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Chemistry of the anions from isoxazolin-5-ones ; Lactone synthesis via β-keto ester dianion alkylaton Tischler, Samuel Arthur 1981

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I. CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES I I . LACTONE SYNTHESIS VIA B-KETO ESTER DIANION ALKYLATION by SAMUEL ARTHUR TISCHLER B . S c , The U n i v e r s i t y of B r i t i s h Columbia, 1976 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA January 1981 Samuel Arthur T i s c h l e r , 1981 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced degree at the 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 , I ag ree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d that c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y o f B r i t i s h Co lumbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 ABSTRACT In p a r t I of t h i s t h e s i s an examination o f the u t i l i t y of i s o x a z o l i n - 5 - o n e s , e.g. 114, as B-keto e s t e r d i a n i o n e q u i v -a l e n t s i s presented. Generation o f the anion o f i s o x a z o l i n - 5 -one 114 and r e a c t i o n with v a r i o u s e l e c t r o p h i l e s gave products 140 i n f a i r to good y i e l d s . In p a r t i c u l a r , the cases where E=TMS, Br, CgHt-S, and CgH^Se i l l u s t r a t e t h a t the chemistry of the anion o f i s o x a z o l i n - 5 - o n e s i s complimentary to that of B-keto e s t e r d i a n i o n s . S e v e r a l routes or p o t e n t i a l routes to the p r e p a r a t i o n of unsaturated i s o x a z o l i n - 5 - o n e s are a l s o d i s -cussed. One of these pathways i n v o l v e s the condensation of W i t t i g reagent 141 with aldehydes. The success of t h i s plan was i i demonstrated by the p r e p a r a t i o n of unsaturated i s o x a z o l i n - 5 - o n e s 142, R=CgH 5- and C H 3 ( C H 2 ) 4 ~ , R'=H. F i n a l l y , s e v e r a l s t r a t e g i e s f o r the cleavage of i s o x a z o l i n - 5 - o n e s to B-keto e s t e r s were i n v e s t i g a t e d . In p a r t II of t h i s d i s s e r t a t i o n , the s y n t h e s i s of l a r g e r i n g l a c t o n e s v i a an i n t e r n a l B-keto e s t e r d i a n i o n a l k y l a t i o n i s d e s c r i b e d (equation i ) . The B-keto e s t e r h a l i d e s 262 were (i) 262 prepared by the a l c o h o l y s i s of a c e t y l Meldrum's a c i d 253 with 1,n-bromoalcohols. The study of the c y c l i z a t i o n of B-keto e s t e r i i i h a l i d e 262g r e v e a l e d t h a t e l i m i n a t i o n as w e l l as i n t r a m o l e c u l a r a l k y l a t i o n o f t e n o c c u r r e d (equation i i ) . The e f f e c t of temperature, l e a v i n g group, s o l v e n t , and c o u n t e r i o n on the c y c l i z a t i o n process was t h e r e f o r e examined. The r e s u l t s of t h i s i n v e s t i g a t i o n have shown t h a t c y c l i z a t i o n was optimized when the h a l i d e 262 was added to three e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l -amide i n t e t r a h y d r o f u r a n (0° -*• RT) . These c o n d i t i o n s provided B-keto l a c t o n e s when the chain l e n g t h n >^  9, while e l i m i n a t i o n predominated when n < 8. F i n a l l y , the p r e p a r a t i o n and i n t r a m o l e c u l a r a l c o h o l y s i s of the hydroxy a c y l Meldrum's a c i d 295 was conducted and gave the fourteen-membered B-keto l a c t o n e 266e i n f a i r y i e l d . 295 26£e i v TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS V LIST OF SCHEMES v i LIST OF TABLES v i i LIST OF ABBREVIATIONS v i i i ACKNOWLEDGEMENTS i x INTRODUCTION - GENERAL BACKGROUND 1 SECTION I: CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES 22 I n t r o d u c t i o n 22 R e s u l t s and D i s c u s s i o n 59 Co n c l u s i o n s I l l Experimental . . 113 SECTION I I : LACTONE SYNTHESIS VIA 8~KETO ESTER DIANION ALKYLATION 142 I n t r o d u c t i o n 142 A. S y n t h e s i s of M a c r o c y c l i c Lactones v i a t o - H a l o c a r b o x y l i c A c i d s 145 B. S y n t h e s i s o f M a c r o c y c l i c Lactones v i a w-Hydroxycarboxylic A c i d s . . . . 147 C. The Present Approach 175 R e s u l t s and D i s c u s s i o n 180 Co n c l u s i o n s 221 Experimental 225 BIBLIOGRAPHY 260 SPECTRAL APPENDIX 272 v LIST OF SCHEMES Scheme T i t l e Page 1 Resonance Hybrids f o r Mono- and Dianions of B-Diketones 7 2 P r e p a r a t i o n of y,y-Disubstituted B-Keto E s t e r s . 13 3 Synt h e s i s of Jasmone (3_2) 14 4 S e l e c t e d Reactions of 1 , 3 - B i s ( t r i m e t h y l s i l y l ) -1-methoxybuta-l ,3-diene (8_7) 45 5 Mechanism f o r Thiamine C a t a l y z e d Decarboxyla-t i o n of P y r u v i c A c i d (9_8) 50 6 Isoxazolin-5-ones as B-Keto E s t e r Dianion E q u i v a l e n t s 59 7 P o s s i b l e Mechanism f o r the Formation of P y r r o l e (115) 61 8 C l a s s i c a l P r e p a r a t i o n of Nazarov Reagent 146 . . 89 9 Lactone Formation v i a Double A c t i v a t i o n Using 2 - P y r i d i n e t h i o l E s t e r s 158 10 Mechanism Proposed f o r Palladium C a t a l y z e d C y c l i z a t i o n s 172 11 Proposed Plan f o r M a c r o c y c l i c 8 -Keto Lactone Formation 178 12 P r e p a r a t i o n of B-Keto E s t e r Benzenesulfonate 277 204 13 P r e p a r a t i o n of P h e n y l t h i o B-Keto E s t e r 278 . . . 