t h e e a s e o f h e t e r o l y t l c f i s s i o n w h i c h i s t h e n o r m a l mode o f c l e a v a g e . In s p i t e o f t h i s l i m i t a t i o n , c e r t a i n i m p o r t a n t g e n e r a l i t i e s c a n be m a d e . B o n d s t o s i l i c o n a r e s t r o n g e r t h a n t h e c o r r e s p o n d i n g b o n d s t o c a r b o n w i t h t h e e x c e p t i o n o f S I - H and S I - C b o n d s . In p a r t i c u l a r , t h e S I - 0 and S I - F b o n d s a r e c o n s i d e r a b l y s t r o n g e r t h a n t h e c o r r e s p o n d i n g C - 0 and C - F b o n d s . T h e s t r o n g e r b o n d s o f o x y g e n , n i t r o g e n , and h a l o g e n s t o s i l i c o n h a s b e e n I n t e r p r e t e d in t e r m s o f p ^ - d u i n t e r a c t i o n i n v o l v i n g t h e h e t e r o a t o m l o n e p a i r e l e c t r o n s and t h e empty d o r b i t a l s o f s i l i c o n . 5 1 T a b l e V . B o n d D i s s o c i a t i o n E n e r g i e s f o r S i - X and C - X a S i l l c o n b o n d B D E ( k c a 1 / m o l e ) C a r b o n b o n d B D E ( k c a I / m o l e ) S l - C 76 C - C 80 S i - H 81 C - H 100 S I - O 127 C - O 81 S i - N 80 C - N 70 S i - F 193 C - F 108 S i - C I 1 13 C - C I 80 S i - B r 96 C - B r 64 S I - I 77 C - 1 51 a T a k e n f r o m r e f . 50 and 5 2 . 66 T h e e l e c t r o n e g a t i v i t i e s , on t h e P a u l I n g s c a l e , o f s i l i c o n a n d e l e m e n t s commonly b o n d e d t o It a r e shown in T a b l e V I . S i n c e s i l i c o n i s m a r k e d l y m o r e e l e c t r o p o s i t i v e t h a n c a r b o n , t h e r e Is p o l a r i z a t i o n o f t h e c o v a l e n t S I - C b o n d s r e s u l t i n g In a t e n d e n c y f o r n u c l e o p h i l i c a t t a c k t o o c c u r a t s i l i c o n and e l e c t r o p h i l i c a t t a c k t o o c c u r a t c a r b o n l e a d i n g t o b o n d h e t e r o -l y s i s in t h e d i r e c t i o n S l + C - . 5 0 Tab Ie V I . R e l a t i v e E l e c t r o n e g a t i v i t y 3 E l e m e n t E l e c t r o n e g a t i v i t y S i 1 . 8 C 2 .5 H 2 . 1 F 4 .0 C l 3 .0 Br 2 .8 1 2 .4 O 3 . 5 S 2 . 5 N 3 .0 a T a k e n f r o m r e f . 5 1 . T h e S I - C bond i s o n l y w e a k l y p o l a r i z e d when c o m p a r e d w i t h t h o s e o f o t h e r o r g a n o m e t a l I i c c o m p o u n d s and a s a c o n s e q u e n c e , o r g a n o s I I I c o n c o m p o u n d s a r e r e l a t i v e l y u n r e a c t i v e t o w a r d e I e c t r o p h i I e s . T h i s l a c k o f r e a c t i v i t y l e a d s t o o n e o f t h e m a i n a d v a n t a g e s o f s i l i c o n o v e r o t h e r m e t a l s In o r g a n i c s y n t h e s i s . In g e n e r a l , o r g a n o s i I i c o n c o m p o u n d s c a n be h a n d l e d e a s i l y , w i t h o u t t h e n e e d f o r a n h y d r o u s c o n d i t i o n s o r i n e r t a t m o s p h e r e s . One o f t h e f i r s t a p p l i c a t i o n s o f o r g a n o s I I i c o n c o m p o u n d s t o 67 organic synthesis was the conversion of polar organic compounds, such as alcohols and amines to their more v o l a t i l e t r i a IkyIsI IyI derivatives for gas chromatographic a n a l y s i s 5 7 and for the protection of active hydrogen-containing functiona-l i t i e s . 5 8 The order of r e a c t i v i t y towards s l l y l a t i n g agents is r e p o r t e d 5 9 as ROH>ArOH>COOH>NH>CONH>SH. The usefulness of trI a IkyIsI IyI groups as protecting reagents arises mainly from the ease with which the protected derivatives are formed, their s t a b i l i t y in the presence of carbon nucIeophiIes, oxidizing agents and reducing agents, and the ease with which the protecting group Is removed. 5 8 Alcohols have been converted into trimethyIsiIyI ethers, amines into trimethyIsI IyI amides, and carboxylic acids into trimethyIsiIyI esters using a wide variety of s i l y l a t i n g agents such as chIorotrimethyIsi Iane, hexamethyIdIsI Iazane, trlmethyi-s i I y I Im I dazo I e, b I str Imethy I s I I y 1 urea , and N,Q_-b i str imethy I -si I y I a c e t a m i d e . 5 7 - 5 9 However, the s o l v o l y t l c l a b i l i t y of the trimethyIsI IyI group limits Its usefulness. This problem has been circumvented with the use of trI organosI IyI groups with greater s t e r l c requirements. The approximate r e l a t i v e rates of hydrolysis for some t r i a IkyIsI IyI groups are shown below. 6 0 Thus, the use of more hindered s i l y l groups such as RNH2 ROH ROSiMe3 RNHSiMe3 RCOgH RC02SiMe3 Me 3Si(1) > E t 3 S i ( 1 0 - 2 ) > i-BuMe 2SI(10 - 4) 68 triethyIsI IyI 6 1 , i-butyIdimethy Isi IyI 6 2 , t-butyId IphenyI -s i l y l 6 3 , and trIphenyIsI IyI 6 4 has added tremendously to the range of s t a b i l i t i e s of the resulting s i l y l d erivatives. Removal of s i l y l protecting groups can be achieved readily In the cases of l a b i l e groups by treatment with nucleophiles such as methanol or by mild acid or base h y d r o l y s i s . 5 8 Although highly hindered s i l y l groups are not e a s i l y removed by hydrolysis, they are readily cleaved by f l u o r i d e Ion for example from tetra-n-butyIammonI urn f l u o r i d e (TBAF). 6 2 The high thermodynamic s t a b i l i t y of the SI-F bond Is responsible for the success of t h i s f l u o r i d e cleavage. Over the past decade, several protecting groups have been designed such that they are s e l e c t i v e l y cleaved by a fragmenta-tion p r o c e s s . 5 8 The silicon-based protecting groups which have been devised take advantage of the s e l e c t i v i t y of fluoride ion for s i l i c o n in the deprotection step and these deprotec-tions are f a c i l i t a t e d by the formation of gaseous by-products. S i e b e r 6 5 and G e r l a c h 6 6 Independently reported the use of the 2-trimethyIsiIyIethyI group as a carboxyl protecting group. The carboxylic acid reacted with 2-trImethyIsi IyI -ethanol (8J£) and £ t , H ' -d I eye I ohexy I carbod I lm I de (DCC) in the presence of pyridine to give the 2-trImethyIsiIyIethyI ester 89. Removal of the 2-trImethyIsI IyIethyI group occurs with 0 fi& as. o aa. 69 TBAF In t e t r a h y d r o f u r a n (THF) o r £4, N -d i m e t h y I f ormam i de (DMF) t o g i v e t h e c a r b o x y l a t e a n i o n t o g e t h e r w i t h e t h y l e n e and t r i -m e t h y l s i l y l f l u o r i d e . A r e l a t e d a m i n o p r o t e c t i n g g r o u p was r e p o r t e d by C a r p i n o e_t a j _ . 6 7 I n t r o d u c t i o n o f t h e B - ( t r I m e t h y I s I I y I ) e t h o x y c a r b o n y I g r o u p i s e a s i l y c a r r i e d o u t by r e a c t i o n o f t h e a m i n e w i t h c h I o r o f o r m a t e SQ_. D e p r o t e c t l o n Is a c c o m p l i s h e d by t r e a t m e n t o f c a r b a m a t e S I w i t h TBAF in a c e t o n l t r i l e t o r e g e n e r a t e t h e a m i n e a l o n g w i t h c a r b o n d i o x i d e , e t h y l e n e , and t r i m e t h y I s I IyI f I u o r I d e . 0 0 RNH2 + C l ^ c y ^ S i M e 3 - R N H A 0 ^ S i M e 3 aa 21 ^ S i M e 3 1)n-Bu4NF RNH CT J CTTCN R N H 2 + °°2 + CH2=CH2 + Me3SiF 3 2) H20 T h e 3 - ( t r i m e t h y I s I I y I ) e t h o x y m e t h y I g r o u p was r e p o r t e d t o b e a g o o d h y d r o x y l p r o t e c t i n g g r o u p by L i p s h u t z and P e g r a m . 6 8 T h e a l c o h o l r e a c t e d w i t h 3 - ( t r I m e t h y I s i I y I ) e t h o x y m e t h y I c h l o r i d e (32) In t h e p r e s e n c e o f dI I s o p r o p y I e t h y I am Ine in d i -c h I o r o m e t h a n e t o g i v e h i g h y i e l d s o f e t h e r s 33 and r e m o v a l o f t h e g - ( t r I m e t h y I s I I y I ) e t h o x y m e t h y I g r o u p i s a g a i n a c c o m p l i s h e d vI a r e a c t i o n w i t h TBAF In T H F . + .SiMes l-Pr.NEt 92 CH2CI2 .SiMe3 n-Bu4NF P D ^ C T ^ _ u _ 4 ROH + CRp + CH2=CH2 + Me3SiF - as. T H F 70 2 A . 1 . 2 P r o p o s e d P r o t e c t i n g G r o u p A f r e q u e n t l y u s e d m e t h o d f o r c o n v e r t i n g t h e h y d r o x y l g r o u p o f a l c o h o l s t o a g o o d l e a v i n g g r o u p f o r s u b s e q u e n t u s e in n u c l e o p h i l i c d i s p l a c e m e n t s Is t o f o r m t h e c o r r e s p o n d i n g s u l f o n a t e e s t e r s . T h e s e a r e g e n e r a l l y p r e p a r e d f r o m an a l c o h o l and s u l f o n y l c h l o r i d e In t h e p r e s e n c e o f a b a s e . Among t h e many s u l f o n a t e e s t e r s w h i c h a r e a v a i l a b l e , t h e m o s t w i d e l y u t i l i z e d o n e s i n o r g a n i c s y n t h e s i s a r e m e t h a n e s u 1 f o n a t e s 94. t r i f I u o r o m e t h a n e s u I f o n a t e s 25_, and v a r i o u s a r y I s u I f o n a t e s s u c h a s D_-to I u e n e s u I f o n a t e s 96. 6 9 » 7 0 0 0 0 _ RO-S-CH3 RO-S-CF3 RO-S-^^-Chb 0 0 0 21 9_5_ 2JI A n o t h e r a p p l i c a t i o n o f s u l f o n y l c h l o r i d e s Is in t h e p r o t e c t i o n o f a m i n e s . A l t h o u g h a I k y I s u I f o n a m I d e s a r e t o o s t a b l e t o be u s e d a s p r o t e c t i n g g r o u p s , v a r i o u s a r y l s u l f o n a -m i d e s s u c h a s c - t o I u e n e s u I f o n a m I d e s 22 h a v e b e e n u s e d w i t h s u c c e s s . 5 8 A r y I s u I f o n a m i d e s a r e g e n e r a l l y q u i t e s t a b l e and R 1 R 2 N - S - ^ ^ - C H 3 0 2Z r e q u i r e r e l a t i v e l y d r a s t i c c o n d i t i o n s f o r c l e a v a g e s u c h a s N a / N H 3 , s o d i u m n a p h t h a I en Ide , o r H B r / H O A c . 7 1 T h u s , m i l d e r c l e a v a g e m e t h o d s f o r s u l f o n a m i d e s w o u l d be a u s e f u l i m p r o v e -ment o v e r t h e e x i s t i n g m e t h o d s . 71 O n g o i n g work In o u r l a b o r a t o r y p r o m p t e d u s t o I n v e s t i g a t e t h e p o s s i b i l i t y o f u s i n g 4 - [ ( t r i m e t h y I s I I y I ) m e t h y I ] b e n z e n e -s u l f o n y l c h l o r i d e (9_S) a s a b l o c k i n g r e a g e n t f o r a m i n e s and SO2CI CH2SiMe3 p o s s i b l y f o r a l c o h o l s . T r e a t m e n t o f s u l f o n a t e s 9J£ o r s u l f o n a -m i d e s 100 w i t h f l u o r i d e Ion s h o u l d l e a d t o d e s I l y l a t l o n t o g i v e a b e n z y l i c a n i o n i n i t i a l l y w h i c h m i g h t be e x p e c t e d t o s u b s e q u e n t l y u n d e r g o an I n t r a m o l e c u l a r d i s p l a c e m e n t o f an a l k o x l d e o r a m i d e a n i o n w i t h c o n c o m i t a n t f o r m a t i o n o f s u I f e n e 101 . Q u e n c h i n g o f t h e r e a c t i o n w i t h w a t e r s h o u l d g i v e p_-to I u e n e s u I f on I c a c i d a l o n g w i t h t h e a l c o h o l o r a m i n e . An o b v i o u s a d v a n t a g e o f o u r p r o p o s e d p r o t e c t i n g g r o u p f o r a m i n e s Is t h a t t h e e n v i s a g e d d e p r o t e c t l o n vI a a f I u o r i d e - I n d u c e d f r a g m e n t a t i o n p r o c e s s w o u l d be v e r y m i l d and s e l e c t i v e . P r e c e d e n c e f o r t h e a b o v e t y p e o f e l i m i n a t i o n t o g i v e a 72 s u I f e n e 7 2 comes f r o m s e v e r a l s o u r c e s . T h e r e i s s t r o n g e v i d e n c e t h a t t h e f o r m a t i o n o f m e t h a n e s u I f o n a t e e s t e r s £ 4 and 0 0 CH3-S-CI 2 ^ L C H 2= SO2 J — » RO-S-CH3 0 o i n g e n e r a l , t h e r e a c t i o n o f b a s e s w i t h a I k a n e s u I f o n y I c h l o r i d e s c o n t a i n i n g a t l e a s t o n e a h y d r o g e n t a k e s p l a c e by an e l i m i n a t i o n - a d d i t i o n m e c h a n i s m g o i n g t h r o u g h a s u I f e n e I n t e r -m e d i a t e s u c h a s 1 0 2 . 7 3 S i m i l a r i n t e r m e d i a t e s h a v e a l s o been p r o p o s e d in t h e c a s e s o f a r y I s y s t e m s in s p i t e o f t h e f a c t t h a t d i s r u p t i o n o f t h e a r o m a t i c s y s t e m must o c c u r . R e c e n t l y , t h e f i r s t e v i d e n c e f o r t h e e x i s t e n c e o f a s u I f o -q u i n o n e I n t e r m e d i a t e in a r e a c t i o n p a t h w a y came f r o m t h e b a s e C H 3 v O CH3 o 73 h y d r o l y s i s o f s u l f o n a t e 1 0 3 . 7 4 I n i t i a l i o n i z a t i o n o f 103 f o l l o w e d by u n i m o l e c u l a r b r e a k d o w n o f t h e c o n j u g a t e b a s e 104 p r o v i d e s t h e s u l f o q u i n o n e s u l f e n e 105 and 2 , 4 - d i n i t r o p h e n o I a t e w h i c h u p o n q u e n c h i n g w i t h w a t e r g i v e s s u l f o n i c a c i d 106 and 2 , 4 - d l n i t r o p h e n o l ( 1 0 7 ) . In a n o t h e r c a s e , t h e t e m p o r a r y d i s r u p t i o n o f t h e a r o m a t i c s y s t e m w h i c h o c c u r s In t h e p r o p o s e d e l i m i n a t i o n s e q u e n c e i s a l s o p o s t u l a t e d t o o c c u r in t h e f I u o r I d e - i n d u c e d 1 , 6 - e I i m i n a -t i o n o f 4 - [ ( t r i m e t h y I s I l y I )methy I ] b e n z y I t r Imethy lammon i urn I o d i d e ( 1 0 8 ) . 7 5 T r e a t m e n t o f compound 108 in r e f l u x i n g a c e t o n l t r I l e w i t h TBAF Is r e p o r t e d t o g i v e a 56% y i e l d o f [ 2 . 2 ] p a r a c y c l o p h a n e (110 ) r e s u l t i n g f r o m d l m e r l z a t i o n o f i n t e r -m e d i a t e 109 . T h i s f r a g m e n t a t i o n i s n o t c o n f i n e d t o s y s t e m s w i t h c a x a - s u b s t I t u t e d g r o u p s . An a n a l o g o u s 1 , 4 - e I l m I n a t i o n has b e e n o b s e r v e d in t h e o r t h o s y s t e m . 7 6 74 2 A . 2 D i s c u s s i o n 2 A . 2 . 1 P r e p a r a t i o n o f 4 - [ ( T r I m e t h y I s i I y I ) m e t h y I ] b e n z e n e -s u l f o n a m i d e s and - s u l f o n a t e s In o r d e r t o d e t e r m i n e t h e p l a u s i b i l i t y o f t h e a b o v e p r o p o s e d d e p r o t e c t i o n p r o c e s s , It was n e c e s s a r y t o p r e p a r e s u l f o n a t e s 3 2 and s u l f o n a m i d e s 100 . T h e s e c o m p o u n d s s h o u l d be r e a d i l y a c c e s s i b l e f r o m t h e r e a c t i o n o f 4 - [ ( t r i m e t h y I s i I y I ) -m e t h y I ] b e n z e n e s u I f o n y I c h l o r i d e (23) w i t h a l c o h o l s and a m i n e s , r e s p e c t I v e I y . 0 _ FO- S - ^ ^ - CH2SiMe3 0 0 _ R1 R2N- S - ^ ^ ~ CH2SiMe3 0 100 T h e s y n t h e s i s o f s u l f o n y l c h l o r i d e 2 3 was accompI I s h e d by an e f f i c i e n t f i v e - s t e p r o u t e a s shown on t h e f o l l o w i n g p a g e . C o m m e r c i a l l y a v a i l a b l e 4 - c h I o r o t o I u e n e (111) was t r e a t e d w i t h J N J - b r o m o s u c c I n im I de (NBS) In r e f l u x l n g c a r b o n t e t r a c h l o r i d e w h i l e b e i n g I r r a d i a t e d t o e f f e c t b e n z y l I c b r o m l n a t i o n g i v i n g a 90% y i e l d o f 4 - c h I o r o b e n z y I b r o m i d e ( 1 1 2 ) . B r o m i d e 112 was t h e n r e f l u x e d w i t h e x c e s s s o d I urn and c h I o r o t r i m e t h y I s i Iane in t o l u e n e t o a f f o r d [ 4 - ( t r i m e t h y I s I I y I ) b e n z y I ] t r i m e t h y I s I Iane (113) in 79% y i e l d . T h e s i n g l e t s a t 6 0 . 0 0 and 6 0 . 2 4 in t h e 1 H nmr s p e c t r u m o f 113 w e r e a t t r i b u t e d r e s p e c t i v e l y t o t h e 75 NBS CCI4 CH2SiMe3 2S. SOCIa DMF CH2Br 112. Na,Me3SiCI PhCH3,A CH2SiMe3 115. NaOH HgO CH2SiMe3 H3. SOg CCI4 S020SiMe3 CH2SiMe3 1 1 1 n i n e p r o t o n s o f t h e t r i m e t h y I s I IyI g r o u p a t t a c h e d t o t h e b e n z y l i c c a r b o n a n d t o t h e n i n e p r o t o n s o f t h e t r i m e t h y I s i IyI g r o u p a t t a c h e d t o t h e a r o m a t i c r i n g . The s i n g l e t a t 6 2 . 0 6 was a s s i g n e d t o t h e m e t h y l e n e p r o t o n s and t h e d o u b l e t s a t 6 6 . 9 8 and 6 7 . 3 6 w e r e a t t r i b u t e d t o t h e f o u r a r o m a t i c p r o t o n s . S i l a n e 113 r e a c t e d w i t h s u l f u r t r i o x l d e 7 7 i n c a r b o n t e t r a c h l o r i d e t o g i v e s u l f o n a t e 114 w h i c h was t h e n h y d r o l y z e d w i t h a q u e o u s s o d i u m h y d r o x i d e t o f u r n i s h s o d Ium 4—[( t r imethy I -s i l y l ) m e t h y I ] b e n z e n e s u I f o n a t e (115 ) in 95% y i e l d f o r two s t e p s . T h e s i n g l e t a t 6 0 . 1 2 in t h e 1 H nmr s p e c t r u m o f s o d i u m s u l f o n a t e 115 was a t t r i b u t e d t o t h e n i n e p r o t o n s o f t h e t r i -m e t h y l s i l y l g r o u p and t h e s i n g l e t a t 6 1 .63 was d u e t o t h e m e t h y l e n e p r o t o n s . The r e s o n a n c e s o f t h e f o u r p h e n y l p r o t o n s a p p e a r e d a s d o u b l e t s a t 6 7 . 2 5 and 6 7 . 7 0 . S o d i u m s u l f o n a t e 115 r e a c t e d w i t h t h i o n y l c h l o r i d e in 76 D M F 7 8 t o a f f o r d t h e d e s i r e d 4-[ ( t r I m e t h y I s I I y I ) m e t h y I ] -b e n z e n e s u I f ony I c h l o r i d e (9J1) a s a w h i t e s o l i d In 89% y i e l d . S u l f o n y l c h l o r i d e 9_8_ showed S=0 s t r e t c h e s a t 1375 and 1175 c m - 1 and S I - C s t r e t c h e s a t 1250 and 850 c m - 1 i n t h e Ir s p e c t r u m . T h e 1 H nmr s p e c t r u m showed s i n g l e t s a t 6 0 . 0 5 and 6 2 . 2 6 a t t r i b u t a b l e t o t h e n i n e p r o t o n s o f t h e t r I m e t h y I s i IyI g r o u p a n d t h e b e n z y l I c p r o t o n s , r e s p e c t i v e l y . D o u b l e t s a t 6 7 . 2 0 and 6 7 . 8 8 w e r e d u e t o t h e f o u r a r o m a t i c p r o t o n s . A s e r i e s o f s u l f o n a t e s 9_9_ and s u l f o n a m i d e s 100 w e r e t h e n p r e p a r e d by o n e o f t h r e e m e t h o d s ( T a b l e V I I ) . M e t h o d A was g e n e r a l l y u s e d and i n v o l v e d r e a c t i n g s u l f o n y l c h l o r i d e 9_S_ w i t h 1 .05 e q u i v a l e n t s o f an a l c o h o l o r a m i n e in t h e p r e s e n c e o f 0.1 e q u i v a l e n t o f 4 - d I m e t h y I am I n o p y r I d I n e (DMAP) a n d two e q u i v a -l e n t s o f t r i e t h y I am Ine In d I c h I o r o m e t h a n e . M e t h o d B was u s e d f o r a m i d e s a n d It I n v o l v e d d e p r o t o n a t I on o f t h e a m i d e w i t h s o d i u m h y d r i d e in THF t o g i v e t h e s o d i u m s a l t w h i c h was t h e n r e a c t e d w i t h s u l f o n y l c h l o r i d e £8_. L a s t l y , m e t h o d C was u s e d w h e r e s e l e c t i v e s u l f o n a t i o n o f an a m i n o p h e n o l was d e s i r e d and i t i n v o l v e d r e a c t i o n o f s u l f o n y l c h l o r i d e £8 . w i t h an a m i n o p h e n o l in t h e p r e s e n c e o f 1 , 8 - d i a z a b i e y e I o [ 5 . 4 . 0 ] u n d e c - 7 - e n e (DBU) in d i c h I o r o m e t h a n e . 7 9 M o d e s t t o e x c e l l e n t p u r i f i e d y i e l d s o f t h e s u l f o n a t e s and s u l f o n a m i d e s w e r e o b t a i n e d . T h e s e new c o m p o u n d s e x h i b i t e d s p e c t r a l ( 1 H nmr , I r , and m a s s ) and m i c r o a n a l y t i c a l d a t a w h i c h w e r e c o n s i s t e n t w i t h t h e i r p r o p o s e d s t r u c t u r e s . 77 T a b l e V I I . P r e p a r a t i o n o f 4 - [ ( T r I m e t h y I s i I y I ) m e t h y I ] b e n z e n e -s u I f o n a t e s and - s u l f o n a m i d e s S t a r t i n g m a t e r i a l M e t h o d 3 P r o d u c t 1 3 Y l e l d ( % ) 87 H2N~O~0H <^-CH2NH 2 o N H 2 NH; C 6 COfeEt 2 - H C I ON H £1 3 PrT o N H ^ ^ - N H S O j j A r 1 0 0 b B B 5 u - 0 t - B u — & / V O S C f e A r 22£ H2N~(\ />-0eO2Ar 22d A < £ ^ C H 2 N H S 0 2 A r 1 0 0 a A < ^ ^ - N H S 0 2 A r 1 0 0 b NHSOaAr O [ ^ N S O a A r 1 0 0 d 1 0 0 c r^ N S O a A r a 100e NSQjAr 1 0 0 f 99 81 87 92 92 51 60 90 3 M e t h o d A : A r S 0 2 C I , D M A P , E t 3 N , C H 2 C I 2 , M e t h o d B : 1) N a H , T H F 2) A r S 0 2 C I , M e t h o d C : A r S 0 2 C I , D B U , C H 2 C I 2 • b A r = $ - ^ ^ - C H 2 S i M e 3 c n - B u 4 N O H , P h C H 2 B r , H 2 0 - C H 2 C I 2 . 78 2A.2.2 F l u o r i d e C l e a v a g e s o f 4 - [ ( T r i m e t h y I s i I y I ) m e t h y I ] -b e n z e n e s u I f o n a m I d e s and - s u l f o n a t e s We i n i t i a l l y c o n s i d e r e d u s i n g T B A F 6 2 as t h e f l u o r i d e s o u r c e f o r t h e d e p r o t e c t I o n s . However, It i s known t h a t d r y i n g o f TBAF by p r o l o n g e d h e a t i n g a t e l e v a t e d t e m p e r a t u r e s r e s u l t s i n i t s d e c o m p o s i t i o n t o g i v e HF w h i c h w o u l d be an u n d e s i r e d s o u r c e o f p r o t o n s . 8 0 ' 8 1 The d e c o m p o s i t i o n o c c u r s e v e n d u r i n g d r y i n g by a z e o t r o p i c removal o f w a t e r In r e f l u x I n g t o l u e n e o r b e n z e n e . An a l t e r n a t e s o u r c e o f f l u o r i d e Ion i s b e n z y l t r i -methyIammoniurn f l u o r i d e ( B T A F ) . 8 2 S i n c e BTAF c a n be d r i e d by h e a t i n g a t 100°C i n v a c u o w i t h o u t any d e c o m p o s i t i o n , i t c a n in p r i n c i p l e be o b t a i n e d i n a d r i e r s t a t e t h a n TBAF. Hence, BTAF was p r e p a r e d by n e u t r a l i z a t i o n o f b e n z y I t r i m e t h y I a m m o n I urn h y d r o x i d e w i t h h y d r o f l u o r i c a c i d and d r i e d a c c o r d i n g t o t h e r e p o r t e d p r o c e d u r e . 8 2 D e p r o t e c t I o n s w i t h BTAF were a t t e m p t e d on v a r i o u s s u l f o n a t e s and s u l f o n a m i d e s ( T a b l e V I I I ) . T h e s e r e a c t i o n s were c a r r i e d o u t by s t i r r i n g t h e compound and BTAF In a n h y d r o u s s o l v e n t a t room t e m p e r a t u r e u n t i l a l l t h e s t a r t i n g m a t e r i a l had r e a c t e d as shown by t h i n - l a y e r c h r o m a t o g r a p h y ( t i c ) . The r e a c t i o n m i x t u r e was t h e n quenched w i t h w a t e r and worked-up t o g i v e t h e c r u d e p r o d u c t w h i c h was t h e n p u r i f i e d by column c h r o m a t o g r a p h y t o a f f o r d t h e p r o d u c t s shown. The d e p r o t e c t l o n o f s u l f o n a t e 99c was examined I n i t i a l l y . 79 S u l f o n a t e 9 9 c Is f a r more l i k e l y t o u n d e r g o t h e d e s i r e d d e p r o t e c t i o n p r o c e s s t h a n t h e o t h e r s u l f o n a t e s and s u l f o n a m i d e s p r e p a r e d s i n c e i t c a n n o t u n d e r g o n u c l e o p h i l i c d i s p l a c e m e n t r e a c t i o n s and t h e s t a b l e i - b u t y I p h e n o x i d e a n i o n w i l l be f o r m e d upon d e p r o t e c t i o n . T r e a t m e n t o f s u l f o n a t e 99c w i t h BTAF p r o v i d e d t h e d e s i r e d i - b u t y I p h e n o I (116) r e s u l t i n g f r o m f I u o r I d e - I n d u c e d f r a g m e n t a t i o n a l o n g w i t h t h e u n d e s l r e d p r o t o -d e s I I y I a t e d s u I f o n a t e 96c ( T a b Ie V I I I , e n t r I e s 1 - 4 ) . In an a t t e m p t t o I n c r e a s e t h e y i e l d o f i - b u t y I p h e n o I , t h e s o l v e n t and T a b l e V I I I . D e p r o t e c t i o n s w i t h BTAF E n t r y Compound BTAF ( e q u I v ) R e a c t I on c o n d 1 1 i o n s a P r o d u c t s Y i e l d ( % ) 1 9 9 c 2 . 4 0 . 3 7 / T H F / 5 . 5 h 113. 9 6 c 29 41 2 99c 1 . 9 0 . 3 3 / D M F / 4 h 1 1 6 96c 36 39 3 9 9 c 1 . 0 0 . 6 0 / T H F / 3 . 5 h 116 96c 33 36 4 b 9 9 c 2 . 0 0 . 5 0 / T H F / 3 h 116 96c 35 36 5 99a 1 .3 0 . 4 5 / T H F / 4 . 5 h 119 96a 17 40 6 99d 3 . 3 0 . 2 5 / T H F / 2 h 96d 80 7 100a 2 . 5 0 . 1 5 / T H F / 2 2 h 22a 97 8 100f 2 . 5 0 . 2 0 / T H F / 5 h 97f 90 9 1000 2 . 1 0 . 3 3 / T H F / 4 h 97d 60 10 10Qe 1 .8 0 . 3 7 / T H F / 2 4 h 32s. 88 a C o m p o u n d c o n c e n t r a t i o n in M / s o I v e n t / t i m e . b R e a c t i o n was q u e n c h e d w i t h D 2 O . 80 amount o f BTAF w e r e v a r i e d b u t t h e s e c h a n g e s d i d n o t s i g n i f i c a n t l y a f f e c t t h e c o u r s e o f t h e r e a c t i o n . i - B u t y I p h e n o I (116 ) and s u l f o n a t e 96c w e r e f o r m e d In p u r i f i e d y i e l d s o f 2 9 -36% and 3 6 - 4 1 % , r e s p e c t i v e l y . T h e r e was a p o s s i b i l i t y t h a t i - b u t y I p h e n o I (116 ) may h a v e come f r o m h y d r o l y s i s o f e i t h e r s u l f o n a t e 99c o r p r o t o d e s i I y I -a t e d s u l f o n a t e 9 6 c u n d e r t h e r e a c t i o n and w o r k - u p c o n d i t i o n s e m p l o y e d . To t e s t t h i s p o s s i b i l i t y , s u l f o n a t e 9 6 c . p r e p a r e d f r o m i - b u t y I p h e n o I and p_-to I u e n e s u I f ony I c h l o r i d e u s i n g t h e m e t h o d A c o n d i t i o n s , was s t i r r e d w i t h 2 . 7 e q u i v a l e n t s o f BTAF a t a c o n c e n t r a t i o n o f 0 . 6 7 M In THF a t room t e m p e r a t u r e f o r 1 7 . 5 h o u r s . T i c o f t h e r e a c t i o n m i x t u r e showed o n l y o n e s p o t w i t h Rf 0 . 2 3 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) c o r r e s p o n d i n g t o t h e s t a r t i n g m a t e r i a l . W o r k - u p o f t h e r e a c t i o n m i x t u r e by q u e n c h i n g w i t h w a t e r , d i l u t i o n w i t h e t h e r , and w a s h i n g w i t h w a t e r a f f o r d e d a 99% r e c o v e r y o f s u l f o n a t e 9 6 c . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on s i l i c a g e l g a v e a 97% r e c o v e r y o f s u l f o n a t e 9 6 c . S i n c e t h e r e a c t i o n , w o r k - u p , and p u r i f i c a t i o n c o n d i t i o n s d i d n o t c a u s e any h y d r o l y s i s , It c a n be c o n c l u d e d t h a t t h e i - b u t y I p h e n o I f o r m e d by t r e a t m e n t o f s u l f o n a t e 99c w i t h BTAF came f r o m t h e e x p e c t e d f I u o r i d e - I n d u c e d f r a g m e n t a t i o n p r o c e s s . T h e p o s s i b i l i t y t h a t t h e i n i t i a l l y f o r m e d b e n z y l I c a n i o n r e s u l t i n g f r o m d e s l l y l a t i o n was q u e n c h e d w i t h a p r o t o n s o u r c e and d i d n o t h a v e a d e q u a t e t i m e t o u n d e r g o t h e f r a g m e n t a t i o n was a l s o I n v e s t i g a t e d ( T a b l e V I M , e n t r y 4 ) . T h e r e a c t i o n o f s u l f o n a t e 9 9 c w i t h BTAF was q u e n c h e d w i t h d e u t e r i u m o x i d e I n s t e a d o f w a t e r w i t h t h e e x p e c t a t i o n t h a t a n y a n i o n r e m a i n i n g 81 wo u l d become p a r t i a l l y d e u t e r a t e d . However, t h e 1H nmr and mass s p e c t r a o f t h e I s o l a t e d s u l f o n a t e 96c from t h i s r e a c t i o n s e q u e n c e d i d not show any d e u t e r i u m I n c o r p o r a t i o n a t t h e b e n z y l Ic p o s i t i o n s u g g e s t i n g t h a t t h e a n i o n had a l r e a d y become p r o t o n a t e d . The most l i k e l y s o u r c e o f w a t e r In t h e r e a c t i o n Is due t o I n c o m p l e t e d r y i n g o f BTAF. To t e s t t h i s h y p o t h e s i s , a p p r o x i m a t e l y one gram o f BTAF was s t i r r e d w i t h 20 mL o f D 2 O f o r 24 h o u r s and t h e n d r i e d a s b e f o r e . T h i s D 2 0 - t r e a t e d BTAF was t h e n u s e d i n a s u b s e q u e n t s e r i e s o f d e p r o t e c t I o n s ( T a b l e I X ) . If t h e d r i e d BTAF was not c o m p l e t e l y a n h y d r o u s , t h e n q u e n c h i n g o f t h e a n i o n w o u l d o c c u r t o some e x t e n t , r e s u I t i n g i n d e u t e r i u m i n c o r p o r a t i o n a t t h e b e n z y l I c p o s i t i o n g i v i n g s u l f o n a t e s 117 o r s u l f o n a m i d e s 118. 0 _ 0 _ R O - S - c £ ^ - C H 2 D R 1 R 2 N - S - ^ ^ - C H 2 D O 0 111 113. The d e p r o t e c t l o n o f s u l f o n a t e 99c w i t h t h e D 2 0 - t r e a t e d BTAF gave c o m p a r a b l e y i e l d s o f t h e d e s i l y l a t e d p r o d u c t (44%) t - B u — ( ^ ^ - 0 H H g . /=\ 9 / = \ D20-treated / = \ n* / = \ t B u H J ~ ° " « " W * C H 2 S i M e 3 "BTAF^  ^ t B u " \ > C > - S - ^ _ C H 3 0 0 mi 99c 0 t - B u - Q - O - S - Q - C H a D 0 HXa 82 and t h e d e s i r e d i - b u t y I p h e n o I (116) (28%) a s w i t h t h e o r i g i n a l B T A F . T h e c o m p o s i t i o n o f t h e d e s i l y l a t e d p r o d u c t was d e t e r m i n e d t o be a 7 0 : 3 0 m i x t u r e o f d e u t e r a t e d s u l f o n a t e 117c t o n o n - d e u t e r a t e d s u l f o n a t e 96c by 1 H nmr s p e c t r a l a n a l y s i s a n d m a s s s p e c t r o m e t r y . It w o u l d a p p e a r t h e r e f o r e t h a t t h e o r i g i n a l h y p o t h e s i s o f a f I u o r I d e - i n d u c e d f r a g m e n t a t i o n i s v a l i d . T h e o v e r a l l e f f i c i e n c y o f t h e p r o c e s s , In t h e c a s e o f s u l f o n a t e 9 9 c . Is l i m i t e d by t h e a v a i l a b i l i t y o f a c o m p l e t e l y a n h y d r o u s s o u r c e o f f l u o r i d e I o n . Tab Ie IX. D e p r o t e c t I o n s w i t h D 2 0 - t r e a t e d BTAF BTAF R e a c t i o n Y i e l d ( % ) C o m p o u n d ' ( e q u I v ) c o n d i t i o n s 3 P r o d u c t s ( 1 1 7 : 9 6 o r 1 1 8 : 9 7 ) 9 9 c 1.8 0 . 3 8 / T H F / 4 h 116 28 1 1 7 c . 9 6 c 44 ( 7 0 : 3 0 ) IQOf 2 . 4 0 . 3 3 / T H F / 2 4 h 1 1 8 f . 9 7 f 72 ( 6 9 : 3 1 ) a C o m p o u n d c o n c e n t r a t i o n In M / s o I v e n t / t i m e . T h e i n i t i a l m o d e s t s u c c e s s o f t h e f I u o r I d e - I n d u c e d d e p r o t e c t i o n o f s u l f o n a t e 99c t o g i v e t h e d e s i r e d i - b u t y I p h e n o l ( 116 ) p r o m p t e d a t t e m p t s t o d e p r o t e c t some o f t h e o t h e r s u l f o n a t e s and s u l f o n a m i d e s w h i c h w e r e p r e p a r e d . T r e a t m e n t o f s u l f o n a t e 99a w i t h BTAF g a v e a 40% y i e l d o f t h e p r o t o d e s i l y l -a t e d s u l f o n a t e 96a a l o n g w i t h a 17% y i e l d o f s u l f o n a t e 119 p r e s u m a b l y r e s u l t i n g f r o m n u c l e o p h i l i c d i s p l a c e m e n t o f A r S 0 2 0 ~ f r o m s u l f o n a t e s 99a o r 96a by t h e i n i t i a l l y f o r m e d b e n z y l i c a n i o n ( T a b l e V I I I , e n t r y 5 ) . None o f t h e e x p e c t e d 83 1 - o c t a n o l was i s o l a t e d . The 'H nmr s p e c t r u m o f s u l f o n a t e 119 e x h i b i t e d t r i p l e t s a t 64.04 and 62.70 a t t r i b u t a b l e t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e o x y g e n and t h e b e n z y l i c p r o t o n s , r e s p e c t i v e l y . The s t r u c t u r e o f 119 was s u p p o r t e d by t h e mass s p e c t r u m w h i c h showed a weak p a r e n t peak a t m/z 396. The f o r m a t i o n o f c o u p l i n g p r o d u c t 119 was n o t u n e x p e c t e d i f t h e l i f e t i m e o f t h e p r o p o s e d b e n z y l i c a n i o n was s u f f i c i e n t l y l o n g . It i s a p p a r e n t from t h e r e s u l t s t h a t t h e a n i o n i s i n d e e d formed and i s r e a s o n a b l y s t a b l e i n r e l a t i o n t o d e c o m p o s i t i o n v i a t h e s u I f e n e . Our I n i t i a l a t t e m p t a t d e p r o t e c t i o n o f a s u l f o n a m i d e was c a r r i e d o u t u s i n g 100a ( e n t r y 7 ) . None o f t h e d e s i r e d b e n z y l -amlne r e s u l t i n g f r o m t h e f I u o r I d e - I n d u c e d f r a g m e n t a t i o n o f 100a was fo r m e d , b u t i n s t e a d , a 97% y i e l d o f t h e u n d e s i r e d p r o t o d e -s i l y l a t e d s u l f o n a m i d e 97a was o b t a i n e d . E v i d e n c e f o r t h e removal o f t h e t r I m e t h y I s i I y I g r o u p came from t h e 1H nmr 0 {^y~ CH2NH- S - ^ ^ - CH2SiMe3 0 1QQa 84 s p e c t r u m w h i c h l a c k e d t h e r e s o n a n c e o f t h e n i n e m e t h y l p r o t o n s a t 6 0 . 0 0 . T h e i s o l a t i o n o f s u l f o n a m i d e 97a I n d i c a t e d t h a t t h e a n i o n r e s u l t i n g f r o m d e s i l y l a t l o n had a g a i n b e e n p r o t o n a t e d b e f o r e It had t h e o p p o r t u n i t y t o u n d e r g o t h e d e s i r e d f r a g m e n t a -t i o n . An a d d i t i o n a l p o s s i b l e p r o t o n s o u r c e in t h i s c a s e i s t h e N-H g r o u p p r e s e n t In s u l f o n a m i d e 1 0 0 a . S u l f o n a m i d e 1OOf w h i c h d o e s n o t p o s s e s s s u c h an a c i d i c h y d r o g e n was p r e p a r e d i n 90% y i e l d by a l k y l a t i o n o f s u l f o n a m i d e 100b w i t h b e n z y l b r o m i d e u n d e r p h a s e t r a n s f e r c a t a l y s i s 8 3 c o n d i t i o n s u s i n g t e t r a - n - b u t y I a m m o n I urn h y d r o x i d e in w a t e r and d i c h I o r o m e t h a n e . S u l f o n a m i d e 1OOf was t h e n r e a c t e d w i t h BTAF in o r d e r t o t e s t w h i c h o f t h e two p r o t o n s o u r c e s ( i n t e r n a l N - H o r a d v e n t i t i o u s w a t e r ) may be o p e r a t i n g . T h e r e was no e v i d e n c e o f a n y o f t h e d e s i r e d b e n z y I e y e IohexyI a m i n e b e i n g f o r m e d and a 90% y i e l d o f t h e p r o t o d e s I I y I a t e d s u l f o n a m i d e 97 f was o b t a i n e d ( e n t r y 8 ) . A g a i n i t a p p e a r s t h a t t h e i n t e r m e d i a t e b e n z y l i c a n i o n i s q u e n c h e d by w a t e r in t h e r e a c t i o n m e d i u m . T h e d e p r o t e c t i o n o f s u l f o n a m i d e 1OOe i s m o r e l i k e l y t o o c c u r t h a n f o r 1OOf s i n c e t h e a m i d e a n i o n 120 r e s u l t i n g f r o m f r a g m e n t a t i o n o f t h e b e n z y l i c a n i o n i s m o r e s t a b l e . H o w e v e r , t r e a t m e n t o f s u l f o n a m i d e 1OOe w i t h BTAF g a v e o n l y t h e c o r r e s p o n d i n g p r o t o d e s i I y I a t e d s u l f o n a m i d e 97e ( e n t r y 10) and none o f t h e d e s i r e d a m i d e 121 . 85 T h e a b o v e r e s u l t s I n d i c a t e t h a t t h e s u c c e s s o f o u r h y p o t h e s i s w o u l d d e p e n d on t h e u s e o f a n h y d r o u s f l u o r i d e s and t h u s o t h e r s o u r c e s o f f l u o r i d e Ion w e r e a l s o i n v e s t i g a t e d . C l a r k 8 1 f o u n d t h a t TBAF c o u l d be r e n d e r e d a n h y d r o u s by b i n d i n g i t t o s i l i c a g e l . H o w e v e r , a p o t e n t i a l p r o b l e m in o u r a p p l i c a t i o n o f t h e T B A F - s i l l c a g e l r e a g e n t Is t h a t t h e s i l i c a g e l s u r f a c e c o n t a i n s h y d r o x y l g r o u p s w h i c h may a g a i n q u e n c h t h e I n i t i a l l y f o r m e d a n i o n f r o m d e s I IyI a t I o n . N e v e r t h e l e s s , t h e T B A F - s i l l c a g e l r e a g e n t was p r e p a r e d and u s e d In t h e a t t e m p t e d d e p r o t e c t l o n o f s u l f o n a t e 9 9 a . O n c e a g a i n , a g o o d y i e l d o f s u l f o n a t e 96a r e s u l t i n g f r o m p r o t o d e s I IyI a t I on was o b t a i n e d . T h e c l e a v a g e o f g - t r I m e t h y I s I l y l e t h y l g l y c o s i d e s h a s been r e p o r t e d t o o c c u r w i t h l i t h i u m t e t r a f I u o r o b o r a t e a s w e l l a s w i t h a m i x t u r e o f l i t h i u m f l u o r i d e and b o r o n t r l f l u o r i d e e t h e r a t e . 8 4 T h e a t t e m p t e d d e p r o t e c t I o n s o f s u l f o n a t e 9 9 c and s u l f o n a m i d e IQOf w e r e c a r r i e d o u t u s i n g f i v e e q u i v a l e n t s e a c h 86 of LIF and BF3^Et20 In refluxlng a c e t o n i t r i l e for twenty hours. No reaction took place and there was a quantitative recovery of the s t a r t i n g material in both cases. Other Inorganic fluorides which were used in the attempted deprotections were cesium f l u o r i d e 8 5 and potassium fl u o r i d e with 18-crown-6. 8 6 A mixture of sulfonate 99c and 7.4 equivalents of CsF In THF was refluxed for 21 hours to afford a 95% y i e l d of the protodesI IyIated sulfonate 96c along with a 1.2% y i e l d of i-butyIphenoI (116). The reaction of sulfonate 99c with four equivalents of KF and 0.1 equivalent of 18-crown-6 In refluxlng THF for nineteen hours also gave sulfonate 96c and i-butyIphenoI In yi e l d s of 90% and 2%, respectively. The greatly diminished yi e l d s of i-butyIphenoI (116) and Increased y i e l d s of protodesI IyIated sulfonate 96c from those obtained using BTAF Is a r e f l e c t i o n of the d i f f i c u l t y In getting CsF and KF in an anhydrous state. The results of the above investigation into the deprotec-tion of sulfonates 9J> and sulfonamides 100 c l e a r l y indicate 0 0 RO-S-^^CH 2SiMe 3 R1 R 2N-S-c^^-CH 2SiMe 3 o b aa. 1 oo that the use of the 4-[(trimethyIsI IyI)methyIJbenzenesuIfonyI moiety as a protecting group would not be generally applicable, and thus Its development was not Investigated further. The fIuoride-Induced fragmentation of the proposed protecting group with various f l u o r i d e sources on d i f f e r e n t sulfonates and sulfonamides occurred with only limited success. 87 2 A . 2 . 