206 14 P r e p a r a t i o n of Hydroxy A c y l Meldrum's A c i d 295 216 v i LIST OF TABLES Table T i t l e Page 1 A l k y l a t i o n of L i t h i u m Sodium Methyl Aceto-a c e t a t e i n T e t r a h y d r o f u r a n 14 2 A l d o l Reactions of L i t h i u m Sodium Methyl A c e t o a c e t a t e i n T e t r a h y d r o f u r a n 18 3 A c y l a t i o n of L i t h i u m Sodium Methyl A c e t o a c e t a t e 19 4 Baldwins' Rules 38 5 P r e p a r a t i o n of 2-Methylisoxazolin-5-ones 103 r R=Me 57 6 E v a l u a t i o n of Bases f o r Deprotonating 2,3,4-T r i m e t h y l i s o x a z o l i n - 5 - o n e (114) . . 65 7 Reaction of 2,3,4-Trimethylisoxazolin-5-one (114) With Simple E l e c t r o p h i l e s 72 8 A l k y l a t i o n of 2 , 3 , 4 - T r i m e t h y l i s o x a z o l i n - 5 - o n e (114) With Unusual E l e c t r o p h i l e s 81 9 The Reduction of Unsaturated Ketone 163 With V a r i o u s Reducing Agents 108 10 C y c l i z a t i o n of; 2 - P y r i d i n e t h i o l E s t e r s of c j-Hydroxycarboxylic A c i d s 160 11 P r e l i m i n a r y Study of the P r e p a r a t i o n of 6-Keto E s t e r H a l i d e s 255 183 12 P r e p a r a t i o n of Long Chain B-Keto E s t e r Bromides 262 192 13 Attempted C y c l i z a t i o n of B - K e t o E s t e r Bromides 262 213 v i i LIST OF ABBREVIATIONS DIBAL = d i i s o b u t y l a l u m i n u m hydride DBN = 1 , 5 - d i a z a b i c y c l o [4 .3 . (3] non-5-ene DMF = dimethyIformamide DMSO = dimethyl s u l f o x i d e ether = e t h y l ether Im2CO = N,N-carbonyIdiimidazole IR = i n f r a r e d LDA = l i t h i u m d i i s o p r o p y l a m i d e MsCl = methanesulfonyl c h l o r i d e NCS = N - c h l o r o s u c c i n i m i d e NMR = proton n u c l e a r magnetic resonance py p y r i d i n e RT = room temperature THF = t e t r a h y d r o f u r a n TLC = t h i n l a y e r chromatography TMS = t r i m e t h y l s i l y l p_-TsOH = p a r a - t o l u e n e s u l f o n i c a c i d VPC = vapour phase chromatography A b b r e v i a t i o n s f o r m u l t i p l i c i t i e s of NMR s i g n s = s i n g l e t d = d o u b l e t t = t r i p l e t q = q u a r t e t dd = d o u b l e t of d o u b l e t s bs broad s i n g l e t m m u l t i p l e t T h i s t h e s i s has been w r i t t e n i n conformance with the "Handbook fo r Authors", p u b l i s h e d by the American Chemical S o c i e t y ; Washington, D.C, 1978 . v i i i ACKNOWLEDGEMENTS I would l i k e to express my a p p r e c i a t i o n to P r o f e s s o r L a r r y Weiler f o r h i s encouragement and guidance throughout the course of t h i s work, and f o r h i s a s s i s t a n c e d u r i n g the p r e p a r a t i o n of t h i s t h e s i s . I am indebted to P r o f e s s o r G.S. Bates, P r o f e s s o r J.R. S c h e f f e r , and P r o f e s s o r P. Legzdins f o r readi n g through the manuscript of t h i s t h e s i s and p r o v i d i n g i n v a l u a b l e s u g g e s t i o n s . The e f f i c i e n t c o o p e r a t i o n of the s t a f f of the NMR, mass spectroscopy, and m i c r o a n a l y t i c a l s e r v i c e s i s g r a t e f u l l y acknowledged. F i n a l l y , I wish to extend a s p e c i a l thanks to my parents f o r t h e i r p a t i e n c e , constant encouragement and support through-out the course of my e d u c a t i o n . i x 1 GENERAL INTRODUCTION One of the most e x c i t i n g and c h a l l e n g i n g areas i n o r g a n i c chemistry l i e s i n the t o t a l s y n t h e s i s of n a t u r a l l y o c c u r r i n g compounds. These n a t u r a l products are o f t e n prepared because of t h e i r b i o l o g i c a l a c t i v i t y or as proof of t h e i r s t r u c t u r e , while at other times because they o f f e r a c h a l l e n g e to the s k i l l and i n g e n u i t y of the o r g a n i c chemist. I f there i s any key to success i n d e s i g n i n g a s y n t h e s i s , i t i s to work the problem"backwards. The t a r g e t molecule i s m e t h o d i c a l l y broken a p a r t , p i e c e by p i e c e , i n such a way t h a t the fragments can be reassembled with reasonable assurance of success. I t i s when the molecular framework has been unrav-e l l e d to an a c c e s s i b l e s t a r t i n g m a t e r i a l and p r o p o s a l s made to r e j o i n each component back to the t a r g e t molecule, that the s y n t h e t i c plan i s i n hand. A most thorough knowledge of or g a n i c r e a c t i o n s and t h e i r scope and l i m i t a t i o n s i s t h e r e -f o r e c r i t i c a l to the pl a n n i n g p r o c e s s , f o r t h i s knowledge p r o v i d e s the t o o l s f o r s y n t h e s i s . These t o o l s must be con-s t a n t l y re-examined and improved to provide s o l u t i o n s f o r i n c r e a s i n g l y d i f f i c u l t t a s k s . The p a s t twenty to t h i r t y years have seen a tremendous a c c e l e r a t i o n i n the development of new s y n t h e t i c methods. The r e s u l t s of t h i s e x p l o s i v e growth have been made apparent by the p r e p a r a t i o n of n a t u r a l products and novel o r g a n i c 2 compounds of i n c r e a s i n g complexity. A few r e c e n t examples in c l u d e the s y n t h e s i s of g i b b e r e l l i c a c i d ( 1 ) ^ and c y t o c h a l a -s i n B ( 2 ) 2 . 