3 C o n c l u s i o n T h e p r e p a r a t i o n o f 4 - [ ( t r i m e t h y I s I I y I ) m e t h y I ] b e n z e n e -s u l f o n y l c h l o r i d e (2Ji) , a new s u l f o n y l c h l o r i d e , was a c c o m p l i s h e d by an e f f i c i e n t f i v e - s t e p r o u t e s t a r t i n g f r o m c o m m e r c i a l l y a v a i l a b l e 4 - c h I o r o t o I u e n e . T h i s c h l o r i d e was r e a c t e d w i t h v a r i o u s a l c o h o l s and a m i n e s t o a f f o r d t h e c o r r e s p o n d i n g s u l f o n a t e s 22. and s u l f o n a m i d e s 100 . T h e p r o p o s e d d e p r o t e c t i o n o f s u l f o n a t e s 2 2 and s u l f o n -a m i d e s 100 v i a a f I u o r I d e - I n d u c e d f r a g m e n t a t i o n p r o c e s s d o e s a p p e a r t o p r o c e e d t h r o u g h t h e e n v i s a g e d s u l f e n e i n t e r m e d i a t e 101 a s e v i d e n c e d by o u r r e s u l t s on t h e r e a c t i o n o f s u l f o n a t e 99c ( R = 4 - i - b u t y I p h e n y I ) w i t h B T A F . H o w e v e r , t h i s r e a c t i o n a f f o r d e d t h e d e s i r e d i - b u t y I p h e n o I (116) in p o o r y i e l d s due t o t h e d i f f i c u l t y in o b t a i n i n g an a n h y d r o u s s o u r c e o f f l u o r i d e I o n . T h e p r e s e n c e o f p r o t o n s o u r c e s r e s u l t s in q u e n c h i n g o f t h e i n i t i a l l y f o r m e d b e n z y l I c a n i o n t o p r o v i d e t h e p r o t o d e -s i l y l a t e d p r o d u c t . In a d d i t i o n , t h e i n a b i l i t y o f c o m p o u n d s p o s s e s s i n g l e a v i n g g r o u p s o t h e r t h a n a h I g h I y s t a b I I I z e d p h e n o x i d e - t y p e a n i o n t o u n d e r g o t h e d e s i r e d f r a g m e n t a t i o n and a c o m p e t i n g n u c l e o p h i l i c d i s p l a c e m e n t r e a c t i o n make o u r p r o p o s e d p r o t e c t i n g m e t h o d I m p r a c t i c a l . 8 8 PART B. STUDIES ON THE DEVELOPMENT OF A DEOXYGENATI ON METHOD 2 B . 1 I n t r o d u c t I o n 2 B . 1 . 1 E x i s t i n g D e o x y g e n a t I on Methods D e o x y g e n a t I o n methods In w h i c h OH g r o u p s a r e r e p l a c e d by H a r e I m p o r t a n t In t h e s y n t h e s i s o f n a t u r a l p r o d u c t s . They a r e p a r t i c u l a r l y I m p o r t a n t In s y n t h e s e s o f complex compounds w h i c h u t i l i z e c a r b o h y d r a t e s as c h e a p c h i r a l s t a r t i n g m a t e r i a l s . Numerous methods a r e a v a i l a b l e f o r t h e d e o x y g e n a t i o n o f a l c o h o l s . One o f t h e most w i d e l y u s e d t e c h n i q u e s I n v o l v e s c o n v e r t i n g t h e h y d r o x y l g r o u p t o a good l e a v i n g g r o u p i n i t i a l l y by f o r m i n g d e r i v a t i v e s s u c h as p_-to I uenesu I f o n a t e s o r methane-s u l f o n a t e s . T h e s e a r e t h e n t r e a t e d w i t h h y d r i d e r e d u c i n g a g e n t s 8 7 s u c h as l i t h i u m aluminum h y d r i d e , s o d i u m c y a n o b o r o -h y d r i d e , o r l i t h i u m t r I e t h y I b o r o h y d r I d e t o e f f e c t n u c l e o p h i l i c -"CHzPH TMs'cn ' RCHsOTs H » RCH3 (MSCI) ( M s ) d i s p l a c e m e n t o f t h e l e a v i n g g r o u p w i t h H~. D e o x y g e n a t I o n s have a l s o been a c c o m p l i s h e d by n u c l e o p h i l i c r e p l a c e m e n t o f t h e OH g r o u p by h a l i d e o r t h l o l a t e f o l l o w e d by r e d u c t i v e d e h a l o -g e n a t i o n 8 8 o r d e s u I f u r I z a t I o n . 8 9 The above d e o x y g e n a t i o n methods i n v o l v e n u c l e o p h i l i c d i s p l a c e m e n t a t t h e c a r b o n - o x y g e n bond and t h u s a r e p r o n e t o s t e r i c f a c t o r s . T h e s e r e a c t i o n s c an b e s t be a p p l i e d t o s i m p l e , s t e r l c a l l y u n h i n d e r e d a l c o h o l s . D e o x y g e n a t i o n methods b a s e d on r a d i c a l p r o c e s s e s a r e l e s s 89 s u s c e p t i b l e to s t e r i c f a c t o r s . In c o n t r a s t to the above S^2 processes, the carbon-oxygen bond In these r e a c t i o n s Is c l e a v e d homo Iy11caI Iy. The v a r i o u s methods for the r a d i c a l deoxy-genat ion of a l c o h o l s have r e c e n t l y been r e v i e w e d . 9 0 These r a d i c a l processes g e n e r a l l y Involve i n i t i a l c o n v e r s i o n of an a l c o h o l to a s u i t a b l e d e r i v a t i v e 122 f ollowed by c o n v e r s i o n to an intermediate r a d i c a l 123 which fragments by $ cleavage to f u r n i s h an a l k y l r a d i c a l R• and a carbonyl compound 124. R-OH R - O ® 122. R-O®-123 R- + O^X) 124 H-RH Subsequent r e a c t i o n of the a l k y l r a d i c a l R- with a hydrogen atom donor y i e l d s the d e s i r e d hydrocarbon. An example of a r a d i c a l deoxygenatI on is the deoxygenat I on of the thlobenzoate d e r i v a t i v e of c h o l e s t a n o l (125) r e p o r t e d by Barton and McComble. 9 1 Treatment of ©_-cho I estany I t h l o b e n z o a t e (126) with an excess of trI - n-butyIstannane in r e f l u x i n g toluene gave a 70-75% y i e l d of c h o l e s t a n e (122) along with S_-tr i -n-buty I -stan n y l t h l o b e n z o a t e (128). 0 II Ph-C-S-SnBu3  128 fjCjL/ 125. R = 0H Hfi. R = 0-CSPh qT^^^ 12Z R = H 90 2B.1.2 P r o p o s e d D e o x y g e n a t i o n Method Our theme o f d e v e l o p i n g u s e f u l r e a g e n t s whose e f f e c t i v e n e s s i s b a s e d on c l e a v a g e o f t h e s i l i c o n - c a r b o n bond i s c o n t i n u e d in t h i s s e c t i o n . An e a r l i e r s e c t i o n o f t h i s t h e s i s ( P a r t A) p r e s e n t e d s e v e r a l examples o f s i l i c o n - b a s e d p r o t e c t i n g g r o u p s t h a t have been u t i l i z e d In s y n t h e s i s . One o f t h e s e w h i c h was o f p a r t i c u l a r I n t e r e s t t o us was t h e 2 - t r I m e t h y I s I I y I e t h y I g r o u p u s e d as a c a r b o x y l p r o t e c t i n g g r o u p . 6 5 ' 6 6 The 2 - t r i -m e t h y I s i I y I e t h y I g r o u p has been removed s e l e c t i v e l y w i t h f l u o r i d e Ion t o g i v e t h e c a r b o x y l a t e a n i o n a l o n g w i t h e t h y l e n e and t r i m e t h y I s I IyI f l u o r i d e . S i m i l a r f r a g m e n t a t i o n s I n v o l v i n g t h e u s e o f f l u o r i d e Ion have been o b s e r v e d f o r o t h e r p r o t e c t i n g O R ^ 0 r ^ ^ S ' M e 3 " — RC0 2" + CH2=CH2 + Me3SiF We e n v i s a g e d t h a t upon " r e v e r s a l " o f t h e e s t e r f u n c t i o n -a l i t y i n Ji9_ t o g i v e 129. t h e r e w o u l d now be t h e p o s s i b i l i t y o f g r o u p s . 6 7 ' 6 8 ' 9 2 F RO" + CO + CH2=CH2 + Me3SiF O R 129 R" + COg + CH2=CH2 + Me3SiF Me 3Si7C7-0R 91 f o r m a t i o n o f e i t h e r c a r b o n m o n o x i d e o r c a r b o n d i o x i d e a f t e r i n i t i a t i o n o f t h e s e q u e n t i a l e l i m i n a t i o n p r o c e s s w i t h f l u o r i d e i o n . F o r m a t i o n o f c a r b o n m o n o x i d e w o u l d r e s u l t In g e n e r a t i o n o f an a I k o x I d e a n i o n w h e r e a s f o r m a t i o n o f c a r b o n d i o x i d e w o u l d g i v e an a l k y l a n i o n . S i m i l a r l y , two c l e a v a g e p a t h w a y s a r e a l s o p o s s i b l e w i t h e s t e r 130 In w h i c h s i l i c o n i s b o n d e d d i r e c t l y t o t h e c a r b o n y l c a r b o n . T h e r e f o r e , t h e p o s s i b i l i t y o f u t i l i z i n g e s t e r s 129 and 130 in a d e o x y g e n a t I on p r o c e s s was i n v e s t i -g a t e d . * If t h e f r a g m e n t a t i o n o c c u r s vI a p a t h w a y B , t h e n t h i s d e o x y g e n a t i o n m e t h o d c o u l d s e r v e a s a u s e f u l c o m p l e m e n t t o t h e r a d I c a I - b a s e d m e t h o d s s i n c e i t t o o s h o u l d be a p p l i c a b l e t o s t e r l c a l l y h i n d e r e d a l c o h o l s . T h e t h e r m o d y n a m i c s o f t h e two p o s s i b l e f r a g m e n t a t i o n r o u t e s w e r e e x a m i n e d t o d e t e r m i n e t h e f e a s i b i l i t y o f t h e p r o p o s e d d e o x y g e n a t i o n m e t h o d . S i n c e t r I m e t h y I s I IyI f l u o r i d e and e t h y l e n e a r e f o r m e d f r o m e s t e r 129 by b o t h p a t h w a y s , It i s o n l y n e c e s s a r y t o c o n s i d e r t h e e n e r g y d i f f e r e n c e s in t h e f o r m a t i o n o f c a r b o n d i o x i d e v e r s u s c a r b o n m o n o x i d e and o f a l k y l a n i o n v e r s u s a l k o x i d e a n i o n . A s i m i l a r a n a l y s i s h o l d s f o r t h e d e c o m p o s i t i o n o f 130 . H e n c e , t h e n e t e n e r g y d i f f e r e n c e be tween p a t h w a y s A and B i s t h e same f o r e s t e r s 129 and 130 . and f o r s i m p l i c i t y e s t e r 130 w i l l be c o n s i d e r e d . It s h o u l d be s t r e s s e d a t t h e o u t s e t o f t h e t h e r m o d y n a m i c t r e a t m e n t t h a t i t i s n o t t h e a b s o l u t e v a l u e s o f t h e r m o d y n a m i c p a r a m e t e r s t h a t a r e i m p o r t a n t * A t t h e i n i t i a t i o n o f t h e s e s t u d i e s , we w e r e u n a w a r e o f a r e p o r t on t h e a n a l o g o u s b a s e - c a t a l y z e d e l i m i n a t i o n r e a c t i o n s o f t r i p h e n y I s I I a n e c a r b o x y I i c a c i d and i t s m e t h y l e s t e r . 9 3 92 b u t r a t h e r t h e d i f f e r e n c e s in t h e s e v a l u e s , and t h e s e d i f f e r e n c e s s h o u l d be r e g a r d e d a s b e i n g o n l y a p p r o x i m a t e . T h e s t a n d a r d h e a t o f f o r m a t i o n o f c a r b o n d i o x i d e i s - 9 4 k c a I / m o Ie w h e r e a s t h a t o f c a r b o n m o n o x i d e i s - 2 6 k c a I / m o I e . 9 4 T h i s i n d i c a t e s t h a t c a r b o n d i o x i d e f o r m a t i o n i s f a v o r e d by 68 k c a I / m o Ie . U s i n g o c t y l a s a r e p r e s e n t a t i v e a l k y l g r o u p in e s t e r 130. t h e s t a n d a r d h e a t o f f o r m a t i o n 9 5 o f o c t a n e a s c a l c u l a t e d f r o m h e a t o f c o m b u s t i o n d a t a 9 4 Is - 6 4 k c a l / m o l e w h e r e a s t h a t o f o c t a n o l Is - 1 0 5 k c a I / m o I e . In o r d e r t o o b t a i n t h e h e a t o f f o r m a t i o n o f t h e c o r r e s p o n d i n g a n i o n s , t h e bond d i s s o c i a t i o n e n e r g y ( B D E ) 9 4 and t h e e l e c t r o n a f f i n i t y ( E A ) 9 4 m u s t be c o n s i d e r e d . T h u s , t h e c a l c u l a t e d h e a t o f f o r m a t i o n o f o c t y l AHf°= -64 kcal/mole BDE= 98 kcal/mole AHf°= -105 kcal/mole C h l 3 ^ \ ^ s ^ s ^ > QH 104 kcal/mole EA= -21 kcal/mole CH3' AH( calc)= 13 kcal/mole •9 kcal/mole AHf(calc)= -10 kcal/mole a n i o n i s 13 k c a l / m o l e and t h a t o f o c t a n o l a t e a n i o n Is - 1 0 k c a l / m o l e I n d i c a t i n g t h a t o c t a n o l a t e a n i o n f o r m a t i o n i s f a v o r e d by 23 k c a l / m o l e . T h e r e f o r e , t h e f o r m a t i o n o f c a r b o n d i o x i d e a n d o c t y l a n i o n ( p a t h w a y B) i s f a v o r e d by a p p r o x i m a t e l y 45 k c a I / m o Ie . 93 An example where t h e a l k y l a n i o n formed i s s t a b i l i z e d i s t h e c a s e o f t h e jp_-n i t r o b e n z y I e s t e r o f 130. The s t a n d a r d h e a t o f f o r m a t i o n o f c - n i t r o t o I u e n e Is -8 k c a l / m o l e w h e r e a s t h a t o f C - n I t r o b e n z y I a l c o h o l i s -48 k c a l / m o l e . 9 4 By a s i m i l a r t y p e o f a n a l y s i s as above u s i n g bond d i s s o c i a t i o n e n e r g i e s 9 4 * 9 6 and e l e c t r o n a f f i n i t i e s 9 4 , t h e f o r m a t i o n o f a - n i t r o b e n z y I a l c o h o l a t e c a n be shown t o be f a v o r e d o v e r t h e f o r m a t i o n o f o_-n I t r o b e n z y I a n i o n by o n l y 12 k c a l / m o l e . The f o r m a t i o n o f c a r b o n d i o x i d e and t h e o.-n I t r o b e n z y I a n i o n (pathway B) i s now f a v o r e d by a p p r o x i m a t e l y 56 k c a l / m o l e . T h e r e f o r e , t h e d e s i r e d pathway B becomes even more f a v o r a b l e as t h e s t a b i l i t y o f t h e a l k y l a n i o n I n c r e a s e s r e l a t i v e t o t h e a l k o x i d e a n i o n . The above t h e r m o d y n a m i c d a t a * a r e f o r s p e c i e s In t h e gas p h a s e . In s o l u t i o n , t h e e f f e c t o f t h e s o l v e n t c a n e x e r t a c o n s i d e r a b l e I n f l u e n c e on a c i d and b a s e s t r e n g t h s by d i f f e r e n t i a l s o l v a t i o n . 9 7 Thus, t h e a c t u a l outcome o f t h e f r a g m e n t a t i o n must be d e t e r m i n e d e x p e r i m e n t a l l y . From t h e above a n a l y s i s o f t h e two p o s s i b l e c l e a v a g e p r o c e s s e s o f e s t e r 130. t h e p r o p o s e d d e o x y g e n a t I on method s h o u l d be thermodynamIcaI Iy f e a s i b l e . We were aware, however, t h a t t h e outcome o f t h e f I u o r I d e - i n d u c e d f r a g m e n t a t i o n o f e s t e r s 129 and 130 may a l s o be I n f l u e n c e d by s t e r e o e I e c t r o n i c f a c t o r s . Such e f f e c t s c a n have p r o f o u n d i n f l u e n c e s on t h e outcome o f a r e a c t i o n 9 6 ' 9 9 , and o t h e r e f f e c t s s u c h as " l e a s t m o t i o n " a r e a l s o an o v e r r i d i n g p o s s i b i l i t y . 1 0 0 * l n t h e o r y , AG v a l u e s s h o u l d be u s e d . However, AS v a l u e s a r e not r e a d i l y a v a i l a b l e . We have assumed t h a t t h e d i f f e r e n c e in AS between t h e two pathways i s s m a l l so t h a t e n t h a l p y d a t a c a n be compared. 94 2 B . 2 D I s c u s s I on 2 B . 2 . 1 P r e p a r a t i o n o f 3 - ( T r i m e t h y I s i I y I ) p r o p a n o i c E s t e r s and A t t e m p t e d F l u o r i d e C l e a v a g e s E s t e r s 129 and 130 w e r e r e q u i r e d t o t e s t t h e p r o p o s e d d e o x y g e n a t I on m e t h o d . T h e s e e s t e r s s h o u l d be a v a i l a b l e f r o m t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d s s o t h e p r e p a r a t i o n s o f 3 - ( t r i m e t h y I s I I y I ) p r o p a n o i c a c i d (131) a n d t r i m e t h y I s I I a n e -c a r b o x y l l c a c i d ( 132a ) w e r e u n d e r t a k e n I n i t i a l l y . 0 0 ^ 11 li M e a S i ^ ^ ^ O R M e 3 S i - C - 0 R 123. 130 M e 3 S i ' ^ ^ ' C X ^ H MeaSi-COsH 121 132a 3 - ( T r i m e t h y I s I I y I ) p r o p a n o i c a c i d (131 ) was p r e p a r e d by t h e p r e v i o u s l y r e p o r t e d p r o c e d u r e . 1 0 1 A c e t o n i t r i l e was d e p r o t o n a t e d w i t h l i t h i u m d i I s o p r o p y I am Ide (LDA) and t h e n a l k y l a t e d w i t h c h l o r o m e t h y I t r i m e t h y I s i Iane t o a f f o r d 3 - ( t r i -m e t h y I s i l y I ) p r o p i o n i t r i l e (133) in 68% y i e l d . N i t r l l e 133 was t h e n h y d r o l y z e d w i t h a q u e o u s b a s i c h y d r o g e n p e r o x i d e a t r e f l u x t o g i v e an 82% y i e l d o f a c i d 131 . M e 3 SiCH 2 CI " » • M e a S i ^ ™ ™ Q • M e 3 S i ^ < ^ H A s e r i e s o f e s t e r s w e r e p r e p a r e d in 84-94% y i e l d by t r e a t i n g a c i d 131 and v a r i o u s a l c o h o l s w i t h o n e e q u i v a l e n t o f 95 Tab Ie X . P r e p a r a t i o n o f 3 - ( T r I m e t h y I s I I y I ) p r o p a n o I c E s t e r s 0 M e a S I ^ - 0 ^ " ™ , D M A P ' M e 3 S i ^ ^ O R 121 C H 2 C I 2 122. E s t e r Y l e l d ( X ) 129a R- 91 129P R= $-0" !- B u 94 129c R= 88 129d R= 84 D C C 1 0 2 a n d a c a t a l y t i c amount o f DMAP i n d i c h I o r o m e t h a n e ( T a b l e X ) . T h e s e e s t e r s e x h i b i t e d s p e c t r a l d a t a ( 1 H nmr , i r and m a s s ) and m i c r o a n a l y t i c a l d a t a w h i c h w e r e c o n s i s t e n t w i t h t h e i r p r o p o s e d s t r u c t u r e s . T h e d e o x y g e n a t I o n s w e r e a t t e m p t e d on o c t y l 3 - ( t r i m e t h y I -sI I y I ) p r o p a n o a t e ( 129a ) u s i n g v a r i o u s f l u o r i d e s o u r c e s ( T a b l e X I ) . A l l a t t e m p t s t o r e m o v e t h e t r I m e t h y I s i IyI m o i e t y f a i l e d a n d t h e e s t e r was r e c o v e r e d In h i g h y i e l d s . O x y g e n n u c l e o -p h l l e s a r e a l s o g o o d "sI IaphI I e s " 5 0 b u t when p o t a s s I urn J t - b u t o x l d e was u s e d , t h e C l a i s e n c o n d e n s a t i o n p r o d u c t g - k e t o 96 e s t e r 134 was o b t a i n e d in 51% y i e l d a l o n g w i t h a 30% y i e l d o f a c i d 1 3 1 . Tab Ie X I . A t t e m p t e d F l u o r i d e C l e a v a g e s o f E s t e r 129a R e a c t i o n c o n d i t i o n s P r o d u c t Y i e l d ( % ) JI-BU4NBF4 , L I F , CH3CN, A 129a 93 L i F , B F 3 . E t 2 0 , E t 2 0 . A 129a 97 L I F , B F 3 • E t 2 0 , C H 3 C N , A 129a 95 C s F , C H 3 C N 129a 97 B T A F , T H F , A 129a 96 a N o n e o f t h e d e s i r e d o c t a n e o r 1 - o c t a n o l was o b s e r v e d . In c o n t r a s t t o e s t e r 8_9_ w h i c h i s r e a d l l y c l e a v e d by f l u o r i d e Ion t o g i v e t h e c a r b o x y l a t e a n i o n 6 5 ' 6 6 , e s t e r 129 e x h i b i t s s u r p r i s i n g f l u o r i d e s t a b i l i t y . T h i s s t a b i l i t y may be d u e t o t h e i n a b i l i t y o f 129 t o a d o p t an a d e q u a t e c o n f o r m a t i o n t o a l l o w c o n c o m i t a n t l o s s o f e t h y l e n e and e i t h e r c a r b o n m o n o x i d e o r c a r b o n d i o x i d e . S i n c e t h e e s t e r f u n c t i o n a l i t y i s " r e v e r s e d " , e s t e r 129 d i f f e r s f r o m £9_ in t h e h y b r i d i z a t i o n and b o n d a n g l e a b o u t t h e l a s t bond t o be b r o k e n . 97 2 B . 2 . 2 A t t e m p t e d P r e p a r a t i o n s o f SI I a n e c a r b o x y I Ic A c i d s C o n c u r r e n t l y w i t h t h e p r e p a r a t i o n o f 3 - ( t r I m e t h y I s ! I y I ) -p r o p a n o i c a c i d ( 1 3 1 ) . t h e s y n t h e s i s o f t r i m e t h y I s I I a n e c a r b o x y -I i c a c i d ( 132a ) was a l s o i n v e s t i g a t e d . A s e a r c h o f t h e l i t e r -a t u r e r e v e a l e d f o u r m e t h o d s o f m a k i n g s i I a n e c a r b o x y I Ic a c i d s . T r I p h e n y I s i I a n e c a r b o x y I i c a c i d ( 1 3 2 e ) was t h e f i r s t s i l a n e -c a r b o x y l i c a c i d r e p o r t e d and It was p r e p a r e d in 61% y i e l d by I n i t i a l t r e a t m e n t o f pheny I I s o p r o p y I t r I p h e n y I s I Iane (135) w i t h s o d i u m - p o t a s s i u m a l l o y f o l l o w e d by c a r b o n a t l o n o f t h e r e s u l t i n g t r i p h e n y I s i IyI p o t a s s i u r n . 1 0 3 H o w e v e r , t h e s e a u t h o r s r e p o r t t h a t t r I m e t h y I s I I a n e c a r b o x y I Ic a c i d c o u l d n o t be p r e p a r e d f r o m p h e n y l I s o p r o p y 1 1 r i m e t h y I s i l a n e . CH3 Ph-C-SiPh3 g| c N Q a / K * PhaSi-OOfeH CH3 2 132e 135 An i m p r o v e d s y n t h e s i s o f a c i d 132e was r e p o r t e d l a t e r . C l e a v a g e o f h e x a p h e n y I d I s i I a n e ( 1 3 6 e ) w i t h s o d i u m - p o t a s s i u m a l l o y f o l l o w e d by c a r b o n a t l o n a f f o r d e d a 74% y i e l d o f a c i d 132e.104 Ph3Si-SiPh3 ^ | c N Q a / K * PhaSi-COgH lMe. 2 122s. T h e f i r s t p r e p a r a t i o n o f a s i I a n e c a r b o x y I Ic a c i d p o s s e s s i n g b o t h a l k y l and a r y l s u b s t l t u e n t s was t h a t o f d I m e t h y I p h e n y I -s i I a n e c a r b o x y I i c a c i d ( 1 3 2 b ) . 1 0 5 C l e a v a g e o f t h e s y m m e t r i c d i s l l a n e 136b by l i t h i u m f o l l o w e d by c a r b o n a t i o n g a v e a 30% 98 y i e l d o f a c i d 132b CH3 CH3 CH3 Ph-Si—Si-Ph 1?,H;THF * Ph-Si-CCzH l 1 2) C0 2 1 CH3 CH3 CH3 13gb 132b T h e f i r s t s y n t h e s i s o f a t r i a I k y I s i I a n e c a r b o x y I i c a c i d was a c h i e v e d in 1971 . T r f m e t h y I s I I a n e c a r b o x y I Ic a c i d ( 132a ) was p r e p a r e d in 42% y i e l d by c a r b o n a t i o n o f t r i m e t h y I s i IyI I i t h i u r n g e n e r a t e d f r o m b i s ( t r i m e t h y I s I I y I ) m e r c u r y by a m e t a l - m e t a l e x c h a n g e . 1 0 6 T h e d a n g e r s i n h e r e n t In h a n d l i n g v o l a t i l e o r g a n o m e r c u r y c o m p o u n d s p r e c l u d e d o u r a t t e m p t s t o p r e p a r e a c i d Me3SiCI N a / H g (Me3Si)2Hg 2j C Q T H F » MeaSi-CCaH 2 122a 132a u s i n g t h i s r o u t e . A l t h o u g h a r y l c o n t a i n i n g s i l a n e c a r b o x y -l i e a c i d s a p p e a r e d t o be a c c e s s i b l e , t h e l a c k o f a g e n e r a l r o u t e t o b o t h a r y l and t r i a l k y l s y s t e m s p r o m p t e d u s t o s e a r c h f o r a m o r e g e n e r a l and c o n v e n i e n t m e t h o d f o r m a k i n g s l l a n e -c a r b o x y l i c a c i d s . S e v e r a l m e t h o d s h a v e r e c e n t l y b e e n r e p o r t e d f o r t h e e f f i c I e n t J _ Q S I t u g e n e r a t I on o f t r i m e t h y I s I I y I I I t h I urn, t r i -m e t h y I s I IyI s o d I urn, o r t r i m e t h y I s I IyI p o t a s s I urn f r o m h e x a m e t h y l -d i s i l a n e . 1 0 7 - 1 1 1 T h e s e t r i m e t h y I s I IyI a n i o n s h a v e b e e n r e -p o r t e d t o u n d e r g o r e a c t i o n w i t h v a r i o u s e I e c t r o p h i I e s 1 0 8 - 1 1 1 s u c h a s k e t o n e s , e n o n e s , e p o x i d e s , and a l k y l h a i i d e s t o a f f o r d a v a r i e t y o f f u n c t i o n a I I z e d o r g a n o s I I I c o n c o m p o u n d s in m o d e s t t o h i g h y i e l d s . H o w e v e r , t h e r e h a s n o t b e e n a r e p o r t o f t h e i r 99 r e a c t i o n w i t h c a r b o n d i o x i d e t o g i v e t r i m e t h y I s i I a n e c a r b o x y I i c a c i d s o t h e c a r b o n a t i o n o f s i l y l a n i o n s was I n v e s t i g a t e d . H e x a m e t h y I d i s i I a n e ( 1 3 6 a ) was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f S e i t z and F e r r e I r a . 1 1 2 C h I o r o t r i m e t h y I s i Iane was r e f l u x e d In THF w i t h l i t h i u m d i s p e r s i o n c o n t a i n i n g 2% s o d i u m t o g i v e a 68% y i e l d o f h e x a m e t h y I d I s I I a n e . L i . T H F M e 3 S i C I j • Me3Si-SiMe3 O u t l i n e d in T a b l e XII a r e t h e s i l y l a n i o n g e n e r a t i o n m e t h o d s t h a t w e r e p e r f o r m e d . Upon t r e a t m e n t o f h e x a m e t h y I d i -s i l a n e C136a) w i t h methy I I I thI urn ( e n t r i e s 1 and 2) and s o d i u m m e t h o x i d e ( e n t r y 3 ) , r e d s o l u t i o n s w e r e o b t a i n e d i n d i c a t i n g s u c c e s s f u l g e n e r a t i o n o f t h e t r i m e t h y I s I IyI a n i o n . T h e r e d c o l o r d i s s i p a t e d when c a r b o n d i o x i d e was b u b b l e d i n t o t h e Tab Ie X I I . A t t e m p t e d S y n t h e s i s o f T r I m e t h y I s I I a n e c a r b o x y I i c A c i d vI a S i l y l A n i o n s M e 3 S i - S i M e 3 M e 3 S i - C 0 2 H 136a 132a E n t r y R e a c t i o n c o n d i t i o n s 1 1 ) M e L I , D M E - E t 2 0 2) C 0 2 2 1 ) M e L i , H M P A - E t 2 0 2) C 0 2 3 1 ) NaOMe,HMPA 2) C 0 2 4 1 ) L I O B u - i . H M P A 2) C 0 2 5 1 ) KH.HMPA 2) C 0 2 100 s o l u t i o n s u g g e s t i n g t h a t c a r b o n a t l o n o f t h e a n i o n was a c h i e v e d . In a l l a t t e m p t s , h o w e v e r , none o f t h e d e s i r e d t r i m e t h y I s i l a n e c a r b o x y I i c a c i d was i s o l a t e d and t h e r e was v e r y I i t t l e m a s s r e c o v e r y . * C o n c u r r e n t l y w i t h t h e a b o v e c a r b o n a t l o n o f s i l y l a n i o n s , t h e o x i d a t i o n o f t r i m e t h y I s I I y Imethano I (138) was a l s o p e r f o r m e d . T r e a t m e n t o f c h I o r o m e t h y I t r I m e t h y I s i Iane w i t h s o d I urn a c e t a t e and a c a t a l y t i c amount o f t e t r a - n - b u t y I a m m o n I urn i o d i d e In c a r b o n t e t r a c h l o r i d e g a v e a c e t a t e 137 in 76% y i e l d and s u b s e q u e n t c l e a v a g e o f a c e t a t e 137 w i t h l i t h i u m a l u m i n u m h y d r i d e a f f o r d e d an 89% y i e l d o f a l c o h o l 1 3 8 . 1 1 3 S e v e r a l Me3SiCH2CI ^ a ? ^ ° M , — - Me3SiCH2OAc — - Me3SiCH2OH 3 2 n-Bu4NI d * Et 2 0, A CCI4, A ISZ 123. o x i d a t i o n m e t h o d s w e r e a t t e m p t e d ( p o t a s s i u m p e r m a n g a n a t e 4 7 , s o d i u m h y p o c h l o r i d e 1 1 4 , and Swern o x i d a t i o n c o n d i t i o n s 1 1 5 ) . In e a c h c a s e t h e r e was an i n d i c a t i o n t h a t a r e a c t i o n had o c c u r r e d , h o w e v e r , none o f t h e d e s i r e d p r o d u c t c o u l d be i s o l a t e d ( T a b l e X I I I ) . * * l t was f o u n d l a t e r t h a t t r i m e t h y I s i I a n e c a r b o x y I Ic a c i d i s v e r y d i f f i c u l t t o h a n d l e . The h y d r o l y t i c i n s t a b i l i t y o f t h i s a c i d Is t h e l i k e l y r e a s o n f o r o u r f a i l u r e t o i s o l a t e t h i s m a t e r i a l f r o m t h e a b o v e r o u t e s . 101 Tab Ie X I I I . O x i d a t i o n o f T r I m e t h y I s I I y Imethano I Me3SiCH2OH »- Me3Si-CC2H or Me3Si-CH0 138 E n t r y R e a c t i o n c o n d i t i o n s 1 K M n 0 4 , n - B u 4 N I , C H 2 C I 2 . H 2 0 , H 0 A c 2 N a O C I , n - B u 4 N B r , E t 0 A c , H 2 0 3 1) ( C O C I ) 2 , D M S 0 , C H 2 C I 2 2) E t 3 N 102 2 B . 2 . 3 S i I a n e c a r b o x y I Ic A c i d s f r o m B I s - s I I y I a c e t y I e n e s A l k y n e s h a v e b e e n r e p o r t e d t o be o x i d i z e d w i t h r u t h e n i u m t e t r o x i d e 1 1 6 g e n e r a t e d f r o m s o d i u m h y p o c h l o r i d e and a c a t a l y t i c amount o f r u t h e n i u m d i o x i d e a s w e l l a s w i t h o z o n e 1 1 7 i n t h e p r e s e n c e o f an J_a s i t u r e d u c i n g a g e n t t o g i v e a - d i k e t o n e s in y i e l d s o f 59-92% a l o n g w i t h v a r y i n g a m o u n t s o f c a r b o x y l i c a c i d s . The o x i d a t i o n o f a l k y n e s t o a - d l k e t o n e s In y i e l d s o f 41 -93% h a s a l s o b e e n a c c o m p l i s h e d u s i n g p o t a s s i u m p e r m a n g a n a t e . 1 1 8 T h e s e r e p o r t s a l o n g w i t h r e p o r t s t h a t 0 0 Ru0 4 II H R - C e C - R o r K M n Q 4 • R - C - C - R and RCO^H or Oo a - d l k e t o n e s c a n be c l e a v e d w i t h h y p o c h l o r i t e 1 1 9 and p e r i o d a t e 1 2 0 t o a f f o r d c a r b o x y l i c a c i d s p r o m p t e d us t o i n v e s t i g a t e t h e o x i d a t i o n o f s i l i c o n - s u b s t i t u t e d a l k y n e s a s a p o s s i b l e m e t h o d o f p r e p a r i n g sI I a n e c a r b o x y I i c a c i d s . I n i t i a l l y , b i s ( t r I m e t h y I s I I y I ) a c e t y I e n e (139a ) was p r e p a r e d In 80% y i e l d f r o m d l l i t h i u m a c e t y l I d e and c h I o r o t r I m e t h y I s i I a n e in THF a n d h e x a n e . 1 2 1 O t h e r s y m m e t r i c b i s - s I I y I a c e t y I e n e s w e r e s i m i l a r l y p r e p a r e d in y i e l d s o f 75 -87% ( T a b l e X I V ) . T h e s e a l k y n e s e x h i b i t e d s p e c t r a l ( 1 H nmr , I r , and m a s s ) and m i c r o -a n a l y t i c a l d a t a c o n s i s t e n t w i t h t h e i r p r o p o s e d s t r u c t u r e s . B 1 s ( t r i m e t h y I s I I y I ) a c e t y I e n e (139a ) was t r e a t e d w i t h two e q u i v a l e n t s o f s o d I urn h y p o c h l o r i t e and a c a t a l y t i c amount o f r u t h e n i u m d i o x i d e in c a r b o n t e t r a c h l o r i d e and w a t e r a t 0 ° C . 1 1 6 A f t e r t h r e e h o u r s a l l t h e s o d i u m h y p o c h l o r i t e had 103 Tab Ie X I V . P r e p a r a t i o n o f B I s - s I I y I a c e t y I e n e s H - C E E C - H 1 ) " - B " L I THF-hexane -78°-*- A 2) R1R2R3SiCI.A R* I I R n-Si-CsC-Si-R R3 R3  139 A I k y n e Y I e I d (%) 139a R 1 . R 2 . R 3 = M e 80 139b R 1 = P h , R 2 , R 3 = M e 80 139c R 1 = i - B u , R 2 , R 3 = M e 87 139d R 1 = ± - B u , R 2 , R 3 = P h 80 139e R l , R 2 , R 3 = P h 75 r e a c t e d a n d w o r k - u p o f t h e r e a c t i o n g a v e a 40% r e c o v e r y o f t h e s t a r t i n g a I kyne b u t no a -d I k e t o n e o r a c i d was i s o l a t e d . When a l k y n e 139a was o x i d i z e d w i t h p o t a s s i u m p e r m a n g a n a t e and a c a t a l y t i c amount o f t e t r a - n - b u t y I a m m o n I urn I o d i d e in a c i d i c a q u e o u s d i c h I o r o m e t h a n e 1 1 8 , a brown p r e c i p i t a t e f o r m e d a f t e r o n e h o u r a t r e f l u x . H o w e v e r , o n l y a s m a l l amount o f s t a r t i n g a l k y n e ( c a . 15%) was r e c o v e r e d and a g a i n none o f t h e d e s i r e d a - d I k e t o n e o r a c i d was i s o l a t e d . B i s ( t r I m e t h y I s I I y I ) a c e t y I e n e ( 1 3 9 a ) was a l s o s u b j e c t e d t o o z o n o l y s i s In d i c h I o r o m e t h a n e a t - 7 8 ° C and a r e d u c t i v e w o r k - u p w i t h d i m e t h y l s u l f i d e g a v e la p a l e y e I low I I q u i d . T h e c r u d e p r o d u c t e x h i b i t e d a s i n g l e t in t h e 1 H nmr s p e c t r u m a t 6 0 . 2 9 d u e t o t h e m e t h y l p r o t o n s and a b r o a d s i n g l e t o f 6 9 . 4 0 a t t r i b u t a b l e t o t h e c a r b o x y l p r o t o n . T h e i r s p e c t r u m showed a b s o r b a n c e s a t 3050 and 1655 c m - 1 w h i c h a r e d u e r e s p e c t i v e l y 104 t o h y d r o x y l and c a r b o n y l s t r e t c h e s . T h e s e s p e c t r a l f e a t u r e s a r e c o n s i s t e n t w i t h t h o s e r e p o r t e d f o r t r i m e t h y I s I I a n e c a r b o x y -I i c a c i d 1 0 6 , and t h u s a 37% y i e l d * was o b t a i n e d . The i n i t i a l s u c c e s s o f p r e p a r i n g t r I m e t h y I s I I a n e c a r b o x y I Ic a c i d ( 1 3 2 a ) f r o m b i s ( t r i m e t h y I s I I y I ) a c e t y I e n e (139a ) by o z o n o l y s i s was v e r y e n c o u r a g i n g and t h i s p r o m p t e d a m o r e c o m p l e t e s t u d y t o d e t e r m i n e t h e g e n e r a l a p p l i c a b i l i t y o f t h e o z o n o l y s i s r e a c t i o n t o s y n t h e s i z e o t h e r sI I a n e c a r b o x y I Ic a c i d s . D u r i n g t h e c o u r s e o f t h e o z o n o l y s i s o f a l k y n e 1 3 9 a . i t was f o u n d t h a t d i m e t h y l s u l f i d e i s n o t e s s e n t i a l s i n c e w o r k - u p o f t h e r e a c t i o n by e v a p o r a t i o n o f t h e s o l v e n t g a v e a c i d 132a d i r e c t l y in c o m p a r a b l e y i e l d s . T h e low y i e l d o f 132a was a g a i n a t t r i b u t e d t o I t s h y d r o l y t l c and t h e r m a l i n s t a b i l i t y . T h e r e was a s l o w e v o l u t i o n o f a g a s upon t r e a t m e n t o f a c i d 132a w i t h w a t e r , a n d a t t e m p t e d p u r i f i c a t i o n o f a c i d 132a by d i s t i l l a t i o n r e s u l t e d in I t s d e c o m p o s i t i o n . We e n v i s a g e d t h a t t h e s t a b i l i t y o f t h e s i I a n e c a r b o x y I i c a c i d w o u l d be i n c r e a s e d by I n c r e a s i n g t h e b u I k I n e s s o f t h e s l l y l g r o u p . T h e o z o n o l y s i s o f an a l k y n e p o s s e s s i n g s t e r l c a l l y h i n d e r e d s i l y l g r o u p s , b I s ( i - b u t y I d I p h e n y I s I | y I ) a c e t y I e n e ( 1 3 9 d ) . was exam I n e d . I n i t i a l l y , o z o n o l y s i s o f 139d was c a r r I e d o u t In d I c h I o r o m e t h a n e a t - 7 8 ° C b u t a q u a n t i t a t i v e r e c o v e r y o f t h e s t a r t i n g m a t e r i a l was o b t a i n e d d u e t o i t s I n s o l u b i l i t y a t t h a t t e m p e r a t u r e . When t h e o z o n o l y s i s was r e p e a t e d a t - 2 4 ° C , t h e r e was a g o o d m a s s r e c o v e r y o f a p a l e y e l l o w s y r u p w h i c h was shown * Y l e l d b a s e d on t h e o r e t l e a l y i e l d o f two m o l e s o f a c i d f r o m o n e m o l e o f a l k y n e . 105 t o be e s s e n t i a l l y o n e compound by t i c . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t by s i l i c a g e l c o l u m n c h r o m a t o g r a p h y f o l l o w e d by r e c r y s t a I I I z a t i o n f r o m e t h y l a c e t a t e g a v e a w h i t e s o l i d . The 80 MHz 1 H nmr s p e c t r u m e x h i b i t e d s i n g l e t s a t 5 1 .00 and 61 .21 a n d a muI t i p l e t a t 6 7 . 2 3 - 7 . 8 3 and t h e i r s p e c t r u m had an a b s o r b a n c e a t 1665 c m - 1 . Due t o t h e a b s e n c e o f a c a r b o x y l p r o t o n r e s o n a n c e i n t h e 1 H nmr s p e c t r u m and an 0 - H s t r e t c h i n g b a n d in t h e Ir s p e c t r u m , It was r a p i d l y c o n c l u d e d t h a t t h e o z o n o l y s i s p r o d u c t was n o t t h e e x p e c t e d i - b u t y I d I p h e n y I s I I a n e -c a r b o x y l i e a c I d . F rom t h e a b o v e s p e c t r a l d a t a , t h e o z o n o l y s l s p r o d u c t was I n i t i a l l y a s s u m e d t o be an a -d I k e t o n e b e c a u s e o f t h e p r e c e d e n c e f o r t h e f o r m a t i o n o f a - d i k e t o n e s in t h e o z o n o l y s l s o f a l k y n e s . 1 1 7 ' 1 2 2 We r e a s o n e d t h a t If t h i s new compound was Indeed an a -d I k e t o n e , It must e x i s t in some l o c k e d r o t a m e r i c f o r m m a k i n g t h e two i - b u t y I g r o u p s n o n - e q u i v a l e n t s i n c e two w e l l r e s o l v e d s i n g l e t s w e r e d i s p l a y e d In t h e 1 H nmr s p e c t r u m . Ph Ph I I o t - B u - S i - C s C - S i - t - B u 2 ^ "diketone" i i CHoCU Ph Ph 2 4 0 139d W h i l e a w a i t i n g m a s s s p e c t r a l and m i c r o a n a l y t i c a l r e s u l t s , a h i g h t e m p e r a t u r e 1 H nmr s t u d y was p e r f o r m e d in t h e h o p e s o f s e e i n g t h e two s i n g l e t s c o a l e s c e a t some t e m p e r a t u r e t h a t w o u l d b r i n g a b o u t f r e e r o t a t i o n o f t h e C - C s i n g l e b o n d . H e a t i n g o f t h e s u s p e c t e d d i k e t o n e f r o m 1 0 0 ° t o 1 7 0 ° C in DMSO-ds d i d in f a c t b r i n g a b o u t a g r a d u a l c o a l e s c e n c e o f t h e two i - b u t y I s i g n a l s i n t o o n e , b u t i t s p o s i t i o n a t 6 1 . 0 4 was n o t a t t h e m i d -106 p o i n t o f t h e two o r i g i n a l s i g n a l s . Upon c o o l i n g o f t h e 1 H nmr s a m p l e , t h e two o r i g i n a l s i g n a l s d i d n o t r e a p p e a r and t h e r e w e r e a l s o c h a n g e s in t h e a r o m a t i c p a t t e r n . T i c o f t h e s o l u t i o n showed a s i n g l e s p o t w i t h Rf 0 . 5 2 ( p e t r o l e u m e t h e r - e t h y l a c e t a t e , 1 9 : 1 ) c o m p a r e d t o Rf 0 . 4 0 f o r t h e o r i g i n a l c o m p o u n d . M o r e I m p o r t a n t l y , t h e Ir s p e c t r u m o f t h e t h e r m a l i z e d p r o d u c t i s o l a t e d by s i l i c a g e l c o l u m n c h r o m a t o g r a p h y d i d n o t show a c a r b o n y l s t r e t c h i n g b a n d . T h e s e o b s e r v a t i o n s c l e a r l y showed t h a t t h e t h e r m o l y s i s o f t h e s u s p e c t e d d l k e t o n e p r o d u c e s a new c o m p o u n d . Upon r e c e i p t o f t h e mass s p e c t r a l d a t a i t was a p p a r e n t t h a t o u r o z o n o l y s i s p r o d u c t was n o t a d l k e t o n e , b u t was in f a c t i - b u t y I d I p h e n y I s i IyI i - b u t y I d i p h e n y I s i I a n e c a r b o x y I a t e ( 1 4 0 d ) . T h i s s t r u c t u r e was l a t e r c o n f i r m e d by an x - r a y c r y s t a l s t r u c -t u r e a n a l y s i s ( F i g u r e 9 ) . * E s t e r 140d showed a b s o r p t i o n s F i a u r e 9 . ORTEP d i a g r a m o f e s t e r 1 4 0 d . * 0 b t a i n e d by t h e d e p a r t m e n t a l x - r a y c r y s t a l l o g r a p h y l a b a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a . 107 Ph Ph Ph 0 Ph I I 0 3 I 11 I t-Bu-Si-CaC-Si-t-Bu pqjrq t-Bu-Si—C-OSi-t-Bu I I O M 2 O I 2 1 1 Ph Ph . 2 4 o Ph Ph 139d 14Qd a t 1665 and 1150 c m - 1 i n t h e Ir s p e c t r u m c o r r e s p o n d i n g t o C=0 s t r e t c h i n g and C - 0 s t r e t c h i n g , r e s p e c t i v e l y . T h e s i n g l e t s a t 6 1 . 0 0 a n d 6 1 . 2 1 In t h e 1 H nmr s p e c t r u m c o u l d now e a c h be a t t r i b u t e d t o t h e n i n e i - b u t y l p r o t o n s o f t h e s i l i c o n b o n d e d t o t h e c a r b o x y l o x y g e n and o f t h e s i l i c o n b o n d e d t o t h e c a r b o n y l c a r b o n , r e s p e c t i v e l y . The r e s o n a n c e s o f t h e p h e n y l p r o t o n s a p p e a r e d a s a m u l t i p l e t a t 6 7 . 2 3 - 7 . 8 3 . T h u s , In c o n t r a s t t o t h e o z o n o l y s l s o f a l k y n e 139a In w h i c h t r i m e t h y I s i I a n e c a r b o x y -I i c a c i d ( 1 3 2 a ) was o b t a i n e d , t h e o z o n o l y s i s o f a l k y n e 139d a f f o r d e d e s t e r I40d In 83% y i e l d . T h e t h e r m o l y s i s p r o d u c t o f 140d was i d e n t i f i e d a s s i l o x a n e 141d in w h i c h t h e r e h a s been l o s s o f c a r b o n m o n o x i d e . T h i s r e a r r a n g e m e n t Is a v e r y c l e a n r e a c t i o n s i n c e s i l o x a n e 141d was Ph 0 Ph Ph Ph I II I A I I t-Bu-Si—C-OSi-t-Bu *- t-Bu-Si-OSi-t-Bu + CO I I 1 1 Ph Ph Ph Ph 140d 141d i s o l a t e d In q u a n t i t a t i v e y i e l d . S i l o x a n e 141d e x h i b i t e d a S I - 0 s t r e t c h i n g b a n d a t 1060 c m - 1 i n t h e i r s p e c t r u m . T h e 1 H nmr s p e c t r u m showed a s i n g l e t a t 6 1 . 0 4 d u e t o t h e e i g h t e e n i - b u t y l p r o t o n s and a m u l t i p l e t a t 6 7 . 1 0 - 7 . 6 0 d u e t o t h e p h e n y l p r o t o n s . T h e t h e r m a l r e a r r a n g e m e n t o f s i l y l sI I a n e c a r b o x y I a t e s w i l l be exam Ined In more d e t a I I In P a r t C . 108 T a b l e X V . O z o n o l y s l s o f B i s - s I I y I a c e t y I e n e s R2 R2 R2 0 R2 R2 R 1 -Si-CsC-Si-R 1 » R 1-Si-C-0Si-R 1 or ^-Si-COaH ', C H 2 C I 2 ' 3 I o R3 R3 2 4 o R3 R3 R3 122. 1AQ. i o 2 a) R 1,R 2R 3=Me ^ b) R1=Ph, R2,R3=Me d) R1=t-Bu, R2,R3=Ph c) R1=t-Bu, R 2 R3=Me e) R 1,R 2R 3=Ph A I k y n e P r o d u c t Y l e l d ( % ) a 139a 132a 74 139b 132b 88 139c 14QC 8 7 b 139d 8 3 b 139e 140e 8 0 b a Y I e I d b a s e d on t h e o r e t i c a l y i e l d o f o n e m o l e o f a c i d o r e s t e r f r o m o n e m o l e o f a l k y n e . D P u r i f i e d y i e l d . A l k y n e s 1 3 9 b . 1 3 9 c . and 139e w e r e t h e n s u b j e c t e d t o o z o n o l y s e s in d I c h I o r o m e t h a n e . The r e s u l t s o f t h e s e o z o n o l y s e s a r e s u m m a r i z e d In T a b l e X V . An 88% y i e l d * o f d i m e t h y l -p h e n y I s i I a n e c a r b o x y I Ic a c i d C132b) was o b t a i n e d f r o m a l k y n e 1 3 9 b . In c o n t r a s t , o z o n o l y s e s o f a l k y n e s 139c and 139e a f f o r d e d an 87% y i e l d o f i - b u t y I d I m e t h y I s I IyI i - b u t y I d i m e t h y I -sI I a n e c a r b o x y I a t e ( 1 4 0 c ) and an 80% y i e l d o f t r I p h e n y I s I Iy l t r I p h e n y I s i I a n e c a r b o x y I a t e ( 1 4 0 e ) . r e s p e c t i v e l y . T h e p r o p o s e d m e c h a n i s m f o r t h e o z o n o l y s l s o f b i s - s i l y l -* Y i e l d b a s e d o n t h e o r e t i c a l y i e l d o f o n e m o l e o f a c i d f r o m o n e m o l e o f a l k y n e . 109 a c e t y l e n e 139 Is shown b e l o w . A d d i t i o n o f o z o n e t o t h e t r i p l e bond e v e n t u a l l y g i v e s a s h o r t - l i v e d e x c i t e d s t a t e a n h y d r i d e 142 w h i c h d e c o m p o s e s by s i l y l g r o u p m i g r a t i o n w i t h c o n c o m i t a n t l o s s o f c a r b o n m o n o x i d e t o a f f o r d s i l y l s i I a n e c a r b o x y I a t e 140 . In c a s e s w h e r e t h e s l l y l g r o u p Is s m a l l , sI I a n e c a r b o x y I Ic a c i d 132 and s i i a n o l 143 a r e a f f o r d e d p r e s u m a b l y f r o m s u b s e q u e n t h y d r o l y s i s o f t h e I n i t i a l l y f o r m e d c o r r e s p o n d i n g s l l y l sI I a n e c a r b o x y I a t e in t h e p r e s e n c e o f a d v e n t i t i o u s w a t e r . R R 1 1 ' 1 R — Si—CsC—Si-R I _ i „ R 1-Si-C=C-Si-R 1 122. R 2 0 _ 0 R l i. I I I R 1-Si-C-0-C-Si-R 1 142. RJ FT o_o R^  1 1 1 1 1 1 R 1 -S i -C-C-Si -R 1 i 0 i R2 0 R2 I II I R1-Si—C-OSi-R1 + CO l _ i 140_ HgO R^  R1-Si-C02H R3 R 1-Si-0H 132 143. 1 10 A p r e c e d e n t f o r an e x c i t e d s t a t e a n h y d r i d e comes f r o m work by DeMore who f o u n d t h a t o z o n o l y s i s o f d i m e t h y I a c e t y I e n e (144) g a v e a c e t i c a c i d and k e t e n e . 1 2 2 S p e c t r o s c o p i c e v i d e n c e f o r t h e e x i s t e n c e o f t h e e x c i t e d s t a t e a n h y d r i d e was p r e s e n t e d . C H 3 C S C C H 3 144 O3 0'''H>SCH2 II I C H 3 ( ^ c y A o CH3C02H + CH2C0 T h e e n e r g y r e q u i r e d f o r s i l y l g r o u p m i g r a t i o n in e x c i t e d s t a t e a n h y d r i d e 142 h a s b e e n e s t i m a t e d by u s t o be on t h e o r d e r o f a p p r o x i m a t e l y 32 k c a l / m o l e ( s e e P a r t C o f t h i s t h e s i s ) . H e n c e , e x c i t e d s t a t e a n h y d r i d e 142 must c o n t a i n a min imum o f 32 k c a l / m o l e o f v i b r a t i o n a l e n e r g y . * We a n t i c i p a t e d t h a t sI I a n e c a r b o x y I i c a c i d s 1 3 2 c . 1 3 2 d . and 132e s h o u l d be r e a d i l y o b t a i n a b l e by h y d r o l y s i s o f t h e c o r r e s p o n d i n g s i l y l sI I a n e c a r b o x y I a t e s . I n d e e d , a c i d - c a t a l y z e d CH3 0 CH3 I 11 I t-Bu-Si — C-OSi-t-Bu CHa CH3  140c O 11 Ph3Si-C-OSiPh3  140e THF-H20 H2S04 THF-H20 CH3 t-Bu-Si—CO2H + CH3 132C CH3 t-Bu-Si-OH I CHa 143c Ph3Si-C02H 132e + Ph3Si-0H 143e * T h e o z o n o l y s i s o f b I s - s I I y I a c e t y I e n e s 139 t o g i v e s i l y l sI I a n e c a r b o x y I a t e s 140 and c a r b o n m o n o x i d e Is a f a v o r a b l e p r o c e s s . U s i n g B e n s o n ' s a d d l t l v i t y r u l e s 9 5 , t h i s r e a c t i o n i s d e t e r m i n e d t o h a v e an a p p r o x i m a t e AH o f - 2 5 0 k c a l / m o l e . T h e h i g h l y e x o t h e r m i c n a t u r e o f t h e r e a c t i o n m o r e t h a n a c c o u n t s f o r t h e amount o f e n e r g y r e q u i r e d f o r t h e s l l y l g r o u p m i g r a t i o n In t h e e x c i t e d s t a t e a n h y d r i d e . 111 h y d r o l y s i s o f e s t e r s 140c and 140e p r o c e e d e d s m o o t h l y a t room t e m p e r a t u r e w i t h a q u e o u s s u l f u r i c a c i d in THF t o a f f o r d a c i d s 132c and 132e in 95% and 85% y i e l d , r e s p e c t i v e l y . The i r s p e c t r u m o f i - b u t y I d I m e t h y I s I I a n e c a r b o x y I Ic a c i d ( 1 3 2 c ) showed t h e c a r b o n y l s t r e t c h a t 1650 c m - 1 and a b r o a d 0 - H s t r e t c h a t 3050 c m - 1 . In t h e 1 H nmr s p e c t r u m , t h e s i n g l e t s a t 6 0 . 2 8 a n d 6 1 . 0 5 w e r e d u e , r e s p e c t i v e l y , t o t h e s i x m e t h y l p r o t o n s and t h e n i n e i - b u t y l p r o t o n s . A v e r y b r o a d s i n g l e t a t 6 9 . 7 was a s s i g n e d t o t h e c a r b o x y l p r o t o n . F o r t r I p h e n y I s i I a n e c a r b o x y I i c a c i d ( 1 3 2 e ) . t h e C=0 band o c c u r r e d a t 1675 c m - 1 and t h e b r o a d 0 - H s t r e t c h i n g band was a t 3050 c m - 1 in t h e i r s p e c t r u m . The 1 H nmr s p e c t r u m d i s p l a y e d a m u l t i p l e t a t 6 7 . 1 8 - 7 . 9 5 a s s i g n e d t o t h e p h e n y l p r o t o n s and a v e r y b r o a d s i n g l e t a t 610 due t o t h e c a r b o x y l p r o t o n . H o w e v e r , It was f o u n d t h a t a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 140d d i d n o t p r o c e e d a t room t e m p e r a t u r e . When t h e h y d r o l y s i s was c a r r i e d o u t a t 7 0 ° C f o r 45 h o u r s , a 47% y i e l d o f a c i d 132d was o b t a i n e d a l o n g w i t h some i - b u t y I d I p h e n y I s i l a n o l ( 1 4 3 d ) and r e c o v e r e d e s t e r . In a c o n t r o l e x p e r i m e n t , It was f o u n d t h a t a c i d 132d I t s e l f was u n s t a b l e a t 7 0 ° C d e c o m p o s i n g t o s i l a n o l 143d t o an e x t e n t o f 19% a f t e r 42 h o u r s . T h u s , t h e h i g h e r t e m p e r a t u r e r e q u i r e d f o r t h e a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 140d a l s o l e d t o a s l o w d e c o m p o s i t i o n o f t h e f o r m e d a c i d 132d t o s I I a n o I 1 4 3 d . * i - B u t y I d I p h e n y I s I I a n e c a r b o x y I i c * D e c o m p o s i t i o n o f a c i d 132d a c t u a l l y g i v e s t h e f o r m a t e i - B u P h 2 S I 0 C H 0 w h i c h Is h y d r o l y z e d in t h e I s o l a t i o n p r o c e s s t o g i v e 1 4 3 d . T h i s r e a r r a n g e m e n t w i l l be d i s c u s s e d in d e t a i I i n P a r t C . 1 12 Ph O Ph Ph Ph l II I H2S04 l I t-Bu-Si—C-OSi-t-Bu THF-H20 " t-Bu-Si-C02H + t-Bu-Si-OH Ph Ph 7 0 o Ph Ph 14Qd 132d 143d a c i d ( 1 3 2 d ) * had a b s o r b a n c e s i n t h e Ir s p e c t r u m a t 1650 and 3000 c m - 1 d u e t o C=0 s t r e t c h i n g and 0 - H s t r e t c h i n g , r e s p e c t i v e l y . In t h e 1 H nmr s p e c t r u m , t h e s i n g l e t a t 6 1 . 2 3 was d u e t o t h e n i n e i - b u t y l p r o t o n s , t h e m u l t i p l e t a t 6 7 . 2 8 -7 . 8 3 was d u e t o t h e p h e n y l p r o t o n s , and t h e b r o a d s i n g l e t a t 6 1 2 . 8 was d u e t o t h e c a r b o x y l p r o t o n . It was f o u n d l a t e r t h a t a v e r y e f f i c i e n t m e t h o d o f o b t a i n i n g a c i d 132d i s t o p e r f o r m an a c i d - c a t a l y z e d m e t h a n o l y -s l s o f e s t e r 1 4 0 d . A 98% y i e l d o f t h e d e s i r e d a c i d was An a l t e r n a t e r o u t e t o a c i d 132d i s shown b e l o w . T h i s r o u t e i n v o l v e s h y d r o l y s i s o f a m i x e d s i l a n e e s t e r w h i c h p r o c e e d s u n d e r m i l d c o n d i t i o n s u n d e r w h i c h t h e d e s i r e d a c i d i s s t a b l e A l k v n e 145 was p r e p a r e d f r o m b I s ( t r I m e t h y I s I I y I ) a c e t y I e n e in 70% y i e l d . O z o n o I y s i s o f a l k y n e 145 f o l l o w e d by m i l d a c I d -c a t a l y z e d h y d r o l y s i s o f t h e o z o n o l y s l s p r o d u c t s g a v e t h e d e -s i r e d a c i d JJ i2d in 48% y i e l d a l o n g w i t h e s t e r 146 i n 26% y i e l d . T h e r e c a n o n l y be a maximum o f 50% y i e l d o f e a c h o f M e 3 S i - C e c - S i M e 3  139a 0 Ph 11 I M e 3 S i - C - 0 S i - t - B u 1 Ph 14£ Ph I t - B u - S i - C C f e H Ph 132d 1) n-BuLi THF-hexane 2) t-BuPh 2SiCI H 2 0-Et 2 0 Ph I M e 3 S i - C s C - S i - t - B u ™ IAS. C H 2 C I 2 , - 2 4 ° Ph + t - B u - S i -1 Ph O Ph ii I M e 3 S i - C - O S i - t - B u 1 Ph 0 II C - 0 S i M e 3 t h e s e c o m p o u n d s b e c a u s e o f t h e two p o s s i b l e r e a r r a n g e m e n t r o u t e s o f t h e e x c i t e d s t a t e a n h y d r i d e . A c i d 132e was a l s o s i m i l a r l y p r e p a r e d by t h e o z o n o I y s i s o f a l k y n e 1 4 7 . M e 3 S i - C H C - S i P h 3 1A1 1 13 a c h i e v e d . T h e d e t a i l s o f t h e a c i d - c a t a l y z e d a l c o h o l y s i s and h y d r o l y s i s o f s i l y l sI I a n e c a r b o x y I a t e s wI I I be d e s c r i b e d l a t e r In P a r t D o f t h i s t h e s i s . T h e b I s - s I I y I a c e t y I e n e s r e q u i r e d f o r t h e o z o n o l y s i s a r e r e a d i l y p r e p a r e d f r o m a c e t y l e n e , n -bu ty I I I th i urn, and t h e a p p r o p r i a t e c h I o r o s I I a n e . O z o n o l y s l s o f b I s - s I I y I a c e t y I e n e s p r o c e e d s s m o o t h l y t o g i v e h i g h y i e l d s o f e i t h e r s i l y l s i l a n e -c a r b o x y l a t e s o r s i I a n e c a r b o x y I Ic a c i d s d i r e c t l y in c a s e s o f l e s s s t e r i c a l l y h i n d e r e d s i l y l g r o u p s . S u b s e q u e n t a c i d -c a t a l y z e d h y d r o l y s i s o r m e t h a n o l y s l s o f s i l y l s i I a n e c a r b o x y -l a t e s a f f o r d s t h e d e s i r e d sI I a n e c a r b o x y I Ic a c i d s . The o z o n o l y s l s o f b I s - s I I y I a c e t y I e n e s 139 r e p r e s e n t s a new, c o n v e n i e n t , and g e n e r a l m e t h o d f o r t h e p r e p a r a t i o n o f s l l y l s i I a n e c a r b o x y I a t e s 140 and s i l a n e c a r b o x y l i c a c i d s 132 v i a s u b s e q u e n t h y d r o l y s i s o f s i l y l s i I a n e c a r b o x y I a t e s . 1 14 2 B . 2 . 4 P r e p a r a t i o n o f SI I a n e c a r b o x y I Ic E s t e r s a n d F l u o r i d e C I e a v a g e s H a v i n g e s t a b l i s h e d a g e n e r a l p r o c e d u r e f o r m a k i n g s i l a n e -c a r b o x y l l c a c i d s , we now w i s h e d t o p r e p a r e a l k y l e s t e r s o f t h e s e sI I a n e c a r b o x y I Ic a c i d s in o r d e r t o t e s t o u r o r i g i n a l h y p o t h e s i s . E s t e r s o f i - b u t y I d i m e t h y I s i I a n e c a r b o x y I Ic a c i d w e r e c h o s e n a s t h e y a r e l i k e l y t o h a v e s u f f i c i e n t t h e r m a l and T a b l e XVI . A t t e m p t e d A c t i v a t i o n o f i - B u t y I d I m e t h y I s I I a n e -c a r b o x y l i e A c I d CH 3 CH 3 0 C H 3 O CH 3 CH 3 I I 11 I 11 I I t-Bu-Si—CO2H — t - B u - S i — C - C C a H ^ t - B u - S i — C - O S i - t - B u t - B u - S i - O C s H ^ CH 3 CH 3 CH 3 C H 3 C H 3 132c H B . 112. A c t i v a t i o n c o n d i t i o n s Y i e 1 d (%) a E n t r y ( e q u l v ) So 1 v e n t 148 140c 14? 1 1) ( C O C l ) 2 ( D 2) 1 - o c t a n o l , l - P r 2 N E t C H 2 C 1 2 0 0 40 2 1) S O C I 2 (1) 2) 1 - o c t a n o l , i - P r 2 N E t C H 2 C I 2 0 0 49 3 CDI ( 0 . 5 ) C H 2 C 1 2 0 41 0 4 CD I ( 0 . 5 ) h e x a n e 0 87 0 5 1) DCC ( 1 ) , 1 - o c t a n o l C H 2 C I 2 0 79 0 6 DCC ( 0 . 5 ) C H 2 C 1 2 0 93 0 7 ( E t O ) 2 P O C I ( 0 . 5 ) , E t 3 N THF 0 81 0 8 1) l * * ^ (1 ) 2) 1 - o c t a n o l , E t 3 N * N ^ B r I" C H 3 C H 2 C I 2 b 0 60 1 6 a Y i e l d s a f t e r c h r o m a t o g r a p h y on s i l i c a g e l and a r e b a s e d on s i l i c o n b a l a n c e . b R e a c t i o n a t r e f l u x . 1 15 h y d r o l y t i c s t a b i l i t y f o r e a s e o f h a n d l i n g . T h e r e a r e many m e t h o d s f o r t h e c o n v e r s i o n o f c a r b o x y l i c a c i d s I n t o e s t e r s and t h e s e m e t h o d s h a v e b e e n r e v i e w e d . 1 2 3 Our i n i t i a l a t t e m p t s t o e s t e r I f y 1 - b u t y I d i m e t h y I s I I a n e c a r b o x y -I i c a c i d ( 1 3 2 c ) a r e s u m m a r i z e d in T a b l e X V I . A f r e q u e n t l y u s e d m e t h o d o f p r e p a r i n g e s t e r s i s t o c o n v e r t t h e c a r b o x y l i c a c i d t o t h e a c i d c h l o r i d e w i t h s u b s e q u e n t r e a c t i o n w i t h an a l c o h o l in t h e p r e s e n c e o f a b a s e . 1 2 4 I n s I t u p r e p a r a t i o n m e t h o d s u s i n g o x a i y l c h l o r i d e and t h i o n y l c h l o r i d e ( e n t r i e s 1 and 2) w i t h 1 - o c t a n o l a f f o r d e d m o d e s t y i e l d s o f s l l y l e t h e r 149 . The f o r m a t i o n o f s i l y l e t h e r 149 was r a t i o n a l i z e d a s shown b e l o w by g e n e r a t i o n o f i - b u t y I d I m e t h y I s I IyI c h l o r i d e f r o m t h e s i l a n e a c i d w h i c h t h e n r e a c t s w i t h 1 - o c t a n o l . T h e s i l y l c h l o r i d e may CH3 t-Bu-Si-C02H + (COCI)2 I II II II t-Bu-Si—C-O-C-C-CI + HCl C H 3 O 0 0 CH3 -CO 11 t-Bu-Si-CI -Bu-Si— C-CI CH3 CH3  150 1 -octanol Et3N CH3 t-Bu-Si-CH3 149_ 1 16 be f o r m e d by a t t a c k o f c h l o r i d e i o n on t h e s i I i c o n o f t h e a c t i v a t e d I n t e r m e d i a t e o r by d e c o m p o s i t i o n o f a c i d c h l o r i d e 1 5 0 . C a r b o n - h y d r o g e n b o n d s b r e a k In t h e same d i r e c t i o n , C ~ H + , a s do c a r b o n - s i l i c o n b o n d s , C ~ S I + , and a g o o d i n d i c a t i o n o f t h e l i k e l y b e h a v i o r o f a C - S i bond c a n be p r e d i c t e d by c o n s i d e r a t i o n o f an a n a l o g o u s C - H b o n d . 5 0 S i n c e f o r m y l c h l o r i d e i s u n s t a b l e a t room t e m p e r a t u r e d e c o m p o s i n g t o c a r b o n m o n o x i d e and h y d r o g e n c h l o r i d e 1 2 5 , i t i s a n t i c i p a t e d t h a t a c i d c h l o r i d e 150 w o u l d a l s o be u n s t a b l e . In c o n t r a s t t o f o r m y l c h l o r i d e , 1 - f o r m y I i m I d a z o I e i s s t a b l e 1 2 6 and we a t t e m p t e d t o p r e p a r e t h e a n a l o g o u s s y s t e m f r o m a c i d 1 3 2 c . When a c i d 132c was r e a c t e d w i t h o n e e q u i v a -work-up CH3 t-Bu-Si-OH I CH3  143c 1 17 l e n t o f 1 , 1 ' - c a r b o n y I d I i m i d a z o l e ( C D I ) 1 2 7 , s i l y l e s t e r 140c was o b t a i n e d and i t was f o u n d t h a t t h e r e a c t i o n p r o c e e d e d e q u a l l y w e l l w i t h o n l y 0 . 5 e q u i v a l e n t o f CDI ( e n t r y 3 ) . The y i e l d o f e s t e r 140c c o u l d be i n c r e a s e d by u s i n g h e x a n e a s t h e r e a c t i o n s o l v e n t I n s t e a d o f d I c h I o r o m e t h a n e ( e n t r y 4 ) . The r e a c t i o n c a n be e n v i s a g e d t o p r o c e e d by a t t a c k o f a c i d 132c on t h e s i l i c o n o f t h e a c t i v a t e d i n t e r m e d i a t e t o g i v e e s t e r 1 4 0 c . I m i d a z o l e Is s o l u b l e In d I c h I o r o m e t h a n e s o t h e lower y i e l d o f e s t e r 140c in d i c h I o r o m e t h a n e a s s o l v e n t c a n be a t t r i b u t e d t o f o r m a t i o n o f s i l y l I m i d a z o l e 151 w h i c h i s h y d r o l y z e d on w o r k - u p t o s i l a n o l 1 4 3 c . I m i d a z o l e Is v i r t u a l l y I n s o l u b l e in h e x a n e s o t h e f o r m e d i m i d a z o l e i s p r e c i p i t a t e d t h u s d i m i n i s h i n g t h e f o r m a t i o n o f s i l y l i m i d a z o l e and t h e r e b y I n c r e a s i n g t h e y i e l d o f s i l y l e s t e r 1 4 0 c . DCC h a s b e e n u s e d f r e q u e n t l y f o r t h e c o u p l i n g o f a c i d s w i t h a l c o h o l s t o g i v e e s t e r s . 1 2 8 H o w e v e r , when a c i d 132c was CsHu t-Bu-Si—C-OSi-t-Bu — t-Bu-Si—C-OC-Si-t-Bu I I I I CH3 CH3 CH3 CH3 140c 1 18 reacted with 1-octanol and DCC (entry 5), none of the desired octyl ester 148 was Isolated but instead ester 140c was obtained In 79% y i e l d . When 1-octanol was excluded, ester 140c was again formed. In addition, i t was found that only 0.5 equivalent of DCC was necessary to give a good y i e l d of ester 140c (entry 6). The formation of ester 140c was rat i o n a l i z e d by attack of acid 132c on the s i l i c o n of the activated Intermediate, or less l i k e l y by attack of acid 132c on the carbonyl carbon giving r i s e to an anhydride which then rearranges with loss of carbon monoxide. Other reagents that were used to attempt to activate the carboxyl group were diethyl chIorophosphate 1 2 9 and 2-bromo-1-methyIpyrIdiniurn i o d i d e . 1 3 0 These reagents, again, gave high y i e l d s of s i l y l ester 140c. When 1-octanol was Included in the reaction (entry 8) there was some s i l y l ether 149 formed which Indicates that there is some competition by 1-octanol for attack at the s i l i c o n in the activated intermediate. The above experimental results reveal that sI IanecarboxyI ic acids 132 show an important difference in r e a c t i v i t y from that of "normal" carboxylic acids. Whereas the carboxyl group of carboxylic acids can be activated toward nucleophilic attack at the carbonyl carbon for ester f o r m a t i o n 1 2 3 , the carboxyl group of sI IanecarboxyI Ic acids cannot be s i m i l a r l y activated. In a l l cases, upon attempted act i v a t i o n of the carboxyl group, nucleophiles In the medium Including the si IanecarboxyI Ic acid i t s e l f , rapidly and p r e f e r e n t i a l l y attacked the s i l i c o n atom of the activated intermediate rather than the carbonyl carbon leading to formation of the symmetric ester 140 or the ether 1 19 such as 149. No alkyl ester such as 148 was ever observed. Therefore, ac t i v a t i o n methods can not apparently be applied to the formation of alkyl esters of sI IanecarboxyI Ic acids. A procedure reported to give high y i e l d s of ethyl esters from i-butyIdimethyIsI IyI esters Involved treatment of the s i l y l ester with oxalyl chloride and a c a t a l y t i c amount of DMF to give a carboxylic acid chloride which Is then quenched with excess ethanol and p y r i d i n e . 1 3 1 Control experiments were performed I n i t i a l l y to determine if thi s method could be extended to the use of bulkier s i l y l groups as well as If alkyl esters other than ethyl could be formed. i-ButyIdImethyIsiIyI phenyI acetate (152) and i-butyIdIphenyIsI IyI phenyI acetate (154), prepared from phenylacetlc acid, Imidazole, and the corresponding s i l y l chloride In DMF, were treated with oxalyl 0 CH3 4^-CH 2C-OSi-t-Bu 152 CH3 1) (COCI)2,DMF CH2CI2 2) 1-octanol,Et3N 0 II ^-CH 2C-< 153 0 Ph II I <A^-CH 2C-OSi-t-Bu Ph 154. 1) (COCI)2,DMF CH2CI2 2) 1-octanol,Et3N 0 II 0~CH2C" 153 chloride and DMF followed by 1-octanol and trIethyI am Ine to afford the desired octyl phenyI acetate (153) in yi e l d s of 94% and 95%, respectively. The above ester IfI cat I on method was then t r i e d on s i l y l sI IanecarboxyIates. However, when s i l y l ester 140c was used, 120 two e q u i v a l e n t s o f s i l y l e t h e r 149 w e r e o b t a i n e d In v i r t u a l l y q u a n t i t a t i v e y i e l d (97%). A g a i n , t h e r e was no t r a c e o f any o f t h e d e s i r e d o c t y l e s t e r . The u s e o f o n e e q u i v a l e n t o f DMF CH3O CH3 I 11 I 1 ) (C0CI)2,DMF t-Bu-Si—C-OSi-t-Bu 1 1 CH2CI2 CH3 CH3 2) 1-octanol,Et3N 14QC i n s t e a d o f a c a t a l y t i c amount a l s o g a v e a q u a n t i t a t i v e y i e l d o f s i l y l e t h e r 1 4 9 . T h e r e a c t i o n was r e p e a t e d a t low t e m p e r a t u r e ( - 2 4 ° C ) in t h e h o p e s o f r e t a r d i n g t h e s l l y l c h l o r i d e f o r m a t i o n , b u t a g a i n s i l y l e t h e r 149 was f o r m e d . In o r d e r t o o b t a i n an a l k y l sI I a n e c a r b o x y I Ic e s t e r f o r t h e p u r p o s e o f t e s t i n g t h e p r o p o s e d d e o x y g e n a t I on m e t h o d , i t was d e c i d e d t o r e v e r s e t h e n u c I e o p h I I I c I t y o f t h e e s t e r i f i c a t i o n r e a c t i o n by m a k i n g t h e c a r b o x y l o x y g e n o f t h e s i I a n e c a r b o x y I i c a c i d s t h e n u c l e o p h i l i c s i t e . 1 3 2 S e v e r a l s i m p l e s i l a n e c a r b o -x y l l c e s t e r s w e r e e v e n t u a l l y p r e p a r e d s u c c e s s f u l l y ( T a b l e X V I I ) u s i n g t h i s a p p r o a c h . The sI I a n e c a r b o x y I i c a c i d s w e r e t r e a t e d w i t h s o d I urn c a r b o n a t e in DMF t o g e n e r a t e t h e s o d I urn s a l t s i n  s i t u w h i c h w e r e s u b s e q u e n t l y a l k y l a t e d w i t h i o d o m e t h a n e , 1 - b r o m o o c t a n e , o r D.-n I t r o b e n z y I c h l o r i d e . M o d e s t t o g o o d y i e l d s o f t h e d e s i r e d s i I a n e c a r b o x y I Ic e s t e r s w e r e o b t a i n e d . T h e s e e s t e r s e x h i b i t e d s p e c t r a l ( 1 H nmr, i r , and m a s s ) and m i c r o a n a l y t i c a l d a t a w h i c h w e r e c o n s i s t e n t w i t h t h e i r p r o p o s e d s t r u c t u r e s . H a v i n g f i n a l l y a c h i e v e d t h e p r e p a r a t i o n o f some a l k y l e s t e r s o f sI I a n e c a r b o x y I Ic a c i d s , t h e p r o p o s e d d e o x y g e n a t i o n 121 Tab Ie XV I I. P r e p a r a t i o n o f S i I a n e c a r b o x y I Ic E s t e r s 1 4 8 . 1 5 5 - 1 5 7 R2 R2 0 « 1 Na2C03,RX , I " R1-Si-C02H R1-Si—C-OR R3 R3  132 c) R1=t-Bu, R2,R3=Me d) R1=t-Bu, R2,R3=Ph A c i d RX E s t e r Y l e l d ( % ) 132C Me I CH 3o 1 1  155 t-Bu-Si—C-OMe CH3 87 132d Mel Ph o 1 n 1 56 t-Bu —Si—C-OMe Ph 80 132c C H 3 ( C H 2 ) 7 B r 132c 148 t - B u - S i — 1 CICHz-ck / > - N 0 2 157 t-Bu CH3 CH3O - S i — O OOH^-^y NO2 C H 3 47 59 m e t h o d was t e s t e d . The d e o x y g e n a t I o n s w e r e t r i e d i n i t i a l l y w i t h o c t y l i - b u t y I d i m e t h y I s I I a n e c a r b o x y I a t e (148 ) u s i n g v a r i o u s f l u o r i d e s o u r c e s and n u c l e o p h i l e s ( T a b l e X V I I I ) . The two p o s s i b l e f r a g m e n t a t i o n p a t h w a y s o f e s t e r 148 a r e s u m m a r i z e d b e l o w . T h e u s e o f t e t r a - n - b u t y I a m m o n I urn t e t r a f I u o r o b o r a t e and l i t h i u m f l u o r i d e In a c e t o n l t r i l e r e s u l t e d in c o m p l e t e r e c o v e r y CH3 + CO + t-BuMe2SiF CH3 + CO 2 + t-BuMe2SiF 122 Tab Ie XV I I I. A t t e m p t e d D e o x y g e n a t i o n o f E s t e r 148 N u c I e o p h i I e So I v e n t T lme(h ) P r o d u c t Y l e l d ( X ) n - B u 4 N B F 4 / L I F C H 3 C N a 18 148 100 C S F C H 3 C N 17 149 100 K O B u - i THF 1 . 5 149 99 BTAF THF 3 149 91 L I F / B F 3 . E t 2 0 C H 3 C N 20 158 100 a R e a c t l o n a t r e f l u x . o f t h e s t a r t i n g e s t e r . When c e s i u m f l u o r i d e 8 5 In a c e t o -n i t r l l e , p o t a s s I urn t . - b u t o x i d e In T H F , and B T A F 8 2 In THF w e r e u s e d , an u n e x p e c t e d p r o d u c t , s l l y l e t h e r 1 4 9 . was I s o l a t e d in e x c e l l e n t y i e l d i n a l l t h r e e c a s e s . T h e u s e o f l i t h i u m f l u o r i d e and b o r o n t r i f l u o r i d e e t h e r a t e 8 4 i n a c e t o n l t r i l e g a v e a q u a n t i t a t i v e y i e l d o f 1 - o c t a n o l ( 1 5 8 ) . None o f t h e d e o x y g e n a t I o n p r o d u c t , o c t a n e ( 1 5 9 ) . was e v e r i s o l a t e d in t h e a b o v e c l e a v a g e s . T h e f o r m a t i o n o f s i l y l e t h e r 149 was r a t i o n a l i z e d a s o u t l i n e d on t h e f o l l o w i n g p a g e . I t s f o r m a t i o n i s p r o b a b l y t h e r e s u l t o f t h e p o o r s o l u b i l i t i e s o f t h e n u c l e o p h l l e s In t h e s o l v e n t s u s e d . A s m a l l amount o f n u c l e o p h i l e i n i t i a t e s t h e d e c a r b o n y I a t I on and t h e r e s u l t i n g o c t a n o l a t e a n i o n a t t a c k s t h e s i l i c o n o f a n o t h e r e s t e r m o l e c u l e g i v i n g s i l y l e t h e r 149 and 1 2 3 C H 3 0 t-Bu-Si—i [ CH3 V 14S. "Nuc CH30 I I I t-Bu-Si-I CH3 CHs t-Bu-Si-< CH3 1A2. + CO + CH3 + t-Bu-Si-Nuc + CO ° * m o r e o c t a n o l a t e . T h e p r o c e s s o f o c t a n o l a t e a n i o n a t t a c k i n g e s t e r c o n t i n u e s u n t i l a l l t h e e s t e r Is c o n s u m e d . T h i s p r o c e s s s h o u l d be c a t a l y t i c , and t h i s was d e m o n s t r a t e d when e s t e r 140d was t r e a t e d w i t h a c a t a l y t i c amount o f TBAF in THF t o g i v e an 81% y i e l d o f s i l o x a n e 1 4 1 d . Ph O Ph I 11 I t-Bu-Si—C-OSi-t-Bu 1 1 Ph Ph J4M n-Bu4NF THF Ph Ph I I t-Bu-Si-O-Si-t-Bu Ph Ph 141d O u r e a r l i e r t h e r m o d y n a m i c e x a m i n a t i o n o f t h e two p o s s i b l e c l e a v a g e p a t h w a y s i n d i c a t e d t h a t a p_-n i t r o b e n z y I e s t e r was more l i k e l y t o u n d e r g o t h e p r o p o s e d d e o x y g e n a t i o n t h a n an o c t y l e s t e r . H o w e v e r , t r e a t m e n t o f e s t e r 157 w i t h BTAF in THF CH30 t-Bu —Si—C—CCH2—<^^—NO2 CH3. 1 5 1 BTAF THF HOCH2—(£^-N02 160 1 2 4 a f f o r d e d a 96% y i e l d o f p_-n I t r o b e n z y I a l c o h o l ( 1 6 0 ) . " None o f t h e d e s i r e d d e o x y g e n a t I on p r o d u c t , p.-n I t r o t o I u e n e , c o u l d be d e t e c t e d by 1 H nmr s p e c t r o s c o p y , g a s c h r o m a t o g r a p h y , o r t h i n -l a y e r c h r o m a t o g r a p h y . T h e a b o v e e x p e r i m e n t a l r e s u l t s d e m o n s t r a t e t h a t f l u o r i d e -i n d u c e d c l e a v a g e o f sI I a n e c a r b o x y I Ic e s t e r s p r o c e e d s by f o r m a t i o n o f c a r b o n m o n o x i d e a n d an a l c o h o l I n s t e a d o f t h e d e s i r e d c a r b o n d i o x i d e and an a l k a n e . None o f t h e d e o x y g e n a -t l o n p r o d u c t s , o c t a n e and a - n I t r o t o I u e n e , c o u l d be I s o l a t e d o r d e t e c t e d In t h e c l e a v a g e s o f o c t y l i - b u t y I d i m e t h y I s I I a n e c a r -b o x y l a t e ("148) and D.-n I t r o b e n z y I i - b u t y I d i m e t h y I s I I a n e c a r b o x y -l a t e ( 1 5 7 ) . T h e f o r m a t i o n o f c a r b o n m o n o x i d e I n s t e a d o f c a r b o n d i o x i d e may be r a t i o n a l i z e d in t e r m s o f t h e p r i n c i p l e o f l e a s t m o t i o n . 1 0 0 A c c o r d i n g t o t h i s p r i n c i p l e , t h o s e e l e m e n t a r y r e a c t i o n s w i l l be f a v o r e d t h a t I n v o l v e t h e l e a s t c h a n g e In a t o m i c p o s i t i o n and e l e c t r o n i c c o n f i g u r a t i o n . T h i s p r i n c i p l e h a s b e e n u s e d t o r a t i o n a l i z e d i s p a r i t i e s b e t w e e n r a t e s and e q u i l i b r i a in c a r b a n i o n f o r m a t i o n s . F o r e x a m p l e , a l t h o u g h n i t r o e t h a n e i s a s t r o n g e r a c i d t h a n p h e n y I a c e t y I e n e by a f a c t o r o f a b o u t 1 0 1 1 , h y d r o x i d e Ions r e a c t w i t h p r o t o n s f r o m p h e n y l -a c e t y l e n e a t a r a t e o f 4 6 - 4 6 0 t i m e s t h a t w i t h w h i c h t h e y r e a c t w i t h p r o t o n s f r o m n i t r o e t h a n e . Upon d e p r o t o n a t i o n o f p h e n y I -a c e t y l e n e t h e r e i s l i t t l e c h a n g e In t h e s t r u c t u r e o f t h e r e s t o f t h e m o l e c u l e , w h e r e a s t h e d e p r o t o n a t I on o f n i t r o e t h a n e r e s u l t s in s i g n i f i c a n t s t r u c t u r a l c h a n g e s . 1 0 0 0 In t h e f I u o r I d e - I n d u c e d f r a g m e n t a t i o n o f s I I a n e c a r b o x y I i c e s t e r s , t h e f o r m a t i o n o f c a r b o n d i o x i d e r e q u i r e s a s h i f t o f t h e 1 25 C - 0 b o n d s u c h t h a t t h e O - C - 0 b o n d a n g l e b e c o m e s 1 8 0 ° , w h e r e a s no c h a n g e In a t o m i c p o s i t i o n Is n e c e s s a r y f o r t h e f o r m a t i o n o f c a r b o n m o n o x i d e . T h e r e f o r e , a l t h o u g h t h e d e o x y g e n a t I on p r o c e s s i s a p p a r e n t l y f a v o r e d t h e r m o d y n a m I c a I Iy , t h e a l t e r n a t i v e r o u t e r e s u l t i n g in d e s i l y l a t l o n and d e c a r b o n y I a t i o n was o b s e r v e d s i n c e t h i s r o u t e I n v o l v e d t h e l e a s t c h a n g e In a t o m i c p o s i t i o n s . T h i s e f f e c t d o m i n a t e s and d i r e c t s t h e r e a c t i o n e x c l u s i v e l y a l o n g p a t h w a y A . 126 2 B . 2 . 5 C o n c l u s i o n 3 - ( T r I m e t h y I s i I y I ) p r o p a n o i c a c i d (131) was p r e p a r e d in two s t e p s f r o m c h I o r o m e t h y I t r I m e t h y I s I Iane in 56% y i e l d . A c i d 131 was r e a c t e d w i t h v a r i o u s a l c o h o l s In t h e p r e s e n c e o f DCC and DMAP t o g i v e e s t e r s 129 in 84-94% y i e l d . T r e a t m e n t o f e s t e r s 129 w i t h f l u o r i d e Ion r e s u l t e d in r e c o v e r y o f t h e s t a r t i n g e s t e r s . A new m e t h o d o f p r e p a r i n g sI I a n e c a r b o x y I i c a c i d s h a s b e e n d e v e l o p e d . O z o n o l y s l s o f b I s - s I I y I a c e t y I e n e s 139 in d i c h l o r o -m e t h a n e a t - 2 4 ° C g i v e s e i t h e r t h e s y m m e t r i c s i l y l s i l a n e -c a r b o x y l a t e s 140 (80 -87% y i e l d ) o r sI I a n e c a r b o x y I i c a c i d s 132 (74 -88% y i e l d ) d i r e c t l y in c a s e s w h e r e t h e s i l y l g r o u p Is n o t s t e r i c a l l y h i n d e r e d . S i l y l sI I a n e c a r b o x y I a t e s 140 a r e r e a d i l y c o n v e r t e d by a c I d - c a t a I y z e d h y d r o l y s i s o r m e t h a n o l y s l s t o sI I a n e c a r b o x y I i c a c i d s . P r e p a r a t i o n o f a l k y l e s t e r s o f 132 v i a v a r i o u s common a c t i v a t i o n m e t h o d s was u n s u c c e s s f u l . T h e f I u o r I d e - I n d u c e d f r a g m e n t a t i o n o f e s t e r s 148 and 157 d i d n o t g i v e a n y o f t h e d e s i r e d d e o x y g e n a t i o n p r o d u c t s o c t a n e and p.-n I t r o t o I u e n e , r e s p e c t i v e l y , b u t i n s t e a d g a v e q u a n t i t a t i v e y i e l d s o f 1 - o c t a n o l and p_-n i t r o b e n z y I a l c o h o l . T h e f a i l u r e o f t h e p r o p o s e d d e o x y g e n a t I on m e t h o d i s a t t r i b u t e d t o t h e e f f e c t o f I e a s t mot I o n . 127 PART C . THERMAL REARRANGEMENT OF S I L A N E C A R B O X Y L I C ACIDS AND E S T E R S 2 C . 1 I n t r o d u c t I on 2 C . 1 . 1 I n i t i a l O b s e r v a t i o n s and P r e v i o u s Work In C h a p t e r I I , P a r t B o f t h i s t h e s i s , t h e I d e n t i t y o f t h e o z o n o l y s i s p r o d u c t f r o m b I s ( 1 - b u t y I d I p h e n y I s I I y I ) a c e t y I e n e ( 1 3 9 d ) was n o t i m m e d i a t e l y known and In o u r a t t e m p t t o i d e n t i f y t h i s p r o d u c t , we f o u n d t h a t h e a t i n g i t p r o v i d e d a new c o m p o u n d . T h e o z o n o l y s i s p r o d u c t was s u b s e q u e n t l y i d e n t i f i e d a s s i l y l s i I a n e c a r b o x y I a t e 140d and i t s t h e r m o l y s i s a f f o r d e d s i l o x a n e 141d r e s u l t i n g f r o m a r e a r r a n g e m e n t I n v o l v i n g e l i m i n a t i o n o f c a r b o n m o n o x i d e . Ph Ph ^ Ph 0 Ph I I 03 I II I t-Bu —Si-CeC—Si-t-Bu r u p i *~ t-Bu-Si — C-OSi-t-Bu Ph Ph - 2 4 ° Ph Ph 139d 140d A Ph Ph I l t-Bu-Si-OSi-t-Bu + CO I i Ph Ph 141 d T h i s t y p e o f r e a r r a n g e m e n t had b e e n b r i e f l y s t u d i e d by B r o o k in t h e 1 9 5 0 ' s . 1 3 3 T r I a r y I s I I a n e c a r b o x y I Ic a c i d s and t h e i r e s t e r s w e r e f o u n d t o d e c a r b o n y I a t e r e a d i l y a t t e m p e r a -t u r e s o f 1 2 2 - 2 3 0 ° C , t h e a c i d s r e p o r t e d t o g i v e a m i x t u r e o f t h e c o r r e s p o n d i n g s l l a n o l , s i l o x a n e , s l l y l f o r m a t e and c a r b o n 128 m o n o x i d e , w h i l e t h e e s t e r s g a v e o n l y t h e s i l o x a n e and c a r b o n m o n o x i d e . It was s u g g e s t e d t h a t t h e r e a r r a n g e m e n t Is an I n t r a m o l e c u l a r p r o c e s s o c c u r r i n g t h r o u g h a t h r e e - m e m b e r e d c y c l i c I n t e r m e d i a t e f o r m e d by a t t a c k o f o x y g e n on t h e s i l i c o n . R^=M^SjAj^_^ Ar3Si-OR + CO > S V 0 R'=ITS». " ^Ar 3Si-OC-H + Ar3Si-OH + CO In t h e c a s e o f sI I a n e c a r b o x y I Ic e s t e r s , f o r m a t i o n o f t h e S i - 0 b o n d and r e l e a s e o f c a r b o n m o n o x i d e r e s u l t s In g e n e r a t i o n o f t h e s i l o x a n e . T h e f o r m a t i o n o f some s i l y l f o r m a t e in a d d i t i o n t o t h e e x p e c t e d s i l a n o l in t h e r e a r r a n g e m e n t o f sI I a n e c a r b o x y -I i c a c i d s was a c c o u n t e d f o r by a s e c o n d o p e r a t i n g p a t h w a y i n v o l v i n g a 1 , 2 - h y d r o g e n s h i f t . H o w e v e r , o n l y g e n e r a l r e l a t i v e r a t e s o f r e a r r a n g e m e n t w e r e o b t a i n e d and no s t u d i e s on s y s t e m s o t h e r t h a n t r I a r y I s I I a n e c a r b o x y I Ic a c i d s and t h e i r e s t e r s w e r e p e r f o r m e d . We had e a r l i e r p r o p o s e d t h a t an e x c i t e d s t a t e a n h y d r i d e a n h y d r i d e was an i n t e r m e d i a t e In t h e o z o n o l y s l s o f b i s - s I IyI -a c e t y l e n e s . The s i l y l sI I a n e c a r b o x y I a t e s 140 w e r e s u g g e s t e d t o be f o r m e d a s a r e s u l t o f d e c o m p o s i t i o n o f a s h o r t - l i v e d e x c i t e d a n h y d r i d e 142 by s i l y l g r o u p m i g r a t i o n . T h e d e c o m p o s i t i o n o f 0 II Ar 3Si-C-0R Ar3Si—CT 'R' . Rz 0 O R I II II I R 1-Si-C-0-C-Si-R 1 R3 R 142. R 2 0 R2 1 ' " 1 1 R 1-Si-C-OSi- R + CO ' 3 *3 R3 R3 1ASL 129 an a n h y d r i d e t o an e s t e r and t h e t h e r m a l r e a r r a n g e m e n t o f an e s t e r t o a s i l o x a n e a r e s i m i l a r in t h a t b o t h p r o c e s s e s i n v o l v e s i l y l g r o u p m i g r a t i o n w i t h c o n c o m i t a n t l o s s o f c a r b o n m o n o x i d e . An i n v e s t i g a t i o n o f t h e e n e r g y b a r r i e r f o r t h e r e a r r a n g e m e n t o f s i l y l sI I a n e c a r b o x y I a t e s m i g h t y i e l d I n f o r m a t i o n a b o u t t h e amount o f v i b r a t i o n a l e n e r g y c o n t a i n e d in t h e e x c i t e d s t a t e a n h y d r i d e I n t e r m e d i a t e . In a d d i t i o n , t h e I n f l u e n c e o f any s t e r l c f a c t o r s In t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I i c e s t e r s c a n be p r o b e d by v a r y i n g t h e t y p e o f e s t e r a n d t h e s i z e o f t h e s l l y l m o i e t y . T h e r e f o r e , a k i n e t i c s t u d y on t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I Ic e s t e r s was u n d e r t a k e n in o r d e r t o d e t e r m i n e a c t i v a t i o n p a r a m e t e r s . 130 2 C . 1 . 