1 Z,R = H The development of new s y n t h e t i c methods has evolved along two pathways. The f i r s t and more c l a s s i c a l approach i n v o l v e s the s y s t e m a t i c study of the fundamental chemistry of c e r t a i n c l a s s e s of o r g a n i c compounds. Some examples i n c l u d e 3 the study o f organomagnesium compounds by G r i g n a r d and more 4 r e c e n t l y , work by Brown on the chemistry of organoboranes . The second approach i s one i n which c e r t a i n s y n t h e t i c opera-t i o n s , not f e a s i b l e by p r e - e x i s t i n g r e a c t i o n s , become the primary g o a l of r e s e a r c h . An example i s a process which allows t r a n s f o r m a t i o n of the normally e l e c t r o p h i l i c carbon of aldehydes i n t o a n u c l e o p h i l i c c e n t r e through formation of the corresponding d i t h i o a c e t a l s 3 (equations 1 and 2 ) . 3 V Reagents which t e m p o r a r i l y r e v e r s e the c h a r a c t e r i s t i c r e a c -t i v i t y o f an atom i n a f u n c t i o n a l group are termed umpolung r e a g e n t s ^ from the c o r r e s p o n d i n g German word meaning "change the p o l a r i t y " . For a number o f y e a r s our l a b o r a t o r y has been i n v e s t i -g a t i n g the c h e m i s t r y o f B - k e t o e s t e r s . T h i s i n t e r e s t stemmed from a d e s i r e t o f u n c t i o n a l i z e the y carbon atom i n a B - k e t o e s t e r 4_ i n an attempt t o s y n t h e s i z e a c e t o g e n i n s , f o r example 6 7 r e s i s t o m y c i n (5) ' . 8 E a r l y work by Geuther i n 1863 had shown t h a t the mono-anio n 1_ o f e t h y l a c e t o a c e t a t e c o u l d be g e n e r a t e d u s i n g sodium e t h o x i d e i n anhydrous e t h a n o l ( e q u a t i o n 3 ) . I t remained, 0 0 0 0 however, f o r W i s l i c e n u s 3 i n 1877 t o r e p o r t the f i r s t e x t e n s i v e s t u d y o f the p r o p e r t i e s o f e t h y l a c e t o a c e t a t e {6). In p a r -t i c u l a r , t h i s author demonstrated the n u c l e o p h i l i c i t y o f the a n i o n 7 f o r the f i r s t t i m e , by i t s r e a c t i o n w i t h iodoethane t o form e t h y l 2 - e t h y l a c e t o a c e t a t e (8_) . T h i s s t u d y p r o v i d e d 0 0 0 0 EtI OEt OEt 1 the impetus f o r other workers, and there f o l l o w e d a p e r i o d of over s i x t y years d u r i n g which the r e a c t i o n s of g - d i c a r b o n y l compounds and t h e i r monoanions were e x p l o r e d and e x t e n s i v e l y u t i l i z e d 1 0 . A new chapter i n ft-dicarbonyl chemistry was opened i n 1958 when Hauser and H a r r i s observed t h a t the d i p o t a s s i u m s a l t s of 1-phenylbutane-1,3-dione (9) and pentane-2,4-dione (11) c o u l d be generated by t r e a t i n g the B - d i c a r b o n y l compound with potassium amide i n l i q u i d ammonia 1 1. These dip o t a s s i u m s a l t s r e a c t e d r a p i d l y with one e q u i v a l e n t of benzyl c h l o r i d e and gave the compounds IC) and 1_2 i n 77 and 60% y i e l d r espec-t i v e l y . 0 0 2KNH C 6 H 5 CH 2 Cl 2 ,R=C 6H 5 0 0 ll,R=Me IQ,R=C6H5 12, R= Me 6 Compound 10_ w a s shown by a molecular weight d e t e r m i n a t i o n not to be a d i b e n z y l a t e d d e r i v a t i v e and by the mixed m e l t i n g p o i n t method not to be 2-benzyl-l-phenylbutane-1,3-dione (14), which c o u l d be prepared from the monoanion 13 and benzyl c h l o r i d e . The s t r u c t u r e was f i n a l l y confirmed as 10 by 0 0 0 0 C 6H BAA * C 6 H 5 C H 2 C l * C 6 ^ -C 6 H 5 a l k a l i n e cleavage to form acetophenone (1J5), and by an in d e -pendent s y n t h e s i s of 10 i n v o l v i n g the a c y l a t i o n of a c e t o -phenone (15) with methyl hydrocinnamate (]Jj) (equation 4) . o 0 0 j t 1) NaNH 2 , E t 2 0 II jf C 6 H 5 2) C 6 H 5 C H 2 C H 2 C 0 0 M e C g H r / ^ ^ ^ C ^ 16 15 ID. A measure of the r e a c t i v i t y of these d i p o t a s s i u m c a r -banions may be seen by comparison of t h e i r r a t e s of r e a c t i o n with those of the c o r r e s p o n d i n g monoanions. The a l k y l a t i o n of monoanions of 3-diketones proceeds s l o w l y , even at e l e -vated temperatures, while the d i a n i o n s a l t s r e a c t r a p i d l y a t low temperatures. T h i s r e s u l t i s c o n s i s t e n t with resonance (A) 7 s t a b i l i z a t i o n arguments. The monoanion i s s t a b i l i z e d by both adjacent c a r b o n y l groups. In the d i a n i o n the c a r b o n y l groups must s t a b i l i z e two negative charges. Hence the l a t t e r would be expected to be a more r e a c t i v e s p e c i e s (Scheme 1 ) . 0 0 0 0" "0 0 0 0 < > R-0" 0" Scheme 1; Resonance h y b r i d s f o r mono- and d i a n i o n s of B-diketones The i n i t i a l communication by Hauser and H a r r i s stimu-l a t e d f u r t h e r i n t e r e s t i n the chemistry of B - d i c a r b o n y l 12 13 d i a n i o n s . In p a r t i c u l a r , work on t h e i r a l k y l a t i o n ' , as 14 11 w e l l as a l d o l and C l a i s e n condensations was conducted and 15 16 the chemistry extended to the d i a n i o n s of B-keto aldehydes ' , 17 18 — 21 B-keto l a c t o n e s , and other r e l a t e d c a r b o n y l compounds Most of t h i s r e s e a r c h was c a r r i e d out by Hauser and coworkers, 22 and the r e l e v a n t l i t e r a t u r e ( u n t i l 1966) has been reviewed The i n v e s t i g a t i o n of B~keto e s t e r s i n d i c a t e d t h a t t h e i r d i a n i o n s c o u l d a l s o be prepared by u s i n g two e q u i v a l e n t s of 23 potassium amide i n l i q u i d ammonia . A l k y l a t i o n of the 8 d i a n i o n 17 of e t h y l a c e t o a c e t a t e w i t h m e t h y l i o d i d e and e t h y l bromide gave the d e s i r e d p r o d u c t s 18_, however, i n o n l y 37 and 29% y i e l d r e s p e c t i v e l y , w h i l e a l d o l c o n d e n s a t i o n w i t h benzo-phenone a f f o r d e d the ( 6 - h y d r o x y - B - k e t o e s t e r 19 i n 50% y i e l d . 0 0 AA R-X OEt 0 0 17 0 0 'OEt OEt 18a,R=Me 18b. R=Et HO 0 0 C 6 H 5 ' C 6 H 5 12 OEt No improvement i n y i e l d s was observ e d by v a r y i n g the time f o r d i a n i o n g e n e r a t i o n or a l k y l a t i o n . In a d d i t i o n , attempted a l k y l a t i o n s w i t h n - b u t y l bromide and b e n z y l c h l o r i d e were u n s u c c e s s f u l . These workers were a b l e t o show t h a t d i a n i o n 17_ does n ot decompose a p p r e c i a b l y under the r e a c t i o n c o n d i t i o n s and t h e r e -f o r e a t t r i b u t e d the low y i e l d s t o i n c o m p l e t e c o n v e r s i o n o f the g-keto e s t e r t o i t s d i a n i o n . T h i s , i t was f e l t , would l e a v e a p p r e c i a b l e amounts of amide i o n i n the r e a c t i o n mix-t u r e t o compete f o r the e l e c t r o p h i l i c r e a g e n t s . 9 In s t u d i e s i n our l a b o r a t o r y on the s y n t h e s i s of r e s i s -tomycin (5_) , as s t a t e d e a r l i e r , a method to f u n c t i o n a l i z e the Y carbon atom of a g-keto e s t e r was r e q u i r e d . The generation HO 0 OH L of the d i a n i o n _17 by means of potassium amide i n l i q u i d ammonia appeared, however, to impose severe r e s t r i c t i o n s on the r e a c t i o n s of g-keto e s t e r s . F i r s t l y , r e a c t i o n s would be l i m i t e d to those which would proceed at a reasonable rate at low temperature (-33° or lower), and secondly, the r e a c t i o n s might be complicated by r e a c t i o n of the s o l v e n t ammonia with reagents or pr o d u c t s . E t h y l ether and 1,2-dimethoxyethane have been employed f o r r e a c t i o n s of the d i a n i o n _17 of e t h y l 23 24 acetoacetate ' , but t e t r a h y d r o f u r a n has a b e t t e r s o l v a t i n g 25 a b i l i t y f o r a l k y l l i t h i u m s . What remained, t h e r e f o r e , was the search f o r an a l t e r n a t e base po s s e s s i n g a high proton a b s t r a c t i n g a b i l i t y and low n u c l e o p h i l i c i t y . 10 I t i s w e l l known t h a t a c a r b o n y l group may be p r o t e c t e d from n u c l e o p h i l i c a t t a c k by formation of i t s e n o l a t e anion. For example, s e l e c t i v e c o n v e r s i o n of the e s t e r f u n c t i o n a l i t y of B-keto e s t e r 20_ i n t o an a l c o h o l was achieved by s e q u e n t i a l 2 6 treatment of 2_0 with sodium hydride and excess m e t h y l l i t h i u m (equation 5) . 1) NaH,THF — 5 2) xs MeLi 20. T r e a t i n g methyl a c e t o a c e t a t e (21) with two e q u i v a l e n t s of n - b u t y l l i t h i u m , however, y i e l d e d c a r b o n y l a d d i t i o n products 27 . • only . In a subsequent communication, B r i e g e r and Spencer 0 0 A A OMe 21 were able to show t h a t i n the r e a c t i o n of g-keto e s t e r s with a l k y l l i t h i u m s the p r i n c i p a l products were ketones, even i n 28 the presence of excess o r g a n o l i t h i u m reagent . T h e r e f o r e , the r e a c t i o n of n - b u t y l l i t h i u m (three e q u i v a l e n t s ) with e t h y l 11 2 - n - b u t y l a c e t o a c e t a t e (22) gave 5-decanone (23_) as the major p r o d u c t i n 24% y i e l d . C a r e f u l e x a m i n a t i o n of the r e a c t i o n p r o d u c t s l e d t o the c o n c l u s i o n t h a t , i n the case o f B-keto e s t e r s , the e s t e r c a r b o n y l group i s a t t a c k e d p r e f e r e n t i a l l y w i t h f o r m a t i o n o f a B - d i k e t o n e . T h i s B-diketone then r e a c t s f u r t h e r t o g i v e the f i n a l p r o d u c t ketones by c l e a v a g e of the i n t e r m e d i a t e a d d i t i o n p r o d u c t . T h i s c o n c l u s i o n was s u p p o r t e d by the i s o l a t i o n o f 2-hexanone, 2-heptanone, and 5-nonanone from the r e a c t i o n m i x t u r e . S t u d i e s conducted by Hauser and coworkers had shown t h a t the d i a n i o n 25 of p h e n y l a c e t o n e was r e a d i l y produced v i a 29 the monoanion 2_4 by d e p r o t o n a t i o n w i t h n - b u t y l l i t h i u m . T h i s r e s u l t s u g g ested t h a t g e n e r a t i o n of the monoanion of m e t h y l o n-BuLi THF C 6H 5 Ok Ik 25. 