2 . K i n e t i c T h e o r y K i n e t i c s Is t h e a r e a o f c h e m i s t r y c o n c e r n e d w i t h t h e r a t e s o f c h e m i c a l r e a c t i o n s and o f t h e i n f l u e n c e o f c o n d i t i o n s s u c h a s t e m p e r a t u r e and c o n c e n t r a t i o n on t h e s e r a t e s . It Is a p p r o -p r i a t e a t t h i s t i m e t o b r i e f l y p r e s e n t some b a c k g r o u n d m a t e r i a l on k i n e t i c t h e o r y w h i c h i s p e r t i n e n t t o t h e k i n e t i c e x p e r i m e n t s in P a r t s C a n d D o f t h i s t h e s i s . F o r a t h o r o u g h and d e t a i l e d t r e a t m e n t o f k i n e t i c s , r e f e r e n c e s h o u l d be made t o b o o k s w h i c h h a v e a p p e a r e d on t h i s s u b j e c t . 1 3 4 T h e m o l e c u l a r l t y o f a r e a c t i o n Is d e r i v e d f r o m t h e m e c h a n i s m o f t h e r e a c t i o n and Is d e f i n e d a s t h e number o f I n d i v i d u a l m o l e c u l e s w h i c h r e a c t in t h e s l o w e s t o r r a t e d e t e r m i n i n g s t e p o f t h e r e a c t i o n . A u n i m o l e c u l a r r e a c t i o n i n v o l v e s o n l y o n e m o l e c u l e in t h e r a t e d e t e r m i n i n g s t e p w h e r e a s a b i m o l e c u l a r r e a c t i o n I n v o l v e s two m o l e c u l e s . T h e g e n e r a l r e a c t i o n aA + bB + . . . -* p r o d u c t s h a s t h e g e n e r a l r a t e e q u a t I o n - ^ = k [ A ] x [ B ] y • • • w h e r e - d [ A ] / d t i s t h e r a t e o f d i s a p p e a r a n c e o f A a n d k Is t h e r a t e c o n s t a n t w h i c h Is a c o n s t a n t f o r t h e g i v e n r e a c t i o n a t a c e r t a i n t e m p e r a t u r e . T h e o r d e r o f a r e a c t i o n Is t h e sum o f t h e o r d e r s w i t h r e s p e c t t o e a c h c o m p o n e n t a p p e a r i n g In t h e r a t e e q u a t i o n , a n d t h e o r d e r o f e a c h c o m p o n e n t Is t h e e x p o n e n t t o w h i c h t h e c o n c e n t r a t i o n o f t h a t p a r t i c u l a r r e a c t a n t i s r a i s e d . T h u s , t h e m o l e c u l a r l t y and t o t a l o r d e r o f a r e a c t i o n a r e n o t n e c e s s a r i l y e q u a l . 131 F i r s t - o r d e r r e a c t i o n s In a f i r s t - o r d e r r e a c t i o n , t h e r a t e i s d i r e c t l y p r o p o r t i o n -a l t o t h e c o n c e n t r a t i o n o f t h e r e a c t i n g s p e c i e s . It h a s t h e r a t e e q u a t I on w h i c h upon r e a r r a n g e m e n t and I n t e g r a t i o n g i v e s e q u a t i o n 5 w h e r e [ A ] Q and [ A ] t a r e t h e i n i t i a l c o n c e n t r a t i o n o f A a n d t h e c o n c e n t r a t i o n o f A a t t i m e t , r e s p e c t i v e l y . If we s u b s t i t u t e X = f r a c t i o n a l amount o f A u n r e a c t e d f o r r . A ] - t / [ A ] 0 i n t o e q u a t i o n 5, t h e n e q u a t i o n 6 Is o b t a i n e d . T h u s , f o r a f i r s t -o r d e r r e a c t i o n , a p l o t o f - I n X a g a i n s t t i m e w i l l be l i n e a r w i t h a s i o p e o f k. S e c o n d - o r d e r r e a c t i o n s A s e c o n d - o r d e r r e a c t i o n I n v o l v i n g o n e m o l e c u l e o f e a c h o f two d i f f e r e n t r e a c t i n g s p e c i e s A and B may be r e p r e s e n t e d by (4) (5) -InX = kt (6) A + B products s o t h a t t h e r e a c t i o n r a t e i s g i v e n by (7) a s s u m i n g f i r s t - o r d e r in b o t h A and B . R e a r r a n g e m e n t o f e q u a t i o n 7 and I n t e g r a t i o n g i v e s 132 IA]„ - [B] 0 'n [AlolA], 1 " R t ( 8 ) F o r e q u a t i o n 7 w i t h [ A ] 0 = [ B ] 0 o r f o r t h e r e a c t i o n 2A p r o d u c t s , t h e r a t e e q u a t i o n b e c o m e s . m = k[Ai 2 o) dt w h i c h upon r e a r r a n g e m e n t and I n t e g r a t i o n g i v e s e q u a t i o n 10 . T h e r e f o r e , f o r a s e c o n d - o r d e r r e a c t i o n w i t h [ A ] 0 = [ B ] 0 a p l o t o f l / [ A ] t a g a i n s t t i m e w i l l be l i n e a r w i t h a s l o p e o f k and y - i n t e r c e p t o f 1 / [ A ] 0 . P s e u d o - o r d e r r e a c t i o n s If o n e o f t h e r e a c t a n t s Is In g r e a t e x c e s s o r i s r e g e n e r a t e d ( c a t a l y s t ) s o t h a t i t s c o n c e n t r a t i o n Is e s s e n t i a l l y c o n s t a n t , t h e c o n c e n t r a t i o n t e r m in t h e r a t e e q u a t i o n f o r t h a t c o m p o n e n t w i l l a p p e a r a s p a r t o f t h e r a t e c o n s t a n t u n l e s s s p e c i a l e f f o r t Is t a k e n t o s e p a r a t e i t s c o n t r i b u t i o n . F o r t h e r e a c t i o n w i t h t h e r a t e e q u a t i o n . m . k[A] x[B]y (ID w h e r e t h e c o n c e n t r a t i o n o f B Is h i g h r e l a t i v e t o t h a t o f A , t h e r a t e e q u a t i o n s i m p l i f i e s t o e q u a t i o n 12 w h e r e t h e p s e u d o - f i r s t -o r d e r r a t e c o n s t a n t k ^ = k [ B ] y . If x=1 , r e a r r a n g e m e n t and - IP = k^A]* (12) - m j £ - V 133 i n t e g r a t i o n o f e q u a t i o n 12 g i v e s e q u a t i o n 13 . T h u s , f o r a p s e u d o - f i r s t - o r d e r r e a c t i o n a p l o t o f - I n X v e r s u s t i m e w i l l be l i n e a r w i t h a s l o p e o f k^ . If t h e r e a c t i o n Is n o t f i r s t - o r d e r i n A , t h e p l o t o f - I n X v e r s u s t i m e w o u l d n o t y i e l d a s t r a i g h t I I n e . S i n c e k ^ = k [ B ] v , a p l o t o f k^ a g a i n s t [B ] w i l l be l i n e a r w i t h a s l o p e o f k w h i c h Is t h e s e c o n d - o r d e r r a t e c o n s t a n t p r o v i d i n g y=1 . The l i n e a r i t y o f a p l o t o f k^ v e r s u s [B ] s u g g e s t s a f i r s t - o r d e r d e p e n d e n c e on t h e c o n c e n t r a t i o n o f B . In a d d i t i o n , f r o m k^=k[B]Y It f o l l o w s t h a t In k ^  = In k + yln [B] (14) T h e r e f o r e , f r o m a p l o t o f In k^ a g a i n s t In [B ] t h e o r d e r w i t h r e s p e c t t o B c a n be o b t a i n e d f r o m t h e s l o p e and t h e r a t e c o n s t a n t k f r o m t h e y - i n t e r c e p t . S i m i l a r l y , f o r t h e r e a c t i o n A + B + C -*• p r o d u c t s w i t h t h e r a t e e q u a t i on dfAl d t = k[A][B][C] (15) w h e r e t h e c o n c e n t r a t i o n o f B Is h i g h r e l a t i v e t o A and C i s a c a t a l y s t , t h e r a t e e q u a t i o n s i m p l i f i e s t o dfA] ' ~ = M A ] ( 1 2 ' } w h e r e k ^ = k [ B ] [ C ] . T h u s , f r o m e q u a t i o n 13 , a p l o t o f - I n X v e r s u s t i m e w i l l be l i n e a r w i t h a s l o p e o f k^ If t h e r e a c t i o n i s f i r s t - o r d e r In A . P r o v i d i n g t h e r e a c t i o n i s f i r s t - o r d e r in B and in C , a p l o t o f k^ v e r s u s [B ] w i l l be l i n e a r w i t h a s l o p e o f k [ C ] . 134 A c t i v a t i o n p a r a m e t e r s A c c o r d i n g t o t h e E y r i n g t r a n s i t i o n s t a t e t h e o r y , t h e r e a c t a n t s f o r m an a c t i v a t e d c o m p l e x u n d e r e q u i l i b r i u m c o n d i t i o n s w h i c h u n d e r g o e s d e c o m p o s i t i o n t o t h e p r o d u c t s a c c o r d i n g t o t h e m e c h a n i s m A + B « * (AB)+ *~ products reactants activated complex F o r t h i s p r o c e s s t h e r a t e e q u a t i o n c a n be s h o w n 1 3 5 t o be rate = *f e-AG+/RT[A][B] and s i n c e t h e r a t e e q u a t i o n f o r t h e o v e r a l l r e a c t i o n Is g i v e n by rate = k[A][B] t h e n i t f o l l o w s t h a t K = K K T e-AG*/RT ( 1 6 ) h w h e r e k i s t h e r a t e c o n s t a n t , K Is t h e t r a n s m i s s i o n c o e f f i c i e n t a s s u m e d t o be 1, K I S B o l t z m a n n ' s c o n s t a n t , h Is P l a n c k ' s c o n s t a n t , T i s a b s o l u t e t e m p e r a t u r e , A G * Is t h e f r e e e n e r g y o f a c t i v a t i o n , and R i s t h e g a s c o n s t a n t . The f r e e e n e r g y o f a c t i v a t i o n A G * i s r e l a t e d t o t h e e n t h a l p y o f a c t i v a t i o n A H + and e n t r o p y o f a c t i v a t i o n A S * by e q u a t i o n 17 . E q u a t i o n 16 c a n be A G * = A H * - T A S * ( 1 7 ) A G * = 4 .575T(10 .319 - log k/T) (18) r e a r r a n g e d t o g i v e e q u a t i o n 18 and s u b s t i t u t i o n o f e q u a t i o n 17 i n t o 18 g i v e s e q u a t i o n 19 w h i c h upon r e a r r a n g e m e n t g i v e s 135 AH* - TAS* = 4.575T(10.319 - log k/T) (19) log k/T = 10.319 + A S * - — (20) y 4.575 4.575T { ' e q u a t i o n 2 0 . T h u s , f r o m a p l o t o f l o g k / T v e r s u s 1 /T t h e e n t h a l p y and e n t r o p y o f a c t i v a t i o n a r e g i v e n by e q u a t i o n s a n d 2 2 , r e s p e c t i v e l y . AH += -4.575 x slope (21) AS* = 4.575(y-intercept - 10.319) (22) T h e a b o v e d i s c u s s i o n on k i n e t i c s h a s a s s u m e d t h a t a l l r e a c t i o n s a r e h o m o g e n e o u s and n o n - r e v e r s I b I e . 136 2 C . 2 P i S C U S S | o p 2 C . 2 . 1 R e a r r a n g e m e n t o f S l I a n e c a r b o x y I i c A c i d s and E s t e r s : D e t e r m i n a t i o n o f A c t i v a t i o n P a r a m e t e r s T h e k i n e t i c s o f t h e r e a r r a n g e m e n t s w e r e d e t e r m i n e d f o r sI I a n e c a r b o x y I Ic a c i d 132d and e s t e r s 1 4 0 d . 155 . 156 . 161 . and 162 ( T a b l e X I X ) . E s t e r 140d was p r e p a r e d by o z o n o l y s l s o f b l s - s l l y l a c e t y l e n e 139d and a c i d 132d was o b t a i n e d by a c l d -c a t a l y z e d h y d r o l y s i s o f e s t e r 1 4 0 d . E s t e r s 155 . 156 . 161 . and J_6_£. w e r e p r e p a r e d f r o m t h e c o r r e s p o n d i n g s I I a n e c a r b o x y I I c a c i d s by t r e a t m e n t w i t h s o d i u m c a r b o n a t e and m e t h y l I o d i d e in DMF ( P a r t B ) . F o r t h e k i n e t i c s t u d y , t h e r e a r r a n g e m e n t s w e r e m o n i t o r e d by 1 H nmr s p e c t r o s c o p y b e c a u s e t h e r e was a s u f f i c i e n t c h e m i c a l s h i f t d i f f e r e n c e b e t w e e n t h e c h a r a c t e r i s t i c r e s o n a n c e s in t h e s t a r t i n g m a t e r i a l s and t h e p r o d u c t s t o a l l o w a c c u r a t e d e t e r m i n a t i o n s o f peak h e i g h t s o r i n t e g r a l s ( T a b l e X I X ) . o_-D I c h I o r o b e n z e n e was u s e d a s a c o n v e n i e n t s o l v e n t f o r t h e r e a r r a n g e m e n t s b e c a u s e i t c a n be r e a d i l y d r i e d , i s h i g h bo I I i n g , a n d d o e s n o t p o s s e s s 1 H nmr r e s o n a n c e s in t h e r e g i o n s o f I n t e r e s t . T h e i - b u t y I r e s o n a n c e s w e r e m o n i t o r e d f o r e s t e r 140d and a c i d 132d w h e r e a s t h e m e t h y l r e s o n a n c e s w e r e f o l l o w e d f o r m e t h y l e s t e r s 155 . 156 . 161 . and 162 . T h e r e a r r a n g e m e n t s w e r e c o n v e n i e n t l y c a r r i e d o u t In 1 H nmr t u b e s c o n t a i n i n g 3 0 - 4 5 mg o f compound in 0 . 4 0 mL o f o_-d i c h I o r o b e n z e n e . The c a p p e d t u b e was p l a c e d In a c o n s t a n t t e m p e r a t u r e o i l b a t h and p e r i o d i c a l l y It was r e m o v e d f r o m t h e o i l b a t h and immersed i m m e d i a t e l y I n t o an I c e - w a t e r b a t h t o 137 Tab Ie X I X . T h e r m a l R e a r r a n g e m e n t o f SI I a n e c a r b o x y I Ic A c i d s and E s t e r s In o_-D i c h l o r o b e n z e n e E n t r y Compound P r o d u c t C h a r a c t e r i s t I c r e s o n a n c e s (6) Compound P r o d u c t Ph O P h I II I t -Bu-Si—C-OSi - t -Bu 140d i • Ph Ph Ph 0 l H t-Bu —Si—C-OMe I Ph CH3O I 11 Ph—Si—C-OMe 1S1 CH3 O 11 P h 3 S i -C-OMe 1£2 Ph Ph I I t - B u - S i - O - S i - t - B u 141 d Ph Ph Ph I t -Bu-S i -OMe 163a Ph CH3 Ph—Si—OMe 164a CH 3 Ph 3Si-OMe 165a 1 . 0 0 , 1 . 2 1 3 . 7 3 3 . 6 8 3 . 7 8 1 . 0 4 3 . 56 3 . 5 1 3 . 73 CH 3 0 l 11 t -Bu-Si—C-OMe 155. Chb Ph I t-Bu-Si—CO2H Ph CH3 t-Bu-Si—OMe 166a Chfe Ph O I II t - B u - S i - O C - H i £ Z Ph 3 . 6 3 1 . 2 3 3 . 4 5 1 . 0 2 q u e n c h t h e r e a c t i o n . T h e p r o g r e s s o f t h e r e a r r a n g e m e n t was m o n i t o r e d by f o l l o w i n g t h e c h a n g e In t h e r e l a t i v e peak h e i g h t s o r i n t e g r a l s o f t h e c h a r a c t e r i s t i c m e t h y l o r i - b u t y l r e s o n a n c e s . D e t e r m i n a t i o n o f t h e amount o f m e t h y l e s t e r o r a c i d r e m a i n i n g d u r i n g t h e r e a r r a n g e m e n t s Is s t r a i g h t f o r w a r d b e c a u s e t h e p e a k s a r e g e n e r a l l y b a s e l i n e r e s o l v e d . A s t h e s t a r t i n g m a t e r i a l p e a k d e c r e a s e s in i n t e n s i t y t h e p r o d u c t peak i n c r e a s e s i n i n t e n s i t y by a p r o p o r t i o n a t e a m o u n t . If t h e peak i n t e g r a l s 138 o f t h e c h a r a c t e r i s t i c m e t h y l o r i - b u t y I r e s o n a n c e s o f t h e s t a r t i n g m a t e r i a l and t h e p r o d u c t a r e r e p r e s e n t e d by u and v r e s p e c t i v e l y , t h e n t h e f r a c t i o n a l amount o f s t a r t i n g m a t e r i a l r e m a i n i n g , X , Is g i v e n by x 1L_ * _ U + V A c o m p l e t e t r e a t m e n t o f k i n e t i c d a t a Is g i v e n f o r t h e r e a r r a n g e m e n t o f e s t e r 1 4 0 d . D e t e r m i n a t i o n o f t h e amount o f e s t e r 140d r e m a i n i n g Is s l i g h t l y m o r e c o m p l i c a t e d due t o o v e r l a p o f some s i g n a l s . The h i g h f i e l d p o r t i o n s o f t h e 60 MHz 1 H nmr s p e c t r u m f o r t h e t h e r m a l r e a r r a n g e m e n t o f e s t e r 140d a t 1 4 0 ° C ( r u n 1) a f t e r 10 , 2 5 , and 45 m i n u t e s a r e shown in F i g u r e 10 . T h e s i n g l e t s a t 6 1 .00 and 61 .21 a r e due t o t h e n i n e i - b u t y l p r o t o n s o f t h e s i l i c o n a t t a c h e d t o t h e e s t e r o x y g e n and t o t h e c a r b o n y l c a r b o n , r e s p e c t i v e l y . T h e s i n g l e t a t 6 1 .04 i s due t o t h e e i g h t e e n i - b u t y l p r o t o n s o f s i l o x a n e 1 4 1 d . The peak I n t e g r a l a t 6 1 . 0 4 , v , i s o b t a i n e d by s u b t r a c t i o n o f t h e peak i n t e g r a l a t 6 1 . 2 1 , u , f r o m t h e t o t a l I n t e g r a l o f t h e r e s o n a n c e s a t 6 1 . 0 0 and 6 1 . 0 4 . The f r a c t i o n o f u n r e a c t e d e s t e r , X , i s t h e n g i v e n by A l l k i n e t i c d a t a o b t a i n e d a r e shown In T a b l e s A . 1 and A . 7 . * * T a b l e s A . 1 t o A . 1 4 a r e In A p p e n d i x A . T h e s e t a b l e s c o n t a i n k i n e t i c d a t a f o r t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y -l i c a c i d s and e s t e r s . 139 — i 1 — | 1 1 r 1.5 1 1.5 1 1.5 1 (a ) (b ) ( c ) F i g u r e 10 . P a r t i a l 60 MHz 1 H nmr s p e c t r a o f r e a r r a n g e m e n t o f e s t e r 140d In o_-d i c h I o r o b e n z e n e a t 1 4 0 ° C ( r u n 1) ( a ) 10 m i n , (b) 25 m i n , ( c ) 45 m i n . T h e r e a r r a n g e m e n t i s a f i r s t - o r d e r p r o c e s s and f r o m e q u a t i o n 6 , a p l o t o f - I n X v e r s u s t i m e s h o u l d g i v e a s t r a i g h t l i n e w i t h t h e r a t e c o n s t a n t k = s l o p e . P l o t s o f - I n X v e r s u s -InX = kt (6) t i m e f o r r u n 3 a t f i v e d i f f e r e n t t e m p e r a t u r e s ( 1 1 0 ° , 1 2 0 ° , 1 3 0 ° , 1 4 0 ° , and 1 4 5 ° C ) i n d e e d g a v e s t r a i g h t l i n e s ( F i g u r e 1 1 ) . 140 F i g u r e 11 . R a t e o f r e a r r a n g e m e n t o f e s t e r 140d ( r u n 3 ) . X= f r a c t i o n o f 140d u n r e a c t e d . T = 1 1 0 ° C , a v e r a g e k= 1 . 3 9 X 1 0 - 5 S _ 1 ; 1 2 0 ° C , 3 . 7 7 x 1 0 ~ 5 S - 1 ; 1 3 0 ° C , 9 . 9 3 X 1 0 - 5 S _ 1 ; 1 4 0 ° C , 2 . 3 5 x 1 0 " 4 s - 1 ; 1 4 5 ° C , 3 . 6 9 X 1 0 - 4 S ~ 1 . -6.0 " CD O -7.0 -2.3 2.4 2.5 1/T(1/K X1000) 2.6 2.7 F i g u r e 12 . E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 1 4 0 d . A H + = 2 8 . 8 k c a l / m o l e ; A S * = - 6 . 0 c a l / m o l e - K . 141 • 130°C • 140°C A 150°C • 155°C x 160°C Time (sec x 0.001) F i g u r e 13 . R a t e o f r e a r r a n g e m e n t o f e s t e r 156 ( r u n 2 ) . X= f r a c t i o n o f 156 u n r e a c t e d . T = 1 3 0 ° C , a v e r a g e k= 1 . 5 2 x 1 0 - 5 s ~ 1 ; 1 4 0 ° C , 4 . 2 4 x 1 0 ~ 5 S - 1 ; 1 5 0 ° C , 1 . 1 7 x 1 0 - 4 S - 1 ; 1 5 5 ° C , 1 . 8 3 x 1 0 - 4 S - 1 ; 1 6 0 ° C , 2 . 8 6 x 1 0 - 4 S ~ 1 . 2.2 2.3 2.4 2.5 2.6 1/T(1/K X1000) F i g u r e 14 . E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 156 . A H 4 = 3 3 . 4 k c a l / m o l e ; A S * = 1.8 c a I / m o I e - K . 142 1.6 -i • X T 1 1 1 r 20 30 40 Time (sec x 0.001) 130°C 140°C 145°C 150°C 160°C F i a u r e 15 . R a t e o f r e a r r a n g e m e n t o f e s t e r 161 ( r u n 1 ) . X = f r a c t I on o f 1.43x10 6 S-1 7 . 0 9 x 1 0 - 6 S - 1 ; 150°C, 3 . 0 1 x 1 0 ~ 4 S - 1 161 u n r e a c t e d . T = 1 3 0 ° C , a v e r a g e k= 140°C, 4 . 1 6 X 1 0 - 5 S ~ 1 ; 145°C, 1.12x10 -A. 1 160°C, -6.0 -o -7.0 2.2 2.3 2.4 1/T(1/K X1000) 2.5 2.6 F i g u r e 16. E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 161 AH*=34.5 k c a l / m o l e ; LS*=A.3 c a l / m o l e - K . 143 F i g u r e 17. R a t e o f r e a r r a n g e m e n t o f e s t e r 162 ( r u n 1 ) . X= f r a c t i o n o f 162 u n r e a c t e d . T = 1 2 0 ° C , a v e r a g e k= 2 . 8 3 x 1 0 - 5 s ~ 1 ; 130°C, 6 . 7 1 x 1 0 ~ 5 S - 1 ; 140°C, 1 . 8 6 x 1 0 - 4 S - 1 ; 160°C, 9 . 9 8 x 1 0 ~ 4 S - 1 . -6.0 -o 2.3 T 1 1 « r 2.4 2.5 2.6 1/T(1/K X1000) l 2.7 F i g u r e 18. E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 162. AH*=29.6 k c a l / m o l e ; AS*=-4.6 c a l / m o l e - K . 144 F i g u r e 19 . R a t e o f r e a r r a n g e m e n t o f e s t e r 155 ( r u n 1 ) . X= f r a c t i o n o f 155 u n r e a c t e d . T = 1 3 0 ° C , a v e r a g e k= 6 . 6 0 x 1 0 _ 6 S - 1 ; 1 4 0 ° C , 1 . 9 8 x 1 0 ~ 5 S - 1 ; 1 5 0 ° C , 5 . 2 3 x 1 0 - 5 S - 1 ; 1 6 0 ° C , 1 . 4 7 X 1 0 ~ 4 S - 1 ; 1 7 0 ° C , 3 . 5 6 x 1 0 - 4 s - 1 . -6.0 " T 2.4 1 / T ( 1 / K X 1 0 0 0 ) 2.6 F i g u r e 2 Q . E y r i n g p l o t f o r r e a r r a n g e m e n t o f e s t e r 155 . A H * = 3 4 . 7 k c a l / m o l e ; A S * = 3 . 4 c a I / m o I e - K . 145 X c A • X T 20 30 40 Time (sec x 0.001) 100°C 110°C 120°C 130°C 135°C F i a u r e 2 1 . R a t e o f r e a r r a n g e m e n t o f a c i d 132d ( r u n 1 ) . X = f r a c t i o n o f 132d u n r e a c t e d . T = 1 0 0 ° C , a v e r a g e k= 1 . 7 3 x 1 0 - 5 s _ 1 ; 1 1 0 ° C , 5 . 7 5 X 1 0 - 5 S _ 1 ; 1 2 0 ° C , 1 . 3 6 x 1 0 - 4 s - 1 ; 1 3 0 ° C , 3 . 7 3 x 1 0 ~ 4 s - 1 ; 1 3 5 ° C , 5 . 1 4 x 1 0 - 4 s _ 1 . c o o 2.4 T • 1 1 r 2.5 2.6 2.7 1/T(1/K X1000) F i a u r e 2 2 . E y r i n g p l o t f o r r e a r r a n g e m e n t o f a c i d 1 3 2 d . A H * = 2 8 . 5 k c a l / m o l e ; AS + = - 4 . 2 c a I / m o I e - K . 146 The b e s t l e a s t - s q u a r e s f i t s w e r e drawn t h r o u g h t h e d a t a p o i n t s and t h e r a t e c o n s t a n t s w e r e o b t a i n e d f r o m t h e s l o p e s o f t h e s e l i n e s . The a v e r a g e r a t e c o n s t a n t f o r e a c h o f t h e d i f f e r e n t t e m p e r a t u r e s was d e t e r m i n e d f r o m t h e a v e r a g e o f t h r e e r u n s . F rom t h e a v e r a g e r a t e c o n s t a n t k, a p l o t o f l o g k / T v e r s u s 1 /T was o b t a i n e d ( F i g u r e 1 2 ) . The b e s t l i n e a r l e a s t - s q u a r e s f i t was drawn t h r o u g h t h e d a t a p o i n t s and f r o m e q u a t i o n s 21 and 2 2 , t h e e n t h a l p y a n d e n t r o p y o f a c t i v a t i o n f o r t h e t h e r m a l m o l e and - 6 . 0 c a l / m o l e - K , r e s p e c t i v e l y . K i n e t i c d a t a ( T a b l e s A . 2 - A . 6 and A . 8 - A . 1 2 ) f o r t h e r e a r r a n g e m e n t o f e s t e r s 166 . 161 . 162 . 155 and a c i d 132d a r e t r e a t e d s i m i l a r l y t o g i v e p l o t s o f - I n X v e r s u s t i m e and l o g k / T v e r s u s 1 /T ( F i g u r e s 1 3 - 2 2 ) . In a c o m p a r i s o n o f t h e r a t e c o n s t a n t s f o r t h e r e a r r a n g e -ment o f t h e m e t h y l e s t e r s a t 1 2 0 ° C ( T a b l e X X , e n t r i e s 3 - 6 ) , i t i s a p p a r e n t t h a t t h e r e i s a m o d e s t I n c r e a s e in t h e r a t e o f r e a r r a n g e m e n t w i t h I n c r e a s i n g number o f p h e n y l g r o u p s b o n d e d t o t h e s i l i c o n a t o m . T h i s e f f e c t may be d u e t o I n d u c t i v e s t a b i l i z a t i o n o f t h e b u i l d - u p o f n e g a t i v e c h a r g e on t h e s i l i c o n by t h e p h e n y l g r o u p s In t h e t h r e e - m e m b e r e d c y c l i c t r a n s i t i o n s t a t e . AH* = -4.575 x slope (21) AS* = 4.575(y-intercept - 10.319) (22) r e a r r a n g e m e n t o f e s t e r 140d w e r e d e t e r m i n e d t o be 2 8 . 8 k c a I / 147 T a b l e X X . R a t e C o n s t a n t s f o r R e a r r a n g e m e n t o f SI I a n e c a r b o x y I i c A c i d s a n d E s t e r s a t 1 2 0 ° C E n t r y Compound k x 1 0 5 ( s e c - 1 ) a R e l a t i v e r a t e Ph l t - B u - S i - C C f e H 132d 1 3 . 9 65 Ph Ph O Ph l u I t - B u - S i - C - O S i - t - B u H O d 3 . 7 7 18 i i Ph Ph O P h 3 S i - C - O M e 152 2 . 7 3 13 Ph o l ii 4 t - B u - S i — C - O M e 155. 0 . 5 1 0 2 . 4 i Ph CH3O I 11 5 P h - S i — C - O M e l £ i 0 . 4 6 3 2 . 2 1 CH3 CHbO I 11 6 t - B u - S i — C - O M e 155. 0 . 2 1 3 1 1 a R a t e c o n s t a n t s o b t a i n e d f r o m l e a s t - s q u a r e s l i n e o f l o g k / T v s . 1 /T p l o t s . A c o m p a r i s o n ( e n t r i e s 1 , 2 , 4 ) o f t h e r a t e c o n s t a n t s f o r t h e r e a r r a n g e m e n t o f an a c i d 1 3 2 d . a s i l y l e s t e r 1 4 0 d . and a m e t h y l e s t e r 156 shows t h e e f f e c t o f t h e g r o u p b o n d e d t o t h e c a r b o x y l o x y g e n . T h e r e a r r a n g e m e n t o f a s i l y l e s t e r Is f a s t e r t h a n a m e t h y l e s t e r I n d i c a t i n g t h a t s i z e h a s an e f f e c t . The l a r g e r , i - b u t y I d I p h e n y I s I IyI g r o u p a c c e l e r a t e s t h e r e a c t i o n and t h i s e f f e c t may p o s s i b l y be d u e t o a g r e a t e r r e l i e f o f s t e r i c s t r a i n d u r i n g t h e d e c o m p o s i t i o n o f t h e t h r e e - m e m b e r e d c y c l i c 148 t r a n s i t i o n s t a t e . However, t h e r e a r r a n g e m e n t o f a c i d 132d o c c u r s s i g n i f i c a n t l y f a s t e r t h a n f o r s i l y l e s t e r 140d and m e t h y l e s t e r 156 i n d i c a t i n g t h a t t h e r e a r r a n g e m e n t o f s i l a n e -c a r b o x y l l c a c i d s may be o c c u r r i n g by a d i f f e r e n t pathway. Indeed, t h e t h e r m a l r e a r r a n g e m e n t o f a c i d 132d a f f o r d e d s i l y l f o r m a t e 167 and not t h e c o r r e s p o n d i n g s i l a n o l . * Ph 0 I II t - B u - S i - O C - H i Ph 131 A summary o f t h e a c t i v a t i o n p a r a m e t e r s f o r t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I i c a c i d 132d and e s t e r s I40d. Tab Ie XXI. A c t i v a t i o n P a r a m e t e r s f o r R e a r r a n g e m e n t o f S i l a n e -c a r b o x y l i c A c i d s and E s t e r s In o_-D i c h I o r o b e n z e n e E n t r y Compound P r o d u c t AH* (kcaI/mo Ie) AS* (caI/mo Ie-K) A G l 2 0 ° C (kca1/mo 1e) 1 140d 141d 28.8 -6.0 31.2 2 156 163a 33 .4 1 .8 32 . 7 3 161 164a 34.5 4.3 32 . 8 4 162 165a 29 . 6 -4. 6 31.4 5 155 166a 34.7 3 .4 33 .4 6 132d 167 28.5 -4 . 2 30.2 *The t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I i c a c i d s i s d i s c u s s e d i n g r e a t e r d e t a i l i n t h e f o l l o w i n g s e c t i o n 2C.2.2. 149 1 5 5 . 1 5 6 . 1 6 1 . a n d 162 i s p r e s e n t e d In T a b l e X X I . The t h e r m a l r e a r r a n g e m e n t s h a v e a l a r g e e n t h a l p y o f a c t i v a t i o n ( a v e r a g e A H * = 32 k c a l / m o l e ) a n d o n l y a s m a l l v a r i a b l e ( p o s i t i v e / n e g a t i v e ) c o n t r i b u t i o n f r o m t h e e n t r o p y o f a c t i v a t i o n . The f r e e e n e r g y o f a c t i v a t i o n A G * a t 120°C Is v e r y s i m i l a r f o r t h e d i f f e r e n t c o m p o u n d s w i t h an a v e r a g e o f 32±2 k c a l / m o l e . I t i s i n t e r e s t i n g t o n o t e t h a t t h e f r e e e n e r g y o f a c t i v a t i o n v a l u e s a r e f a i r l y c o n s i s t e n t e v e n t h o u g h t h e r e a r e r e l a t i v e l y l a r g e v a r i a t i o n s In t h e e n t h a l p y a n d e n t r o p y o f a c t i v a t i o n v a l u e s . T h i s e f f e c t h a s a l s o b e e n o b s e r v e d by o t h e r s . 1 3 5 A 150 2C.2.2 R e a r r a n g e m e n t o f SI I a n e c a r b o x y I i c A c i d s : F o r m a t i o n o f F o r m a t e s In c o n t r a s t t o t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y -l l c e s t e r s In w h i c h o n l y t h e c o r r e s p o n d i n g s i l o x a n e was o b t a i n e d , t h e t h e r m o l y s i s o f sI I a n e c a r b o x y I Ic a c i d 132d ( T a b l e XIX, e n t r y 6) d i d not p r o d u c e t h e e x p e c t e d s i l a n o l 143d but I n s t e a d gave t h e c o r r e s p o n d i n g f o r m a t e 167 In h i g h y i e l d . Ph Ph 0 I A I II t-Bu-Si-COfcH t-Bu-Si-OC-H I I Ph Ph 132d 1£7_ T h e s e and l a t e r r e s u l t s d i f f e r s i g n i f i c a n t l y from t h o s e o f an e a r l i e r i n v e s t i g a t i o n by B r o o k 1 3 3 3 on t h e t h e r m a l r e a r r a n g e m e n t o f t r i p h e n y I s I I a n e c a r b o x y I i c a c i d (132e) l n ~ t o l u e n e . T r I p h e n y I s i IyI f o r m a t e (168) and t r i p h e n y I s I IanoI (143e) were o b t a i n e d In 55% and 27% y i e l d , r e s p e c t i v e l y . Brook s u g g e s t e d t h a t t h e r e a r e two c o m p e t i n g pathways f o r t h e r e a r r a n g e m e n t o f s i I a n e c a r b o x y I Ic a c i d s , a pathway a n a l o g o u s t o Ph 3 Si -CC2H 1222. toluene ^0 Ph3Si--<CT H J Ph3Si-0H + CO l!2e_ 0 II Ph3Si-0C-H IM. t h a t f o r sI I a n e c a r b o x y I Ic e s t e r s g i v i n g s i l a n o l 143e and an a l t e r n a t e pathway i n v o l v i n g a 1,2-hydrogen s h i f t In t h e t h r e e -membered t r a n s i t i o n s t a t e g i v i n g f o r m a t e 168. 151 The d e t e c t i o n of the formate proton by 1H nmr s p e c t r o -scopy dur i n g the t h e r m o l y s i s of a c i d 132d was precluded by the use of o_-d i ch I orobenzene as s o l v e n t due to masking by the aromatic protons of c-dIchIorobenzene. The rearrangement of a c i d 132d was t h e r e f o r e repeated In decane at 125°C, and the progress of the rearrangement was monitored by f o l l o w i n g the change In the r e l a t i v e peak areas of the formate resonance at 68.1 and the aromatic resonances at 6 7 . 2 - 7 . 8 (Table A.13). The low f i e l d p o r t i o n s of the 60 MHz 1H nmr s p e c t r a a f t e r 65, 110, and 240 minutes are shown in F i g u r e 23. The f r a c t i o n a l amount of a c i d 132d remaining, X, is given by where u Is the peak i n t e g r a l of the aromatic resonances and v i s the peak i n t e g r a l of the a l d e h y d i c resonance. A p l o t of -In X versus time ( F i g u r e 24) gave a s t r a i g h t X = u - 10v u 6 (a) (b) (c) F i g u r e 23. P a r t i a l 60 MHz 'H nmr s p e c t r a of rearrangement of a c i d 132d in decane at 125°C (a) 65 min, (b) 1 1 0 min, (c) 240 min. 152 Time (sec x 0.001) F i g u r e 25. R a t e o f r e a r r a n g e m e n t o f a c i d 132d In t o l u e n e - d 8 a t 10O°C. X = f r a c t i o n o f 132d u n r e a c t e d . k=2.36x 1 0 _ 5 s - 1 . 153 l i n e a n d t h e b e s t l i n e a r l e a s t - s q u a r e s f i t was drawn t h r o u g h t h e d a t a p o i n t s . The r a t e c o n s t a n t f o r t h e r e a r r a n g e m e n t o f a c i d 132d In d e c a n e a t 1 2 5 ° C was d e t e r m i n e d t o be 1.4 x 1 0 - 4 s e c - 1 . A f t e r t h e r e a c t i o n was c o m p l e t e d , t h e r e was I n t e r n a l a g r e e -ment b e t w e e n t h e peak a r e a s o f t h e f o r m a t e p r o t o n and t h e a r o m a t i c p r o t o n s I n d i c a t i n g t h a t t h e o n l y p r o d u c t was l i k e l y t o be f o r m a t e 167 . In a d d i t i o n , t h e Ir s p e c t r u m o f t h e r e a c t i o n s o l u t i o n showed a s t r o n g C=0 s t r e t c h a t 1720 c m - 1 . T h e 0 - H s t r e t c h i n g band In s i l a n o l 143d w h i c h o c c u r s a t 3430 c m - 1 was a b s e n t In t h i s s p e c t r u m . A t i c o f t h e r e a c t i o n s o l u t i o n however showed two UV a c t i v e s p o t s . T h e f a s t e r m o v i n g s p o t w i t h Rf 0 . 3 9 ( p e t r o l e u m e t h e r - e t h y l a c e t a t e , 9 : 1 ) i s d u e t o f o r m a t e 167 . w h e r e a s t h e s p o t w i t h Rf 0 . 2 2 was f o u n d t o be due t o s i l a n o l 1 4 3 d . We s u s p e c t t h a t t h e s i l a n o l may h a v e a r i s e n f r o m d e c o m p o s i t i o n o f t h e f o r m a t e on t h e s i l i c a g e l o f t h e t i c p l a t e u s e d in t h e a n a l y s i s . T h e t h e r m o l y s i s o f a c i d 132d was c a r r i e d o u t in a lower b o i l i n g s o l v e n t t o f a c i l i t a t e I s o l a t i o n o f t h e p r o d u c t . The r e a r r a n g e m e n t was e f f e c t e d In t o l u e n e - d g a t 1 0 0 ° C u n t i l c o m p l e t i o n a s m o n i t o r e d by 1 H nmr s p e c t r o s c o p y . T h e amount o f a c i d r e m a i n i n g , X , i s g i v e n by u + v w h e r e u a n d v a r e t h e peak h e i g h t s o f t h e i - b u t y l r e s o n a n c e s o f t h e a c i d a n d f o r m a t e , r e s p e c t i v e l y ( T a b l e A . 1 4 ) . A p l o t o f - I n X v e r s u s t i m e g a v e a s t r a i g h t l i n e ( F i g u r e 25) and t h e r a t e c o n s t a n t was d e t e r m i n e d t o be 2 . 4 x 1 0 - 5 s e c - 1 . 1 54 T h e p r o d u c t was t h e n I s o l a t e d by e v a p o r a t i o n o f t o l u e n e -d g . T h e 1 H nmr s p e c t r u m o f t h e p r o d u c t showed a s i n g l e t a t 6 8 . 2 2 c o r r e s p o n d i n g t o t h e f o r m a t e p r o t o n , a m u l t i p l e t a t 6 7 . 2 - 7 . 7 due t o t h e t e n a r o m a t i c p r o t o n s , and a s i n g l e t a t 6 1 . 1 7 d u e t o t h e n i n e i - b u t y l p r o t o n s . The Ir s p e c t r u m e x h i b i t e d a C=0 s t r e t c h a t 1720 c m - 1 . T h e s e d a t a r e p r e s e n t c l e a r e v i d e n c e f o r f o r m a t i o n o f f o r m a t e 167 . T h e r e was no s p e c t r o s c o p i c e v i d e n c e f o r t h e p r e s e n c e o f s l l a n o l . A l i m i t a t i o n o f 1 H nmr s p e c t r o s c o p y a s a m e t h o d f o r d e t e r m i n i n g t h e amount o f s l l a n o l p r o d u c e d i s t h a t i t Is n o t a c c u r a t e b e l o w a b o u t 5%. An a l t e r n a t e and m o r e p r e c i s e m e t h o d f o r d e t e r m i n i n g t h e amount o f s l l a n o l f o r m e d Is t o d e t e r m i n e t h e amount o f c a r b o n m o n o x i d e e v o l v e d s i n c e t h e f o r m a t i o n o f s i l a n o l Is a c c o m p a n i e d by t h e c o n c o m i t a n t r e l e a s e o f c a r b o n m o n o x i d e . G a s c h r o m a t o g r a p h y was u s e d f o r t h i s a n a l y s i s . A c o l u m n p a c k e d w i t h 5A m o l e c u l a r s i e v e s was e m p l o y e d . 1 3 6 N i t r o g e n and c a r b o n m o n o x i d e w e r e i n i t i a l l y I n j e c t e d s e p a r a t e l y i n t o t h e g a s c h r o m a t o g r a p h t o e s t a b l i s h t h e i r r e t e n t i o n t i m e s . T h e s e two g a s e s w e r e f o u n d t o be w e l I o s e p a r a t e d by t h e 5A m o l e c u l a r s i e v e c o l u m n a t a c o l u m n t e m p e r a t u r e o f 3 0 ° C ; t h e n i t r o g e n peak was u s e d a s an i n t e r n a l s t a n d a r d f o r d e t e r m i n i n g t h e r e l a t i v e amount o f c a r b o n m o n o x i d e f o r m e d . T h e t h e r m a l r e a r r a n g e m e n t s o f e s t e r 140d and a c i d s 132d and 132e w e r e c a r r i e d o u t w i t h 0 .0631 mmol o f compound In 0 . 4 0 mL o f o_-d i c h I o r o b e n z e n e In 1 H nmr t u b e s . The a i r a b o v e t h e s o l u t i o n was r e p l a c e d by n i t r o g e n and t h e n t h e t u b e s w e r e s e a l e d w i t h s e r u m c a p s . T h e t u b e s w e r e p l a c e d ln a c o n s t a n t 155 Ph O Ph l II I t-Bu-Si—C-OSi-t-Bu Ph Ph 140d Ph Ph I I • t-Bu-Si-OSi-t-Bu + CO I I Ph Ph 141 d CO 100% • 1 1 1 1 1 — 0 2 4 6 8 10 min. F i g u r e 2 6 . G a s c h r o m a t o g r a m o f h e a d s p a c e g a s In r e a r r a n g e m e n t o f e s t e r 1 4 0 d . 156 Ph I t-Bu-Si-CCfeH Ph 132d Ph O l ll t - B u - S i - O C - H I Ph 131 Ph l t -Bu-S i -OH + CO i CO 2.0% — r -10 mm. F i g u r e 2 7 . G a s c h r o m a t o g r a m o f h e a d s p a c e g a s In r e a r r a n g e m e n t o f a c i d 1 3 2 d . 157 Ph3Si-CX^H O ll Ph3Si-OC-H 168 Ph3Si-OH + 143e CO ro en x co ro x CO 3.4% 1 0 min. F i g u r e 2 8 . G a s c h r o m a t o g r a m o f h e a d s p a c e g a s In r e a r r a n g e m e n t o f a c I d 1 3 2 e . 158 t e m p e r a t u r e o i l b a t h and removed when t h e r e a r r a n g e m e n t s w e r e e s s e n t i a l l y c o m p l e t e . G a s c h r o m a t o g r a m s o f t h e h e a d s p a c e g a s e s w e r e o b t a i n e d ( F i g u r e s 2 6 - 2 8 ) . S i n c e t h e r e a r r a n g e m e n t o f e s t e r 140d had b e e n f o u n d t o g i v e a q u a n t i t a t i v e y i e l d o f s i l o x a n e 1 4 1 d . t h e amount o f c a r b o n m o n o x i d e e v o l v e d was a s s u m e d t o r e p r e s e n t 100% c o n v e r s i o n . By a c o m p a r i s o n o f t h e c o m p o s i t i o n o f t h e h e a d s p a c e g a s e s f o r t h e two a c i d s t o t h a t f o r e s t e r 140d a f t e r n o r m a l i z a t i o n o f t h e n i t r o g e n p e a k , t h e amount o f c a r b o n m o n o x i d e e v o l v e d In t h e r e a r r a n g e m e n t s o f a c i d s 132d and 132e was e s t i m a t e d t o be a p p r o x i m a t e l y 2 .0% and 3 .4%, r e s p e c t i v e l y ( T a b l e X X I I ) . T h e a b o v e r e s u l t s s u g g e s t t h a t t h e r e a r r a n g e m e n t o f a c i d 132d g i v e s a p r o d u c t c o m p o s i t i o n o f 98% f o r m a t e 167 and 2% s l l a n o l 143d and t h a t o f a c i d 132e g i v e s 96 .6% f o r m a t e 168 and 3.4% s i l a n o l 1 4 3 e . T h u s , t h e maximum y i e l d o f s l l a n o l f r o m Tab Ie X X I I . D e t e r m i n a t i o n o f C a r b o n M o n o x i d e by G a s C h r o m a t o g r a p h y A r e a a ( m m 2 ) N o r m a l i z e d A r e a ( m m 2 ) Compound N 2 CO N 2 CO % CO Ph o P h t-Bu-Si—C-OSi-t-Bu 14M 206 1 3 8 6 . 6 206 1 3 8 6 . 6 100 i i Ph Ph Ph I t-Bu-Si-COsH 122d 322 4 4 . 1 206 2 8 . 2 2 . 0 Ph Ph3Si-CC2H 2 9 5 6 7 . 2 206 4 6 . 9 3 . 4 132e a A r e a = p e a k h e i g h t x peak w i d t h a t 1/2 h e i g h t . 159 t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I Ic a c i d s Is a p p r o x i m a t e l y 2 -3%. T h e s e f i n d i n g s d i f f e r g r e a t l y f r o m t h o s e r e p o r t e d e a r l i e r by B r o o k . 1 3 3 a The e a r l i e r f i n d i n g o f a s i g n i f i c a n t y i e l d o f s i l a n o l Is l i k e l y an a r t i f a c t o f t h e w o r k - u p p r o c e d u r e . We b e l i e v e t h a t t h e s m a l l amount o f s i l a n o l f o r m e d In o u r e x p e r i m e n t s Is n o t t h e r e s u l t o f a c o m p e t i n g r e a r r a n g e m e n t p r o c e s s b u t r a t h e r Is t h e r e s u l t o f t r a c e s o f w a t e r in t h e r e a c t i o n m e d i u m . T h i s w a t e r c a n r e a c t w i t h t h e s i l y l f o r m a t e f o r m e d In t h e t h e r m a l r e a r r a n g e m e n t t o g i v e t h e c o r r e s p o n d i n g s i l a n o l * and f o r m i c a c i d . The l a t t e r d e c o m p o s e s u n d e r t h e r e a c t i o n c o n d i t i o n s t o a f f o r d c a r b o n m o n o x i d e and w a t e r . 1 3 7 In c o n c l u s i o n , t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y -l l c a c i d s p r o c e e d s by. o n l y o n e p a t h w a y i n v o l v i n g a 1 , 2 - h y d r o g e n s h i f t i n t h e t h r e e - m e m b e r e d c y c l i c t r a n s i t i o n s t a t e t o g i v e t h e c o r r e s p o n d i n g s i l y l f o r m a t e s . * S e e P a r t D o f t h i s t h e s i s r e g a r d i n g t h e a n a l o g o u s h y d r o l y s i s o f s i l y l e s t e r s . 160 2 C . 2 . 3 C o n c l u s i o n T h e k i n e t i c s o f t h e t h e r m a l r e a r r a n g e m e n t o f a c i d 132d and e s t e r s 140d . 155 . 156 . 161 . and 162 in o_-d i c h I o r o b e n z e n e w e r e s t u d i e d by m o n i t o r i n g t h e p r o g r e s s o f t h e r e a c t i o n s by 1 H nmr s p e c t r o s c o p y . T h e r a t e o f t h e f i r s t - o r d e r r e a r r a n g e m e n t s o f R2 0 R2 R1-Si—C-OR R1—Si-OR + CO R 3 R 3 s i I a n e c a r b o x y I Ic e s t e r s t o s l l o x a n e s w i t h c o n c o m i t a n t d e c a r -b o n y l a t i o n Is f o u n d t o be d e p e n d e n t on b o t h e l e c t r o n i c and s t e r i c e f f e c t s . T h e f r e e e n e r g y o f a c t i v a t i o n a t 1 2 0 ° C f o r t h e r e a r r a n g e m e n t s Is d e t e r m i n e d t o be 3 2 ± 2 k c a l / m o l e . By g a s c h r o m a t o g r a p h i c a n a l y s i s o f t h e h e a d s p a c e g a s and 1 H nmr and Ir d a t a o f t h e r e a c t i o n I n v o l v i n g t h e t h e r m a l r e a r r a n g e m e n t o f sI I a n e c a r b o x y I Ic a c i d s , i t was c o n c l u d e d t h a t t h e r e a c t i o n p r o c e e d s vI a o n e p a t h w a y t o g i v e t h e c o r r e s p o n d i n g s i l y l f o r m a t e s . T h i s r e s u l t i s In c o n t r a s t t o t h e t h e r m a l R2 R2 0 1 1 A 1 1 1 1 R1-Si-CC2H R 1-Si-0C-H R3 R3 r e a r r a n g e m e n t o f s I I a n e c a r b o x y I Ic e s t e r s w h i c h p r o c e e d s by a d i f f e r e n t p a t h w a y t o a f f o r d o n l y t h e c o r r e s p o n d i n g s l l o x a n e s . 161 PART D. A C I D - C A T A L Y Z E D HYDROLYSIS OF S I L Y L E S T E R S : EVIDENCE FOR THE A A L 2 MECHANISM 2D.1 I n t r o d u c t I o n 2 D . 1 . 1 A c i d - a n d B a s e - c a t a l y z e d H y d r o l y s i s o f E s t e r s T h e h y d r o l y s i s o f e s t e r s Is u s u a l l y c a t a l y z e d by a c i d s o r b a s e s . 1 3 8 In a q u e o u s b a s i c s o l u t i o n , t h e a t t a c k i n g s p e c i e s i s t h e p o w e r f u l n u c l e o p h i l e h y d r o x i d e Ion and t h e s a l t o f t h e c a r b o x y l i c a c i d i s f o r m e d . In a c i d i c s o l u t i o n , t h e c a r b o n y l o x y g e n i s i n i t i a l l y p r o t o n a t e d and Is t h e r e f o r e m o r e s u s c e p t i b l e t o a t t a c k by t h e n u c l e o p h i l e w a t e r . B o t h t h e a c i d - and b a s e - c a t a l y z e d h y d r o l y s e s a r e e q u i l i -b r i u m p r o c e s s e s . The p o s i t i o n o f t h e e q u i l i b r i u m in a c i d i c s o l u t i o n d e p e n d s on t h e r e l a t i v e c o n c e n t r a t i o n s o f w a t e r and a l c o h o l and t h u s in a q u e o u s a c i d i c s o l u t i o n , h y d r o l y s i s t o t h e 0 » i H+,H20 1 R-C-OR1 , ^ • RC0 2H + R1OH I »- RCCV + R1OH c a r b o x y l i c a c i d i s g e n e r a l l y f a v o r e d . In a q u e o u s b a s i c s o l u t i o n , h y d r o l y s i s i s e s s e n t i a l l y I r r e v e r s i b l e and t h e e q u i l i b r i u m l i e s f a r t o t h e r i g h t b e c a u s e t h e c a r b o x y l a t e a n i o n i s a much w e a k e r b a s e t h a n t h e h y d r o x i d e i o n . I n g o l d 1 3 9 h a s c l a s s i f i e d t h e a c i d - and b a s e - c a t a l y z e d h y d r o l y s e s o f e s t e r s I n t o e i g h t p o s s i b l e m e c h a n i s m s ( T a b l e X X I I I ) d e p e n d i n g on t h e f o l l o w i n g c r i t e r i a : (1) a c i d - o r b a s e -c_ 33 0 CD 3 13 3 -I 0 s. a — C — 0 a> (D «< a o> 3 -1 a o 3 w 0 3 • Cfl - CD z - i CD O s 3" -< 0 > -1 a < 3 z o to -< a O T — 1 O CO D) 00 3 Ul — - n T3 o 3 to CA} 3 CO — 01 w • r t < Basic catalysis Alkyl cleavage Acyl cleavage Acid catalysis Alkyl cleavage Acyl cleavage as > t/1 z z z > > z I I o so 6 x 90 I I o 90 3 0 I 9 0 I I o 'I' o—c.—o © I x o I I o 90 »! O l I o I o 90 I O—<"i< x I o 90 I —o© lit O z ~© 90 d z 0=n I o z o 30 I 0=0 I o o 0=' o 90 0=n I I o z + o© '11 o z o + 90 90 d x o z 90 I 0=0 I o 90 I O - O © 1 A 90 O—n—o ® x I J= o ll 90 I O - n - o xo® S i 90 I o—n ® 11 o=o I o z I I o I O - o ® x | o 90 I z o ® 90 90 o = n © file II 90 O—o® 1 i z =•11 90 I 0=0 I o z 2 9 1 . 163 c a t a l y z e d , (2) u n i m o l e c u l a r o r b l m o l e c u l a r , and (3) a c y I c l e a v a g e o r a l k y l c l e a v a g e . In t h e e i g h t m e c h a n i s t i c d e s i g n a t i o n s , t h e A d e n o t e s a c i d and t h e B b a s e c a t a l y s i s . A c y I - o x y g e n and a Iky I - o x y g e n c l e a v a g e s a r e r e p r e s e n t e d by t h e s u b s c r i p t s AC and A L , r e s p e c t i v e l y . The n u m b e r s 1 i n d i c a t e s t h e u n i m o l e c u l a r and 2 t h e b l m o l e c u l a r n a t u r e o f t h e r a t e -d e t e r m i n i n g s t e p . O f t h e e i g h t m e c h a n i s m s , a l l b u t t h e A A L 2 and B A C 1 m e c h a n i s m s h a v e b e e n d o c u m e n t e d in t h e h y d r o l y s i s o f c a r b o x y l i c e s t e r s . T h e m o s t common m e c h a n i s m s a r e t h e t e t r a -h e d r a l m e c h a n i s m s , A ^ c 2 f o r a c i d c a t a l y s i s and B A c 2 f ° r b a s e c a t a l y s i s . It i s p o s s i b l e t o s h i f t e s t e r h y d r o l y s i s away f r o m t h e n o r m a l A A Q 2 and B A Q 2 m e c h a n i s m s by s t r u c t u r a l c h a n g e s in t h e s u b s t r a t e . A c i d - c a t a l y z e d h y d r o l y s i s o f t e n s h i f t s t o t h e A A L 1 m e c h a n I s m when R 1 I s t e r t i a r y a l k y l , a l l y l , o r b e n z y I . Th i s s h i f t Is d u e t o t h e s t a b i l i t y o f t h e c a r b o n i u m Ion f o r m e d a s a r e s u l t o f t h e a I k y I - o x y g e n c l e a v a g e . An e x a m p l e o f t h i s m e c h a n i s m i s t h e h y d r o l y s i s o f b e n z y l e s t e r s . A l t h o u g h b e n z y l 0 + 0 H 169 slow 164 a c e t a t e (169 ) h y d r o I y z e s by t h e A A c 2 m e c h a n i s m in d i l u t e s u l f u r i c a c i d , t h e m e c h a n i s m c h a n g e s t o A ^ L 1 , n c o n c e n t r a t e d s u l f u r i c a c I d . 1 4 0 T h e B A I_1 m e c h a n i s m Is a c t u a l l y u n c a t a l y z e d and l i k e t h e A A|_1 m e c h a n i s m , o c c u r s o n l y w i t h R 1 t h a t g i v e s s t a b l e c a r b o c a t I o n s . In a d d i t i o n , t h e B A i _ 1 m e c h a n i s m o c c u r s o n l y In n e u t r a l o r w e a k l y b a s i c s o l u t i o n s w h e r e t h e r a t e o f a t t a c k by h y d r o x i d e Ion i s s l o w e d t o an e x t e n t t h a t t h e n o r m a l l y s l o w u n i m o l e c u l a r c l e a v a g e d o m i n a t e s . An e x a m p l e o f t h i s m e c h a n i s m i s t h e h y d r o l y s i s o f e s t e r 170 in a q u e o u s s o d i u m c a r b o n a t e . 1 4 0 b 0 _ "020—^^C-OCHCH=CHCI-b S ' ° W * " Q j C — C O T + CH3CHCH=CHCH3 CHaCHCH^HCHg — CH3CHCH=CHCH3 O H + OH2 T h e A A C 1 m e c h a n i s m o p e r a t e s o n l y w h e r e R i s v e r y b u l k y a n d o n l y in I o n i z i n g s o l v e n t s . T h i s m e c h a n i s m i s t h e r e s u l t of s t e r l c h i n d r a n c e t o w a r d n u c l e o p h i l i c a t t a c k a t t h e c a r b o n y l c a r b o n a s w e l l a s d e c r e a s e d a v a i l a b i l i t y o f n u c l e o p h i l i c w a t e r in v e r y s t r o n g l y a c i d i c s o l u t i o n s . T h e A A c 1 m e c h a n i s m h a s b e e n d e m o n s t r a t e d f o r 2 , 4 , 6 - t r I m e t h y I b e n z o I c e s t e r s 171 in s t r o n g s u l f u r i c a c i d . 1 4 1 T h e B A i _ 2 m e c h a n i s m i s v e r y r a r e a s i t r e q u i r e s h y d r o x i d e i o n t o a t t a c k an a l k y l c a r b o n when an a c y I c a r b o n i s a l s o a v a i l a b l e . T h i s m e c h a n i s m i s l i k e l y t o o c c u r w h e r e R i s v e r y b u l k y t h u s s t e r i c a l l y h i n d e r i n g n u c l e o p h i l i c a t t a c k a t t h e 165 c a r b o n y l c a r b o n and w h e r e R 1 Is v e r y s m a l l . An e x a m p l e o f t h e B A 1 _2 m e c h a n i s m Is In t h e a l k a l i n e h y d r o l y s i s o f m e t h y l 2 , 4 , 6 - t r I - i - b u t y I b e n z o a t e ( 1 7 2 ) . 1 4 2 t-Bu 0 t-Bu + MeOH 122. The a b o v e d e s c r i p t i o n s a r e a p p l i c a b l e t o s o l u t i o n r e a c t i o n s . In t h e g a s p h a s e , t h e r e a c t i o n p r o d u c t s c a n be d i f f e r e n t t h a n t h o s e o b s e r v e d In s o l u t i o n . 1 4 3 F o r e x a m p l e , t h e g a s p h a s e r e a c t i o n o f d e u t e r i o m e t h o x I d e a n i o n w i t h m e t h y l b e n z o a t e (±22.) y i e l d e d b e n z o a t e a n i o n and e t h e r 174 . 1 4 3 a T h e s e p r o d u c t s a r e t h o s e t h a t w o u l d be e x p e c t e d f r o m a B A |_2 0 _ C-OMe + CD3Q- - ^"^-CCfe" + CD3OCH3 122, ^ 166 m e c h a n i s m , b u t in s o l u t i o n t h e r e a c t i o n a c t u a l l y p r o c e e d s by t h e B A C 2 m e c h a n i s m . T h e two m e c h a n i s m s t h a t h a v e n o t b e e n d o c u m e n t e d in s o l u t i o n a r e t h e B ^ c 1 and A A L 2 m e c h a n i s m s . T h e B A C 1 m e c h a n i s m Is an u n c a t a l y z e d S|sj 1 p r o c e s s r e s u l t i n g In a c y I -o x y g e n c l e a v a g e . T h e r e q u i r e m e n t s f o r s u c h a m e c h a n i s m w o u l d 0 0 R - C - O R 1 S ' ° W » R - C + + " O R 1 " 0 H - RC02H + " O R 1 RC02" + H O R 1 I n c l u d e : (1 ) v e r y b u l k y R g r o u p t o p r e v e n t a t t a c k o f h y d r o x i d e i o n a t t h e c a r b o n y l c a r b o n , ( 2 ) b u l k y R 1 g r o u p t o p r e v e n t a t t a c k o f h y d r o x i d e i o n a t R 1 , (3 ) s t a b i l i z e d _ 0 R 1 , and (4) u s e o f an i o n i z i n g s o l v e n t t o p r o m o t e i o n i z a t i o n . T h e A A | _ 2 m e c h a n i s m i n v o l v e s a t t a c k o f H 2 O a t R 1 i n an S(sj2 r e a c t i o n r e s u l t i n g i n a Iky I - o x y g e n c l e a v a g e . In 0 +0H 0 " 1 " 1 " + 1 R— 0— OR + H + 4 R — C - O R 1 4 r R - C - O R 1 1 H HgO slow H + + R10H * h R10H2 + RC02H d e s i g n i n g an e s t e r t h a t w o u l d u n d e r g o an A ^ L 2 h y d r o l y s i s m e c h a n i s m , i t s h o u l d be e x p e c t e d t o p o s s e s s t h e f o l l o w i n g c h a r a c t e r i s t i c s : (1) a b u l k y R g r o u p t o p r e v e n t a t t a c k o f w a t e r a t t h e c a r b o n y l c a r b o n a n d ( 2 ) h i g h a f f i n i t y o f w a t e r f o r R 1 o v e r t h e c a r b o n y l c a r b o n . 1 6 7 2 D . 1 . 2 The AAI_2 M e c h a n i s m : P r e v i o u s Work To d a t e t h e r e h a v e b e e n no r e p o r t s o f a c a r b o x y l i c e s t e r h y d r o l y s i s p r o c e e d i n g by t h e A ^ L 2 m e c h a n i s m . 1 3 8 H o w e v e r , t h e r e h a s b e e n a s t u d y on t h e h y d r o l y s i s o f an a n a l o g o u s s y s t e m 1 4 4 and a l s o a s t u d y t o d e t e r m i n e t h e l i k e l i h o o d o f t h e A A L 2 m e c h a n i s m u s i n g a mode l e s t e r s y s t e m . 1 4 5 T h e a c i d - c a t a l y z e d h y d r o l y s i s o f I m i d a t e e s t e r s 1 7 5 p r o c e e d s t h r o u g h a t e t r a h e d r a l i n t e r m e d i a t e t o g i v e an e s t e r and a m i n e . 1 4 6 In m o r e c o n c e n t r a t e d a c i d s , b e n z i m i d a t e s h a v e OR1 R—C=NR 2 + H + 1Z5. OR1 OR1 •!+ o H p • 2 R—0=NHR 4 R—C—NHR I + 0H2 + C H OR1 R—C—OR1 + R 2 NH 2 k R—C—NH 2 R 2 li OH 0 R - C - O R 1 + H 4 b e e n f o u n d t o g i v e some a m i d e and a l c o h o l 1 4 7 , and t h i s o b s e r v a t i o n s u g g e s t s an a l t e r n a t e h y d r o l y s i s p a t h w a y e x i s t s . 1 4 8 168 A s t u d y o f t h e a c i d - c a t a l y z e d h y d r o l y s i s o f 2 , 6 - d i m e t h y I -b e n z i m i d a t e e s t e r s 176 showed t h a t a p a t h a n a l o g o u s t o t h e A A | _ 2 m e c h a n i s m was o p e r a t i v e in t h e s e t y p e s o f s y s t e m s . 1 4 4 T h e r e Is v i r t u a l l y q u a n t i t a t i v e c o n v e r s i o n o f t h e s e e s t e r s t o + ROH 176 R=Me,Et 177 2 , 6 - d I m e t h y I b e n z a m I d e (177) and t h e c o r r e s p o n d i n g a l c o h o l i n d i c a t i n g o n l y o n e m e c h a n i s t i c p a t h w a y . T h e c l e a v a g e o f t h e a l k y l - o x y g e n bond was d e m o n s t r a t e d by t h e h y d r o l y s i s o f u n l a b e l l e d i m i d a t e s In 1 s O - I a b e I Ied w a t e r w h i c h g a v e u n l a b e l l e d 2 , 6 - d I m e t h y I benzam I de . O t h e r e v i d e n c e f o r an A A |_2 t y p e m e c h a n i s m I n c l u d e t h e o b s e r v a t i o n t h a t t h e r a t e d e c r e a s e s a s t h e a c i d i t y i s I n c r e a s e d . T h i s h a s b e e n e x p l a i n e d by c o n s i d e r i n g t h a t i m i d a t e e s t e r s a r e f u l l y p r o t o n a t e d e v e n in d i l u t e a c i d s and I n c r e a s e s in a c i d i t y m e r e l y s e r v e t o d e c r e a s e t h e amount o f n u c l e o p h i l i c w a t e r . T h e I m i d a t e e s t e r s a b o v e d i f f e r f r o m c a r b o x y l i c e s t e r s by h a v i n g a c a r b o n d o u b l e b o n d e d t o n i t r o g e n I n s t e a d o f t o o x y g e n and t h u s r e p r e s e n t o n l y m o d e l s f o r c a r b o x y l i c e s t e r s y s t e m s . In a m o r e r e c e n t s t u d y 1 4 5 , t h e i m p o r t a n c e o f t h e A A L 2 m e c h a n i s m a s c o m p a r e d t o t h e n o r m a l A A Q2 m e c h a n i s m was e v a l u a t e d u s i n g d l m e t h o x y - 2 , 4 , 6 - t r I m e t h y I p h e n y I c a r b o n I urn Ion (123.) a s a mode l f o r c a r b o n y l p r o t o n a t e d e s t e r s . S i n c e t h e a Ikoxy g r o u p s a r e p r i m a r y m e t h y l s , t h e r e i s I i t t l e p o s s i b i I I ty f o r u n i m o l e c u l a r r e a c t i o n s . The a c i d - c a t a l y z e d h y d r o l y s i s o f 169 t h i s i o n g i v e s t h e e x p e c t e d p r o d u c t s o f m e t h y l m e s i t o a t e (171a ) and m e t h a n o l f r o m an S|\j2 r e a c t i o n . M a s s s p e c t r a l a n a l y s i s o f t h e h y d r o l y s i s p r o d u c t s o f 178 In 1 8 0 - 1 a b e I Ied w a t e r p e r m i t s a d i r e c t c o m p a r i s o n o f t h e two r o u t e s . A I k y I - o x y g e n c l e a v a g e was f o u n d t o o c c u r t o an e x t e n t o f 18% i n 19.4% H2SO4 b u t i n c r e a s e d t o 75% In s t r o n g e r ( 63 .8% H2SO4) a c i d . O t h e r e v i d e n c e f o r an A ^ L 2 t y p e m e c h a n i s m I n c l u d e s t h e n e g a t i v e e n t r o p y o f a c t i v a t i o n ( - 2 0 . 7 c a l / m o l e - K w i t h 31.4% H2SO4) and t h e I n v e r s e d e p e n d e n c y on a c i d i t y o f t h e r a t e s f o r b o t h p r o c e s s e s , b o t h b e i n g i n d i c a t i v e o f b i m o l e c u l a r p r o c e s s e s I n v o l v i n g w a t e r . 1 4 4 F o r i o n 178 . t h e r e i s a f i n e l y b a l a n c e d c o m p e t i t i o n b e t w e e n t h e a l k y l - o x y g e n and a c y I - o x y g e n c l e a v a g e r o u t e s . T h u s , u n h i n d e r e d e s t e r s do n o t d e a l k y l a t e b e c a u s e o f t h e r a p i d w a t e r a t t a c k a t t h e c a r b o n y l c a r b o n w h e r e a s h i n d e r e d e s t e r s do n o t d e a l k y l a t e b e c a u s e o f a c y I I urn i o n f o r m a t i o n . 1 4 9 T h e s t u d y c o n c l u d e d t h a t " t h e A ^ | _ 2 r e a c t i o n w i l l n o t be o b s e r v e d , e x c e p t p e r h a p s f o r t h e c a s e o f a s t e r l c a l l y c o n g e s t e d e s t e r w h i c h w o u l d g i v e a d e s t a b i l i z e d a c y I I urn I o n . " 1 4 5 170 2 D . 1 . 3 P r o p o s e d I n v e s t i g a t i o n D e s p i t e McCIe I l a n d ' s f i n d i n g s 1 4 5 , we n o t i c e d f r o m o u r e a r l i e r work ( C h a p t e r I I , P a r t B o f t h i s t h e s i s ) on t h e a c i d -c a t a l y z e d h y d r o l y s i s o f s i l y l s I I a n e c a r b o x y I a t e s 140 t h a t t h e s e e s t e r s m i g h t be u n d e r g o i n g h y d r o l y s i s by t h e A A | _ 2 m e c h a n i s m . S i l y l sI I a n e c a r b o x y I a t e s p o s s e s s a somewhat h i n d e r e d c a r b o n y l R2 0 R I .1 I R1-Si—C-OSi-R1 140 H2SO4 THF-H20 R R* R1-Si-C0i>H + R 1-Si-0H R3 R3  132 1_43_ c a r b o n t h u s r e t a r d i n g a c y I a t t a c k . M o r e I m p o r t a n t l y , t h e y c o n t a i n a s i l i c o n a tom a t t h e Q - a l k y l p o s i t i o n . W a t e r and o t h e r o x y g e n n u c l e o p h i l e s w o u l d be e x p e c t e d t o p r e f e r e n t i a l l y a t t a c k t h e s i l i c o n a t o m , d u e t o t h e s t r o n g a f f i n i t y o f o x y g e n n u c l e o p h i l e s f o r s i l i c o n , r e s u l t i n g in s i I y I - o x y g e n c l e a v a g e . * T h e m e t h o d s o f p r e p a r a t i o n and r e a c t i o n s o f s i l y l c a r b o x y -l a t e s h a v e b e e n r e v i e w e d . 1 5 0 In g e n e r a l , o x y g e n a n d n i t r o g e n n u c l e o p h i l e s a t t a c k a t s i l i c o n 1 5 1 w h e r e a s c a r b o n n u c l e o p h i l e s a t t a c k a t t h e c a r b o n y l c a r b o n . 1 5 2 T h e r e h a v e b e e n e x a m p l e s o f s i l y l e s t e r h y d r o l y s e s In n a t u r a l p r o d u c t s s y n t h e s i s 1 5 3 ' 1 5 4 b u t no c o m m e n t s w e r e made a b o u t t h e m e c h a n i s m i n v o l v e d . As f a r * A I k y I - o x y g e n c l e a v a g e i s r e g a r d e d a s t h e a n a l o g o u s s i IyI — o x y g e n c l e a v a g e In c a s e s w h e r e t h e e s t e r c o n t a i n s a s i I i c o n a t t h e Q - a l k y l p o s i t i o n . 171 a s we a r e a w a r e , t h e r e h a s n o t b e e n a c o m p r e h e n s i v e s t u d y on t h e a c i d - c a t a l y z e d h y d r o l y s i s o f s l l y l c a r b o x y l a t e s , a l i k e l y c a n d i d a t e f o r t h e A A | _ 2 h y d r o l y s i s m e c h a n i s m . T h e r e f o r e , an i n v e s t i g a t i o n o f t h e a c i d - c a t a l y z e d h y d r o l y s i s o f t h e s e s y s t e m s was u n d e r t a k e n in o r d e r t o d e t e r m i n e t h e m e c h a n i s m o f t h e h y d r o l y s i s a s w e l l a s t o d e t e r m i n e t h e a c t i v a t i o n p a r a m e t e r s f o r t h e h y d r o l y s i s . 172 2 D . 2 D l s c u s s i o n 2 D . 2 . 1 A c i d - c a t a l y z e d M e t h a n o l y s l s o f S l l y l S i I a n e c a r b o x y -l a t e s : C h e m i c a l E v i d e n c e f o r t h e A A |_2 M e c h a n i s m A s m e n t i o n e d e a r l i e r , o u r I n t e r e s t in t h e a r e a o f a c i d -c a t a l y z e d h y d r o l y s i s o f s l l y l c a r b o x y l a t e s stemmed f r o m t h e p r e l i m i n a r y r e s u l t In t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I -d I m e t h y I s I IyI i - b u t y I d I m e t h y I s I I a n e c a r b o x y I a t e ( 1 4 0 c ) . The h y d r o l y s i s o f t h e s e t y p e s o f e s t e r s was I n v e s t i g a t e d i n i t i a l l y b e f o r e m o v i n g on t o t h e s t r u c t u r a l l y s i m p l e r s i l y l c a r b o x y l a t e s . D i s t i n c t i o n b e t w e e n t h e two a c y I - o x y g e n c l e a v a g e p a t h w a y s ( A A C 1 a n d A A C 2 ) a n d t n e t w o a Iky I - o x y g e n c l e a v a g e p a t h w a y s ( A A L 1 a n d A A L 2 ) ( T a b l e X X I I I ) c o u l d In p r i n c i p l e be a c h i e v e d by p e r f o r m i n g t h e h y d r o l y s i s w i t h 1 8 0 - I a b e I Ied w a t e r . A c y I - o x y g e n c l e a v a g e w o u l d r e s u l t in t h e l a b e l a p p e a r i n g i n t h e a c i d w h e r e a s a Iky I - o x y g e n c l e a v a g e w o u l d l e a d t o I n c o r p o r a t i o n o f t h e l a b e l In t h e a l c o h o l . H o w e v e r , c o m p l i c a t i o n s w i l l a r i s e i f t h e u n l a b e l l e d a c i d and a l c o h o l c o u l d a l s o e x c h a n g e w i t h t h e l a b e l l e d w a t e r . T h e e x c h a n g e b e t w e e n c a r b o x y l i c a c i d s and w a t e r Is known t o be a c i d -c a t a l y z e d . 1 5 5 F o r e x a m p l e , a c e t i c a c i d u n d e r w e n t 4 .6% e x c h a n g e a f t e r s i x t e e n h o u r s a t 2 5 ° C w i t h no a d d e d m i n e r a l a c i d ( l e . t h e e x c h a n g e p r o c e s s i s a u t o c a t a I y t i c ) and t h e r a t e o f e x c h a n g e i n c r e a s e d s t e a d i l y a s t h e pH was l o w e r e d . 1 5 5 b In a d d i t i o n , 1 8 0 - l a b e l l e d w a t e r i s e x p e n s i v e and h i g h i n c o r p o r a t i o n l e v e l s a r e g e n e r a l l y r e q u i r e d f o r a c c u r a t e m e a s u r e m e n t s . A m o r e c o n v e n i e n t m e t h o d o f d i s t i n g u i s h i n g b e t w e e n a c y I -173 o x y g e n and a I k y I - o x y g e n c l e a v a g e s w o u l d be t o p e r f o r m a c i d -c a t a l y z e d m e t h a n o l y s i s and d e t e r m i n e t h e c o m p o s i t i o n o f t h e f o r m e d p r o d u c t s . A t t a c k o f m e t h a n o l a t t h e s i l i c o n a tom b o n d e d t o t h e c a r b o x y l o x y g e n o f s l l y l sI I a n e c a r b o x y I a t e s 140 w o u l d g i v e sI I a n e c a r b o x y I Ic a c i d s 132 and s i l o x a n e s ( P a t h A ) , w h e r e a s a t t a c k a t t h e c a r b o n y l c a r b o n w o u l d g i v e m e t h y l e s t e r s and s i I a n o I s 143 ( P a t h B ) . T h u s , t h e n a t u r e o f t h e p r o d u c t s i s d i a g n o s t i c o f t h e p r o c e s s i n v o l v e d . R2 0 R2 1 ' " 1 1 R1-Si—C-OSi-R1 R3 R3 HQ. H\MeOH Path A (AA L) hT.MeOH Path B (AA C) R1-Si-C02H + 132 R2 0 1 1 11 R -Si—C-OMe + R3 R1-Si-0Me I _ I -Si-OH '# 1A2. I n i t i a l e x p e r i m e n t s w e r e c o n t r o l s t o d e t e r m i n e t h e e a s e o f e s t e r I f i c a t I on o f i - b u t y I d I p h e n y I s I I a n e c a r b o x y I Ic a c i d (132d) . T h e e s t e r If I c a t I on o f t h i s a c i d Is a p o t e n t i a l p r o b l e m b e c a u s e i f t h i s o c c u r s t o a s i g n i f i c a n t e x t e n t , o n e w o u l d n o t be a b l e t o d i s t i n g u i s h b e t w e e n p a t h s A and B s i n c e a n y a c i d f o r m e d v i a p a t h A w o u l d be c o n v e r t e d t o m e t h y l e s t e r w h i c h Is a p a t h B p r o d u c t . T r e a t m e n t o f a c i d 132d w i t h a c i d i c m e t h a n o l a t room t e m p e r a t u r e f o r f o u r t e e n h o u r s r e s u l t e d In a v i r t u a l l y q u a n t i -t a t i v e r e c o v e r y o f t h e s t a r t i n g a c i d ( T a b l e X X I V , e n t r y 1 ) . T h u s , t h e e s t e r I f i c a t I on o f a c i d 132d i s n o t a p r o b l e m i f t h e Table XXIV. Acid-catalyzed Methanolysis of Si 1anecarboxy!ic Esters Ph Ph 0 Ph C H 3 I I II I l possible products: t -Bu-Si -CCfcrl t - B u - S i -C - O M e t -Bu-Si-OMe t-Bu-Si-OMe Ph Ph Ph C H 3 122A 155. lfiaa JLSfia Concentration Catalyst MeOH Time9 Yield(%)b  Entry Substrate (M) (equiv) (equiv) Solvent (h) 132d 156 163a or 166a 1 132d 0.125 H2S04(0.10) 198 MeOH 14 98 0 0 2 179 0.125 H2S04(0.10) 198 MeOH 1.25 96 0 o c 3 140d 0.10 H2S04(0.10) 148 Me0H/CH2Cl2 46 98 l d 94 4 140d 0.20 p-Ts0H(0.10) 10 MeOH/THF 40 3 e 0 0 5 140d 0.20 p-Ts0H(0.10) 50 MeOH/THF 96 96 0 63 Reactions were performed at room temperature. DIsolated yields. Lost due to volatil ity. Formation probably due to subsequent esterification of acid 132d. eRecovered 97% of ester 140d. 175 a c i d - c a t a l y z e d m e t h a n o I y s I s i s p e r f o r m e d a t room t e m p e r a -t u r e . * T h e a c i d - c a t a l y z e d m e t h a n o l y s l s o f i - b u t y I d i m e t h y I s i IyI i - b u t y I d I p h e n y I s I I a n e c a r b o x y I a t e (179) p r o c e e d e d r e a d i l y a t room t e m p e r a t u r e t o a f f o r d a 96% y i e l d o f a c i d 132d ( e n t r y 2 ) . Due t o i t s h i g h v o l a t i l i t y , t h e o t h e r b y - p r o d u c t , s i l o x a n e 1 6 6 a . was l o s t on w o r k - u p . S i n c e t h e r e was no m e t h y l e s t e r 156 d e t e c t e d , It was c o n c l u d e d t h a t t h e m e t h a n o l y s l s o f e s t e r 179 d i d n o t i n v o l v e a t t a c k o f m e t h a n o l on t h e c a r b o n y l c a r b o n . Ph 0 CH3 Ph 0 Ph I ii I I II I t-Bu-Si—C-OSi-t-Bu t-Bu-Si—C-OSi-t-Bu I i > • Ph CHg Ph Ph 179 140d T h e m e t h a n o l y s l s o f t h e m o r e h i n d e r e d s i l y l e s t e r 140d was p e r f o r m e d a t room t e m p e r a t u r e ( e n t r y 3) and a 98% y i e l d o f a c i d 132d was o b t a i n e d a l o n g w i t h a 94% y i e l d o f s i l o x a n e 163a a g a i n i n d i c a t i n g t h a t t h e m e t h a n o l y s l s p r o c e e d e d by a s i l y l - o x y g e n c l e a v a g e m e c h a n i s m . T h e v e r y s m a l l amount o f m e t h y l e s t e r 156 ( c a . 1%) i s o l a t e d was most l i k e l y d u e t o s u b s e q u e n t e s t e r i f I c a -t i o n o f a c i d 132d c o n s i d e r i n g t h e l o n g r e a c t i o n t i m e . When t h e a c i d c a t a l y s t was c h a n g e d f r o m s u l f u r i c a c i d t o D_-to I u e n e -s u l f o n l c a c i d , t h e m e t h a n o l y s l s a l s o p r o c e e d e d s m o o t h l y t o g i v e an e x c e l l e n t y i e l d o f a c i d 132d ( e n t r y 5 ) . *When t h e m e t h a n o l y s l s o f a c i d 132d was p e r f o r m e d a t r e f l u x f o r two h o u r s , a m i x t u r e o f 68% a c i d 1 3 2 d . 21% m e t h y l e s t e r 156. and 11% s i l o x a n e 163a was o b t a i n e d . 176 The a b o v e r e s u l t s o f t h e a c I d - c a t a I y z e d m e t h a n o l y s i s o f s l l y l sI I a n e c a r b o x y I a t e s i n d i c a t e t h a t s i l y l - o x y g e n c l e a v a g e i s o c c u r r i n g and h e n c e t h e l i k e l y m e c h a n i s m s a r e e i t h e r t h e AA|_1 o r t h e A A i_2 r o u t e s . T h e s e two m e c h a n i s m s a r e b r i e f l y o u t l i n e d b e l o w f o r t h e m e t h a n o l y s i s o f e s t e r 179 . C h e m i c a l e v i d e n c e f a v o r s s i l y l - o x y g e n c l e a v a g e f o r s l l y l sI I a n e c a r b o x y -l a t e s b u t o t h e r e x p e r i m e n t s a r e n e e d e d t o d e t e r m i n e If s i l y l c a r b o x y l a t e s r e a c t s i m i l a r l y and t h e s e e x p e r i m e n t s a r e d i s c u s s e d b e l o w . Ph o CH 3 I I I I t-Bu-Si—C-OSi-t-Bu I i Ph CH3 17_9_ t A A L 1 A A L2 Ph+OH CH3 I I I I t-Bu-Si— C-OSi-t-Bu I i Ph CH3 Ph CH3 I I t-Bu-Si—COfeH + t-Bu-Si + 1 1 Ph CH3 132d MeOH CH 3 t-Bu-Si-OMe 1 CH 3  166a Ph+OH Chb I 11 1 t-Bu-Si—C— OSi-t-Bu I 1 Ph CHs] MeOH Ph 1 t-Bu-Si—COfeH + Ph 13 2cJ CH3 t-Bu-Si—OMe 1 CH3 166a 177 2 D . 2 . 2 A c i d - c a t a l y z e d A I c o h o I y s i s o f S i l y l C a r b o x y l a t e s We n e x t I n v e s t i g a t e d t h e h y d r o l y s i s o f t h e s t r u c t u r a l l y s i m p l e r s i l y l c a r b o x y l a t e s w h e r e t h e e f f e c t o f t h e b u l k y s l l y l g r o u p a d j a c e n t t o t h e c a r b o n y l c a r b o n Is now a b s e n t . A s w i t h t h e s i l y l sI I a n e c a r b o x y I a t e s , t h e n a t u r e o f t h e p r o d u c t s In t h e a c i d - c a t a l y z e d a l c o h o l y s l s o f s i l y l c a r b o x y l a t e s 180 w o u l d i n d i c a t e i f s i l y l - o x y g e n o r a c y I - o x y g e n c l e a v a g e o c c u r s . 0 * " 1 1 R-C-OSi-R1 1 8 0 H+,R4OH (A A L) H+,R4OH ( A A c ) R-CO2H + O 11 R^Si-OR4 1 _ I R-C-OR4 + R1-Si-OH 1. A s i l y l c a r b o x y l a t e was r e q u i r e d In w h i c h t h e s i l y l g r o u p i s n o t t o o l a b i l e In o r d e r t o f a c i l i t a t e l a t e r k i n e t i c s t u d i e s and y e t n o t t o o h i n d e r e d f o r n u c l e o p h l l e s t o a t t a c k . In a d d i t i o n , t h e c a r b o n y l c a r b o n must n o t be s t e r i c a l l y h i n d e r e d s u c h t h a t t h e r e i s some b i a s f o r s i l y l - o x y g e n c l e a v a g e o v e r a c y l - o x y g e n c l e a v a g e . i - B u t y I d I m e t h y I s I IyI pheny I a c e t a t e (152) was c h o s e n a s It s a t i s f i e s t h e a b o v e two r e q u i r e m e n t s and in a d d i t i o n , i t p o s s e s s e s a c h r o m o p h o r e f o r e a s y c h r o m a t o g r a p h i c d e t e c t I o n . O CH3 /=\ " ' ^y-CH2C-OSi-t-Bu 132. CH3 178 A g a i n , t h e i n i t i a l e x p e r i m e n t s c o n d u c t e d w e r e t o d e t e r m i n e t h e e a s e o f e s t e r If I c a t I on o f p h e n y l a c e t l c a c i d (181) u s i n g v a r i o u s a l c o h o l s ( T a b l e X X V ) . p_-To I u e n e s u I f on I c a c i d was u s e d a s t h e a c i d c a t a l y s t f o r t h e s e s t u d i e s . U n d e r t h e same r e a c t i o n c o n d i t i o n s o f 50 e q u i v a l e n t s o f a l c o h o l , p h e n y l a c e t i c a c i d c o n c e n t r a t i o n o f 0 . 1 2 5 M In d I c h I o r o m e t h a n e a s s o l v e n t and r e a c t i o n t i m e o f 2 3 . 5 h a t room t e m p e r a t u r e , m e t h a n o l g a v e c o m p l e t e e s t e r i f i c a t I o n , e t h a n o l g a v e 58% e s t e r i f I c a t i o n and i s o p r o p a n o l g a v e no e s t e r If I c a t I on ( e n t r i e s 1 - 3 ) . T h i s t r e n d r e f l e c t s t h e e x p e c t e d r e a c t i v i t i e s o f t h e s e a l c o h o l s in n u c l e o -p h i l i c s u b s t i t u t i o n r e a c t i o n s . 1 5 6 E s t e r i f I c a t i o n o f p h e n y l -a c e t l c a c i d w i t h m e t h a n o l and e t h a n o l c o u l d be m i n i m i z e d by u s i n g l e s s a l c o h o l and s h o r t e r r e a c t i o n t i m e s ( e n t r i e s 4 and 5 ) . T h u s , t h e e s t e r I f i c a t I on o f a n y p h e n y l a c e t i c a c i d (181) f o r m e d by s l l y l - o x y g e n c l e a v a g e o f e s t e r 152 c a n be e f f e c t i v e l y T a b l e X X V . A c i d - c a t a l y z e d E s t e r I f I c a t I on o f P h e n y l a c e t i c A c i d 0 Q - C H ^ H g H S ° H » Q - C H 2 C - 0 R 181 182 a) R=Me c) R=i-Pr b) R=Et [lai] T i m e a Y l e l d ( % ) E n t r y R O H ( e q u i v ) S o l v e n t (M) (h ) 181 182 1 MeOH (50 ) C H 2 C I 2 0 . 125 23 . 5 0 100 2 E t O H (50 ) C H 2 C I 2 0 . 125 23 . 5 42 58 3 1 - P r O H (50 ) C H 2 C I 2 0 . 125 23 .5 100 0 4 MeOH (10 ) THF 0 . 20 1 : 25 98 t r a c e 0 5 E t O H (10 ) THF 0 . 20 2 . 5 82 t r a c e 0 a R e a c t i o n s p e r f o r m e d a t room t e m p e r a t u r e w i t h 0 . 1 0 e q u i v a l e n t o f G - T S O H . ° D e t e c t e d by t i c b u t n o t i s o I a b l e . 179 c o n t r o I I e d . A c i d - c a t a l y z e d a l c o h o l y s e s o f i - b u t y I d i m e t h y I s i I y I p h e n y l -a c e t a t e (1 52) u s i n g m e t h a n o l , e t h a n o l , and i s o p r o p a n o l w e r e c a r r i e d o u t u n d e r c o n d i t i o n s w h i c h had b e e n shown t o n o t c a u s e a n y e s t e r If I c a t I on o f p h e n y l a c e t i c a c i d (181) ( T a b l e X X V I ) . T h e r e a c t i o n c o n d i t i o n s e m p l o y e d w e r e e s t e r c o n c e n t r a t i o n o f 0 . 2 0 M in T H F , t e n e q u i v a l e n t s o f a l c o h o l , 0 . 1 0 e q u i v a l e n t o f SL-to I u e n e s u I f on I c a c i d , and r e a c t i o n t i m e s o f 8 . 5 , 2 . 5 , and 1.5 h o u r s a t room t e m p e r a t u r e f o r i s o p r o p a n o l , e t h a n o l , and m e t h a n o l , r e s p e c t i v e l y ( e n t r i e s 1 - 3 ) . E x c e l l e n t y i e l d s o f p h e n y l a c e t i c a c i d w e r e o b t a i n e d In e a c h c a s e . A g a i n , t h e a l c o h o l s h a v e a t t a c k e d t h e s i l i c o n a tom r e s u l t i n g in a l c o h o l y s i s vI a an s i l y l - o x y g e n c l e a v a g e m e c h a n i s m . In Tab I e XXV I . A c I d - c a t a l y z e d A l c o h o l y s i s o f i - B u t y I d i m e t h y I s i l y l Pheny I a c e t a t e 0 CH3 _ CH3 ^^-CH 2C-OSi - t-Bu ^ 0 H » ^^-CH 2C02H + t-Bu-Si-OR CH3 THF j_8J_ CH3 143c R=H ROH T i m e 3 Y i e l d o f E n t r y ( e q u l v ) (h ) 1 8 1 ( % ) p 166 a) R=Me b) R=Et c) R=i-Pr 1 1 - P r O H (10 ) 8 . .5 84 2 E t O H (10 ) 2 . .5 88 3 MeOH (10 ) 1 . .5 94 4 H 2 0 (10 ) 0. .42 98 5 H 2 0 (10 ) 0. .48 90 6 H 2 0 (1 ) 0 .33 88 a R e a c t i o n s p e r f o r m e d a t room t e m p e r a t u r e w i t h [ e s t e r ] = 0 . 2 0 M in THF and 0 . 1 0 e q u i v a l e n t o f o . - T s O H . b T h e a l c o h o l 143c and e t h e r 166 b y - p r o d u c t s w e r e l o s t in t h e w o r k - u p d u e t o t h e i r e x t r e m e v o l a t i l i t y . 180 a d d i t i o n , a c i d - c a t a l y z e d h y d r o l y s e s , u s i n g w a t e r a s t h e n u c l e o p h l l e , w e r e a l s o p e r f o r m e d ( e n t r i e s 4 - 6 ) and t h e s e a l s o r e s u l t e d in e x c e l l e n t r e c o v e r i e s o f p h e n y l a c e t i c a c i d . T h e s l l o x a n e s 166 f r o m t h e a b o v e a l c o h o l y s e s o f e s t e r 152 c o u l d n o t be I s o l a t e d d u e t o t h e i r v o l a t i l i t y . T h e r e f o r e , a c i d - c a t a l y z e d a l c o h o l y s e s o f i - b u t y I d I p h e n y I s I IyI p h e n y l -a c e t a t e (154) w e r e p e r f o r m e d and w e r e f o u n d t o g i v e g o o d y i e l d s o f i - b u t y I d i p h e n y I m e t h o x y s I l a n e ( 163a ) a n d i - b u t y I d I p h e n y I -e t h o x y s l l a n e ( 163b ) ( T a b l e X X V I I ) . A s w o u l d be e x p e c t e d , no r e a c t i o n t o o k p l a c e when i s o p r o p a n o l was u s e d b e c a u s e o f t h e b u l k i n e s s o f b o t h t h e s i l y l g r o u p and t h e n u c l e o p h i l e . L o n g e r r e a c t i o n t i m e s w e r e r e q u i r e d f o r t h e a l c o h o l y s i s o f e s t e r 154 t h a n o f t h e l e s s b u l k y i - b u t y I d i m e t h y I s I IyI pheny I a c e t a t e (152) and a s a r e s u l t , l a r g e a m o u n t s o f t h e c o r r e s p o n d i n g e s t e r s 182 w e r e I s o l a t e d r e s u l t i n g f r o m s u b s e q u e n t e s t e r If I c a t I on o f Tab Ie XXV I I. A c I d - c a t a I y z e d A l c o h o l y s i s o f i - B u t y I d i p h e n y I -s i l y l P h e n y I a c e t a t e Ph 1 63 a) R=Me 182 a)R=Me b) R=Et c) R=i-Pr b) R=Et c) R=i-Pr E n t r y ROH ( e q u I v ) T i m e a (h ) 154 1SJ. Y i e l d (%) 163 182 2 3 i - P r O H (50 ) E t O H (50) MeOH (50 ) 23 2 6 . 5 3 100 0 0 0 40 34 0 73 77 0 38 46 a R e a c t i o n s p e r f o r m e d a t room t e m p e r a t u r e w i t h [ e s t e r ] = 0 . 1 2 5 M in THF and 0 . 1 0 e q u i v a l e n t o f D_-TsOH. 181 p h e n y l a c e t i c a c i d ( 1 8 1 ) . To p r e v e n t s u b s e q u e n t e s t e r i f I c a t I on o f t h e a c i d f o r m e d in t h e a c I d - c a t a I y z e d m e t h a n o l y s l s o f a s i l y l e s t e r , i - b u t y I d i -p h e n y l s i l y l 2 , 6 - d I m e t h y I b e n z o a t e (183) was c h o s e n a s a s u b s t r a t e . T h e e f f e c t o f t h e o r t h o s u b s t i t u e n t s i s w e l l known t o r e t a r d a c y I a d d i t i o n t o t h e c a r b o n y l . 1 5 7 T h e r e a c t i o n o f e s t e r 183 a t a c o n c e n t r a t i o n o f 0 . 2 0 M In THF w i t h 0 . 1 0 e q u i v a l e n t o f D_- to I u e n e s u I f on I c a c i d and 50 e q u i v a l e n t s o f m e t h a n o l f o r 3 . 5 h o u r s g a v e an 84% y i e l d o f 2 , 6 - d i m e t h y I b e n z o i c a c i d (184 ) a n d an 88% y i e l d o f s i l o x a n e 1 6 3 a . T h e a b o v e r e s u l t s o f t h e a c i d - c a t a l y z e d a l c o h o l y s i s o f s i l y l c a r b o x y l a t e s y i e l d e d i n f o r m a t i o n r e g a r d i n g t h e s i t e o f a t t a c k o f a l c o h o l s . T h e s e r e s u l t s i n d i c a t e q u i t e c o n c l u s i v e l y t h a t a t t a c k by a l c o h o l s o c c u r s a t t h e s i l i c o n a tom r e s u l t i n g in s i l y l - o x y g e n c l e a v a g e . T h e r e f o r e , t h e a c i d - c a t a l y z e d a l c o h o l y s i s a n d h y d r o l y s i s o f s i l y l c a r b o x y l a t e s o c c u r s by e i t h e r t h e known A A | _ 1 o r t h e y e t u n o b s e r v e d A A L 2 m e c h a n i s m . An e x a m i n a t i o n o f t h e k i n e t i c s o f t h e h y d r o l y s i s i s r e q u i r e d t o d e t e r m i n e w h i c h o f t h e two m e c h a n i s m s i s in f a c t o p e r a t I n g . Chfe 0 Ph C H 3 Ph 183 184 163a 182 2 D . 2 . 