12 a c e t o a c e t a t e (21) and subsequent m e t a l l a t i o n would surmount: the d i f f i c u l t y presented by c a r b o n y l a d d i t i o n . Treatment of methyl a c e t o a c e t a t e (23.) with sodium hydride i n t e t r a h y d r o -furan gave the monoanion 26, which upon m e t a l l a t i o n with 27 n - b u t y l l i t h i u m d i d , i n f a c t , g i v e the d i a n i o n i c s p e c i e s 2_7 0 0 0 0 0 0 II jf N Q H ^ II II n-BuLi » 1 ^ ^ ^ O M e T H F ^NrN ) M e / V ^ O M e 21 2SL 21 Formation of the d i a n i o n was confirmed by quenching the r e a c -t i o n mixture with a s o l u t i o n of deuterated t r i f l u o r o a c e t i c a c i d i n deuterium oxide, which gave deuterium i n c o r p o r a t i o n at both the a and y p o s i t i o n s . The deuterium at the a carbon c o u l d , i n a d d i t i o n , be removed by exchange i n aqueous base. The r e s u l t i n g methyl a c e t o a c e t a t e was found to c o n t a i n 0.96 ± 0.03 deuterium at the y p o s i t i o n by NMR and mass s p e c t r o s c o p i c a n a l y s i s (equation 6). 13 The d i a n i o n 27. c o u l d be monoalkylated a t the y carbon r a p i d l y and i n high y i e l d a t 0°C (Table I) , but a t lower temperatures the r a t e of a l k y l a t i o n d i m i n i s h e d markedly. The NMR and mass s p e c t r a of the i s o l a t e d products i n d i c a t e d that a l k y l a t i o n had oc c u r r e d c l e a n l y at the y p o s i t i o n , and f u r -thermore, s p e c t r a l a n a l y s i s of the crude r e a c t i o n mixtures f a i l e d t o g i v e any evidence f o r e i t h e r d i a l k y l a t e d or 0-alky-l a t e d p r o d u c t s . T h i s procedure a l s o p e r m i t t e d the a l k y l a t i o n of s u b s t i -tuted g-keto e s t e r s . T h e r e f o r e , i t was p o s s i b l e to s t a r t with methyl a c e t o a c e t a t e (2_1) , generate the d i a n i o n 2_7 and a l k y l a t e , then regenerate the d i a n i o n u s i n g a second e q u i v a l e n t of n - b u t y l l i t h i u m and add a second a l k y l a t i n g agent to y i e l d y,y-d i s u b s t i t u t e d g-keto e s t e r s 29 (Scheme 2 and Table I ) . In 1) n-BuLi 2) R'-X 0 0 R 21 Scheme 2: P r e p a r a t i o n of y,y-disubstituted g-keto e s t e r s Table I. A l k y l a t i o n of L i t h i u m Sodium Methyl A c e t o a c e t a t e Tetrahydrofuran^7 0 0 23. 1) N a H . T H F 2) a -BuLi OMe 3) R ' -X 0 0 2 2 R HI X Y i e l d H CH 3 I 81 H C 2 H 5 Br 84 H (CH 3) 2CH I 73 H n-C.HQ. Br 72 — 4 9 H CH 2 —CHCH2 Br 83 H C 6 H 5 C H 2 C l 81 H-C 4H 9 CH 2=CHCH 2 Br 77 n-C 4H g C-H _CH ~ 6 5 2 C l 62 (48) CH 3 C 6 H 5 C H 2 C l 76 C 6 H 5 C H 2 CH 3 I 86 a. The y i e l d i n parentheses r e f e r s to t h a t obtained by s u c c e s s i v e treatment of methyl a c e t o a c e t a t e with n - b u t y l bromide and be n z y l c h l o r i d e without i s o l a t i o n of the in t e r m e d i a t e monoalkylated product. 15 g e n e r a l , however, higher y i e l d s were obtained i f the i n t e r -mediate monoalkylated product 2j3 was i s o l a t e d and p u r i f i e d p r i o r to performing the second a l k y l a t i o n (Table I ) . A more thorough study"^ l a t e r r e v e a l e d t h a t the d i a n i o n 27 c o u l d a l s o be generated u s i n g two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e (3_0) or l i t h i u m 2,2, 6,6 ,-tetrame t h y l p i p e r -+ 31 i d i d e (3_1) , the s o - c a l l e d 'H arpoon' base . In a d d i t i o n , the a l k y l a t i o n of 2_7 was found to proceed e q u a l l y w e l l i n e t h y l e t h e r , t e t r a h y d r o f u r a n , 1,2-dimethoxyethane, and hexa-methylphosphoramide. In some ins t a n c e s where the d i a n i o n s of complex B-keto e s t e r s were not s o l u b l e i n t e t r a h y d r o f u r a n , the a d d i t i o n of hexamethylphosphoramide l e d to d i s s o l u t i o n of these d i a n i o n s and the subsequent a l k y l a t i o n then proceeded normally. The s i m p l i c i t y and v e r s a t i l i t y of the sodium hydride -rv-buty H i thium procedure i n the p r e p a r a t i o n of y - s u b s t i t u t e d B-keto e s t e r s has been demonstrated by the e f f i c i e n t synthe-s i s of jasmone (3_2) i n g r e a t e r than 40% o v e r a l l y i e l d from 32 methyl a c e t o a c e t a t e (2_1) (Scheme 3) . 2£L 31 16 0 0 1) K H , THF OMe 2) EtCECCH 2Br' 0 0 21 ^ V ^ O M e ^ • C E C E t H 2 . Pd-BaSO A 0 0 1) NaH, THF OMe 2) n-BuLi  ==ys^$ TMSCECCH2Br 0 0 C TMS HgO.THF H2S0 4 | H 2 0 0 0 OMe NaOH, H 2 0 32 Scheme 3; S y n t h e s i s of jasmone (32) 32 17 The extension of t h i s procedure to the p r e p a r a t i o n of 33 6-hydroxy B-keto e s t e r s 33 v i a a l d o l type condensations (equation 7), and Br<5-diketo e s t e r s 3_4 v i a the a c y l a t i o n of 34 B-keto e s t e r d i a n i o n s and these r e s u l t s are summarized i n Tables II and I I I (equation 8 ) , has a l s o been examined 35 0 0 0 HO 0 0 27 R R 33 OMe (7) 0 0 0 OMe R OR' 0 0 0 27 3A In summary, p r e v i o u s work in our l a b o r a t o r i e s has shown th a t the sodium hydride - n - b u t y l l i t h i u m procedure f o r the g e n e r a t i o n of the d i a n i o n of a B-keto e s t e r p r o v i d e s an excel-l e n t route to the p r e p a r a t i o n of y - s u b s t i t u t e d B-keto e s t e r s . Indeed, s e v e r a l a p p l i c a t i o n s of t h i s s y n t h e t i c method i n the t o t a l s y n t