3 K i n e t i c s o f t h e A c i d - c a t a l y z e d H y d r o l y s i s o f S i l y l C a r b o x y l a t e s : K i n e t i c E v i d e n c e f o r t h e A A |_2 M e c h a n i s m T h e k i n e t i c s o f t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I d I-m e t h y l s i l y l pheny I a c e t a t e (152) w e r e c o n v e n i e n t l y f o l l o w e d by g a s c h r o m a t o g r a p h y . T h e peak due t o t h e p r o d u c t s l l a n o l 143c was f o u n d t o be t o o c l o s e t o t h e s o l v e n t peak t o a l l o w a c c u r a t e p e a k a r e a d e t e r m i n a t i o n . A r e f e r e n c e s t a n d a r d was t h u s i n c l u d e d In t h e r e a c t i o n m i x t u r e . T h i s i n t e r n a l s t a n d a r d must » C H 3 T S 0 H _ C H 3 ^ ^ - C H 2 C - O S i - t - B u —HJJ.THF—*~ ^ ^ C H 2 C 0 2 H + t - B u - S i - O H C H 3 ^ C H 3 be u n a f f e c t e d by t h e r e a c t i n g s y s t e m , i t must n o t be f o r m e d in t h e r e a c t i o n , a n d i t must h a v e a r e t e n t i o n t i m e d i f f e r e n t f r o m t h o s e o f t h e s p e c i e s t o be a n a l y z e d . We f o u n d h e x a d e c a n e t o be a c o n v e n i e n t I n t e r n a l s t a n d a r d . T h e k i n e t i c s o f t h e h y d r o l y s i s w e r e d e t e r m i n e d u n d e r p s e u d o - f i r s t - o r d e r c o n d i t i o n s In THF c o n t a i n i n g a known amount ( e x c e s s ) o f w a t e r , a c a t a l y t i c amount o f p_-to I u e n e s u I f on I c a c i d , a n d h e x a d e c a n e a s an I n t e r n a l s t a n d a r d . T h e h y d r o l y s e s w e r e c a r r i e d o u t u n d e r a n i t r o g e n a t m o s p h e r e . T h e r a t e o f d i s a p p e a r a n c e o f e s t e r 152 was d e t e r m i n e d by g a s c h r o m a t o -g r a p h y . T y p i c a l g a s c h r o m a t o g r a p h i c t r a c e s a t v a r i o u s t i m e s a r e shown In F i g u r e 2 9 . To a c c o u n t f o r v a r i a t i o n s In i n j e c t i o n v o l u m e s , t h e p e a k a r e a s a r e s t a n d a r d i z e d w i t h r e s p e c t t o h e x a d e c a n e a t t i m e t = 0 . P s e u d o - f i r s t - o r d e r r a t e c o n s t a n t s (k^) w e r e o b t a i n e d f r o m t h e s l o p e s o f p l o t s o f - I n X v e r s u s 183 t i m e ( F i g u r e 30) w h e r e X Is t h e f r a c t i o n o f e s t e r 152 r e m a i n i n g . T h e p l o t s o f - I n X v e r s u s t i m e w e r e e s s e n t i a l l y l i n e a r t h r o u g h a t l e a s t t h e f i r s t two h a l f - l i v e s o f e s t e r h y d r o l y s i s e x c e p t f o r a p p r o x i m a t e l y t h e f i r s t t e n p e r c e n t o f t h e r e a c t i o n . T h e s l o p e s w e r e t a k e n a f t e r t h i s i n i t i a l p e r i o d and w e r e o b t a i n e d by a l i n e a r l e a s t - s q u a r e s t r e a t m e n t o f t h e d a t a p o I n t s . CO Ct'. « ] h-iTl CM 05 B C (a) JF fe pa (b ) JF fe 1 a; ? N in Nil) B C ( c ) fl r-in (d ) F i g u r e 2 9 . T y p i c a l g a s c h r o m a t o g r a m s o f a c I d - c a t a I y z e d h y d r o l y s i s o f i - b u t y I d i m e t h y I s i IyI pheny I a c e t a t e ( 1 5 2 ) . R e a c t i o n c o n d i t i o n s : [ E s t e r ] = 0 . 0 4 0 M In T H F , [D. -TSOH ] = 0 . 0 0 2 0 M, [ H 2 0 ] = 0 . 4 0 M, wt . r a t i o e s t e r : h e x a d e c a n e = 3 . 8 3 : 1 , T = 2 5 . 0 ° C . A = s l l a n o l 1 4 3 c . B= h e x a d e c a n e , C = e s t e r 152 . (a ) 2 m i n , (b ) 18 m i n , ( c ) 34 m i n , (d) 65 m I n . 184 m 0.000 M • 0.040 M A 0.100 M • 0.200 M + 0.300 M • 0.400 M D 0.500 M X 0.600 M Time (sec x 0.001) F i g u r e 3 0 . R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f w a t e r c o n c e n t r a t i o n . R e a c t i o n c o n d i t i o n s : [ E s t e r 3=0 .0200 M in T H F , [ D _-TsOH]=0 .0010 M, T = 2 5 . 0 ° C . X = f r a c t i o n o f 152 u n r e a c t e d . [ H g O ^ O . O O O M, =3 . 48x 1 0 - 6 s - 1 ; 0 . 0 4 0 M, 1 . 5 8 x 1 0 - 5 s ~ 1 ; 0 . 1 0 0 M, 3 . 4 6 x 1 0 ~ 5 S _ 1 . 0 2 0 0 M, 9 . 8 0 X 1 0 " 5 S - 1 ; 0 . 3 0 0 M, 1 . 4 5 x 1 0 ~ 4 S - 1 ; 0 . 4 0 0 M, 2 . 0 6 x 1 0 - 4 S - 1 ; 0 . 5 0 0 M, 2 . 6 8 x 1 0 ~ 4 S - 1 ; 0 . 6 0 0 M, 3 .21 X 1 0 ~ 4 S - 1 . K i n e t i c d a t a f o r t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I -d I m e t h y I s i IyI pheny I a c e t a t e (152) a t d i f f e r e n t c o n c e n t r a t i o n s o f w a t e r a n d c o n s t a n t s i l y l e s t e r and p_-to I u e n e s u I f on I c a c i d c o n c e n t r a t i o n s a r e s u m m a r i z e d In T a b l e B . 1 . * A f i r s t - o r d e r d e p e n d e n c e on t h e c o n c e n t r a t i o n o f e s t e r 152 Is s u g g e s t e d by t h e l i n e a r i t y o f t h e p l o t o f - I n X v e r s u s t i m e ( F i g u r e 3 0 ) . * * A p l o t o f t h e p s e u d o - f i r s t - o r d e r r a t e c o n s t a n t k^ v e r s u s * T a b l e s B.1 t o B . 6 a r e in A p p e n d i x B . T h e s e t a b l e s c o n t a i n k i n e t i c d a t a f o r t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y l d i -m e t h y l s l l y l pheny I a c e t a t e ( 1 52) u n d e r d i f f e r e n t c o n d i t i o n s . * T h e g r a p h s in F i g u r e s 3 0 - 3 6 w e r e g e n e r a t e d f r o m t h e a p p r o -p r i a t e d a t a c o n t a i n e d In T a b l e s B.1 t o B . 6 . 185 -1.8 -1.4 -1.0 -0.6 -0.2 In [Water] F i a u r e 3 2 . H y d r o l y s i s o f e s t e r 152: In v e r s u s In [ H 2 0 ] . 186 [ H 2 O ] ( F i g u r e 31) g i v e s a s t r a i g h t l i n e a t h i g h e r c o n c e n -t r a t i o n s o f w a t e r ( f r o m [ H 2 0 ] = 0 . 1 0 0 t o 0 . 6 0 0 M) b u t d e v i a t e s f r o m l i n e a r i t y a t lower c o n c e n t r a t i o n s o f w a t e r p r o b a b l y b e c a u s e o f t h e s h i f t away f r o m f i r s t - o r d e r k i n e t i c s a s we a r e no l o n g e r u s i n g a l a r g e e x c e s s o f w a t e r . T h e s l o p e o f t h e p l o t o f k^ v e r s u s [ H 2 O ] i s e x p e c t e d t o be t h e t h i r d - o r d e r r a t e c o n s t a n t k t i m e s t h e a c i d c a t a l y s t c o n c e n t r a t i o n . D i s r e g a r d i n g t h e p o i n t s f o r [H20]=0 and 0 . 0 4 0 M, a l i n e a r l e a s t - s q u a r e s t r e a t m e n t o f t h e r e m a i n i n g p o i n t s g i v e s a s l o p e o f 5 . 7 3 x 1 0 ~ 4 M ~ 1 s e c _ 1 w h i c h c o r r e s p o n d s t o a t h i r d - o r d e r r a t e c o n s t a n t o f 0 . 5 7 3 M ~ 2 s e c ~ 1 . T h e a p p r o x i m a t e c o n s t a n c y In t h e v a l u e s o f t h e t h i r d - o r d e r r a t e c o n s t a n t s c a l c u l a t e d f r o m t h e f i r s t - o r d e r r a t e c o n s t a n t s Is In a c c o r d w i t h a f i r s t - o r d e r d e p e n d e n c e on t h e c o n c e n t r a -t i o n s o f w a t e r and a c i d c a t a l y s t ( f r o m T a b l e B . 4 ) . The lower t h i r d - o r d e r r a t e c o n s t a n t s when [ H 2 0 ] = 0 . 0 4 0 and 0 . 1 0 0 M p r o b a b l y r e f l e c t s t h e d e v i a t i o n f r o m f i r s t - o r d e r k i n e t i c s a t t h e s e lower c o n c e n t r a t i o n s o f w a t e r . If t h e s e w e r e n e g l e c t e d , t h e a v e r a g e t h i r d - o r d e r r a t e c o n s t a n t k Is 0 . 5 1 2 M - 2 s e c ~ 1 w h i c h a g r e e s q u i t e w e l l w i t h t h e t h i r d - o r d e r r a t e c o n s t a n t k o f 0 . 5 7 3 M - 2 s e c - 1 o b t a i n e d f r o m t h e s l o p e o f t h e p l o t o f v e r s u s [ H 2 O ] . [H 20] ( M ) k (lvr 2sec" 1) 0.040 0.100 0.200 0.300 0.400 0.500 0.600 0.395 0.346 0.490 0.482 0.516 0.536 0.536 187 T h e l i n e a r i t y o f t h e p l o t o f v e r s u s [ H 2 0 ] ( a t h i g h c o n c e n t r a t i o n s o f w a t e r f o r a d h e r e n c e t o f i r s t - o r d e r k i n e t i c s ) a l s o s u g g e s t s a f i r s t - o r d e r d e p e n d e n c e on t h e c o n c e n t r a t i o n o f w a t e r . In t h e o r y , t h e l i n e s h o u l d p a s s t h r o u g h t h e o r i g i n b u t in t h i s c a s e It d o e s n o t . T h e l i n e Is s h i f t e d downwards i n d i c a t i n g t h a t t h e amount o f w a t e r a v a i l a b l e f o r n u c l e o p h i l i c a t t a c k i s l e s s t h a n t h e amount a d d e d . T h i s e f f e c t may be a t t r i b u t e d t o a s s o c i a t i o n o f w a t e r m o l e c u l e s w i t h t e t r a h y d r o -f u r a n by h y d r o g e n b o n d i n g . 1 5 8 T h e h y d r o l y s i s s t i l l p r o c e e d e d , a l t h o u g h o n l y s l o w l y , e v e n when no w a t e r was d e l i b e r a t e l y a d d e d t o t h e r e a c t i o n . T h i s o b s e r v a t i o n s u g g e s t s t h a t some w a t e r was a c c i d e n t a l l y i n t r o d u c e d i n t o t h e r e a c t i o n m i x t u r e . The m o s t l i k e l y s o u r c e o f t h i s w a t e r i s f r o m t h e a c i d c a t a l y s t , p . - to I u e n e s u I f on I c a c i d . * T h e f i r s t - o r d e r d e p e n d e n c e o n t h e c o n c e n t r a t i o n o f w a t e r i s a l s o shown by a p l o t o f In k^ v e r s u s in [H2O] ( F i g u r e 3 2 ) . T h e b e s t l e a s t - s q u a r e s f i t o f t h e d a t a p o i n t s h a s a s l o p e o f 1.1 w h i c h I m p l i e s ( f r o m e q u a t i o n 14 in k i n e t i c i n t r o d u c t i o n s e c t i o n ) t h a t t h e e x p o n e n t t o w h i c h t h e c o n c e n t r a t i o n o f w a t e r * A t t e m p t s t o u s e " a n h y d r o u s " p . - to I u e n e s u I f on I c a c i d , p r e p a r e d by h e a t i n g t h e m o n o h y d r a t e a t 7 0 ° C u n d e r h i g h vacuum o v e r n i g h t w i t h s u b s e q u e n t r e c r y s t a I I I z a t i o n f r o m c h l o r o f o r m , g a v e r e s u l t s w h i c h s t i l l showed some d e v i a t i o n f r o m no a d d e d w a t e r . 188 i s r a i s e d In t h e r a t e e q u a t i o n Is e s s e n t i a l l y o n e . T h e a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 152 was a l s o p e r f o r m e d by v a r y i n g t h e c o n c e n t r a t i o n s o f e s t e r , w a t e r , and a c i d c a t a l y s t t o d e t e r m i n e t h e d e p e n d e n c e on e a c h o f t h e s e r e a c t a n t s . A t t h e d i f f e r e n t c o n c e n t r a t i o n s o f e s t e r 152 . t h e r a t i o s o f e s t e r t o w a t e r ( 1 : 1 0 ) and o f e s t e r t o p _ - t o l u e n e -s u l f o n l c a c i d ( 2 0 : 1 ) w e r e k e p t c o n s t a n t ( T a b l e s B . 2 and B . 5 ) . T h e p s e u d o - f i r s t - o r d e r r a t e c o n s t a n t k^ was a g a i n d e r i v e d f r o m t h e s l o p e o f p l o t s o f - I n X v e r s u s t i m e ( F i g u r e 3 3 ) . T h e l i n e a r i t y o f t h e s e p l o t s a g a i n I n d i c a t e s a f i r s t - o r d e r d e p e n d e n c e on t h e c o n c e n t r a t i o n o f e s t e r 152 . T h e c a l c u l a t e d t h i r d - o r d e r r a t e c o n s t a n t s a r e e s s e n t i a l l y c o n s t a n t i m p l y i n g [Ester] (M) [H20] (M) [p-TsOH] (M) k (lvT2sec'1) 0.0150 0.150 0.00075 0.485 0.0200 0.200 0.0010 0.490 0.0250 0.250 0.00125 0.480 0.0300 0.300 0.0015 0.537 0.0400 0.400 0.0020 0.463 f i r s t - o r d e r d e p e n d e n c i e s on t h e c o n c e n t r a t i o n s o f w a t e r and D_-to I u e n e s u I f o n I c a c i d , and t h e s e t h i r d - o r d e r r a t e c o n s t a n t s a r e s i m i l a r t o t h o s e o b t a i n e d when o n l y t h e c o n c e n t r a t i o n o f w a t e r was v a r i e d . T h e d e p e n d e n c e on t h e c o n c e n t r a t i o n s o f e s t e r , w a t e r , and p_-to I u e n e s u I f on I c a c i d c o u l d be d e t e r m i n e d by an a l t e r n a t i v e m e t h o d . R a t e e q u a t i o n 23 s i m p l i f i e s t o e q u a t i o n 24 u n d e r p s e u d o - f i r s t - o r d e r k i n e t i c s , and e q u a t i o n 25 c a n be c o n v e r t e d 189 X c • X 0.0150 M 0.0200 M 0.0250 M 0.0300 M 0.0400 M i 1 r 10 15 Time (sec x 0.001) F i g u r e 33 R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f e s t e r , w a t e r , a n d a c i d c o n c e n t r a t i o n s . X = f r a c t i o n o f 152 u n r e a c t e d . R e a c t i o n c o n d i t i o n s : [ H 2 O ] = 1 0 [ E s t e r ] , [ E s t e r ]=20 [D . -TsOH] , THF s o l v e n t , T = 2 5 . 0 ° C . [ E s t e r ] = 0 . 0 1 5 0 M, k^ = 5 . 4 6 x 1 0 - 5 S - 1 ; 0 . 0 2 0 0 M, 9 . 8 0 x 1 0 ~ 5 S - 1 ; 0 . 0 2 5 0 M, 1 . 5 0 X 1 0 ~ 4 S - 1 ; 0 . 0 3 0 0 M, 2 . 4 2 x 1 0 ~ 4 S - 1 ; 0 . 0 4 0 0 M, 3 . 7 0 X 1 0 - 4 S - 1 -7-i -10 -2.0 T 1 r •1.6 -1.2 In [Water] -0.8 F i g u r e 3 4 . D e t e r m i n a t i o n o f d e p e n d e n c e on n-TsOH a n d H 2 0 190 - d[^Stei1 = k[Ester]x[H20]y[p-TsOH]z (23) - ^ ar^  - V E s t e r i x ( 2 4 ) where k^ = k[H20]y[p-TsOH]z (25) In = In k + yln [H20] + zln [p-TsOH] and since [H20] = 200[p-TsOH] In k^  - In k - zln 200 + (y+z)ln [H20] (26) t o e q u a t i o n 2 6 . T h u s , t h e s l o p e o f a p l o t o f In k^ v e r s u s In [H2O] y i e l d s t h e sum o f t h e o r d e r s w i t h r e s p e c t t o w a t e r and t h e a c i d c a t a l y s t , and t h e t h i r d - o r d e r r a t e c o n s t a n t Is c a l c u l a t e d f r o m t h e y - i n t e r c e p t . T h e p l o t o f In k^ v e r s u s In [ H 2 0 ] ( F i g u r e 34) i s i n d e e d l i n e a r w i t h a s l o p e o f 2 . 0 w h i c h i m p l i e s a f i r s t - o r d e r d e p e n d e n c e on w a t e r c o n c e n t r a t i o n a s w e l l a s on a c i d c a t a l y s t c o n c e n t r a t i o n . T h e t h i r d - o r d e r r a t e c o n s t a n t i s c a l c u l a t e d t o be 0 . 4 8 4 M - 2 s e c ~ 1 w h i c h i s c o n s i s t e n t w i t h t h e v a l u e s d e t e r m i n e d p r e v i o u s l y by o t h e r m e t h o d s . T h e a b o v e k i n e t i c d a t a a r e t h e r e f o r e c o n s i s t e n t w i t h an o v e r a l l t h i r d - o r d e r r e a c t i o n ( e q u a t i o n 2 3 ' ) w h e r e t h e r a t e c o n s t a n t k i s 0 . 5 0 M - 2 s e c _ 1 . T h e o b s e r v a t i o n t h a t t h e r a t e _ d[Ester] = k[Ester][H20]lp-TsOH] (23') o f a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 152 i s d e p e n d e n t on w a t e r c o n c e n t r a t i o n a s w e l l a s on e s t e r c o n c e n t r a t i o n s t r o n g l y s u g g e s t s t h a t t h e A A |_2 m e c h a n i s m i s o p e r a t i n g . 191 B o.o°c • 15.7°C A 25.0°C • 30.0°C x 35.0°C Time (sec x 0.001) F i a u r e 3 5 . R a t e o f h y d r o l y s i s o f e s t e r 152: V a r i a t i o n o f t e m p e r a t u r e . R e a c t i o n c o n d i t i o n s : [ E s t e r ] = 0 . 0 2 0 0 M In T H F , [ H 2 O ] = 0 . 2 0 0 M, [ D_-TsOH ] =0 . 001 0 M. X = f r a c t i o n o f 152 u n r e a c t e d . T = 0 . 0 ° C , k ^ = 6 . 3 5 x l 0 - 5 S ~ 1 ; 1 5 . 7 ° C , 8 . 4 2 x 1 0 ~ 5 S - 1 ; 2 5 . 0 ° C , 9 . 8 0 x 1 0 ~ 5 S - 1 ; 3 0 . 0 ° C , 1 . 1 6 x 1 0 - 4 s - 1 ; 3 5 . 0 ° C , 1.1 Ox 1 0 ~ 4 S - 1 . F i g u r e 3 6 . E y r i n g p l o t f o r a c i d - c a t a l y z e d h y d r o l y s i s o f e s t e r 152 . A H * = 2 . 2 4 k c a l / m o l e ; A S * = - 5 2 c a l / m o l e - K . 192 T h e a c t i v a t i o n p a r a m e t e r s f o r t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I d I m e t h y I s i IyI pheny I a c e t a t e (152) w e r e d e t e r m i n e d a t s e v e r a l t e m p e r a t u r e s w i t h [ e s t e r ] = 0 . 0 2 0 0 M, [ H 2 O ] = 0 . 2 0 0 M, a n d [p_ -Ts0H]=0 .0010 M. The p l o t s o f - I n X v e r s u s t i m e a t t e m p e r a t u r e s o f 0 . 0 ° , 1 5 . 7 ° , 2 5 . 0 ° , 3 0 . 0 ° , and 3 5 . 0 ° C a r e shown In F i g u r e 3 5 . T h e t h i r d - o r d e r r a t e c o n s t a n t k was d e t e r m i n e d Temp (°C) x 105(sec'1) k (M"2sec"1) 0.0 6.35 0.318 15.7 8.42 0.421 25.0 9.80 0.490 30.0 11.6 0.580 35.0 11.0 0.548 by d i v i d i n g t h e p s e u d o - f i r s t - o r d e r r a t e c o n s t a n t k^ by [ H 2 0 ] and [c—TsOH] ( T a b l e B . 3 ) . A p l o t o f l o g k / T v e r s u s 1 /T ( F i g u r e 36) g a v e e s s e n t i a l l y a s t r a i g h t l i n e and f r o m t h e s l o p e and y -i n t e r c e p t o f t h e b e s t l e a s t - s q u a r e s f i t ( f r o m T a b l e B . 6 ) , t h e e n t h a l p y and e n t r o p y o f a c t i v a t i o n was d e t e r m i n e d t o be 2 . 2 k c a l / m o l e a n d - 5 2 c a l / m o I e - K , r e s p e c t i v e l y . * T h e h y d r o l y s i s o f s i l y l e s t e r s i s e s s e n t i a l l y d o m i n a t e d by t h e e n t r o p y f u n c t i o n . F o r e x a m p l e , t h e c o n t r i b u t i o n f r o m t h e e n t r o p y t e r m a t 2 5 ° C i s 1 5 . 5 k c a l / m o l e w h e r e a s t h a t f r o m t h e e n t h a l p y t e r m i s o n l y 2 . 2 k c a l / m o l e . F rom t h e a b o v e d a t a , t h e * T h e h y d r o l y s e s w h i c h w e r e p e r f o r m e d a t 3 0 . 0 ° a n d 3 5 . 0 ° C g a v e p o i n t s in t h e l o g k / T v e r s u s 1 /T p l o t w h i c h d e v i a t e d s i g n i f i -c a n t l y f r o m t h e l e a s t - s q u a r e s l i n e o b t a i n e d a t t h e t h r e e lower t e m p e r a t u r e s a n d t h u s t h e y w e r e n o t I n c l u d e d . 193 f r e e e n e r g y o f a c t i v a t i o n A G * a t 2 5 ° C f o r t h e a c i d - c a t a l y z e d h y d r o l y s i s o f w a t e r 152 i s a p p r o x i m a t e l y 18 k c a l / m o l e . T h e bImo I e c u Iar i t y o f t h e a c I d - c a t a I y z e d h y d r o l y s i s o f e s t e r 152 w h i c h i s r e q u i r e d o f t h e A A (_2 m e c h a n i s m Is a l s o I m p l i e d by t h e e n t r o p y o f a c t i v a t i o n o f - 5 2 c a I / m o I e - K . N e g a t i v e e n t r o p i e s o f a c t i v a t i o n a r e g e n e r a l l y a s s o c i a t e d w i t h b i m o l e c u l a r a c I d - c a t a I y z e d r e a c t i o n s , and z e r o o r p o s i t i v e e n t r o p i e s o f a c t i v a t i o n w i t h u n i m o l e c u l a r a c i d - c a t a l y z e d p r o c e s s e s . 1 5 9 It s h o u l d be n o t e d t h a t s i n c e t h e e s t e r e x i s t s in I t s u n p r o t o n a t e d f o r m , t h e A S * v a l u e must a l s o c o n t a i n a c o n t r i b u t i o n f r o m t h e p r o t o n a t l o n s t e p . * The e x c e p t i o n a l l y l a r g e n e g a t i v e A S * v a l u e * * Is c o n s i s t e n t w i t h t h e l a r g e amount o f m o l e c u l a r o r d e r i n g e x p e c t e d In t h e t r a n s i t i o n s t a t e o f an A A i _ 2 h y d r o l y s i s i n v o l v i n g a t e r t i a r y a l c o h o l . * T h e A H * a n d A G * v a l u e s a r e a l s o c o m p o s i t e s o f two t e r m s , o n e f r o m t h e e q u i l i b r i u m p r o t o n a t l o n s t e p and o n e f r o m t h e r a t e d e t e r m i n i n g s t e p . * * F o r e x a m p l e , e s t e r h y d r o l y s i s vI a a t e t r a h e d r a l i n t e r -m e d i a t e ( A A Q 2 m e c h a n i s m ) i s c h a r a c t e r i z e d by A S * v a l u e s r a n g i n g f r o m - 1 5 t o - 2 5 c a I / m o I e - K . 1 4 4 • 1 5 9 In a d d i t i o n , t h e w e l l - k n o w n C o p e r e a r r a n g e m e n t w h i c h p r o c e e d s v i a an o r d e r e d c y c l i c t r a n s i t i o n s t a t e h a s A S * v a l u e s r a n g i n g f r o m -11 t o - 1 4 c a l / m o I e - K . 1 6 0 OH CH3 CH3 t-Bu 194 2 D . 2 . 4 C o n c l u s i o n T h e p r o d u c t d i s t r i b u t i o n f r o m a c I d - c a t a I y z e d a l c o h o l y s i s o f s i l y l s I I a n e c a r b o x y I a t e s and s l l y l c a r b o x y l a t e s I n d i c a t e d t h a t t h e s e r e a c t i o n s ( a n d t h o s e o f a c i d - c a t a l y z e d h y d r o l y s e s ) p r o c e e d by a m e c h a n i s m I n v o l v i n g s i l y l - o x y g e n c l e a v a g e . F rom k i n e t i c s t u d i e s , t h e a c i d - c a t a l y z e d h y d r o l y s i s o f i - b u t y I d I-m e t h y l s l l y l p h e n y I a c e t a t e (152) i s d e t e r m i n e d t o be an o v e r a l l t h i r d - o r d e r r e a c t i o n b e i n g f i r s t - o r d e r e a c h in e s t e r , w a t e r , and c - t o I u e n e s u I f o n Ic a c i d . T h e a c i d c a t a l y s t i s n o t i n v o l v e d In t h e r a t e - d e t e r m i n i n g s t e p and t h u s o f t h e f o u r a c i d -c a t a l y z e d h y d r o l y s i s m e c h a n i s m s o n l y t h e A A i _ 2 m e c h a n i s m Is c o n s i s t e n t w i t h t h e r e s u l t s o f b o t h t h e c h e m i c a l and k i n e t i c s t u d i e s . T h i s r e s u l t r e p r e s e n t s t h e f i r s t d e m o n s t r a t i on o f c a r b o x y l i c e s t e r h y d r o l y s i s p r o c e e d i n g by t h e A A L 2 m e c h a n i s m . 195 EXPERI MENTAL 196 Qenera » A l l r e a c t i o n s w e r e p e r f o r m e d u n d e r a n i t r o g e n a t m o s p h e r e . F o r r e a c t i o n s r e q u i r i n g a n h y d r o u s c o n d i t i o n s , g l a s s w a r e was o v e n - d r i e d o v e r n i g h t o r f l a m e - d r i e d and c o o l e d u n d e r n i t r o g e n . S t i r r i n g was a c c o m p l i s h e d u s i n g T e f l o n - c o a t e d m a g n e t i c s t i r r i n g b a r s . C o l d t e m p e r a t u r e b a t h s u s e d f o r v a r i o u s r e a c t i o n s w e r e o b t a i n e d a s f o l l o w s : - 2 4 ° C , C C l 4 / s o l l d C O 2 ; - 7 8 ° C , a c e t o n e / s o l i d C 0 2 ; - 1 0 5 ° C , e t h a n o I / I i q u i d N 2 . S o l v e n t s and r e a g e n t s w e r e p u r i f i e d a s f o l l o w s : e t h e r , t e t r a h y d r b f u r a n ( T H F ) , and 1 , 2 - d I m e t h o x y e t h a n e (DME) w e r e f r e s h l y d i s t i l l e d f r o m s o d i u m b e n z o p h e n o n e k e t y l u n d e r a n i t r o g e n a t m o s p h e r e . N,£J-D Imethy I formam i de (DMF) and h e x a -methy I p h o s p h o r i c t r i a m i d e (HMPA) w e r e d i s t i l l e d f r o m c a l c i u m h y d r i d e a n d s t o r e d o v e r a c t i v a t e d 1_ I nde 4A1 m o l e c u l a r s i e v e s . A c e t o n l t r i l e was p r e - d r l e d o v e r p o t a s s i u m c a r b o n a t e and t h e n d i s t i l l e d f r o m p h o s p h o r u s p e n t o x i d e . D i c h I o r o m e t h a n e , c a r b o n t e t r a c h l o r i d e , a n d t o l u e n e w e r e f i l t e r e d t h r o u g h a c o l u m n o f a c t i v a t e d n e u t r a l a l u m i n a b e f o r e u s e . M e t h a n o l and e t h a n o l w e r e d i s t i l l e d f r o m m a g n e s i u m m e t h o x l d e and m a g n e s i u m e t h o x i d e , r e s p e c t i v e l y . I s o p r o p a n o l was d r i e d by s t o r i n g o v e r a c t i v a t e d L I n d e 3A m o l e c u l a r s i e v e s . DI i s o p r o p y I am Ine a n d t r i e t h y I a m i n e w e r e p u r i f i e d by d i s t i l l i n g f r o m c a l c i u m h y d r i d e . C h l o r o t r i -m e t h y l s i l a n e was d i s t i l l e d f r o m c a l c i u m h y d r i d e and i - b u t y I -c h I o r o d I m e t h y I s I Iane was p u r i f i e d by s u b l i m a t i o n p r i o r t o u s e . S u l f u r t r i o x l d e was o b t a i n e d e i t h e r f r o m t h e A l d r i c h C h e m i c a l Company o r by d i s t i l l a t i o n o f 60% f u m i n g s u l f u r i c a c i d . M e t h y I I I th I urn ( I n e t h e r ) and n - b u t y I I i t h I urn ( I n h e x a n e ) , 197 o b t a i n e d f r o m t h e A l d r i c h C h e m i c a l C o m p a n y , w e r e s t a n d a r d i z e d by t i t r a t i o n a g a i n s t d I p h e n y I a c e t I c a c i d In THF a c c o r d i n g t o t h e p r o c e d u r e o f K o f r o n and B a c I a w s k I . 1 6 1 S o d i u m and p o t a s s i u m h y d r i d e s w e r e o b t a i n e d a s 50% and 25% d i s p e r s i o n s , r e s p e c t i v e l y , In m i n e r a l o i l f r o m A l f a D i v i s i o n , V e n t r o n C o r p o r a t i o n . L - P h e n y I a I an Ine was o b t a i n e d f r o m ICN P h a r m a c e u -t i c a l s , I n c . and L - t y r o s l n e f r o m J . T . B a k e r C h e m i c a l C o . S o d i u m b o r o h y d r i d e , t h l o n y l c h l o r i d e , and t e t r a - n - b u t y I a m m o n I urn i o d i d e w e r e s u p p l i e d by M a t h e s o n , C o l e m a n , and B e l l . 10% P a l l a d i u m on c h a r c o a l was o b t a i n e d f r o m K & K L a b o r a t o r i e s , I n c . A l l o t h e r c h e m i c a l s w e r e o b t a i n e d f r o m t h e A l d r i c h C h e m i c a l Company and w e r e u s e d w i t h o u t f u r t h e r p u r i f i c a t i o n u n l e s s o t h e r w i s e s t a t e d . A M e x t r a c t i o n and c h r o m a t o g r a p h y s o l v e n t s w e r e d i s t i l l e d b e f o r e u s e . P e t r o l e u m e t h e r r e f e r s t o t h e 3 5 - 6 0 ° C b o i l i n g f r a c t i o n . M e l t i n g p o i n t s (mp) w e r e d e t e r m i n e d u s i n g a B u c h i c a p I I I a r y - o I I b a t h m e l t i n g p o i n t a p p a r a t u s and a r e u n c o r r e c t e d . B u l b - t o - b u l b d i s t i l l a t i o n s w e r e p e r f o r m e d by means o f a BuchI K u g e l r o h r a p p a r a t u s . O p t i c a l r o t a t i o n s w e r e o b t a i n e d in c h l o r o f o r m s o l u t i o n u n l e s s o t h e r w i s e s t a t e d and w e r e m e a s u r e d w i t h a P e r k l n - E l m e r mode l 141 p o l a r l m e t e r a t a m b i e n t t e m p e r a t u r e . I n f r a r e d ( I r ) s p e c t r a w e r e r e c o r d e d e i t h e r a s a l i q u i d f i l m o r In s o l u t i o n ( s o l v e n t I n d i c a t e d In p a r e n t h e s e s ) u s i n g a P e r k l n - E l m e r mode l 710B s p e c t r o p h o t o m e t e r ( a n d c a l i b r a t e d w i t h t h e 1601 c m - 1 band o f p o l y s t y r e n e ) o r a P e r k l n - E l m e r mode l 1710 F o u r i e r T r a n s f o r m s p e c t r o p h o t o m e t e r . Low r e s o l u t i o n m a s s s p e c t r a (ms) w e r e r e c o r d e d on a V a r i a n MAT C H 4 - B m a s s s p e c t r o m e t e r . R e l a t i v e i n t e n s i t i e s a r e i n c l u d e d in 198 p a r e n t h e s e s a f t e r t h e m/z v a l u e f o r e a c h p e a k . O n l y t h e p a r e n t peak and p e a k s h a v i n g a r e l a t i v e i n t e n s i t y g r e a t e r t h a n 25% o f t h e b a s e peak a r e r e p o r t e d , u n l e s s p e a k s w i t h lower i n t e n s i t y a r e s t r u c t u r a l l y d i a g n o s t i c . T h e peak w i t h t h e h i g h e s t m / z i s a s s i g n e d a s t h e m o l e c u l a r i o n ( M + ) o r a s a f r a g m e n t o f t h e mo l e u Iar i o n . E x a c t m a s s e s w e r e d e t e r m i n e d by h i g h r e s o l u t i o n m a s s s p e c t r o m e t r y u s i n g a K r a t o s M S - 5 0 m a s s s p e c t r o m e t e r . A l l i n s t r u m e n t s w e r e o p e r a t e d a t an I o n i z i n g p o t e n t i a l o f 70 e V . P r o t o n n u c l e a r m a g n e t i c r e s o n a n c e ( 1 H nmr) s p e c t r a w e r e r e c o r d e d on o n e o r more o f t h e f o l l o w i n g s p e c t r o m e t e r s : V a r i a n A s s o c i a t e s T - 6 0 , E M - 3 6 0 L , X L - 1 0 0 , and X L - 3 0 0 ; N i c o I e t - O x f o r d H 2 7 0 ; a n d B r u k e r WH—400. S p e c t r a w e r e r u n in d e u t e r I o c h I o r o -f o r m s o l u t i o n u n l e s s o t h e r w i s e s t a t e d , and s i g n a l p o s i t i o n s a r e r e p o r t e d In p a r t s p e r m i l l i o n u s i n g t h e s c a l e w i t h t e t r a -m e t h y l s l l a n e a s an i n t e r n a l s t a n d a r d . In t h e c a s e o f c o m p o u n d s c o n t a i n i n g t r I a I k y I s I IyI g r o u p s , t h e c h e m i c a l s h i f t s w e r e d e t e r m i n e d r e l a t i v e t o t h e c h l o r o f o r m s i g n a l ( 6 7 . 2 7 ) . T h e m u l t i p l i c i t y , r e l a t i v e peak a r e a by i n t e g r a t i o n , c o u p l i n g c o n s t a n t s (J. in Hz) ( i f o b s e r v a b l e ) , and s e l e c t e d p r o t o n a s s i g n m e n t s a r e i n d i c a t e d in p a r e n t h e s e s a f t e r e a c h s i g n a l . T h e f o l l o w i n g a b b r e v i a t i o n s a r e u s e d in t h e d e s c r i p t i o n o f t h e m u l t i p l i c i t y o f e a c h s i g n a l : s = s i n g l e t , d = d o u b l e t , t = t r l p l e t , q = q u a r t e t , m = m u I t I p I e t , d d = d o u b l e t o f d o u b l e t s , d t = d o u b l e t o f t r i p l e t s , s e p t = s e p t e t , b r = b r o a d . E l e m e n t a l a n a l y s e s w e r e p e r f o r m e d a t t h e M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y o f B r i t i s h C o j u m b l a . O z o n e was g e n e r a t e d w i t h a W e l s b a c h model T - 2 3 l a b o r a t o r y o z o n a t o r a t an o p e r a t i n g v o l t a g e o f 92 V and a p r e s s u r e o f 2 . 2 5 p s i . 199 A n a l y t i c a l t h i n - l a y e r c h r o m a t o g r a p h y ( t i c ) was c a r r i e d o u t on M e r c k s i l i c a g e l 6OF254 p r e - c o a t e d a l u m i n u m s h e e t s w h i l e p r e p a r a t i v e t i c was c a r r i e d o u t on 20x20 cm g l a s s p l a t e s c o a t e d w i t h M e r c k s i l i c a g e l HF254+366- T , c P l a t e s w e r e v i s u a l i z e d by e i t h e r e x p o s u r e t o u l t r a v i o l e t l i g h t o r s p r a y i n g w i t h an a c i d i c s o l u t i o n (10% H2SO4) o f ammonium m o l y b d a t e ( 0 . 0 6 1 M) f o l l o w e d by h e a t i n g . F l o r l s i l ( 1 0 0 - 2 0 0 mesh) a n d M e r c k s i l i c a g e l ( 7 0 - 2 3 0 mesh) w e r e u s e d f o r c o l u m n c h r o m a t o g r a p h y . M e r c k s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) was u s e d f o r f l a s h c h r o m a t o g r a p h y . Woelm n e u t r a l a c t i v i t y g r a d e 1 a l u m i n a was u s e d f o r t h e d r y i n g o f some r e a c t i o n s o l v e n t s . A l l c h r o m a t o g r a p h y s o l v e n t s y s t e m s a r e e x p r e s s e d In r a t i o s by v o l u m e . A n a l y t i c a l g a s c h r o m a t o -g r a p h y was c a r r i e d o u t on a H e w l e t t - P a c k a r d mode l 5830A g a s c h r o m a t o g r a p h e q u i p p e d w i t h 1.8 m x 0 . 3 cm c o l u m n s p a c k e d w i t h 3% O V - 1 7 o r 3% O V - 1 0 1 . 200 Chapter I 2( S)-Am I no-3-phenv I prooan-1-o I (£2.) OH To a s t i r r e d solution of 25.0 g (151 mmol) of L-Phenyl-alanlne (50.) In 600 mL of absolute ethanol at 0°C was slowly added 15.3 mL (24.9 g, 210 mmol) of thlonyl chloride. The solution was then refluxed for 4 h. After the reaction mixture had cooled to r t , the solvent and excess thlonyl chloride were evaporated to give a white s o l i d . The crude ethyl ester hydrochloride 5_L was dissolved In 375 mL of 50% aqueous ethanol and then added slowly to a s t i r r e d solution of 28.8 g (761 mmol) of sod I urn borohydrlde In 375 mL of 50% aqueous ethanol. The reaction mixture was refluxed for 4 h, cooled to r t , and the bulk of the solvent was evaporated. The residual aqueous phase was saturated with s o l i d NaCl and then extracted with three 400 mL portions of ethyl acetate. The p r e c i p i t a t e of borate ester was hydrolyzed with aqueous 2 M NaOH to release the amino alcohol and the aqueous mixture was extracted twice with additional ethyl acetate. These extracts were combined with the bulk extract above and dried over anhydrous magnesium su l f a t e . Solvent removal gave a white s o l i d and r e c r y s t a l l l -zation from ethyl acetate-petroleum ether yielded 15.7 g (69%) of amino alcohol 5_2. as fine white needles. 2 0 1 mp 9 1 - 9 3 ° C ; [ a ] D - 2 6 . 0 ° ( £ 2 . 0 1 ) ; Ir ( f i l m ) : 3 6 4 0 , 3 3 8 0 , 3 2 0 0 ( b r ) c m " 1 ; m s m / Z : 1 5 2 ( M + + 1 , 0 . 3 ) , 1 2 0 ( 4 8 ) , 9 1 ( 1 5 ) , 6 0 ( 1 0 0 ) ; 1 H nmr (270 MHz) 6: 1 .80 ( b r s , 3 , O H , NH_2) » 2 . 5 0 ( d d , 1 , J = 8 , 1 3 . 6 , C J d 2 p h ) > 2 . 7 9 (dd , 1 , A=5 , 1 3 , CH_2Pn ) , 3 . 0 6 - 3 . 2 0 ( m , 1 , C h l N ) , 3 . 3 6 (dd , 1 , J.=7 , 1 1 ,CH. 2 0 ) , 3 . 6 4 (dd , 1 , J=4 , 1 1 , C H 2 O ) , 7 . 1 5 - 7 . 3 5 ( m , 5 , C 6 t l 5 ) . £j&ac_£ mass, c a l c d . f o r C g H 1 3 N 0 : 1 5 1 . 0 9 9 7 ; f o u n d : 1 5 1 . 0 9 7 3 . 2 ( S ) - B e n z v 1 a z l r I d l n e ( 5_4 ) 4 1 H A s o l u t i o n o f 9 . 3 5 g ( 6 1 . 8 mmol) o f a m i n o a l c o h o l 52. In 37 mL (74 mmol) o f a q u e o u s 2 M H 2 S O 4 was e v a p o r a t e d on a r o t a r y e v a p o r a t o r ( 5 0 ° C , 10 mm H g ) . T h e r e s u l t i n g s a l t was h e a t e d a t 1 4 0 ° C f o r 3 h a t 0 .1 mm Hg t o c o m p l e t e f o r m a t i o n o f t h e h y d r o g e n s u l f a t e . A f t e r t h e r e a c t i o n m i x t u r e had c o o l e d t o r t , 155 mL (310 mmol) o f a q u e o u s 2 M NaOH was a d d e d , and t h i s m i x t u r e was t h e n d i s t i l l e d a t a t m o s p h e r i c p r e s s u r e . T h e d i s t i l l a t e was c o l l e c t e d In an I c e - c o o l e d f l a s k c o n t a i n i n g 40 mL o f e t h e r a n d 2 mL o f a q u e o u s 2 M NaOH. A I i t t l e w a t e r was o c c a s i o n a l l y a d d e d t o t h e d i s t i l l a t i o n f l a s k w h e n e v e r t h e r e s i d u e b e g a n t o c r y s t a l l i z e . When t h e d i s t i l l a t e no l o n g e r had a m i l k y a p p e a r a n c e , t h e e t h e r l a y e r was s e p a r a t e d , and t h e a q u e o u s l a y e r was s a t u r a t e d w i t h s o l i d N a C l and e x t r a c t e d w i t h t h r e e 40 mL p o r t i o n s o f e t h e r . T h e c o m b i n e d e t h e r e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and s o l v e n t r e m o v a l 202 a f f o r d e d the c r u d e a z l r i d i n e 5_4 which was d i s t i I led ( b u l b - t o -b u l b ) , 7 0 ° C (0 .5 mm Hg) , from a p e l l e t of po tass ium h y d r o x i d e to y i e l d 6.75 g (82%) of a c o l o r l e s s l i q u i d . The product was s t o r e d on a p e l l e t of KOH In a r e f r i g e r a t o r . 1 H nmr (270 MHz) 6: 0 .60 (br S ,1 ,NH.) , 1.44 ( d , 1 , J.=4, CH.2N) » 1.80 ( d , 1 ,.,i=6,CH.2N) , 2 . 1 6 - 2 . 2 5 (m,1 ,CHN) , 2 .65 ( d d , 1 ( J l - 6 , 13 .6 ,CH. 2 Ph) . 2 .80 (dd , 1 ,^1=6, 15 ,CH. 2 p h) , 7 . 14-7 .36 (m,5, C6tl5) • 2 -Deuter I o -2 -methv I butano I c a c i d (6_5J To a s t i r r e d s o l u t i o n of LDA (10.0 mmol) In THF-hexane at 0 ° C , p r e p a r e d by the a d d i t i o n of 7.00 mL (10 .0 mmol) of 1.43 M n-butyI I Ithiurn In hexane to 1.40 mL (1.01 g , 10.0 mmol) of dI isopropyI amine In 25 mL of THF at 0 ° C , was added dropwise 0.546 mL (511 mg, 5 .0 mmol) of f r e s h l y d i s t i l l e d 2 - m e t h y l -b u t a n o l c a c i d ( £ 4 J . The m i x t u r e was s t i r r e d fo r 30 min at 0 ° C , quenched w i t h 6 mL (12 mmol) of 2 M D 2 S O 4 In D 2 O , and then a l l o w e d to warm to r t . The THF was removed by r o t a r y e v a p o r a t i o n , and the s o l u t i o n was s a t u r a t e d w i th s o l i d NaCl and e x t r a c t e d w i t h t h r e e 25 mL p o r t i o n s of e t h y l a c e t a t e . The combined e x t r a c t was washed w i th two 5 mL p o r t i o n s of s a t u r a t e d NaCl s o l u t i o n and then d r i e d over anhydrous magnesium s u l f a t e . S o l v e n t removal f o l l o w e d by d i s t i l l a t i o n ( b u l b - t o - b u l b ) , 7 0 ° C [ c t ] D - 5 . 6 0 ° (c. 2 . 0 3 ) ; Ir ( C H C I 3 ) : 3330 cm -1 . D CH3 203 (10 mm H g ) , a f f o r d e d 507 mg (99%) o f t h e a c i d a s a c o l o r l e s s l i q u i d . M a s s s p e c t r a l a n a l y s i s o f t h e d e u t e r a t e d 2 - m e t h y l -b u t a n o i c a c i d showed a d e u t e r i u m I n c o r p o r a t i o n l e v e l o f 3 5 . 9 % . T h e a b o v e p r o c e d u r e was r e p e a t e d t w i c e m o r e on t h e same s a m p l e o f a c i d . A y i e l d o f 70% was o b t a i n e d a f t e r t h e t h i r d d e u t e r a t l o n a n d t h e f i n a l d e u t e r i u m I n c o r p o r a t i o n l e v e l was 7 2 . 3 % . ( + ) - 2 ( S ) - M e t h v l b u t a n o l c a c i d (Ma) To a s t i r r e d m i x t u r e o f 1 .06 g ( 1 2 . 0 mmol) o f ( - ) - 2 ( S _ ) -methy I b u t a n - 1 - o I ( 70a ) ( [ O ] D 2 4 - 6 . 2 8 ° (c_ 1 0 . 2 ) ) and 301 mg ( 2 . 8 4 mmol) o f s o d I urn c a r b o n a t e In 3 mL o f w a t e r was a d d e d a s o l u t i o n o f 2 . 4 7 g ( 1 5 . 6 mmol) o f p o t a s s I urn p e r m a n g a n a t e In 50 mL o f w a t e r o v e r a 4 m i n p e r i o d a t 0 ° C . T h e r e a c t i o n m i x t u r e was a l l o w e d t o warm t o r t and s t i r r i n g was c o n t i n u e d f o r 24 h . T h e e x c e s s p e r m a n g a n a t e was d e c o m p o s e d w i t h s o d I urn s u l f i t e , and t h e p r e c i p i t a t e d m a n g a n e s e d i o x i d e was r e m o v e d by f i l t r a t i o n t h r o u g h a l a y e r o f C e l l t e In a s i n t e r e d g l a s s f u n n e l . T h e f i l t r a t e was e x t r a c t e d w i t h two 25 mL p o r t i o n s o f e t h e r t o r e m o v e a n y u n r e a c t e d a l c o h o l , a c i d i f i e d w i t h c o n c e n t r a t e d H C l , s a t u r a t e d w i t h s o l i d N a C l , and e x t r a c t e d w i t h t h r e e 50 mL p o r t i o n s o f e t h y l a c e t a t e . T h e c o m b i n e d e t h y l a c e t a t e e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d t o g i v e a l i g h t y e l l o w l i q u i d . T h e c r u d e p r o d u c t was d i s t i l l e d 204 ( b u l b - t o - b u l b ) , 70°C (10 mm Hg), t o y i e l d 841 mg (69%) o f a c i d 64a a s a c o l o r l e s s l i q u i d . [ c t] D+16.7° ( £ 5 . 0 1 ) ; i r ( f i l m ) : 3 0 5 0 ( b r ) , 1710 cm- 1; 1H nmr (100 MHz) 6: 0.95 ( t , 3 , J.=7 , CH . 3 C H 2) , 1.18 (d,3,^=7, C U 3 C H ) , 1.3-1.9 ( m , 2 , C h l 2 ) , 2.3-2.6 (m,1,Chl), 9.8 ( b r s , 1 , C O 2 H . ) • E x a c t mass c a l c d . f o r C 5 H 1 Q O 2 : 102.0681; f o u n d : 102.0681. H v d r o l v s i s o f o x a z o l i n e 6_Z A s t i r r e d s o l u t i o n o f 327 mg (1.50 mmol) o f o x a z o l i n e £ 7 and 1.5 mL o f 6 M DC I In D 2 0 was h e a t e d a t r e f l u x f o r 4 h. The m i x t u r e was c o o l e d t o r t and e x t r a c t e d w i t h t h r e e 10 mL p o r t i o n s o f e t h y l a c e t a t e . The combined e x t r a c t was washed w i t h two 2 mL p o r t i o n s o f s a t u r a t e d NaCl s o l u t i o n , d r i e d o v e r a n h y d r o u s magnesium s u l f a t e , and e v a p o r a t e d t o g i v e t h e c r u d e a c i d . D i s t i l l a t i o n ( b u l b - t o - b u l b ) , 6 5 ° C (10 mm Hg), o f t h e c r u d e p r o d u c t gave 146 mg (95%) o f a c i d 6_4_ a s a c o l o r l e s s l i q u i d . Mass s p e c t r a l a n a l y s i s I n d i c a t e d t h e p e r c e n t a g e o f d e u t e r i u m i n c o r p o r a t e d a t t h e a - p o s l t l o n was 0.2%. Ir ( f i l m ) : 3 0 5 0 ( b r ) , 1710 cm- 1; 1H nmr (100 MHz) 5 : 0.95 ( t . 3 , ^ 7 ) , 1.18 ( d ,3,^=7), 1.3-1.9 (m,2), 2.3-2.6 (m,1), 9.8 ( b r s,1 ) . &1 205 H v d r o l v s l s o f dI a s t e r e o m e r I c m i x t u r e o f o x a z o l Ines 67a and 67b o b t a i n e d f r o m c h i r a l a l k y l a t l o n o f o x a z o l i n e H CH3°^6Ja H 67b A s o l u t i o n o f 218 mg ( 1 . 0 0 mmol) o f t h e d I a s t e r e o m e r I c m i x t u r e o f t h e a l k y l a t e d o x a z o l I n e s 67a and 67b and 1 .0 mL o f 6 M DCI in D 2 0 was h e a t e d t o r e f l u x f o r 4 h . T h e m i x t u r e was c o o l e d t o r t a n d e x t r a c t e d w i t h t h r e e 10 mL p o r t i o n s o f e t h y l a c e t a t e . T h e c o m b i n e d e x t r a c t was w a s h e d w i t h two 2 mL p o r t i o n s o f s a t u r a t e d NaCl s o l u t i o n , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , and e v a p o r a t e d t o g i v e t h e a c i d w h i c h was t h e n d i s t i l l e d ( b u l b - t o - b u l b ) , 6 5 ° C (10 mm H g ) , t o a f f o r d 46 .1 mg (45%) o f a c o l o r l e s s l i q u i d . M a s s s p e c t r a l a n a l y s i s showed an c x - d e u t e r l u m i n c o r p o r a t i o n l e v e l o f 0 . 2 % . [ a ] D + 4 - 3 8 ° ( C 2 . 0 1 ) . CC.H H" TCH3 M a CHs^X CH3- H 64b CO2H G e n e r a l m e t h o d f o r p r e p a r a t i o n o f 2 - s u b s t I t u t e d 4 ( S ) - b e n z v l -o x a z o l I n e s 4 1 To a s t i r r e d s o l u t i o n o f 10 mmol o f t h e c a r b o x y l i c a c i d In 10 mL o f THF was a d d e d 1.62 g (10 mmol) o f CDI In s e v e r a l p o r t i o n s o v e r 5 m i n . T h e s o l u t i o n was s t i r r e d a t r t f o r 1 h , and t h e n 1 .33 g (10 mmol) o f 2 ( S _ ) - b e n z y I a z I r I d i ne (5_4) was a d d e d . S t i r r i n g was c o n t i n u e d f o r a n o t h e r 1 h , a n d t h e n 185 mg 206 ( 0 . 5 0 mmol) o f t e t r a - n - b u t y I a m m o n I urn I o d i d e was a d d e d t o t h e t l - a c y I a z I r I d I n e - lm I d a z o I e m i x t u r e and t h e r e a c t i o n m i x t u r e was r e f l u x e d f o r 2 . 5 h . A f t e r t h e r e a c t i o n m i x t u r e had c o o l e d t o r t , i t was d i l u t e d w i t h 60 mL o f e t h e r and w a s h e d w i t h f o u r 15 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d t o g i v e t h e c r u d e p r o d u c t a s a p a l e y e l l o w l i q u i d . B u l b - t o - b u l b d i s t i l l a t i o n ( 6 5 ° C , 0 .1 mm Hg) o f t h e c r u d e p r o d u c t y i e l d e d a c o l o r l e s s l i q u i d . ( - ) - 2 - E t h v l - 4 ( S ) - b e n z v l o x a z o l Ine (5_8_) P r o p a n o i c a c i d (5JZ.) was u s e d and a d i s t i l l e d y i e l d o f 72% was o b t a i n e d . [ a ] D - 3 6 . 5 ° (c_ 1 . 2 2 ) ; Ir ( C H C I 3 ) : 1665 c m " 1 ; ms m / z : 1 8 9 ( M + , 8 ) , 1 2 0 ( 3 0 ) , 9 8 ( 1 0 0 ) , 9 1 ( 2 2 ) ; 1 H nmr (270 MHz) 6: 1.18 ( t , 3 , J.=7 . 8 , CH.3 ) , 2 . 2 9 ( q , 2 , J.=7 . 8 , C H 3 C J J 2 ) » 2 . 6 4 ( d d , 1 ,A=S. 1 4 , C h l 2 P h ) . 3 . 1 3 ( d d , 1 t J i = 5 , 1 4 , C U 2 P h ) . 3 . 9 6 ( t . l . J - 8 , CH 20), 4 . 1 4 ( t , 1 , ^ = 9 , C H . 2 0 ) , 4 . 2 8 - 4 . 4 5 (m,1,CHN), 7 . 1 4 - 7 . 3 7 ( m , 5 , C 6 t l 5 ) . £xad mass c a l c d . f o r C 1 2 H 1 5 N O : 189 .1 154; f o u n d : 1 8 9 . 1 1 5 2 . g - D e u t e r i o - 2 - (2 ' - b u t v I ) - 4 ( S i - b e n z y l o x a z o I Ine (£6_) 207 The f o l l o w i n g amounts o f r e a g e n t s were e m p l o y e d : 142 mg (1.38 mmol) o f 2 - d e u t e r I o-2-methy I b u t a n o I c a c i d (6_5_) ( w i t h d e u t e r i u m I n c o r p o r a t i o n l e v e l o f 72.3%) In 1.4 mL o f THF, 225 mg (1.39 mmol) o f CDI, 0.183 mL (184 mg, 1.38 mmol) o f 2 (3.) - b e n z y I az I r i d I ne (5_4J , and 25.9 mg (0.070 mmol) o f t e t r a -n-butyIammonI urn I o d i d e . A d i s t i l l e d y i e l d o f 184 mg (65%) was o b t a i n e d . Mass s p e c t r a l a n a l y s i s i n d i c a t e d a d e u t e r i u m I n c o r p o r a t i o n l e v e l o f 72.8%. Ir ( f i l m ) : 1665 cm" 1. ( - ) - 2 - ( 2 ' ( S ) - B u t v n - 4 ( S ) - b e n z v l o x a z o l Ine (£7_a) ( + )-2(S_) -Methy I b u t a n o I c a c i d ( 64a) was use d and a d i s t i l l e d y i e l d o f 62% was o b t a i n e d . C O ] D - 1 8 . 1 ° ( £ 3 . 1 2 ) , -61.5° ( £ 2 . 0 0 , C H 3 C N ) ; i r ( f i l m ) : 1665 cm-"1; msm/z: 217(M+,3), 1 2 6 ( 1 0 0 ) , 9 1 ( 7 ) ; 1H nmr (400 MHz) 0.91 ( t , 3 , J1=7,CH3CH 2) , 1.16 ( d , 3,^=7, CH . 3 C H ) , 1.4-1.55 (m, 1 ,CH 3Cti2) . 1.6-1.7 (m , 1 , C H 3 C H 2 > . 2.3-2.5 (m, 1 ,CH 3CH) , 2.65 (dd , 1 , ^ =8 , 14, CH. 2Ph) , 3.12 (dd , 1 , J.=5, 14,CH. 2Ph) , 3.95 ( t , 1 , J = 8 ,Ctt 20) , 4.14 ( t , 1 , J.= 8 , CH. 2° > . 4.3-4.45 (m,,1 ,CHN) . 7.2-7.4 (m,5,C 6H. 5). E_x_ac_i ffliLS-S. c a I c d . f o r C^H-igNO: 217.1466; f o u n d : 217.1463. 208 (-)-2-( 2 ' - P r Q P Y ) ) - 4 ( S ) - b e n z y l p x a ? P l me (6_a) C H 3 CH 3 ) 2-Methy I p r o p a n o I c a c i d (6_9_) was u s e d and a d i s t i l l e d y i e l d o f 8 1 % was o b t a i n e d . [ a ] D - 2 9 . 5 ° ( C 1.16); Ir ( C H C I 3 ) : 1660 cm- 1; 1H nmr (100 MHz) 6: 1.18 (d , 6 ,^ 1=7 , CH3) . 2.50 ( s e p t , 1 ,.,1=7 , CH3CH) , 2.60 (d d , 1 ,A=&, 13,CH.2 ph) > 3-05 (dd , 1 , ^ =4 . 8 , 14 , CH.2Ph). 3.86 ( t , 1 ,.,1=7.6,CH.20) , 4.05 ( t , 1 , J.= 8 , Cfci 20) , 4.1-4.5 (m,1,CHN), 7.0-7.4 (m,5,C 6H. 5). ( - ) - 2 - ( 2 ' - B u t v l ) - 4 ( S ) - b e n z v l o x a z o l Ine (6_7_) 2-Methy I b u t a n o I c a c i d (£4.) was us e d and a d i s t i l l e d y i e l d o f 72% was o b t a i n e d . 1H nmr (400 MHz) s p e c t r a l a n a l y s i s I n d i c a t e d e q u a l q u a n t i t i e s o f d I a s t e r e o m e r s 67a and 67b. C a 3 D - 2 5 . 7 ° (c_ 2 . 0 2 ) , - 7 2 . 9 ° (£ 2.05, CH3CH); i r (CHCI3): 1660 cm- 1; 1H nmr (400 MHz) 6: 0.905 & 0.910 (t,3, Ji=7,CH,3CH 2) , 1-152 & 1.156 (d , 3 , J=7 , CH.3CH ) , 1.4-1.6 (m, 1 ,CH 3CH. 2) » 1.6-1.8 (m, 1 ,CH 3CH. 2) . 2.3-2.5 (m,1, CH3CU), 2.62 ( o v e r l a p p i n g dd,1,^=8,14,CH 2Ph), 3.11 ( o v e r -l a p p i n g dd, 1 tJJ.=4.8, 14,CH.2 P n) » 3.94 ( o v e r l a p p i n g t , 1,J=8, C H . 2 ° ) . 4 - 1 2 ( o v e r l a p p i n g t , 1 t J i - 8 , C U 2 0 ) . 4.3-4.5 (m,1,CUN), 209 7.1-7.4 (m,5,C6hl5)- Ana I . c a l c d . f o r C14H19NO ( 2 1 7 . 3 1 ) : C 77.38, H 8.81, N 6.45; f o u n d : C 77.17, H 8.54, N 6.62. E x a c t mass c a l c d . f o r C^H-igNO: 217.1466; f o u n d : 217.1468. A l k v l a t l o n o f o x a z o l i n e 5_& w i t h m e t h v l I o d i d e A s o l u t i o n o f LDA (1.05 mmol) In THF-hexane was p r e p a r e d by t h e add 11 i o n o f 0.735 mL (1.05 mmoI) o f 1.43 M n-butyI Ii t h i urn In hexane t o a s t I r r e d s o IutI on o f 0.147 mL (106 mg, 1.05 mmoI) o f dI I s o p r o p y I am Ine In 1.0 mL o f THF a t 0 ° C . The r e s u l t i n g s o l u t i o n was c o o l e d t o -78°C and s t i r r e d f o r 10 min p r i o r t o t h e d r o p w l s e a d d i t i o n o f a s o l u t i o n o f 189 mg (1.00 mmol) o f o x a z o l i n e 5_B_ In 3.0 mL o f THF o v e r 3 m i n . The m i x t u r e was s t i r r e d a t - 7 8 ° C f o r 1 h b e f o r e t h e a d d i t i o n o f 0.069 mL (156 mg, 1.10 mmol) o f m e t h y l I o d i d e a t - 7 8 ° C . The r e a c t i o n m i x t u r e was t h e n a l l o w e d t o warm g r a d u a l l y t o r t w h i l e s t i r r i n g was c o n t i n u e d f o r 5 h. The m i x t u r e was d i l u t e d w i t h 8 mL o f s a t u r a t e d NaCl s o l u t i o n and e x t r a c t e d w i t h t h r e e 15 mL p o r t i o n s o f e t h e r . The comb i n e d e t h e r e x t r a c t was d r i e d o v e r a n h y d r o u s magnesium s u l f a t e and e v a p o r a t e d t o g i v e t h e c r u d e p r o d u c t a s a l i g h t y e l l o w l i q u i d . B u l b - t o - b u l b d i s t i l l a t i o n (65°C, 0.1 mm Hg) o f c r u d e 6_8_ gave 169 mg (83%) o f a c o l o r l e s s l i q u i d . Ir and 1H nmr s p e c t r a were i d e n t i c a l t o t h a t o f o x a z o l i n e 6_S. p r e p a r e d from 2 - m e t h y I p r o p a n o i c a c i d by t h e I m l d a z o l l d e r o u t e . 210 [ a ] D - 3 4 . 5 ° ( £ 1 . 1 7 ) . ( + ) - 1 - P r o D a n o v l - 2 ( S ) - b e n z v l a z l r l d l n e (6_3_) 9=0 CH2CH3 To a s t i r r e d s o l u t i o n o f 370 mg ( 5 . 0 mmol) o f p r o p a n o i c a c i d In 5 mL o f THF was a d d e d 811 mg ( 5 . 0 mmol) o f CDI In s e v e r a l p o r t i o n s , and t h e n s t i r r e d a t r t f o r 1 .5 h and u s e d be Iow. T o a s t i r r e d s u s p e n s i o n o f 756 mg ( 5 . 0 mmol) o f a m i n o a l c o h o l 5_£ and 1.31 g ( 5 . 0 mmol) o f t r I p h e n y I p h o s p h I ne in 10 mL o f THF was a d d e d 0 . 7 9 mL (880 mg, 5 . 0 mmol) o f DEAD d r o p w l s e . T h e r e a c t i o n m i x t u r e was h e a t e d a t r e f l u x f o r 2 h , a l l o w e d t o c o o l t o r t , and t h e n t h e p r o p a n o y l I m l d a z o l l d e s o l u t i o n was a d d e d ( a f t e r q u i c k f i l t r a t i o n t h r o u g h g l a s s wool t o r e m o v e I m i d a z o l e ) . T h e r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 1 .5 h , t a k e n up In 75 mL o f e t h e r , and w a s h e d w i t h t h r e e 15 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l . T h e c r u d e p r o d u c t was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 15 g o f f l o r l s l l ( 1 0 0 - 2 0 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 4 : 1 ) a s t h e e l u t i n g s o l v e n t t o g i v e a l i g h t y e l l o w l i q u i d w h i c h was f u r t h e r p u r i f i e d by b u l b -t o - b u l b d i s t i l l a t i o n ( 6 5 ° C , 0 . 1 5 mm Hg) t o a f f o r d 717 mg (76%) o f a c y I a z i r i d i n e 6_3_ a s a c o l o r l e s s l i q u i d . Rf 0 . 6 4 ( E t O A c - p e t r o I e u m e t h e r , 3 : 2 ) ; [ a 3 o + 6 7 . 5 ° 21 1 ( £ 2 . 0 3 ) ; Ir ( f i l m ) : 1685 c m " 1 ; 1 H nmr (100 MHz) 6 : 1 .02 ( 1 , 3 , ^ = 7 , 0 ^ 3 ) , 1 .99 ( d , 1 t J i - 3 , C U 2 N ) , 2 . 1 9 ( q , 2,1=1, C H 3 C h l 2 ) . 2 . 3 2 ( d , 1 , J i =5 ,CM2N) , 2 . 4 4 - 2 . 7 0 ( m , 1 , C H N ) , 2 . 7 8 ( d , 1 , J i = 4 , C H 2 P h ) . 2 . 8 0 (d , 1 , ^ =8 , C H 2 P h ) , 7 . 1 0 - 7 . 3 5 ( m , 5 , C6II5) • A c y l a z l r l d i n e 6_3_ (379 mg, 2 . 0 mmol) was s u b s e q u e n t l y r e a r r a n g e d w i t h a c a t a l y t i c amount o f t e t r a - n - b u t y I a m m o n i u r n i o d i d e ( 3 6 . 9 mg, 0 . 1 0 mmol) In 3 mL o f r e f l u x l n g THF f o r 4 h t o a f f o r d , a f t e r w o r k - u p and p u r i f i c a t i o n by b u l b - t o - b u l b d i s t i l l a t i o n , 348 mg (92%) o f o x a z o l i n e 5 8 . O - B e n z v l - L - t v r o s l n e (Z£) T h i s compound was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f M o r l e y 4 9 w i t h m o d i f i c a t i o n s g a i n i n g In y i e l d . A s o l u t i o n o f 9 . 0 6 g (50 mmol) o f L - t y r o s Ine (23.) i n 50 mL (100 mmol) o f a q u e o u s 2 M NaOH was t r e a t e d w i t h 6 . 2 6 g ( 25 .1 mmol) o f c o p p e r ( l l ) s u l f a t e p e n t a h y d r a t e In 25 mL o f w a t e r . T h e m i x t u r e was s t i r r e d a t r t f o r 15 m i n u n t i l t h e p r e c i p i t a t e d m a t e r i a l had d i s s o l v e d , and t h e n 150 mL o f m e t h a n o l was a d d e d f o l l o w e d by 6 . 0 mL ( 8 . 5 7 g , 50 .1 mmol) o f b e n z y l b r o m i d e . S t i r r i n g was c o n t i n u e d a t r t f o r 24 h . T h e b l u e c o p p e r c o m p l e x was f i l t e r e d a n d w a s h e d s u c c e s s i v e l y w i t h t h r e e 25 mL p o r t i o n s o f w a t e r a n d two 25 mL p o r t i o n s o f m e t h a n o l . T h e semi a l r -d r l e d s o l i d was t r e a t e d w i t h 100 mL o f p r e h e a t e d ( 4 0 ° C ) a q u e o u s 1 M HCl a n d s t i r r e d a t 4 0 ° C f o r 20 m i n . T h e m i x t u r e was c o o l e d 212 In an ice bath and the s o l i d was f i l t e r e d and washed with some water. The s o l i d was s t i r r e d with warm HCl twice more u n t i l the f i l t r a t e was c o l o r l e s s . The r e s u l t i n g white s o l i d was s t i r r e d with 50 mL of aqueous 16.4% NaOAc at 80-90°C for 15 min. The mixture was c o o l e d In an i c e bath, and the s o l i d was f i l t e r e d , washed with water, and d r i e d In vacuo at 50°C over P2O5 to a f f o r d 9.86 g (73%) of Q-benzyI-L-tyrosIne as a whIte so I Id. mp 216-218°C (decomp) ( l i t . , 4 9 224-226°C); ms m/z: 271(M+,4), 226(3), 197(26), 91(100). O - B e n z v l - L - t v r o s l n e e t h v l e s t e r h y d r o c h l o r i d e (7_£) To a s t i r r e d suspension of 1.36 g (5.0 mmol) of Q-benzyI-L-t y r o s l n e (23.) in 30 mL of a b s o l u t e ethanol at 0°C was sl o w l y added 0.44 mL (714 mg, 6.0 mmol) of t h l o n y l c h l o r i d e . The s o l u t i o n was heated at r e f l u x f o r 5 h. A f t e r the r e a c t i o n mixture had c o o l e d to r t , the s o l v e n t and excess t h l o n y l c h l o r i d e was evaporated under reduced p r e s s u r e t o g i v e a yellow s o l i d . The crude product was r e c r y s t a I I ized from ethanol to a f f o r d 1.49 g (88%) of e t h y l e s t e r h y d r o c h l o r i d e 22 as a white sol i d . R f 0.62 (CHCI 3-Me0H, 5:1); mp 188.5-189.5°C (EtOH); [ a] D+18.6° (C 0.97, MeOH); ms m / Z : 299(M+-HCI,8), 226(23), 198(35), 197(100); Ana I . c a l c d . f o r C i 8 H 2 2 N 0 3 c l 213 ( 3 3 5 . 8 3 ) : C 64.38, H 6.60, N 4.17, C l 10.56; f o u n d : C 64.34, H 6.50, N 4.24, C l 10.44. E x a c t mass c a l c d . f o r C 1 8 H 2 2 N 0 3 C I - H C I : 299.1521; f o u n d : 299.1521. 2(S~>-Aml n o - 3 - ( 4 - b e n z v l o x v p h e n v l ) propan-1 -o I ( 8_0_) A s u s p e n s i o n o f 3.36 g (10 mmol) o f e t h y l e s t e r h y d r o -c h l o r i d e 7_9_ i n 40 mL o f THF was added d r o p w l s e t o a s t i r r e d s u s p e n s i o n o f 1.52 g (40 mmol) o f l i t h i u m aluminum h y d r i d e In 15 mL o f THF. The r e a c t i o n m i x t u r e was h e a t e d a t r e f l u x f o r 4 h. The e x c e s s LIAIH4 was decomposed by d r o p w l s e a d d i t i o n o f e t h y l a c e t a t e , e t h a n o l , and t h e n aqueous 2 M NaOH t o o b t a i n a w h i t e p r e c i p i t a t e o f A I ( 0 H ) 3 . The p r e c i p i t a t e was removed by f i l t r a t i o n and washed w i t h some e t h y l a c e t a t e . The f i l t r a t e was d r i e d o v e r a n h y d r o u s magnesium s u l f a t e and e v a p o r a t e d under r e d u c e d p r e s s u r e t o g i v e a w h i t e s o l i d . The c r u d e p r o d u c t was r e c r y s t a l l i z e d from e t h y l a c e t a t e - p e t r o l e u m e t h e r t o a f f o r d 2.26 g (88%) o f amino a l c o h o l QQ. as a w h i t e s o l i d . An a n a l y t i c a l s a m ple was o b t a i n e d by s u b l i m a t i o n a t 100°C (0.1 mm Hg) . mp 1 0 3 . 5 - 1 0 4 . 5 ° C ( E t O A c - p e t r o I e u m e t h e r ) ; [ a ] D - 6 . 9 1 ° (C. 1.99), - 1 3 . 8 ° (£ 1.99, MeOH); i r ( C H C I 3 ) : 3610, 3380 cm- 1; ms m / Z : 257(M+,5), 2 2 6 ( 2 6 ) , 1 9 8 ( 1 0 0 ) , 1 0 7 ( 1 7 ) , 9 1 ( 5 8 ) ; 1H nmr (400 MHz) 6: 1.89 ( b r S . 3 ,0hi, NH2 ) . 2.48 ( d d , 1 ,J=8, 14.4,CHCH. 2Ar ) , 2.73 (dd , 1 ,J=4 . 8 , 14 . 2 ,CHCH .2 A r ) . OH 214 3 . 0 3 - 3 . 1 4 ( m . l . C H N ) , 3 . 3 7 (dd , 1 , J=6 . 8 , 1 0 . 4 , C H . 2 O H ) » 3 . 6 3 ( b r d , 1 , ^ = 8 . 5 , CH.2OH), 5 . 0 4 ( s , 2 , CH. 2 Ph) . 6 . 9 2 ( d , 2 t J i = 8 , C 6 H . 4 ) , 7 . 1 0 ( d , 2 , ^ = 8 , 0 6 ^ 4 ) , 7 . 3 0 - 7 . 4 7 ( m , 5 , C 6 H 5 ) . Ana I . c a l c d . f o r C 1 6 H 1 9 N 0 2 ( 2 5 7 . 3 4 ) : C 7 4 . 6 8 , H 7 . 4 4 , N 5 . 4 4 ; f o u n d : C 7 4 . 3 9 , H 7 . 4 8 , N 5 . 3 4 . E x a c t m a s s c a l c d . f o r C 1 6 H 1 9 N 0 2 : 2 5 7 . 1 4 1 6 ; f o u n d : 2 5 7 . 1 4 1 9 . ( + ) - l - P r o D a n o v I - 2 ( S ) - ( 4 - b e n z v I o x v b e n z v M a z l r l d l n e (QZ) To a s t i r r e d s o l u t i o n o f 8 8 . 9 mg ( 1 . 2 mmol) o f p r o p a n o i c a c i d in 1 mL o f t o l u e n e was a d d e d 195 mg ( 1 . 2 mmol) o f CDI In s e v e r a l p o r t i o n s , and t h e n s t i r r e d a t r t f o r 1 .75 h a n d u s e d be Iow. To a s t i r r e d s u s p e n s i o n o f 257 mg ( 1 . 0 mmol) o f a m i n o a l c o h o l QQ. and 265 mg ( 1 . 0 mmol) o f t r I p h e n y I p h o s p h I n e i n 2 mL o f t o l u e n e was a d d e d 0 . 1 6 0 mL (176 m g , 1 .0 mmol) o f DEAD d r o p w i s e . T h e r e a c t i o n m i x t u r e was h e a t e d a t . r e f l u x f o r 2 h , a l l o w e d t o c o o l t o r t , a n d t h e n t h e p r o p a n o y l I m l d a z o l l d e s o l u t i o n was a d d e d ( a f t e r q u i c k f i l t r a t i o n t h r o u g h g l a s s wool t o r e m o v e I m i d a z o l e ) . The r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 2 h , t a k e n up In 25 mL o f e t h e r , and w a s h e d w i t h t h r e e 5 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l . T h e c r u d e p r o d u c t was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y o n 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g C=0 CH2CH3 215 p e t r o l e u m e t h e r - e t h y l a c e t a t e (7:3) a s t h e e l u t l n g s o l v e n t t o a f f o r d 164 mg (55%) o f a c y I a z l r l d i n e £ £ a s a w h i t e s o l i d . Rf 0 .60 ( E t O A c - p e t r o I e u m e t h e r , 3:2); mp 4 4 - 4 5 ° C ; [ a ] D + 3 9 . 5 ° (c_ 1 . 78 ) ; Ir ( f i l m ) : 1685 c m " 1 ; ms m / Z : 2 9 5 ( M + , 6 ) , 266(3), 2 0 4 ( 5 ) , 91(100); 1 H nmr (400 MHz) 6: 1.08 (t,3,J=7,Cti3) , 2 .03 (d , 1 , J.=3 ,CH. 2 N) . 2 . 2 4 ( q , 2,^=7, CH3CU2). 2 . 3 7 ( d , 1 ,.»i=5,CH.2N> , 2 .55-2 .62 (m,1 ,ChlN), 2 .73 ( d d , 1 ,J.= 6, 14,CHCJd2Ar ) , 2 .83 (dd , 1 , 1=6 , 1 4 , CHCH^Ar ) , 5 . 0 6 ( S , 2 , C M 2 P h ) , 6 . 9 4 ( d,2 , J i = 8 , C 6 H 4 ) , 7 . 1 7 ( d , 2,^=8, C6O.4), 7 . 3 0 - 7 . 5 0 ( m , 5 , C 6 H 5 ) . Ana I . c a l c d . f o r C 1 9 H21 N 02 ( 2 9 5 . 3 8 ) : C 7 7 . 2 6 , H 7 . 1 7 , N 4 . 7 4 ; f o u n d : C 7 7 . 0 7 , H 7 . 3 1 , N 4 . 8 7 . E x a c t mass c a l c d . f o r C 1 9 H21 N°2 : 2 9 5 . 1 5 7 2 ; f o u n d : 2 9 5 . 1 5 7 4 . (-1 -2 - E t h v I -4 (S) - (4 - b e n z v I o x v b e n z v I ) o x a z o I Ine (S_3_) A s t i r r e d s o l u t i o n o f 1 .48 g ( 5 . 0 mmol) o f a c y I a z l r l d i n e £2 . a n d 9 2 . 3 mg ( 0 . 2 5 mmol) o f t e t r a - n - b u t y I ammon I urn I o d i d e in 6 mL o f THF was h e a t e d a t r e f l u x f o r 12 h . A f t e r c o o l i n g t o r t , t h e THF was r e m o v e d u n d e r r e d u c e d p r e s s u r e a n d t h e r e s u l t i n g r e s i d u e was t a k e n up In 50 mL o f e t h e r a n d w a s h e d w i t h t h r e e 10 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l . T h e c r u d e o x a z o l i n e was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y in s e v e r a l p o r t i o n s on 216 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g e t h y l a c e t a t e - p e t r o l e u m e t h e r ( 3 : 2 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 1 .33 g (90%) o f o x a z o l i n e 8_3_ a s a c o l o r l e s s o i l ' w h i c h c r y s t a l l i z e d on. s t a n d i n g . An a n a l y t i c a l s a m p l e was o b t a i n e d by r e c r y s t a l -I i z a t i o n f r o m e t h y l a c e t a t e t o g i v e a w h i t e s o l i d . Rf 0 . 3 4 ( E t O A c - p e t r o l e u m e t h e r , 3 : 2 ) ; mp 1 0 3 - 1 0 3 . 5 ° C ( E t O A c ) ; [ a ] D - 1 7 . 1 ° (c_ 2 . 0 2 ) ; Ir ( f i l m ) : 1660 c m " 1 ; ms m / z : 2 9 5 ( M + , 1 4 ) , 1 9 7 ( 1 9 ) , 9 8 ( 2 0 ) , 9 1 ( 1 0 0 ) ; 1 H nmr (270 MHz) 6: 1 .16 ( t , 3 ,^=7 .6 ,0 *13 ) , 2 . 2 4 ( q , 2 , J=7 . 6 , C H 3 C H . 2 ) , 2 . 6 7 ( d d , 1 , J = 8 . 4 , 1 3 , C H C H 2 A r ) . 3 - 0 0 ( dd , 1 , J.=5 , 1 4 , CHCH. 2 Ar ) , 3 . 9 0 ( t , 1 , j l -8 ,CHCH.20> , 4 . 1 2 ( t , 1 , J = 8 , CHCJJ2O) » 4 . 2 2 - 4 . 3 6 ( m , 1 , C H N ) , 5 . 0 4 ( s , 2 , CH. 2 Ph ) , 6 . 8 9 (d , 2 , J - 8 , C 6 U 4 ) , • 7 . 10 ( d ^ . J - S . C e h U ) . 7 . 2 7 - 7 . 5 2 ( m , 5 , C 6 H . 5 ) . A n a l . c a l c d . f o r C 1 9 H 2 1 N 0 2 ' H 2 0 ; C 7 2 . 8 2 , H 7 . 4 0 , N 4 . 4 7 , 0 1 5 . 3 2 ; f o u n d : C 7 2 . 6 8 , H 7 . 5 0 , N 4 . 4 9 , 0 1 5 . 2 9 . E x a c t mass c a l c d . f o r C 1 9 H 2 1 N ° 2 : 2 9 5 . 1 5 7 3 ; f o u n d : 2 9 5 . 1 5 7 3 . ( - • ) - 2 - E t h v l - 4 ( S 1 - ( 4 - h v d r o x v b e n z v l 1 o x a z o I Ine (JA) A s t i r r e d s u s p e n s i o n o f 148 mg o f 10% p a l l a d i u m on c h a r c o a l In 43 mL o f m e t h a n o l was p l a c e d u n d e r a h y d r o g e n a t m o s p h e r e ( s l i g h t p o s i t i v e p r e s s u r e ) . A s o l u t i o n o f 1 .48 g ( 5 . 0 mmol) o f o x a z o l i n e 8_2. I n 7 mL o f m e t h a n o l was a d d e d v I a s y r i n g e t o t h e p r e h y d r o g e n a t e d c a t a l y s t . T h e r e a c t i o n m i x t u r e was s t i r r e d v i g o r o u s l y f o r 3 h u n t i l t h e u p t a k e o f h y d r o g e n had c e a s e d . 217 T h e c a t a l y s t was r e m o v e d by f i l t r a t i o n t h r o u g h a l a y e r o f C e l i t e and w a s h e d w i t h m e t h a n o l and t h e n e t h y l a c e t a t e . The c o m b i n e d f i l t r a t e and w a s h i n g s w e r e e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 1.02 g (99%) o f o x a z o l i n e ZA a s a w h i t e s o l i d . An a n a l y t i c a l s a m p l e was o b t a i n e d by r e c r y s t a I I I za t I on f r o m e t h y l a c e t a t e t o g i v e w h i t e n e e d l e s . Rf 0.33 ( E t O A c - p e t r o I e u m e t h e r , 3:2); mp 1 5 9 - 1 5 9 . 5 ° C ( E t O A c ) ; [ a ] D - 4 1 . 5 ° (c_2.00, M e O H ) ; Ir (CHCI3): 3 1 0 0 ( b r ) , 1650 c m - 1 ; ms m / z : 2 0 5 ( M + , 6 ) , 107(39), 98(100); 1 H nmr (400 MHz) 6: 1.18 ( t , 3 , .i=7 . 8 , CH3 ) , 2 . 3 0 ( q.2,^7 . 8 , CH3CH2 ) ' 2 . 6 5 ( d d , 1,^-7.6,1 4 . 4 , C h 2 A r ) , 2 .89 ( d d ,1 , ^ = 6 . 4 , 13 . 6 , C t i 2 A r ) , 3.97 ( t , 1 , ^ =8 , CH.20) , 4 . 2 3 ( t , 1 , J - 8 . 5 , ChL 2 0) . 4 . 3 0 - 4 . 4 0 ( m , 1 , C h l N ) , 6 . 6 6 ( d , 2 , ^ =8 , C 6 H . 4 ) , 7.00 ( d , 2,^=8, C 6 h i 4 ) . Ana_L. c a l c d . f o r C 1 2 H i 5 N 0 2 ( 2 0 5 . 2 6 ) : C 70.22, H 7.37, N 6 . 8 2 ; f o u n d : C 7 0 . 4 0 , H 7 . 26 , N 6 . 8 4 . E x a c t m a s s c a l c d . f o r C - | 2 H 1 5N0 2: 2 0 5 . 1 1 0 3 ; f o u n d : 205.1 106 . ( - • ) - 2 - E t h v l - 4 ( S W 4 - m e t h o x v b e n z v l ) o x a z o I Ine (25.) A m i x t u r e o f 205 mg ( 1 . 0 mmol) o f o x a z o l i n e ZA, 3 . 3 mL (1 .1 mmol) o f a q u e o u s 0 . 3 3 6 M t e t r a - n - b u t y I a m m o n i u r n h y d r o x i d e , 0 . 1 2 5 mL (284 m g , 2 . 0 mmol) o f m e t h y l i o d i d e , 1 .7 mL o f w a t e r , and 5 mL o f d I c h I o r o m e t h a n e was s t i r r e d v i g o r o u s l y a t r t f o r 4 h . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s l a y e r was e x t r a c t e d w i t h t h r e e 10 mL p o r t i o n s o f d i c h I o r o m e t h a n e . T h e c o m b i n e d 218 o r g a n i c e x t r a c t was w a s h e d w i t h 10 mL o f w a t e r , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a w h i t e s o l i d . T e t r a - n - b u t y I a m m o n i u r n h y d r o x i d e was r e m o v e d by c o l u m n c h r o m a t o g r a p h y o f t h e w h i t e s o l i d on 20 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 3 : 2 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 196 mg (90%) o f o x a z o I I ne 7_5_ a s a c o I o r I e s s o i l . Rf 0 . 2 2 ( p e t r o l e u m e t h e r - E t O A c , 3 : 2 ) ; [ a ] D - 2 5 . 6 ° ( £ 2 . 0 3 ) ; i r ( f i l m ) : 1660 c m " 1 ; ms m / z : 2 1 9 ( M + , 3 1 ) , 1 2 2 ( 4 4 ) , 1 2 1 ( 1 0 0 ) , 9 8 ( 8 9 ) ; 1 H nmr (400 MHz) 6 : 1 .18 (t,3, :1=8,CH3CH2) , 2 . 2 6 ( q , 2 , JL=8 , CH3CH.2 ) , 2 . 6 0 ( d d , 1,^=8, 1 3 . 6 , C H 2 A r ) , 3 .02 ( d d , 1 , J = 5 . 2 , 1 3 . 4 , C H ^ A r ) , 3 .78 (s,3, CM3O), 3 .92 ( t , 1 , J - 8 . C U 2 0 ) . 4 . 1 4 ( t . 1 , J - 8 , C H 2 0 ) . 4 . 2 7 -4.37 ( m , 1 , C H N ) , 6 . 8 3 (d , 2 , ^ =8 , C 6 H 4 > . 7 .11 ( d , 2 f J i = 8 , C6hl4)- Ana I . c a l c d . f o r C 1 3 H 1 7 N 0 2 ( 2 1 9 . 2 9 ) : C 7 1 . 2 1 , H 7 . 81 , N 6.39; f o u n d : C 70.94, H 7 . 91 , N 6.33. E x a c t m a s s c a l c d . f o r C i 3 H i 7 N 0 2 : 2 1 9 . 1 2 5 9 ; f o u n d : 2 1 9 . 1 2 5 9 . ( - ) - 2 - E t h v I - 4 ( S ) - r 4 - ( 2 - o x a p r o p v l o x v l b e n z v I 1 o x a z o I I ne (7_5_) 0M0M To a s t i r r e d s u s p e n s i o n o f 36 mg ( 1 . 5 mmol) o f s o d I urn h y d r i d e (72 mg o f 50% d i s p e r s i o n In o i l ; w a s h e d t h r e e t i m e s w i t h p e t r o l e u m e t h e r ) In 4 mL o f THF was a d d e d 205 mg ( 1 . 0 mmol) o f o x a z o l i n e 24. A f t e r s t i r r i n g f o r 10 m i n , 0 . 1 1 4 mL (121 mg, 1 .5 mmol) o f c h l o r o m e t h y l m e t h y l e t h e r was a d d e d . The 219 r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 24 h , p o u r e d I n t o 5 mL o f w a t e r , and t h e n e x t r a c t e d w i t h t h r e e 15 mL p o r t i o n s o f e t h y l a c e t a t e . The c o m b i n e d o r g a n i c e x t r a c t was w a s h e d w i t h two 5 mL p o r t i o n s o f s a t u r a t e d NaCl s o l u t i o n , d r i e d o v e r a n h y d r o u s m a g -n e s i u m s u l f a t e , a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l . T h e c r u d e o x a z o l i n e was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 15 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g e t h y l a c e t a t e - p e t r o l e u m e t h e r (1:1) a s t h e e l u t l n g s o l v e n t t o a f f o r d 103 mg (41%) o f o x a z o l i n e 23. a s a c o l o r l e s s o i l . Rf 0 .30 ( p e t r o l e u m e t h e r - E t O A c , 3:2); [ a ] D - 2 3 . 4 ° (£2.11); Ir ( f i l m ) : 1660 c m - " 1 ; m s m / z : 2 4 9 ( M + , 1 7 ) , 152(33), 151(49), 9 8 ( 5 0 ) , 45(100); 1 H nmr (400 MHz) 6: 1.18 ( t , 3 , j l « 8 , C H 3 C H 2 ) , 2 .27 ( q , 2 , ^ = 8 , C H 3 C H 2 ) , 2 .60 (dd,1, .,1=8.4, 1 4 , C H ^ A r ) , 3 . 0 3 ( dd , 1 , ^ =5 . 2 , 1 3 . 6 , C H . 2 A r ) , 3.47 (s,3, CH.3O), 3.93 ( t , 1 ,Ji=8,CHCH20) , 4 . 1 5 ( t , 1 , ^ =8 , C H C H . 2 ° ) . 4.27-4.37 (m,1 ,ChlN), 5 .14 ( s , 2 ,0CH.2°) . 6 . 9 6 ( d , 2 , ^ - 8 , CQti.4) , 7 - 1 1 (d.2,J=8,C 6tl4) • E&a£i m2LS_s_ c a I c d . f o r C14H19NO3: 2 4 9 . 1 3 6 5 ; f o u n d : 2 4 9 . 1 3 6 3 . ( - 1 - 2 - E t h v I - 4 ( S ) - f 4 - ( 2 . 5 - d l o x a h e x v I o x v ^ b e n z v I l o x a z o l I ne (22) OMEM T o a s t i r r e d s u s p e n s i o n o f 36 mg ( 1 . 5 mmol) o f s o d I urn h y d r i d e (72 mg o f 50% d i s p e r s i o n in o i l ; w a s h e d t h r e e t i m e s w i t h p e t r o l e u m e t h e r ) In 4 mL o f THF was a d d e d 205 mg ( 1 . 0 mmoI) o f o x a z o I I n e 2 £ . A f t e r s t i r r i n g f o r 10 m i n , 0 .171 mL 220 (187 mg, 1 .5 mmol) o f B - m e t h o x y e t h o x y m e t h y I c h l o r i d e was a d d e d . T h e r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 24 h , p o u r e d I n t o 5 mL o f w a t e r , and t h e n e x t r a c t e d w i t h t h r e e 15 mL p o r t i o n s o f e t h y l a c e t a t e . T h e c o m b i n e d o r g a n i c e x t r a c t was w a s h e d w i t h two 5 mL p o r t i o n s o f s a t u r a t e d N a C l s o l u t i o n , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l . T h e c r u d e o x a z o l i n e was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 15 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g e t h y l a c e t a t e - p e t r o l e u m e t h e r ( 1 9 : 1 ) a s t h e e l u t l n g s o l v e n t t o a f f o r d 161 mg (55%) o f o x a z o l i n e U_ a s a co I o r I e s s o i l . Rf 0 . 3 8 ( E t O A c - p e t r o l e u m e t h e r , 9 : 1 ) ; [ a ] D - 2 0 . 1 ° (C_ 1 . 9 0 ) ; Ir ( f I Im) : 1660 c m - 1 ; ms m / Z : 293 (M+, 14) , 2 1 8 ( 3 ) , 9 8 ( 3 3 ) , 8 9 ( 1 0 0 ) ; 1 H nmr (400 MHz) 6 : 1 .18 ( t , 3 , J i = 7 . 8 , C U 3 C H 2 ) , 2 . 2 7 ( q , 2 , JL=T . 8 , CH3CH2 ) » 2 . 6 0 ( d d , 1,^=8, 1 4 . 8 , C h i 2 A r ) , 3 . 0 3 ( d d , 1 , J = 5 . 2 , 1 3 . 6 , C ] H 2 A r ) , 3 . 3 8 ( s , 3 , CU3O), 3 . 5 6 ( m , 2 , C H 2 0 C H 3 ) , 3 . 8 2 (m , 2 , C H . 2 C H 2 0 ) , 3 . 9 2 ( t , 1 , . , i - 8 , C H C i i 2 0 ) , 4 . 1 5 ( t , 1 f J l - 9 , C H C H 2 0 ) . 4 . 2 7 - 4 . 3 7 ( m , 1 , C H N ) , 5 . 2 4 ( s , 2 , 0 C M 2 0 ) , 6 . 9 8 (d , 2 , A=8 , C 6 H . 4 ) , 7 .11 ( d , 2 , J . = 8 , C 6M 4). E x a c t mass c a l c d . f o r C i 6 H 2 3 N 0 4 : 2 9 3 . 1 6 2 7 ; f o u n d : 2 9 3 . 1 6 2 9 . C h i r a l a l K Y l a t l P h P f O x a z o l I n e 33. w i t h e t h v l I o d i d e a t - 1 0 5 ° C A s o l u t i o n o f LDA ( 1 . 0 5 mmol) was p r e p a r e d by t h e a d d i t i o n o f 0 . 7 3 5 mL ( 1 . 0 5 mmol) o f 1 .43 M n -bu ty I I i t h I urn In h e x a n e t o a s t i r r e d s o l u t i o n o f 0 . 1 4 7 mL (106 mg, 1 .05 mmol) o f d l l s o p r o -p y l a m l n e i n 1 .0 mL o f THF a t 0 ° C . T h e r e s u l t i n g s o l u t i o n was 221 c o o l e d t o - 7 8 ° C and s t i r r e d f o r 10 m i n p r i o r t o t h e d r o p w i s e a d d i t i o n o f a s o l u t i o n o f 189 mg ( 1 . 0 0 mmol) o f o x a z o l i n e 5_8_ in 3 . 0 mL o f T H F . S t i r r i n g was c o n t i n u e d f o r 30 m i n a t - 7 8 ° C and t h e n t h e s o l u t i o n was c o o l e d t o - 1 0 5 ° C . A f t e r an a d d i t i o n a l 30 m i n , 0 . 0 8 8 mL (172 mg, 1 .10 mmol) o f e t h y l I o d i d e was a d d e d d r o p w i s e t o t h e y e l l o w a n i o n s o l u t i o n and s t i r r i n g was c o n t i n u e d f o r 4 h a t - 1 0 5 ° C . A f t e r a l l o w i n g t h e s o l u t i o n t o warm t o r t , It was d i l u t e d w i t h 8 mL o f s a t u r a t e d N a C l s o l u t i o n and some s o d I urn t h l o s u l f a t e s o l u t i o n , and t h e n e x t r a c t e d w i t h t h r e e 15 mL p o r t i o n s o f e t h e r . T h e c o m b i n e d e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e t h e c r u d e p r o d u c t w h i c h was d i s t i l l e d ( b u l b -t o - b u l b ) , 6 5 ° C (0 .1 mm H g ) , t o y i e l d 150 mg (69%) o f a c o l o r -l e s s l i q u i d . T h e o x a z o l i n e m i x t u r e f o r m e d by a l k y l a t l o n o f 5_8_ a t - 1 0 5 ° C had I d e n t i c a l s p e c t r a l p r o p e r t i e s t o t h a t p r e p a r e d by a l k y l a t l o n o f 5_8_ a t - 7 8 ° C . 1 H nmr s p e c t r a l a n a l y s i s I n d i c a t e d t h a t t h e de o f o x a z o l I n e 67a was 2 4 . 7 % . C a ] D - 2 9 - 4 ° ( C 2 . 4 5 ) . G e n e r a l p r o c e d u r e f o r c h i r a l a l k y l a t l o n o f o x a z o l Ines £8_, 7_5_-22, £3_ w i t h e t h v l I o d i d e a t - 7 8 ° C A s o l u t i o n o f LDA ( 1 . 0 5 mmol) In T H F - h e x a n e was p r e p a r e d by t h e a d d i t i o n o f 0 . 7 3 5 mL ( 1 . 0 5 mmol) o f 1 .43 M n -bu ty I I i t h i u r n In h e x a n e t o a s t i r r e d s o l u t i o n o f 0 . 1 4 7 mL (106 mg, 1 .05 mmol) o f dI i s o p r o p y I am Ine in 1 .0 mL o f THF a t 0 ° C . T h e r e s u l t i n g s o l u t i o n was c o o l e d t o - 7 8 ° C and s t i r r e d f o r 10 m i n p r i o r t o t h e d r o p w i s e a d d i t i o n o f a s o l u t i o n o f 1 .00 mmol, o f t h e 222 o x a z o l i n e In 3 . 0 mL o f T H F . S t i r r i n g was c o n t i n u e d f o r 1 h a t - 7 8 ° C , a n d t h e n 0 . 0 8 8 mL (172 mg, 1 .10 mmol) o f e t h y l I o d i d e was a d d e d t o t h e y e l l o w a n i o n s o l u t i o n and s t i r r i n g was c o n t i n u e d f o r 5 h a t - 7 8 ° C . A f t e r t h e s o l u t i o n had warmed up t o r t , It was d i l u t e d w i t h 8 mL o f s a t u r a t e d N a C l s o l u t i o n and t h e n e x t r a c t e d w i t h t h r e e 15 mL p o r t i o n s o f e t h y l a c e t a t e . The c o m b i n e d o r g a n i c e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e t h e c r u d e a l k y l a t e d o x a z o l i n e a s a y e l l o w o i l . 2 - ( 2 ' - B u t y l 1 - 4 ( S ) - b e n z v l o x a z o l Ine (6_Z) O x a z o l i n e 5J£ (189 mg) was u s e d . T h e c r u d e p r o d u c t was p u r i f i e d by d i s t i l l a t i o n ( b u l b - t o - b u l b ) , 6 5 ° C (0 .1 mm H g ) , t o y i e l d 180 mg (83%) o f a c o l o r l e s s l i q u i d . 1 H nmr s p e c t r a l a n a l y s i s I n d i c a t e d t h a t t h e de o f o x a z o l Ine 67a w i t h t h e S_-c o n f i g u r a t i o n a t t h e a - c h l r a l c e n t e r was 2 2 . 7 % . [ a ] D - 2 3 . 0 ° ( £ 3 . 0 3 ) , - 6 9 . 9 ° ( £ 2 . 0 5 , C H 3 C N ) ; Ir ( f i l m ) : 1665 c m - 1 ; 1 H nmr (400 MHz) 6: 0 . 9 0 4 & 0 . 9 0 9 ( t , 3 , 1 = 7 ) , 1 .152 & 1 .156 ( d , 3 , l = 7 ) , 1 . 4 2 - 1 . 5 7 ( m , 1 ) , 1 . 6 0 - 1 . 7 5 (m, 1 ) , 2 . 3 4 - 2 . 5 0 ( m , 1 ) , 2 . 6 5 ( d d , 1 , 1 = 8 . 4 , 1 4 ) , 3 . 1 2 ( d d , 1 , 1 = 4 . 8 , 1 4 ) , 3 . 9 6 ( o v e r l a p p i n g t , 1 , 1 = 8 ) , 4 . 1 5 ( o v e r l a p p i n g t , 1 , 1 = 8 ) , 4 . 3 3 - 4 . 4 7 ( m , 1 ) , 7 . 1 8 - 7 . 4 0 ( m , 5 ) . Ana I . c a l c d . f o r C 1 4 H 1 9 N 0 ( 2 1 7 . 3 1 ) : C 7 7 . 3 8 , H 8 . 8 1 , N 6 . 4 5 ; f o u n d : C 7 7 . 0 9 , H 8 . 8 9 , N 6 . 6 4 . E x a c t m a s s c a l c d . f o r C ^ H - i g N O : 2 1 7 . 1 4 6 6 ; 223 f o u n d : 2 1 7 . 1 4 6 6 . 2 - ( 2 ' - B u t v l ) - 4 f S ) - ( 4 - b e n z v l o x v b e n z v l ^ o x a z o l i n e (B_7_) CH 3 CH3N 87a CChfePh CH3 CHs* 87b OCH-Ph O x a z o l i n e £2. (295 mg) was u s e d . T h e c r u d e p r o d u c t was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g e t h y l a c e t a t e - p e t r o l e u m e t h e r ( 1 : 1 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 249 mg (77%) o f a c o l o r l e s s o i l . 1 H nmr s p e c t r a l a n a l y s i s I n d i c a t e d t h a t t h e de o f o x a z o l i n e 87a w i t h t h e S_-conf I g u r a t l on a t t h e c t - c h i r a l c e n t e r was 2 0 . 3 % . R f 0 . 3 3 ( E t O A c - p e t r o I e u m e t h e r , 1 : 1 ) ; i r ( f i l m ) : 1660 c m - 1 ; ms m / z : 3 2 3 ( M + , 4 ) , 1 9 7 ( 1 3 ) , 1 2 6 ( 3 1 ) , 9 1 ( 1 0 0 ) ; 1 H nmr (400 MHz) 6 : 0 . 8 8 0 & 0 . 8 8 4 ( t , 3 , 1=7 . 5 ,Ctl 3 C H 2 ) , 1 .124 & 1 .128 ( d , 3 , ! = 7 , C H 3 C H ) , 1 . 4 0 - 1 . 5 1 (m , 1 , C H 3 C H . 2 ) . 1 . 5 7 - 1 . 7 0 (m, 1 ,CH 3 CJd2) . 2 . 3 1 - 2 . 4 0 (m, 1 ,CH 3 CH. ) , 2 . 5 7 ( o v e r l a p p i n g d d , 1 , 1 = 8 , 1 3 . 6 , C H C H 2 A r ) , 3 . 0 0 ( o v e r l a p p i n g d d , 1 , 1 = 4 . 8 , 1 4 . 4 , C H C J d 2 A r ) , 3 . 9 0 ( t , 1 ,1=8 , CH 2 0) , 4 . 1 0 ( t , 1 ,1=8 ,CJd 2 0 ) , 4 . 2 5 -4 . 3 5 ( m , 1 , C M N ) , 5 . 0 2 ( s , 2 , C H . 2 p h > • 6 . 8 9 ( d , 2 ,1=8 , C6H4 ) , 7 . 1 0 ( d , 2 , ! = 8 , C 6 H . 4 > . 7 . 2 7 - 7 . 4 4 ( m , 5 , C 6 H 5 ) . E x a c t m a s s c a l c d . f o r C 2 - | H 2 5 N 0 2 : 3 2 3 . 1 8 8 6 ; f o u n d : 3 2 3 . 1 8 9 0 . 2 - ( 2 ' - B u t v l ) - 4 ( S l - ( 4 - m e t h o x v b e n z v l l o x a z o l i n e (8_4_) 224 O x a z o l i n e 7_5_ (219 mg) was u s e d . T h e c r u d e p r o d u c t was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 3 : 2 ) a s t h e e l u t l n g s o l v e n t t o a f f o r d 208 mg (84%) o f a c o l o r l e s s o i l . 1 H nmr s p e c t r a l a n a l y s i s i n d i c a t e d t h e de o f o x a z o l i n e 84a w i t h t h e £ - c o n f I g u r a t I on a t t h e a - c h l r a l c e n t e r was 2 2 . 2 % . Rf 0 . 3 6 ( p e t r o l e u m e t h e r - E t O A c , 3 : 2 ) ; i r ( f i l m ) : 1660 c m - 1 ; ms m / z : 2 4 7 ( M + , 1 9 ) , 1 2 6 ( 1 0 0 ) , 1 2 2 ( 7 8 ) , 1 2 1 ( 8 6 ) ; 1 H nmr (400 MHz) 6: 0 . 9 0 ( o v e r l a p p i n g t , 3 ,J .=7 .2) , 1 .15 ( o v e r -l a p p i n g d , 3 , J = 7 . 2 ) , 1 . 4 1 - 1 . 5 3 ( m , 1 ) , 1 . 5 8 - 1 . 7 1 ( m , 1 ) , 2 . 3 2 - 2 . 4 2 ( m , 1 ) , 2 . 5 9 ( o v e r l a p p i n g d d , 1 , ^ = 8 , 1 4 . 6 ) , 3 . 0 2 ( o v e r l a p p i n g d d , 1 . J - 5 . 1 4 ) , 3 . 7 8 ( S , 3 , C U 3 0 ) , 3 . 9 2 ( t , 1 , ^ = 8 ) , 4 . 1 2 ( t , 1 , . j > 8 ) , 4 . 2 6 - 4 . 3 7 ( m , 1 ) , 6 . 8 3 ( d , 2 , ^ = 8 ) , 7 .11 ( d , 2 . J - 8 ) . Ana I . c a l c d . f o r C 1 5 H 2 1 N 0 2 ( 2 4 7 . 3 4 ) : C 7 2 , 8 4 , H 8 . 5 6 , N 5 . 6 6 ; f o u n d : C 7 2 . 9 7 , H 8 . 5 4 , N 5 . 6 5 . E x a c t m a s s c a l c d . f o r C 1 5 H 2 1 N 0 2 : 2 4 7 . 1 5 7 2 ; f o u n d : 2 4 7 . 1 5 6 8 . 2 - ( 2 ' - B u t v l )—4(S) —1"4—( 2—oxapropv I o x v ) b e n z v I l o x a z o l Ine ( £ 5 J O x a z o l i n e 2& ( 249 mg) was u s e d . T h e c r u d e p r o d u c t was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 3 : 2 ) a s t h e e l u t l n g s o l v e n t t o a f f o r d 197 mg (71%) o f a c o l o r l e s s o i l . 1 H nmr s p e c t r a l a n a l y s i s I n d i c a t e d t h a t t h e de o f o x a z o l i n e 85a w i t h t h e S - c o n f I g u r a t i o n a t t h e a - c h l r a l c e n t e r was 2 2 . 4 % . 225 R f 0 . 3 5 ( p e t r o l e u m e t h e r - E t O A c , 3 : 2 ) ; i r ( f i l m ) : 1655 c m - 1 ; m s m / Z : 2 7 7 ( M + , 1 0 ) , 1 5 2 ( 3 6 ) , 1 5 1 ( 2 7 ) , 1 2 6 ( 1 0 0 ) ; 1 H nmr (400 MHz) 6 : 0 . 9 0 ( o v e r l a p p i n g t , 3 , 1 = 7 . 6 ) , 1 .15 ( o v e r -l a p p i n g d , 3 , J L - 7 . 4 ) , 1 . 4 2 - 1 . 5 3 ( m , 1 ) , 1 . 5 8 - 1 . 7 1 ( m , 1 ) , 2 . 3 3 - 2 . 4 2 ( m , 1 ) , 2 . 5 9 ( d d , 1 , 1 = 8 , 1 4 . 6 ) , 3 . 0 2 ( d d , 1 , 1 = 5 , 1 2 . 6 ) , 3 . 4 7 ( s , 3 , CH.3O), 3 . 9 2 ( t , 1 , 1 = 8 ) , 4 . 1 2 ( t , 1 , 1 = 8 ) , 4 . 2 7 - 4 . 3 7 ( m , 1 ) , 5 . 1 4 ( s , 2 , 0 C H . 2 0 ) , 6 . 9 7 ( d , 2 , l = 8 ) , 7 . 