h e s i s of n a t u r a l products have r e c e n t l y appeared i n 3 6 the l i t e r a t u r e . N e v e r t h e l e s s , i t was a l s o c l e a r from these i n v e s t i g a t i o n s t h a t c e r t a i n l i m i t a t i o n s were in h e r e n t i n the use of B-keto e s t e r d i a n i o n s . The u t i l i z a t i o n of a p r o t e c t e d A l d o l Reactions of L i t h i u m Sodium Methyl Aceto-a c e t a t e i n Tetrahydrofuran35 0 Me 0 HO 0 0 OMe 23 R" CH 3 CH 3CH 2 H- C4 H9 E- C4 H9 C 6 H 5 o-CH-jOC^H. — 3 6 4 2,3-(CH 30) 2CgH 3 2 - f u r y l CH 3 CH 3CH 2 - ( C H 2 ) 5 -~ ( C H 2 ) 4 -C 6 H 5 o-CH o0C cH. — 3 6 4 C 6 H 5 Y i e l d (%) 26 73 36 82 89 73 68 68 70 56 63 25 77 79 93 Table I I I . A c y l a t i o n of L i t h i u m Sodium Methyl A c e t o a c e t a t e 0 0 0 0 0 0 ^ ^ ^ O M e * R / ^ O R ' ^ R / ' ^ ^ ^ 27 34 R RV Y i e l d (%) CH 3 CH 3 71 H CH 3 69 B " C3 H7 CH 3 67 n-C 3H 7 CH 3CH 2 33 C 6 H 5 CH 3 37 £ - C H 3 O C 6 H 4 CH 3 42 B-keto e s t e r i n an e f f o r t t o overcome these problems was t h e r e f o r e c o n s i d e r e d . For many y e a r s i t has been known t h a t i s o x a z o l i n - 5 - o n e s 36 may be p r e p a r e d by the c o n d e n s a t i o n o f B-keto e s t e r s w i t h N - a l k y l h y d r o x y l a m i n e h y d r o c h l o r i d e s 3_5 i n the presence o f a 37 base, such as p y r i d i n e ( e q u a t i o n 9 ) . Very l i t t l e work, 0 0 OMe RNHOH-HCl Pyridine R ' (9) however, has been r e p o r t e d on the c h e m i s t r y o f these compounds We t h e r e f o r e became i n t r i g u e d by the p o s s i b i l i t y t h a t the monoanion o f i s o x a z o l i n - 5 - o n e s o f type 3_7 may p r o v i d e a new and perhaps c o m p l i m e n t a r y B-keto e s t e r d i a n i o n e q u i v a l e n t ( e q u a t i o n 10.) . 0 R" 0 Base N — 0 (10) 21 P a r t I o f t h i s t h e s i s examines the p r e p a r a t i o n and chemis-t r y of monoanion 3_7 and how i t s r e a c t i v i t y p a r a l l e l s , and i n some c a s e s d i f f e r s from, t h a t o f B-keto e s t e r d i a n i o n s . The f i n a l p o r t i o n o f t h i s t h e s i s d e a l s w i t h the p r e p a r a -t i o n of B-keto e s t e r s o f type 38 and t h e i r c y c l i z a t i o n t o form l a r g e r i n g B-keto e s t e r s 39, w i t h a view towards the s y n t h e s i s of m a c r o l i d e s . The g e n e r a l p h i l o s o p h y i s o u t l i n e d i n e q u a t i o n 11-X - C H 2 ( C H 2 ) n 0 0 (CH 2 ) n 39 22 SECTION I CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES INTRODUCTION The u t i l i t y o f a new s y n t h e t i c method depends upon know-ledge of not only the scope of the process but a l s o i t s l i m i t a -t i o n s . T h i s allows the o r g a n i c chemist to c r i t i c a l l y evaluate any new method i n order to e s t a b l i s h i t s g e n e r a l i t y f o r use i n the s y n t h e s i s of complex molecules. Elements of the scope of B-keto e s t e r d i a n i o n chemistry have been d e s c r i b e d i n the General I n t r o d u c t i o n s e c t i o n of t h i s t h e s i s . S e v e r a l l i m i t a t i o n s , however, have been uncovered d u r i n g the development of t h i s chemistry. One of the major problems, i n t h i s regard, l i e s i n the high r e a c t i v i t y of B-keto e s t e r d i a n i o n s towards e l e c t r o p h i l e s . T h i s i s p a r t i c u l a r l y e v i d e n t i n the attempted Michael r e a c t i o n of d i a n i o n 2_7 with methyl v i n y l ketone (4_0) and cyclohexen-2-one (4_3) . In both cases, no evidence f o r products corresponding to conjugate a d d i t i o n are observed, i . e . 4_1 and JU; i n s t e a d the a l d o l pro-3 5 ducts 42 and 45 are obtained . Indeed, i t has been g e n e r a l l y 23 24 found that the more r e a c t i v e the n u c l e o p h i l e employed, the l e s s 3 8 conjugate a d d i t i o n i s observed The r e a c t i v i t y of B-keto e s t e r d i a n i o n s i s a l s o i l l u s -t r a t e d by t h e i r v i o l e n t r e a c t i o n with a c y l h a l i d e s to give a 27 mixture of products (equation 12). T h i s r e s u l t l e d to the c o n s i d e r a t i o n of milder a c y l a t i n g agents such as e s t e r s f o r the 34 p r e p a r a t i o n of t r i c a r b o n y l compounds (equation 13). 0 0 XX 0 OMe R A V C I mixture of products (12) 27 0 0 0 OMe R OR' 0 0 0 OMe ( 1 3 ) 27 34 I n t e r e s t i n the p r e p a r a t i o n of B-polyketones stems from the p o s t u l a t e d intermediacy of such s p e c i e s i n the b i o s y n t h e s i s of p h e n o l i c n a t u r a l products. The i n i t i a l r e p o r t which sug-gested the p o l y c a r b o n y l o r i g i n of some p h e n o l i c compounds arose from the o b s e r v a t i o n that heptane 2,4,6-trione (4 6) 39 c y c l i z e s to o r c i n o l (Al_) under a c i d i c c o n d i t i o n s . I t was 25 0 0 0 H 47 40 41 t h i s o b s e r v a t i o n , l a t e r c o n f i r m e d by B i r c h and B e t h e l , w h i c h l e d t o f o r m u l a t i o n o f the p o l y a c e t a t e r o u t e t o p h e n o l i c c o m p o u n d s ^ . 