1 2 ( d , 2 , l = 8 ) . E x a c t m a s s c a l c d . f o r C 1 6 H 2 3 N 0 3 : 2 7 7 . 1 6 7 8 ; f o u n d : 2 7 7 . 1 6 8 2 . 2 - ( 2 ' - B u t y l 1 - 4 ( S 1 - r 4 - ( 2 . 5 - d l o x a h e x v l o x V ) b e n z v l l o x a z o l i n e (£6_) O x a z o l I n e U_ (293 mg) was u s e d . T h e c r u d e p r o d u c t was p u r i f i e d by f l a s h c o l u m n c h r o m a t o g r a p h y on 20 g o f s i l i c a g e l ( 2 3 0 - 4 0 0 mesh) u s i n g e t h y l a c e t a t e - p e t r o l e u m e t h e r ( 7 : 3 ) a s t h e e l u t l n g s o l v e n t t o a f f o r d 260 mg (81%) o f a c o l o r l e s s o i l . 1 H nmr s p e c t r a l a n a l y s i s i n d i c a t e d t h e de o f o x a z o l i n e 86a w i t h t h e S - c o n f i g u r a t I o n a t t h e a - c h l r a l c e n t e r was 2 1 . 4 % . Rf 0 . 3 4 ( E t O A c - p e t r o l e u m e t h e r , 7 : 3 ) ; Ir ( f i l m ) : 1655 c m - 1 ; ms m / z : 3 2 1 ( M + , 2 2 ) , 1 9 5 ( 8 ) , 1 2 6 ( 5 8 ) , 8 9 ( 1 0 0 ) ; 1 H nmr (400 MHz) 6: 0 . 9 0 ( o v e r l a p p i n g t , 3 , 1 = 7 . 5 ) , 1 .15 ( o v e r l a p -p i n g d , 3 , 1 = 7 . 5 ) , 1 . 4 2 - 1 . 5 3 ( m , 1 ) , 1 . 5 8 - 1 . 7 0 ( m , 1 ) , 2 . 3 3 - 2 . 4 2 ( m , 1 ) , 2 . 5 9 ( o v e r l a p p i n g d d , 1 , 1 = 8 , 1 4 . 8 ) , 3 . 0 2 ( o v e r l a p p i n g d d , 1 , 1 - 5 , 1 4 . 2 ) , 3 . 3 7 ( s , 3 , C M 3 0 ) , 3 . 5 5 (m, 2 , C H . 2 O C H 3 ) , 3.81 ( m , 2 , C h i 2 C H 2 0 ) , 3 . 9 2 ( t , 1 , 1 = 8 ) , 4 . 1 2 ( t , 1 , 1 - 8 . 8 ) , 4 . 2 7 - 4 . 3 7 ( m , 1 ) , 5 . 2 3 ( s , 2 , 0 C h l 2 0 ) , 6 . 9 8 ( d , 2 , ! = 8 ) , 7 .11 ( d , 2 , ! = 8 ) . 226 A n a l , c a l c d . f o r C 1 8 H 2 7 N 0 4 ( 3 2 1 . 4 2 ) : C 6 7 . 2 6 , H 8 . 4 7 , N 4 . 3 6 ; f o u n d : C 6 7 . 1 7 , H 8 . 6 2 , N 4 . 2 5 . E x a c t m a s s c a l c d . f o r C 1 8 H 2 7 N 0 4 : 3 2 1 . 1 9 4 0 ; f o u n d : 3 2 1 . 1 9 3 5 . 227 C h a p t e r I I P a r t A 4 - C h I o r o b e n z v I b r o m i d e (112) C l C H 2 B r A s t i r r e d m i x t u r e o f 2 5 . 3 g (200 mmol) o f 4 - c h I o r o t o I u e n e (111) and 3 5 . 6 g (200 mmol) o f ^ - b r o m o s u c c I n I m i de In 150 mL o f c a r b o n t e t r a c h l o r i d e was h e a t e d a t r e f l u x f o r 16 h w h i l e b e i n g I r r a d i a t e d w i t h a 150 w a t t I n c a n d e s c e n t l i g h t b u l b . A f t e r t h e r e a c t i o n had c o o l e d t o r t , s u c c i n l m l d e was r e m o v e d by f i l t r a -t i o n and t h e f i l t r a t e was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e 3 6 . 9 g (90%) o f a p a l e y e l l o w s o l i d and l i q u i d . The c r u d e p r o d u c t was p u r i f i e d by s u b l i m a t i o n ( 4 0 - 4 5 ° C , 1 mm Hg) t o a f f o r d b r o m i d e 112 a s a c o l o r l e s s s o l i d . R f 0 . 3 2 ( p e t r o l e u m e t h e r ) ; 1 H nmr (60 MHz) 6 : 4 . 3 5 ( s , 2 ) , 7 . 0 7 - 7 . 5 0 ( m , 4 ) . T 4 - ( T r i m e t h v l s l I v l ) b e n z v l I t r i m e t h v l s l l a n e (JJ_2) C H 2 S i M e 3 A s t i r r e d m i x t u r e o f 4 .11 g (20 mmol) o f 4 - c h I o r o b e n z y I b r o m i d e ( 1 1 2 ) . 2 5 . 4 mL ( 2 1 . 7 g , 200 mmol) o f c h I o r o t r i m e t h y I -s i l a n e , a n d 2 . 3 0 g (100 mmol) o f s o d i u m in 200 mL o f t o l u e n e S i M e 3 228 was h e a t e d a t r e f l u x f o r 24 h . A f t e r t h e r e a c t i o n m i x t u r e had c o o l e d t o r t , t h e s o d I urn s a l t s and e x c e s s s o d I urn w e r e removed by f i l t r a t i o n and w a s h e d w i t h some p e t r o l e u m e t h e r . T h e c o m b i n e d f i l t r a t e and w a s h i n g s w e r e e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w l i q u i d . T h e l i q u i d was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 200 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r a s t h e e l u t i n g s o l v e n t t o a f f o r d 3 . 7 5 g (79%) o f s i l a n e 113 a s a c o l o r l e s s l i q u i d . An a n a l y t i c a l s a m p l e was o b t a i n e d by b u l b - t o - b u l b d i s t i l l a t i o n ( 4 3 - 4 5 ° C , 1 mm Hg) t o a f f o r d a c o l o r l e s s l i q u i d . R f 0 . 4 7 ( p e t r o l e u m e t h e r ) ; Ir ( f i l m ) : 1250 , 1110 , 850 c m - 1 ; ms m / Z : 2 3 6 ( M + , 2 2 ) , 2 2 1 ( 3 3 ) , 1 4 8 ( 1 0 0 ) , 7 3 ( 8 6 ) ; 1 H nmr (80 MHz) 6 : 0 . 0 0 ( s , 9 , t d £ 3 S i C H 2 ) , 0 . 2 4 ( s , 9 , &4e_3S I Ar ) , 2 . 0 6 ( S , 2 , C U 2 ) . 6 . 9 8 ( d , 2 , 1=8 , C 6 hl4 ) , 7 . 3 6 ( d , 2 , 1 = 8 , C 6 h l 4 ) - A n a I . c a l c d . f o r C 1 3 H 2 4 S I 2 ( 2 3 6 . 5 1 ) : C 6 6 . 0 2 , H 1 0 . 2 3 ; f o u n d : C 6 6 . 1 4 , H 1 0 . 2 8 . E x a c t m a s s c a l c d . f o r C i 3 H 2 4 S i 2 : 2 3 6 . 1 4 1 6 ; f o u n d : 2 3 6 . 1 4 1 6 . S o d i urn 4 - T ( t r i m e t h v I s I I v I ) m e t h v I I b e n z e n e s u I f o n a t e (115 ) T o a s t i r r e d s o l u t i o n o f 2 . 3 7 g (10 mmol) o f s i l a n e 113 in 20 mL o f c a r b o n t e t r a c h l o r i d e a t 0 ° C was a d d e d a s o l u t i o n o f 0 . 4 2 mL (10 mmol) o f s u l f u r t r l o x l d e In 10 mL o f c a r b o n t e t r a -c h l o r i d e d r o p w i s e o v e r a 3 m i n p e r i o d . T h e r e a c t i o n m i x t u r e CH2SiMe3 1 1 1 CH2SiMe3 115 . 229 was s t i r r e d a t r t f o r 0 . 5 h and t h e s o l v e n t was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e 3 . 3 g o f s u l f o n a t e 114 a s a p a l e y e l l o w l i q u i d . S u I f o n a t e 114 was h y d r o l y z e d by t h e a d d i t i o n o f some w a t e r and a q u e o u s 0 . 5 M NaOH t o o b t a i n a pH o f 6 . 5 and t h e r e s u l t i n g m i x t u r e was s t i r r e d f o r 15 m i n . T h e t u r b i d s o l u t i o n was w a s h e d w i t h two 15 mL p o r t i o n s o f e t h e r and t h e r e s u l t i n g c l e a r a q u e o u s l a y e r was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 2 . 5 3 g (95%) o f s o d i u m s u l f o n a t e 115 a s a w h i t e s o l i d w h i c h was d r i e d ( 5 0 ° C , 1 mm Hg) o v e r P 2 0 5 -1 H nmr (400 MHz , D 2 0 ) 6: 0 . 1 2 ( s , 9 ) , 1 .63 ( s , 2 ) , 7 . 2 5 ( d , 2 . 1 - 8 ) , 7 . 7 0 ( d , 2 , l = 8 ) . 4 - r ( T r Imethv I s I I v I )methv I I b e n z e n e s u I f o n v I c h l o r I de (S3.) SCfcCI T o a s t i r r e d s u s p e n s i o n o f 2 . 6 6 g (10 mmol) o f s o d I urn s u l f o n a t e 115 in 10 mL o f DMF a t 0 ° C was a d d e d 0 . 8 8 mL ( 1 . 4 3 g , 12 mmol) o f t h i o n y l c h l o r i d e d r o p w l s e . T h e r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 24 h , t a k e n up in 100 mL o f e t h e r , and w a s h e d w i t h f o u r 20 mL p o r t i o n s o f w a t e r . T h e a q u e o u s w a s h i n g s w e r e b a c k - e x t r a c t e d w i t h 25 mL o f e t h e r . T h e c o m b i n e d e t h e r e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a y e l l o w o i l w h i c h c r y s t a l l i z e d on s t a n d i n g . T h e c r u d e s u l f o n y l c h l o r i d e was p u r i f i e d by r e c r y s t a I I i z a t I on f r o m p e t r o l e u m e t h e r t o a f f o r d 2 . 3 3 g (89%) o f s u l f o n y l c h l o r i d e fig a s a p a l e y e l l o w s o l i d . CH 2SiMe 3 230 An a n a l y t i c a l s a m p l e was o b t a i n e d by r e c r y s t a I I I z a t I on f r o m p e t r o l e u m e t h e r t o g I v e a w h i t e s o I I d . Rf 0 . 4 5 ( p e t r o l e u m e t h e r - E t O A c , 9 : 1 ) ; mp 4 5 - 4 5 . 5 ° C ( p e t r o l e u m e t h e r ) ; i r ( C H C I 3 ) : 1375 , 1250 , 1175 , 860 c m - 1 ; ms m / z : 2 6 2 ( M + , 6 ) , 2 2 7 ( 5 ) , 9 0 ( 1 0 0 ) , 7 3 ( 8 7 ) ; ' H nmr (400 MHz) 6 : 0 . 0 5 ( s , 9 , Me_3S I ) , 2 . 2 6 ( S , 2 , C H . 2 ) . 7 . 2 0 ( d , 2 , l = 8 , C 6 H . 4 ) , 7 . 8 8 ( d , 2 , l = 8 , C 6 H . 4 ) . A n a l . c a l c d . f o r C 1 0 H 1 5 ° 2 C I S S I ( 2 6 2 . 8 3 ) : C 4 5 . 7 0 , H 5 . 7 5 , C l 1 3 . 4 9 , S 1 2 . 2 0 ; f o u n d : C 4 5 . 7 8 , H 5 . 8 1 , C l 1 3 . 3 0 , S 1 2 . 1 1 . E x a c t mass c a l c d . f o r C-| 0 H 1 5 0 2 C I SS I : 2 6 2 . 0 2 5 1 ; f o u n d : 2 6 2 . 0 2 5 5 . G e n e r a l p r o c e d u r e f o r p r e p a r a t i o n o f s u l f o n a t e s and s u l f o n a m i d e s : M e t h o d A T o a s t i r r e d s o l u t i o n o f 2 .1 mmol o f an a l c o h o l o r a m i n e a n d 526 mg ( 2 . 0 mmol) o f s u l f o n y l c h l o r i d e j£B_ I n 4 mL o f d I c h I o r o m e t h a n e c o o l e d t o 0 ° C was a d d e d 24 mg ( 0 . 2 0 mmol) o f DMAP f o l l o w e d by 0 . 5 6 mL (405 mg, 4 . 0 mmol) o f t r I e t h y I a m i n e . T h e r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 2 h , t a k e n up in 25 mL o f d I c h I o r o m e t h a n e , and w a s h e d s u c c e s s i v e l y w i t h two 5 mL p o r t i o n s o f a q u e o u s 2 M HCl and 5 mL o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e t h e c r u d e p r o d u c t a s a y e I low oI I o r s o I I d . O c t v l 4 - T ( t r I m e t h v l s l I v l ) m e t h v l I b e n z e n e s u l f o n a t e (99a ) 231 1 - O c t a n o l (273 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 45 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t l n g s o l v e n t a f f o r d e d 618 mg (87%) o f s u l f o n a t e 99a a s a c o l o r l e s s o i l . R f 0 . 2 5 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; Ir ( f i l m ) : 1360 , 1250 , 1180 , 860 c m ~ 1 ; ms m / Z : 3 5 6 ( M + , 1 ) , 2 4 4 ( 7 4 ) , 2 2 8 ( 5 7 ) , 1 5 4 ( 3 1 ) , 9 0 ( 1 0 0 ) , 7 3 ( 6 2 ) ; 1 H nmr (80 MHz) 6: 0 . 0 0 ( s , 9 ) , 0 . 7 8 - 1 . 7 5 ( m , 1 5 ) , 2 .21 ( S . 2 ) , 4 . 0 2 ( t , 2 , 1=6 . 5 , CH20) , 7 . 1 3 ( d , 2 , 1 = 8 ) , 7 . 7 5 ( d , 2 , l = 8 ) . Ana I . c a l c d . f o r C 1 8 H 3 2 0 3 S S i ( 3 5 6 . 6 0 ) : C 6 0 . 6 3 , H 9 . 0 5 , S 8 . 9 9 ; f o u n d : C 6 0 . 6 9 , H 8 . 9 9 , S 8 . 7 3 . EXSSiL majLS. c a I C d . f o r C-\ 8 H 3 2 0 3 S S I : 3 5 6 . 1 8 4 2 ; f o u n d : 3 5 6 . 1 8 4 4 . 2 - P h e n o x v e t h v I 4 - r ( t r i m e t h v I s I I v I ) m e t h v I I b e n z e n e s u I f o n a t e ( 9 9 b ) 0 <Q>- c — - °- jj " Q ~ C H Z S I M E 3 2 - P h e n o x y e t h a n o I (290 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y o n 45 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 9 : 1 ) a s t h e e l u t l n g s o l v e n t a f f o r d e d 519 mg (71%) o f s u l f o n a t e 99b a s a w h i t e s o l i d . Rf 0 . 4 5 ( p e t r o l e u m e t h e r - E t O A c , 4 : 1 ) ; mp 6 4 - 6 5 ° C ; Ir ( C H C I 3 ) : 1360 , 1250 , 1175 , 8 5 0 c m - 1 ; m s m / z : 3 6 4 ( M + , 1 5 ) , 1 2 1 ( 1 0 0 ) , 9 0 ( 3 0 ) , 7 7 ( 3 0 ) , 7 3 ( 5 5 ) ; 1 H nmr ( 8 0 M H z ) 6: 0 . 0 0 ( s , 9 ) , 2 .21 ( S , 2 ) , 4 . 0 7 - 4 . 4 5 ( m , 4 , C H . 2 C H 2 ) , 6 . 8 0 ( d , 2 , J = 8 ) , 6 . 9 3 - 7 . 3 8 ( m , 5 , C 6 H . 5 ) , 7 . 7 8 ( d , 2 , l = 8 ) . Ana I . c a l c d . f o r 232 C 1 8 H 2 4 ° 4 S S I ( 3 6 4 . 5 4 ) : C 5 9 . 3 1 , H 6 . 6 4 , S 8 . 8 0 ; f o u n d : C 5 9 . 4 9 , H 6 . 6 0 , S 8 . 6 5 . E x a c t mass c a l c d . f o r C 1 8 H 2 4 0 4 S S i : 3 6 4 . 1 1 6 5 ; f o u n d : 3 6 4 . 1 1 6 6 . 4 - t - B u t v I p h e n v I 4 - T ( t r I m e t h v I s I I v I ) m e t h v I I b e n z e n e s u I f o n a t e 4 - i - B u t y I p h e n o I (315 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 45 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t i n g s o l v e n t a f f o r d e d 747 mg (99%) o f s u l f o n a t e 99c a s a w h i t e s o l i d . Rf 0 . 2 9 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; mp 8 1 . 5 - 8 3 . 5 ° C ; i r ( C H C 1 3 ) : 1 3 6 5 , 1250 , 1180 , 860 c m - 1 ; ms m / z : 376 (M+, 2 5 ) , 2 2 7 ( 1 8 ) , 1 7 9 ( 3 8 ) , 7 3 ( 1 0 0 ) ; 1 H nmr (80 MHz) 6 : 0 . 0 0 ( s , 9 ) , 1 .26 ( S , 9 , M £ 3 C ) , 2 .21 ( S . 2 ) , 6 . 8 8 ( d , 2 , 1 = 8 . 5 ) , 7 . 0 5 - 7 . 3 5 ( m , 4 , C 6 H 4 ) , 7 . 6 8 ( d , 2 , 1 = 8 . 5 ) . Ana I . c a l c d . f o r c 2 0 H 2 8 ° 3 S S i ( 3 7 6 . 5 9 ) : C 6 3 . 7 9 . H 7 . 4 9 , S 8 . 5 1 ; f o u n d : C 6 3 . 5 2 , H 7 . 5 5 , S 8 . 3 3 . E x a c t m a s s c a l c d . f o r C 2 0 H 2 8 ° 3 S S ' : 3 7 6 . 1 5 2 8 ; f o u n d : 3 7 6 . 1 5 3 3 . N - B e n z v I - 4 - T ( t r I m e t h v I s I I v I ) m e t h v I I b e n z e n e s u I f o n a m i d e (100a ) (SSc.) 0 0 0 0 233 B e n z y l a m l n e (225 mg) was u s e d . P u r i f i c a t i o n by r e c r y s t a l -I I z a t i o n f r o m e t h y l a c e t a t e - p e t r o l e u m e t h e r a f f o r d e d 578 mg (87%) o f s u l f o n a m i d e 100a a s a w h i t e s o l i d . Rf 0 . 3 8 ( p e t r o l e u m e t h e r - E t O A c , 4 : 1 ) ; mp 1 2 7 - 1 2 8 . 5 ° C ( E t O A c - p e t r o I e u m e t h e r ) ; Ir ( C H C I 3 ) : 3 3 5 0 , 1330 , 1250 , 1160 , 860 c m - 1 ; ms m / z : 3 3 3 ( M + , 5 0 ) , 9 1 ( 1 0 0 ) , 7 3 ( 7 5 ) ; 1 H nmr (80 MHz) 6 : 0 . 0 2 ( s , 9 ) , 2 . 1 9 ( S , 2 ) , 4 . 1 4 (d , 2 , 1=6 , CH.2 N ) » 4 . 4 3 - 4 . 6 8 ( m , 1 , N H . ) , 7 .11 ( d , 2 , ! = 8 ) , 7 . 1 8 - 7 . 3 8 ( m , 5 , C 6M5), 7 . 7 3 ( d , 2,1= 8 ) . Ana I . c a l c d . f o r C17H23NO2SSI ( 3 3 3 . 5 3 ) : C 6 1 . 2 2 , H 6 . 9 5 , N 4 . 2 0 , S 9 . 6 1 ; f o u n d : C 6 1 . 2 2 , H 7 . 0 5 , N 4 . 1 9 , S 9 . 5 5 . E x a c t mass c a I c d . f o r C-| 7 H 2 3 N 0 2 S S I : 3 3 3 . 1 2 1 8 ; f o u n d : 3 3 3 . 1 2 1 4 . N - C v c I o h e x v I - 4 - I " ( t r I m e t h v l s l I v I ) m e t h v l I b e n z e n e s u I f o n a m l d e ( 1 0 0 b ) C y c I o h e x y I a m i n e (208 mg) was u s e d . P u r i f i c a t i o n by r e c r y s -t a l l i z a t i o n f r o m e t h y l a c e t a t e - p e t r o l e u m e t h e r a f f o r d e d 597 mg (92%) o f s u l f o n a m i d e 100b a s a w h i t e s o l i d . Rf 0 . 4 2 ( p e t r o l e u m e t h e r - E t O A c , 4 : 1 ) ; mp 9 2 - 9 3 . 5 ° C ( E t O A c - p e t r o I e u m e t h e r ) ; i r (CHCI3): 3 3 8 0 , 1330 , 1250 , 1155 , 850 c m ~ 1 ; ms m / z : 3 2 5 ( M + , 1 0 0 ) , 2 4 3 ( 4 8 ) , 2 2 7 ( 2 6 ) , 9 0 ( 3 9 ) , 7 3 ( 9 0 ) ; 1 H nmr (80 MHz) 6 : 0 . 0 0 ( s , 9 ) , 0 . 9 3 - 1 . 9 0 ( m , 1 0 ) , 2 . 2 0 ( s , 2 ) , 3 . 0 0 - 3 . 2 8 ( m , 1 , C H N ) , 4 . 3 5 (d , 1 ,1=8 , NJd) , 7 . 1 3 ( d , 2 , J .=8), 7 . 7 5 ( d . 2 , 1 - 8 ) . A n a l . c a l c d . f o r C 1 6 H 2 7 N 0 2 S S i ( 3 2 5 . 5 5 ) : C 5 9 . 0 3 , H 8 . 3 6 , N 4 . 3 0 , S 9 . 8 5 ; f o u n d : C 5 9 . 2 1 , 0 0 234 H 8 . 3 1 , N 4 . 3 2 , S 9 . 7 0 . E x a c t mass c a l c d . f o r C 1 6 H 2 7 N 0 2 S S i : 3 2 5 . 1 5 3 1 ; f o u n d : 3 2 5 . 1 5 3 1 . S u l f o n a m l d e 100c N H S SCWv />-CH2SiMe3 L - P h e n y I a I an I ne e t h y l e s t e r h y d r o c h l o r i d e (5_L) (482 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 45 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 4 : 1 ) a s t h e e l u t l n g s o l v e n t a f f o r d e d 770 mg (92%) o f s u l f o n a m i d e 100c a s a c o l o r l e s s o i l . R f 0 . 3 5 ( p e t r o l e u m e t h e r - E t O A c , 4 : 1 ) ; i r ( f i l m ) : 3275 ( b r ) , 1740 , 1340 , 1250 , 1160 , 850 c m " 1 ; ms m / z : 4 1 9 ( M + , 2 8 ) , 3 2 8 ( 2 5 ) , 2 2 7 ( 1 0 0 ) , 9 1 ( 4 2 ) , 7 3 ( 8 7 ) ; 1 H nmr ( 8 0 M H z ) 6 : 0 . 0 0 ( s , 9 ) , 1 . 10 ( t , 3 , l = 7 , C t l 3 C H 2 ) , 2 . 1 8 ( S , 2 ) , 3 . 0 6 ( d , 2 , ! = 6 , C H . 2 P h ) , 3 . 9 4 ( q , 2 , ! = 7 , C H 3 C t i 2 ) , 4 . 1 3 - 4 . 3 6 ( m , 1 , C H ) , 5 . 0 8 ( d , 1 ,1=8 .8 ,NH. ) , 7 . 0 8 ( d , 2 , 1 - 8 ) , 7 . 1 2 - 7 . 3 8 ( m , 5 , C 6 H . 5 ) , 7 . 6 4 ( d , 2 , ! = 8 ) . Ana I . c a l c d . f o r C 2 1 H 2 9 N 0 4 S S I ( 4 1 9 . 6 2 ) : C 6 0 . 1 1 , H 6 . 9 7 , N 3 . 3 4 , S 7 . 6 4 ; f o u n d : C 6 0 . 0 6 , H 6 . 8 8 , N 3 . 3 0 , S 7 . 5 0 . E x a c t mass c a l c d . f o r C 2 •) H 2 g N 0 4 S S i : 4 1 9 . 1 5 8 7 ; f o u n d : 4 1 9 . 1 5 5 9 . G e n e r a l p r o c e d u r e f o r p r e p a r a t i o n o f s u l f o n a m i d e s : M e t h o d B To a s t i r r e d s u s p e n s i o n o f 58 mg ( 2 . 4 mmol) o f s o d i u m h y d r i d e (116 mg o f 50% d i s p e r s i o n In o i l ; w a s h e d t h r e e t i m e s 235 w i t h p e t r o l e u m e t h e r ) In 4 mL o f THF c o o l e d t o 0 ° C was a d d e d 2 . 0 mmol o f t h e a m i d e . A f t e r s t i r r i n g f o r 10 m i n , a s o l u t i o n o f 526 mg ( 2 . 0 mmol) o f s u l f o n y l c h l o r i d e 22 In 2 mL o f THF was a d d e d d r o p w l s e t o t h e t h i c k a n i o n s o l u t i o n . T h e r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 10 h , p o u r e d i n t o 15 mL o f w a t e r , a n d t h e n e x t r a c t e d w i t h t h r e e 10 mL p o r t i o n s o f e t h y l a c e t a t e . T h e c o m b i n e d e x t r a c t was w a s h e d w i t h two 5 mL p o r t i o n s o f s a t u r a t e d N a C l s o l u t i o n , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e t h e c r u d e s u l f o n a m i d e . S u I f o n a m I d e IQOd 2 - P y r r o I IdI none ( 0 . 1 5 2 mL, 170 mg) was u s e d . P u r i f i c a t i o n by r e c r y s t a I I I z a t I on f r o m e t h y l a c e t a t e a f f o r d e d 317 mg (51%) o f s u l f o n a m i d e 1OOd a s a w h i t e s o l i d . Rf 0 . 4 3 ( p e t r o l e u m e t h e r - E t O A c , 3 : 2 ) ; mp 1 3 6 - 1 3 8 ° C ( E t O A c ) ; Ir ( C H C I 3 ) : 1730 , 1360 , 1250 , 1 1 7 0 , 860 c m - " 1 ; ms m / Z : 3 1 K M + . 9 0 ) , 2 4 7 ( 3 6 ) , 9 0 ( 7 6 ) , 7 3 ( 1 0 0 ) ; 1 H nmr (80 MHz) 6: 0 . 0 0 ( s , 9 ) , 1 . 9 8 - 2 . 2 8 (m, 2 , C t L 2 C H 2 N ) , 2 . 2 3 ( s , 2 ) , 2 . 4 8 ( t , 2 , ! = 7 , C t i 2 C 0 ) , 3 . 9 3 ( t , 2 , J.=7 , CH_2N) , 7 . 1 6 ( d , 2 , J = 8 ) , 7 . 9 3 ( d , 2 , J = 8 ) . Ana I . c a l c d . f o r C 1 4 H 2 i N 0 3 S S i ( 3 1 1 . 4 8 ) : C 5 3 . 9 9 , H 6 . 8 0 , N 4 . 5 0 , S 1 0 . 2 9 ; f o u n d : C 5 3 . 8 8 , H 6 . 8 3 , N 4 . 4 8 , S 1 0 . 1 9 . E x a c t m a s s c a I c d . f o r C i 4 H 2 i N 0 3 S S I : 3 1 1 . 1 0 1 1 ; f o u n d : 3 1 1 . 1 0 1 1 . 236 S u I f o n a m I d e IQOe O 5 (S . ) -Benzy I p y r r o I i d I none (350 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 55 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 4 : 1 ) a s t h e e l u t l n g s o l v e n t g a v e 480 mg (60%) o f s u l f o n a m i d e 1OOe a s a w h i t e s o l i d . (CHC13) : 1 7 2 5 , 1 3 5 5 , 1250 , 1 1 6 5 , 860 c m - 1 ; ms m / z : 401 ( M + , 3 9 ) , 3 1 0 ( 9 0 ) , 2 2 7 ( 1 0 0 ) , 9 1 ( 5 2 ) , 7 3 ( 9 4 ) ; 1 H nmr (80 MHz) 6 : 0 .03 ( s , 9 ) , 1 .75-2 .30 (m , 4 , C t l 2 C H , CJd 2 Ph ) • 2 . 2 3 ( s , 2), 2 .90 ( d d , 1 ,1=8.4, 13.6,CH2CO) , 3 . 3 4 (dd , 1 , J=4 , 1 3 , CH_ 2CO) , 4 . 5 0 - 4 . 8 0 ( m , 1 , C J d ) , 7 .17 (d,2,J = 8 ) , 7.20-7.38 ( m , 5 , C 6 H 5 ) , 8.00 (d,2,J.=8). Ana I . c a l c d . f o r C21H27NO3SSI ( 4 0 1 . 6 0 ) : C 6 2 . 8 1 , H 6 . 7 8 , N 3 . 4 9 , S 7 . 98 ; f o u n d : C 6 2 . 5 2 , H 6 . 6 0 , N 3 . 4 4 , S 7 . 78 . E x a c t m a s s c a l c d . f o r C2iH 2 7 N 0 3 S S i : 4 0 1 . 1 4 8 2 ; f o u n d : 4 0 1 . 1 4 8 2 . 4 -Am I n o p h e n v I 4 - T ( t r Imethv I s I I v I )methv I I b e n z e n e s u I f o n a t e (9_9_d) : M e t h o d C Rf 0 . 2 9 ( p e t r o l e u m e t h e r - E t O A c , 4 : 1 ) ; mp 1 0 7 - 1 0 9 ° C ; i r 0 0 To a s t i r r e d s u s p e n s i o n o f 115 mg ( 1 . 0 5 mmol) o f 4-amI n o -p h e n o l i n 2 mL o f d i c h I o r o m e t h a n e c o o l e d t o 0 ° C was a d d e d 0 . 1 5 7 mL (160 m g , 1 .05 mmol) o f DBU f o l l o w e d by 263 mg ( 1 . 0 0 mmol) o f 237 s u l f o n y l c h l o r i d e 33- The r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 1 h , t a k e n up In 20 mL o f d I c h I o r o m e t h a n e , and w a s h e d w i t h t h r e e 5 mL p o r t i o n s o f w a t e r . The o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a l i g h t y e l l o w s o l i d . T h e c r u d e s u l f o n a t e was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 55 g o f s i l i c a g e l (70 -230 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 3 : 2 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 271 mg (81%) o f s u l f o n a t e 99d a s a p a l e y e I Iow s o I I d . R f 0 . 5 4 ( p e t r o l e u m e t h e r - E t O A c , 3 : 2 ) ; mp 1 4 1 - 1 4 2 . 5 ° C ; Ir ( C H C 1 3 ) : 3 3 8 0 , 1370 , 1250 , 1 175 , 860 c m " 1 ; ms m / z : 3 3 5 ( M + , 1 1 ) , 1 0 8 ( 1 0 0 ) , 7 3 ( 1 5 ) ; 1 H nmr (80 MHz) 6: 0 . 0 0 ( s , 9 ) , 2 . 2 0 ( s , 2 ) , 3 . 6 5 ( b r s , 2 , NH. 2 ) » 6 .61 ( q , 4 ,1=9 . 3 , C 6 H . 4 0 ) , 7 . 0 8 ( d , 2 , l = 8 ) , 7 . 6 5 ( d , 2 , l = 8 ) . Ana I . c a l c d . f o r C 1 6 H 2 1 N 0 3 S S I ( 3 3 5 . 5 0 ) : C 5 7 . 2 8 , H 6 . 3 1 , N 4 . 1 7 , S 9 . 5 6 ; f o u n d : C 5 7 . 1 2 , H 6 . 2 5 , N 4 . 1 8 , S 9 . 4 4 . E x a c t m a s s c a l c d . f o r C i 6 H 2 i N 0 3 S S I : 3 3 5 . 1 0 1 2 ; f o u n d : 3 3 5 . 1 0 1 7 . N - B e n z v I - N - c v c I o h e x v I - 4 - r ( t r i m e t h v I s i I v I ) m e t h v I I b e n z e n e s u I f o n -a m l d e ( l O O f ) A m i x t u r e o f 326 mg ( 1 . 0 mmol) o f s u l f o n a m i d e 100b . 0 . 2 4 mL (342 m g , 2 . 0 mmol) o f b e n z y l b r o m i d e , 3 . 3 mL (1 .1 mmol) o f a q u e o u s 0 . 3 3 6 M t e t r a - n - b u t y I a m m o n i u r n h y d r o x i d e , 0 . 7 mL o f w a t e r , a n d 4 mL o f d I c h I o r o m e t h a n e was s t i r r e d v i g o r o u s l y a t r t 238 f o r 62 h . T h e l a y e r s w e r e s e p a r a t e d and t h e a q u e o u s l a y e r was e x t r a c t e d w i t h t h r e e 10 mL p o r t i o n s o f d I c h I o r o m e t h a n e . The c o m b i n e d o r g a n i c e x t r a c t was w a s h e d w i t h two 5 mL p o r t i o n s o f w a t e r , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a p a l e y e l l o w o i l . T h e c r u d e s u l f o n a m i d e was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 65 g o f s i l i c a g e l u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t i n g s o l v e n t . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s s t i l l g a v e s l i g h t l y Impure I Q O f . F u r t h e r p u r i f i c a t i o n by p r e p a r a t i v e t i c u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e d e v e l o p i n g s o l v e n t a f f o r d e d 374 mg (90%) o f p u r e s u l f o n -a m i d e 10Of a s a w h i t e s o I i d . Rf 0 . 3 6 ( p e t r o l e u m e t h e r - E t O A c , 9 : 1 ) ; mp 8 5 - 8 6 . 5 ° C ; i r (CHC13) : 1335 , 1250 , 1150 , 845 c m " 1 ; ms m / z : 4 1 5 ( M + , 1 6 ) , 1 8 8 ( 1 4 ) , 9 1 ( 1 0 0 ) , 7 3 ( 3 4 ) ; 1 H nmr (80 MHz) 6: 0 . 0 3 ( s , 9 ) , 0 . 8 2 - 1 . 7 8 ( m , 1 0 ) , 2 . 1 8 ( S , 2 ) , 3 . 4 5 - 3 . 9 0 ( m , 1 , C H N ) , 4 .41 ( s , 2 , C t t 2 N ) , 7 . 0 8 ( d , 2 ( J i = 8 ) , 7 . 1 8 - 7 . 5 0 ( m , 5 , C 6 H , 5 ) , 7 . 6 7 ( d , 2 , J .=8) . Ana I . c a l c d . f o r C23H33NO2SSI ( 4 1 5 . 6 7 ) : C 6 6 . 4 6 , H 8 . 0 0 , N 3 . 3 7 , S 7 . 7 1 ; f o u n d : C 6 6 . 3 7 , H 8 . 1 6 , N 3 . 3 9 , S 7 . 5 9 . E x a c t m a s s c a l c d . f o r C23H33NO2SSI: 4 1 5 . 2 0 0 2 ; f o u n d : 4 1 5 . 2 0 0 6 . P r e p a r a t i o n o f t e t r a - n - b u t v I a m m o n I urn f l u o r i d e TBAF was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f K u w a j i m a e_t a j _ . 8 0 w i t h m o d i f i c a t i o n s . C o m m e r c i a l 0 . 3 4 M t e t r a - n - b u t y I a m m o n I urn h y d r o x i d e (55 mL) was t i t r a t e d w i t h a q u e o u s 2 . 5 M h y d r o f l u o r i c a c i d u n t i l t h e 239 s o l u t i o n had pH 7.5. The s o l u t i o n was c o o l e d In a r e f r i g e r a t o r o v e r n i g h t r e s u l t i n g In f o r m a t i o n o f a w h i t e c l a t h r a t e . The l i q u i d l a y e r was d e c a n t e d o f f and t h e c l a t h r a t e was w a s h e d w i t h t h r e e 10 mL p o r t i o n s o f I c e - c o l d w a t e r . T h e w a t e r was removed by f r e e z e - d r y i n g a t 0 .1 mm Hg f o r 24 h , and t h e n t h e w h i t e s o l i d was d r i e d f u r t h e r o v e r P2O5 a * r t , 0.1 mm Hg f o r 48 h . TBAF was s t o r e d and w e i g h e d o u t u n d e r a r g o n . P r e p a r a t i o n o f b e n z v 1 1 r I m e t h v I a m m o n I urn f l u o r i d e BTAF was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f K u w a j i m a and N a k a m u r a . 8 2 A m i x t u r e o f 25 mL o f c a . 40% b e n z y I t r I m e t h y I a m m o n i u r n h y d r o x i d e in m e t h a n o l and 10 mL o f w a t e r was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o remove t h e m e t h a n o l . T h e r e s u l t i n g s o l u t i o n was d i l u t e d w i t h 20 mL o f w a t e r and t h e n t i t r a t e d w i t h a q u e o u s 2 . 5 M h y d r o f l u o r i c a c i d t o a pH o f 7 . 0 . T h e b u l k o f t h e w a t e r was r e m o v e d by f r e e z e - d r y i n g a t 0 . 0 4 mm Hg f o r 45 h a n d t h e n d r i e d f u r t h e r a t 9 0 ° C , <1 mm Hg f o r 18 h . The w h i t e s o l i d was f i n e l y p u l v e r i z e d and d r i e d a g a i n a t 1 0 0 ° C , <1 mm Hg f o r 48 h and c o o l e d u n d e r n i t r o g e n . BTAF was s t o r e d and w e i g h e d o u t u n d e r a r g o n t o m i n i m i z e I t s e x p o s u r e t o m o i s t a i r . T y p i c a l p r o c e d u r e f o r d e p r o t e c t i o n o f s u l f o n a t e 9 9 c w i t h BTAF 0 _ _ t-Bu-C^C-S-0"-CH3 t-Bu-Q-OH 0 96c 113. 240 T o a s t i r r e d s o l u t i o n o f 138 mg ( 0 . 3 7 mmol) o f s u l f o n a t e 9 9 c In 1 .0 mL o f THF was a d d e d 150 mg ( 0 . 8 9 mmol) o f B T A F . The r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 5 . 5 h u n t i l a l l t h e s t a r t i n g m a t e r i a l had r e a c t e d by t i c ' , q u e n c h e d w i t h 5 d r o p s o f w a t e r a n d s t i r r e d f o r 1 m i n , t a k e n up in 25 mL o f e t h e r , and w a s h e d w i t h t h r e e 3 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 107 mg o f a w h i t e s o l i d w h i c h was shown t o c o n s i s t o f two c o m p o u n d s by t i c . T h e w h i t e s o l i d was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y o n 20 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 46 mg (41%) o f t h e p r o t o d e s I I y I a t e d s u l f o n a t e 96c and 16 mg (29%) o f i - b u t y I p h e n o I ( 1 1 6 ) . S u l f o n a t e 9 6 c : R f 0 . 2 3 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; mp 1 1 6 - 1 1 8 ° C ; Ir ( C H C I 3 ) : 1373 , 1180 , 1157 c m - 1 ; ms m / z : 3 0 4 ( M + , 4 0 ) , 2 8 9 ( 1 0 0 ) , 1 5 5 ( 5 2 ) , 9 1 ( 7 6 ) ; 1 H nmr (80 MHz) 6: 1 .29 ( s , 9 ) , 2 . 4 5 ( s , 3 ) , 6 . 8 8 ( d , 2 f J i = 8 ) , 7 . 1 8 - 7 . 4 0 ( m , 4 ) , 7 . 7 3 ( d , 2 , l = 8 ) . i - B u t y I p h e n o I ( 1 1 6 ) : Rf 0 . 1 0 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; i r (CHCI3): 3 5 9 8 , 3 4 2 5 ( b r ) c m - 1 ; 1 H nmr (80 MHz) 6: 1 .33 ( S , 9 ) , 4 . 6 5 ( S , 1 ) , 6 . 7 0 - 7 . 3 3 ( m , 4 ) . A t t e m p t e d d e p r o t e c t I o n o f s u l f o n a t e 99a w i t h BTAF T h e a b o v e p r o c e d u r e was u s e d f o r t h e r e a c t i o n o f s u l f o n a t e 99a w i t h B T A F . A 40% y i e l d o f s u l f o n a t e 96a was o b t a i n e d a l o n g w i t h a 17% y i e l d o f s u l f o n a t e 119 . S u l f o n a t e 119: Rf 0 . 3 5 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; ms 241 m / Z : 3 9 6 ( M + , 0 . 2 ) , 2 8 5 ( 1 0 0 ) , 1 7 2 ( 3 5 ) , 1 1 2 ( 8 2 ) , 9 1 ( 7 9 ) ; 1 H nmr ( 80 MHz) 6: 0 . 7 2 - 1 . 8 2 ( m , 3 2 ) , 2 . 7 0 ( t , 2 , 1 = 7 . 5 , C H 2 A r ) , 4 . 0 4 ( 1 , 2 , 1 = 6 , 0 * 1 2 0 ) , 7 . 3 5 (d , 2 , 1=8 ) , 7 . 8 3 ( d , 2 , ! = 8 ) . P r e p a r a t i o n o f D 2 Q - t r e a t e d BTAF A m i x t u r e o f c a . 1 g o f BTAF In 15 mL o f d e u t e r i u m o x i d e was s t i r r e d o v e r n i g h t and t h e n t h e d e u t e r i u m o x i d e was removed by f r e e z e - d r y I n g f o r 65 h . T h e w h i t e s o l i d was d r i e d f u r t h e r a t 1 0 0 ° C , <1 mm Hg f o r 23 h and c o o l e d u n d e r n i t r o g e n . The D 2 0 - t r e a t e d BTAF was s t o r e d and w e i g h e d o u t u n d e r a r g o n . T y p i c a l p r o c e d u r e f o r d e o r o t e c t l o n o f s u l f o n a t e 9 9 c w I t h D 2 Q - t r e a t e d BTAF To a s t i r r e d s o l u t i o n o f 213 mg ( 0 . 5 6 mmol) o f s u l f o n a t e 99c in 1 .5 mL o f THF was a d d e d 170 mg ( 1 . 0 mmol) o f D 2 0 -t r e a t e d B T A F . The r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 4 h , q u e n c h e d w i t h 5 d r o p s o f w a t e r and s t i r r e d f o r 1 m i n , t a k e n up in 25 mL o f e t h e r , and w a s h e d w i t h t h r e e 3 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 138 mg o f a w h i t e s o l i d . T h e w h i t e s o l i d was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 25 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t l n g s o l v e n t t o a f f o r d 75 mg (44%) o f a m i x t u r e o f s u l f o n a t e s 9 6 c a n d 117c and 24 mg (28%) o f i - b u t y I p h e n o I ( 1 1 6 ) . 1 H nmr s p e c t r a l a n a l y s i s i n d i c a t e d a 7 0 : 3 0 m i x t u r e o f t h e d e u t e r a t e d s u l f o n a t e 117c t o 242 t h e n o n - d e u t e r a t e d s u l f o n a t e 9 6 c . A t t e m p t e d d e p r o t e c t i o n o f s u l f o n a t e 9 9 c w i t h C s F To a s t i r r e d s o l u t i o n o f 151 mg ( 0 . 4 0 mmol) o f s u l f o n a t e 9 9 c i n 2 mL o f THF was a d d e d 451 mg ( 3 . 0 mmol) o f c e s i u m f l u o r i d e . T h e r e a c t i o n m i x t u r e was s t i r r e d v i g o r o u s l y and h e a t e d a t r e f l u x f o r 21 h . A f t e r c o o l i n g t o r t , t h e r e a c t i o n m i x t u r e was q u e n c h e d w i t h 5 d r o p s o f w a t e r and s t i r r e d f o r 1 m i n , t a k e n up In 25 mL o f e t h e r , and w a s h e d w i t h t h r e e 3 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e 120 mg o f a w h i t e s o l i d . The c r u d e p r o d u c t was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 20 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 116 mg (95%) o f s u l f o n a t e 9 6 c and 0 . 7 mg (1.2%) o f i - b u t y I p h e n o I ( 1 1 6 ) . 243 C h a p t e r I I. P a r t B 3 - ( T r I m e t h v l s l I v n p r o p I on I t r I l e (123.) T h i s compound was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f F l e m i n g a n d G o l d h l l l . 1 ° 1 A s o l u t i o n o f LDA ( 5 . 0 mmol) in T H F - h e x a n e was p r e p a r e d by t h e a d d i t i o n o f 3 . 8 2 mL ( 5 . 0 mmol) o f 1.31 M n - b u t y I I I th I urn in h e x a n e t o a s t i r r e d s o l u t i o n o f 0 .71 mL (506 mg, 5 . 0 mmol) o f d i I s o p r o p y I am Ine In 10 mL o f THF a t 0 ° C . T h e r e s u l t i n g s o l u t i o n was c o o l e d t o - 7 8 ° C and s t i r r e d f o r 15 m i n p r i o r t o t h e a d d i t i o n o f 0 . 2 6 mL (205 mg, 5 . 0 mmol) o f a c e t o n i t r I Ie . S t i r r i n g was c o n t i n u e d a t - 7 8 ° C f o r 15 m i n , and t h e n 0 . 7 2 mL (638 m g , 5 . 2 mmol) o f c h I o r o m e t h y I t r i m e t h y I s I Iane was a d d e d t o t h e w h i t e t u r b i d s o l u t i o n and s t i r r i n g was c o n t i n u e d a t - 7 8 ° C f o r 1 h a n d t h e n a t 0 ° C f o r 1 h . T h e s o l v e n t was r e m o v e d by e v a p o r a t i o n u n d e r r e d u c e d p r e s s u r e and t h e r e s u l t i n g r e s i d u e was t a k e n up in 25 mL o f e t h e r and w a s h e d s u c c e s s i v e l y w i t h two 5 mL p o r t i o n s o f s a t u r a t e d N a C l s o l u t i o n . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a p a l e y e l l o w l i q u i d . T h e c r u d e n l t r i l e was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on 55 g o f s i l i c a g e l ( 7 0 - 2 3 0 m e s h ) u s i n g d I c h I o r o m e t h a n e a s t h e e l u t l n g s o l v e n t t o a f f o r d 433 mg (68%) o f n l t r i l e 133 a s a c o l o r l e s s l i q u i d . R f 0 . 4 9 ( d i c h l o r o m e t h a n e ) ; 1 H nmr (80 MHz) 6: 0 . 0 5 ( s , 9 ) , 0 . 8 0 - 1 . 0 0 ( m , 2 ) , 2 . 1 8 - 2 . 4 0 ( m , 2 ) . 244 3 - f T r I m e t h v I s I I v I ) p r o p a n o I c a c i d (131) T h i s compound was p r e p a r e d a c c o r d i n g t o t h e p r o c e d u r e o f F l e m i n g and G o l d h l l l . 1 0 1 A m i x t u r e o f 636 mg ( 5 . 0 mmol) o f 3 - ( t r I m e t h y I s I I y I ) p r o p i o -n l t r l l e (122.), 982 mg ( 1 7 . 5 mmol) o f p o t a s s i u m h y d r o x i d e , and 0 . 8 5 mL ( 7 . 5 mmol) o f a q u e o u s 30% h y d r o g e n p e r o x i d e In 7 mL o f w a t e r was s t i r r e d r a p i d l y and h e a t e d a t r e f l u x f o r 24 h . A f t e r t h e r e a c t i o n m i x t u r e had c o o l e d t o r t , i t was d i l u t e d w i t h 15 mL o f w a t e r and w a s h e d w i t h two 5 mL p o r t i o n s o f p e t r o l e u m e t h e r . T h e r e s u l t i n g a q u e o u s s o l u t i o n was a c i d i f i e d w i t h 10 mL o f a q u e o u s 2 M HCl and t h e n e x t r a c t e d w i t h f o u r 25 mL p o r t i o n s o f e t h e r . T h e c o m b i n e d e t h e r e x t r a c t was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 598 (82%) o f a c i d 131 a s a c o l o r l e s s l i q u i d . Ir ( f i l m ) : 3 0 5 0 ( b r ) , 1710 , 1250 , 8 5 5 , 830 c m - 1 ; ms m / z : 1 4 5 ( M + - H , 0 . 2 ) , 1 3 1 ( 6 4 ) , 7 5 ( 1 0 0 ) , 7 3 ( 8 5 ) ; 1 H nmr (80 MHz) 6: 0 .01 ( s , 9 ) , 0 . 7 0 - 0 . 9 8 ( m , 2 ) , 2 . 2 0 - 2 . 4 8 ( m , 2 ) , 1 1 . 1 5 ( b r s , 1 ) . G e n e r a l p r o c e d u r e f o r p r e p a r a t i o n o f 3 - ( t r I m e t h v I s I I v I ) -p r o o a n o a t e e s t e r s 129 To a s t i r r e d s o l u t i o n o f 293 mg ( 2 . 0 mmol) o f 3 - ( t r I m e t h y I -sI I y I ) p r o p a n o I c a c i d (131) in 8 mL o f d i c h I o r o m e t h a n e was a d d e d 433 mg (2 .1 mmol) o f DCC f o l l o w e d by 2 .1 mmol o f an a l c o h o l and 24 mg ( 0 . 2 0 mmol) o f DMAP. The r e a c t i o n m i x t u r e was s t i r r e d a t r t f o r 2 h . T h e w h i t e s o l i d was r e m o v e d by f i l t r a t i o n and 245 w a s h e d w i t h t h r e e 5 mL p o r t i o n s o f d I c h I o r o m e t h a n e . T h e c o m b i n e d f i l t r a t e and w a s h i n g s w e r e w a s h e d s u c c e s s i v e l y w i t h two 5 mL p o r t i o n s o f a q u e o u s 5% a c e t i c a c i d and two 5 mL p o r t i o n s o f w a t e r . T h e o r g a n i c l a y e r was d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e t h e c r u d e e s t e r c o n t a m i n a t e d w i t h some -d I e y e Iohexy I u r e a . T h e c r u d e e s t e r was p u r i f i e d by c o l u m n c h r o m a t o g r a p h y on s i l i c a g e l t o g i v e t h e p u r e e s t e r s . O c t v l 3 - ( t r I m e t h v l s l I v l i p r o p a n o a t e ( 1 2 9 a ) 1 - O c t a n o l ( 0 . 3 3 m L , 273 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 50 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 1 9 : 1 ) a s t h e e l u t l n g s o l v e n t a f f o r d e d 469 mg (91%) o f e s t e r 129a a s a c o l o r l e s s l i q u i d . Rf 0 . 4 7 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; Ir ( f i l m ) : 1740 , 1250 , 8 6 0 , 835 c m - " 1 ; ms m / z : 243 ( M + - C H 3 , 10) , 1 4 7 ( 3 6 ) , 1 3 1 ( 1 0 0 ) , 1 0 1 ( 3 2 ) ; 1 H nmr (80 MHz) 6: 0 . 0 2 ( s , 9 ) , 0 . 7 0 - 1 . 7 5 ( m , 1 7 ) , 2 . 1 2 - 2 . 3 9 ( m , 2 , C H . 2 C 0 2 ) , 4 . 0 5 ( t , 2 , 1=6 . 5 , C t l 2 0 ) . A n a I . c a l c d . f o r C i 4 H 3 0 O 2 S I ( 2 5 8 . 4 8 ) : C 6 5 . 0 6 , H 1 1 . 7 0 ; f o u n d : C 6 5 . 0 0 , H 1 1 . 8 0 . E x a c t m a s s c a l c d . f o r C 1 4 H 3 0 ° 2 S 1 ~ C H 3 : 2 4 3 . 1 7 8 0 ; f o u n d : 2 4 3 . 1 7 8 5 . E s t e r 129a was a l s o p r e p a r e d by an a l t e r n a t e m e t h o d . To a s t i r r e d s u s p e n s i o n o f 360 mg ( 1 . 2 mmol) o f 2 - b r o m o - 1 - m e t h y I -p y r i d i n l u m i o d i d e in 1 .5 mL o f d i c h I o r o m e t h a n e was a d d e d a s o l u t i o n o f 146 mg ( 1 . 0 mmol) o f 3 - ( t r i m e t h y I s I I y I ) p r o p a n o I c 0 246 a c i d ( 1 3 1 ) . 0 . 1 6 mL (130 mg, 1 .0 mmol) o f 1 - o c t a n o l , and 0 . 3 3 mL (243 mg, 2 . 4 mmol) o f t r I e t h y I am Ine In 2 . 5 mL o f d l c h l o r o -m e t h a n e . The r e a c t i o n m i x t u r e was h e a t e d a t r e f l u x f o r 22 h . A f t e r t h e m i x t u r e had c o o l e d t o r t , t h e s o l v e n t was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e a brown r e s i d u e . T h i s r e s i d u e was s u b j e c t e d t o c o l u m n c h r o m a t o g r a p h y on 35 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 4 9 : 1 ) a s t h e e l u t i n g s o l v e n t t o a f f o r d 210 mg (81%) o f e s t e r 129a a s a co I o r I e s s I Iqu i d . 4 - t - B u t v I p h e n v I 3 - ( t r I m e t h v l s l I v l ) p r o p a n o a t e ( 129b ) 4 - t - B u t y I p h e n o I (316 mg) was u s e d . P u r i f i c a t i o n by c o l u m n c h r o m a t o g r a p h y on 50 g o f s i l i c a g e l ( 7 0 - 2 3 0 mesh) u s i n g p e t r o l e u m e t h e r - e t h y l a c e t a t e ( 9 7 : 3 ) a s t h e e l u t i n g s o l v e n t a f f o r d e d 525 mg (94%) o f e s t e r 129b a s a c o l o r l e s s l i q u i d . Rf 0 . 5 4 ( p e t r o l e u m e t h e r - E t O A c , 1 9 : 1 ) ; i r ( f i l m ) : 1760 , 1 2 5 0 , 8 5 0 , 835 c m - 1 ; ms m / z : 2 7 8 ( M + , 7 ) , 1 5 0 ( 5 9 ) , 1 3 5 ( 9 3 ) , 1 2 8 ( 2 6 ) , 1 1 3 ( 4 0 ) , 7 3 ( 1 0 0 ) ; 1 H nmr (80 MHz) 6: 0 . 0 9 ( s , 9 ) , 0 . 8 8 - 1 . 1 3 ( m , 2