34 I n i t i a l e f f o r t s by H u c k i n and W e i l e r had shown t h a t d i a n i o n 2_7 r e a c t s s m o o t h l y w i t h e s t e r s t o g i v e 3 , 6 - d i k e t o e s t e r s 3_4. However, the y i e l d s i n t h e s e c o n d e n s a t i o n s were n o t s a t i s f a c t o r y (30-40%) d e s p i t e t h e i r s i m p l i c i t y . No d o u b t one o f the c o m p l i c a t i o n s i n t h i s r e a c t i o n i n v o l v e d p r o t o n t r a n s f e r from th e monoanion o f 3_4 t o d i a n i o n 2_7 and t h e r e f o r e the a d d i -t i o n o f more base d u r i n g the c o u r s e o f the r e a c t i o n was n e c e s -s a r y t o p r e s e r v e the d i a n i o n i c s p e c i e s . F o l l o w i n g a g r e a t d e a l o f e x p e r i m e n t a t i o n , i t was f o u n d t h a t the r e a c t i o n o f d i a n i o n 21_ w i t h one h a l f e q u i v a l e n t o f e s t e r , then a d d i t i o n o f one more e q u i v a l e n t o f b a s e , and f i n a l l y the r e m a i n i n g one h a l f e q u i v a l e n t o f e s t e r p r o v i d e d a c o n v e n i e n t p r o c e d u r e f o r 3 4 the p r e p a r a t i o n o f s i m p l e 8 , 6 - d i k e t o e s t e r s i n good y i e l d s . N e v e r t h e l e s s , i n the r e a c t i o n o f d i a n i o n 2_7 w i t h a r o m a t i c e s t e r s the y i e l d s o f d i k e t o e s t e r s £8 r e m a i n e d low. 26 R e i n v e s t i g a t i o n of the crude products r e v e a l e d that the c o r r e s -ponding c a r b o x y l i c a c i d s 4_9 were a l s o obtained i n s i g n i f i c a n t amounts. In a d d i t i o n , these c a r b o x y l i c a c i d products were only 22 48, R=Me 4SL R=H d e t e c t e d i n condensations i n v o l v i n g aromatic e s t e r s . T h i s r e s u l t was c o n s i s t e n t with the e a r l i e r f i n d i n g s of Wolfe and coworkers who re p o r t e d t h a t i n the attempted a r o y l a t i o n of e t h y l a c e t o a c e t a t e with methyl benzoate using sodium hydride in 1 ,2-dime thoxyethane o n l y the c a r b o x y l i c a c i d 4J3, Ar=CgH^, 43 c o u l d be i s o l a t e d . The mechanisms of these h y d r o l y s e s , how-ever, remain obscure. The a p p l i c a t i o n of t h i s a c y l a t i o n procedure to the pre -p a r a t i o n of p o l y c a r b o n y l compounds has been d e s c r i b e d by H a r r i s 44 and Murray . They have found that very powerful n u c l e o -p h i l e s , such as d i - and t r i a n i o n s , r e a c t with the monoanion of B-keto e s t e r s to give a c y l a t e d p r o d u c t s . For example, con-densation of the d i a n i o n 5j0 of 1-phenyl-l,3-butanedione with . the monoanion of e t h y l b e n z o y l a c e t a t e (5_1) g i v e s the t e t r a -c a r b o n y l compound 5_2. H a r r i s and coworkers have, i n f a c t , 27 0 0 0 0 - - C 6 H 5 50 51 0 0 0 0 O E t ^ C e H s - ^ 1 ^ ^ £2 used t h i s approach i n the s y n t h e s i s of l i n e a r B-polyketones 44 45 c o n t a i n i n g as many as e i g h t keto-groups ' A s i m i l a r a c y l a t i o n of methyl a c e t o a c e t a t e has a l s o been achieved i n our l a b o r a t o r y . I f , i n the gene r a t i o n of the d i a n i o n of methyl a c e t o a c e t a t e o n l y one-half e q u i v a l e n t of n - b u t y l l i t h i u m i s used, the B-keto e s t e r undergoes s e l f - c o n -densation and methyl o r s e l l i n a t e (5_4) i s obtained (equation 14) 34 0 0 OMe OMe 27 26 53 (14) COOMe 28 I s o l a t i o n of the intermediate t r i k e t o e s t e r _53 may a l s o be e f f e c t e d by quenching the r e a c t i o n mixture c a r e f u l l y with a phosphate b u f f e r (pH 6.5). T h i s m a t e r i a l undergoes spontaneous conver s i o n to methyl o r s e l l i n a t e (5_4) on s t a n d i n g . T h i s r e s u l t was confirmed by H a r r i s and h i s coworkers, who obtained a 59% y i e l d of t r i k e t o e s t e r 5_3 from the r e a c -t i o n of a 10:1 mixture of d i - and monolithium s a l t s of methyl 4 6 acetoacetate i n te t r a h y d r o f uran . E s t e r 5_3 then c y c l i z e d on a c t i v a t e d s i l i c a g e l to give methyl o r s e l l i n a t e (_54) i n 81% y i e l d . In t h i s study, an attempt to prepare 6 - m e t h y l s a l i c y l i c a c i d (58_) and r e l a t e d m e t a b o l i t e s was a l s o conducted using the h i t h e r t o unexplored r e a c t i o n of i o n i z e d B-keto aldehydes with 46 strong e l e c t r o p h i l e s . For example, a l d o l condensation of d i a n i o n 21_ with the sodium s a l t of acetoacetaldehyde (5_5) would be expected to give the hydroxy-diketo e s t e r 5_6, which upon c y c l i z a t i o n to cyclohexanone 51_ and l o s s of two moles of water would a f f o r d phenol _59_. N e v e r t h e l e s s , only a t r a c e (2.5%) of methyl 6 - m e t h y l s a l i c y l a t e (5_9) was obtained by t h i s 4 6 approach . Instead, i t was found that s e l f - c o n d e n s a t i o n , 29 0 0 0 0 0 0 H 0 0 Na* 55 27 56 OMe OH 6c 58,R=H 53,R=Me - 2 H 2 0 OMe c f . equation 14, predominated and the c y c l i z a t i o n conditions produced methyl o r s e l l i n a t e (5_4) . A similar outcome has occurred upon treatment of methyl acetoacetate dianion with the 46 monoanion of ethyl benzoylacetate . These experiments appear to indicate that dianion 21_ is a s u f f i c i e n t l y strong base to deprotonate the monoanion of acetoacetaldehyde. The resulting monoanion of the keto ester can then react with residual dianion 21_ to inevitably give methyl o r s e l l i n a t e (5_4) as per equation 14. Further work has revealed that this problem can be e l i -minated by the use of 3-keto esters having more bulky alkoxy groups which hinder nucleophilic attack on the ester group. 30 For example, condensation of t - b u t y l acetoacetate d i a n i o n (60) with the monoanion 5_5 of acetoacetaldehyde proceeds s a t i s f a c t o r i l y to give t - b u t y l 6 - m e t h y l s a l i c y l a t e (6_1) upon c y c l i z a t i o n and d e h y d r a t i o n ^ . 0 0 0 0 A A H 0C(CH3) ^ > fil, R= C(CH 3 ) 3 Subsequently, H a r r i s and Hubbard have reported t h a t the problem of s e l f condensation may a l s o be a l l e v i a t e d by using 4 7 the d i a n i o n of a B-keto amide . Treatment of N,N-dimethyl acetoacetamide (62) with two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l -amide at -20°C, or one e q u i v a l e n t of sodium hydride followed by one e q u i v a l e n t of n - b u t y l l i t h i u m at 0°C a f f o r d e d the d i a n i o n 63. 0 0 0 0 2LDA or > J\ fi NMe 2 NaH, n-Buii A ^ r ^ N M e 2 62 61 The condensation of d i a n i o n 63_ with the monoanion 26^  of methyl acetoacetate gave the t r i k e t o amide 6_4 i n 56% y i e l d , uncon-taminated by e i t h e r the t r i k e t o e s t e r 5_3 or methyl o r s e l l i n a t e 31 (54). S i m i l a r l y , the r e a c t i o n of d i a n i o n £3 with methyl ben-zoate gave the d i k e t o amide 6_5 in 88% y i e l d , uncontaminated by any d i k e t o a c i d . 0 0 SI NMe-0 0 0 0 0 0 26 OMg 0 0 0 c^C00Me> CHAXXNMe, C 6 H 5 1 £ 5 In g e n e r a l , the t r i k e t o amides prepared i n t h i s study were found to be s i g n i f i c a n t l y more s t a b l e than the corresponding t r i k e t o e s t e r s . I t was suggested t h a t s t e r i c i n t e r a c t i o n s i n the t r a n s i t i o n s t a t e r e t a r d a l d o l c y c l i z a t i o n of the N,N-dimethylamides, thereby s t a b i l i z i n g the i n i t i a l l y formed acy-47 l a t e d products A t h i r d d i f f i c u l t y i n the chemistry of d i a n i o n s arose from a d e s i r e to prepare r i n g compounds by the a l k y l a t i o n of a 8-keto e s t e r d i a n i o n . E a r l i e r work in our l a b o r a t o r y had shown that the a l k y l a t i o n of d i a n i o n 2_7 with excess 1,3-dibromo-propane, or one e q u i v a l e n t of 1,3-dibromopropane under high 32 d i l u t i o n c o n d i t i o n s gave methyl 2-oxocyclohexanecarboxylate (6j6) 3 5 . The e x t e n s i o n of t h i s p r i n c i p l e to the p r e p a r a t i o n of OH 67 The s y n t h e s i s of p r o s t a g l a n d i n s has been e x t e n s i v e l y 49 s t u d i e d over the past ten to f i f t e e n years . G e n e r a l l y , most of the approaches to t h e i r s y n t h e s i s i n v o l v e the formation of a s u i t a b l e five-membered r i n g compound, which i s subsequently e l a b o r a t e d by the a d d i t i o n of the two s i d e c h a i n u n i t s . The use of an i n t r a m o l e c u l a r d i a n i o n a l k y l a t i o n o f f e r s the p o s s i -b i l i t y of employing an a l t e r n a t e approach to the s y n t h e s i s of 33 p r o s t a g l a n d i n s , i n which the cyclopentane r i n g i s formed l a t e in the s y n t h e t i c sequence. The key step i n t h i s proposed s y n t h e s i s i s o u t l i n e d i n equation 15. The y a l k y l a t i o n of 0 0 68 0 0 C5H11 (15) 69 d i a n i o n 2_7 with compound (68_) , followed by i n t e r n a l c y c l i z a t i o n at the a-carbon would give cyclopentanone 6_9. T h i s key i n t e r -mediate has a l r e a d y been used i n a number of syntheses of p r o s -t a g l a n d m s U n f o r t u n a t e l y , the r e a c t i o n of d i a n i o n 21_ with model com-pound 7_0 f a i l e d to give the d e s i r e d cyclopentanone 71. and in s t e a d o n l y the y - a l k y l a t e d product 7_2 was obt a i n e d . T h i s compound could not be c y c l i z e d to 71 under a v a r i e t y of con-d i t i o n s 48 Th i s r e s u l t was f u r t h e r confirmed by the f a i l u r e 34 to o b t a i n other types of cyclopentane r i n g s i n r e l a t e d c y c l i -z a t i o n s . For example, i n the r e a c t i o n of 2_7 with e p i c h l o r o -h y d r i n , o n l y the O - c y c l i z e d compound 73_ c o u l d be i s o l a t e d 5 1 . 0 0 0 OMe COOMe 27 73 A p o s s i b l e e x p l a n a t i o n f o r the f a i l u r e of these systems to undergo c y c l i z a t i o n to cyclopentanone d e r i v a t i v e s has been sug-52 gested by Baldwin and coworkers 35 R e c e n t l y , Baldwin has r e p o r t e d a study of the r i n g c l o -52a sures of a number of ketone e n o l a t e s . In t h i s i n v e s t i g a t i o n , the ketobromide 7_4 was converted i n t o e i t h e r i t s potassium or l i t h i u m e n o l a t e _75. In both cases, the s o l e r e a c t i o n product was the e n o l ether 7_6> whereas under the same c o n d i t i o n s keto-bromide 7_7 y i e l d e d only the cyclohexanone 78. 36 Baldwin suggests that the remarkable d i f f e r e n c e between these two c y c l i z a t i o n s r e s u l t s from s t e r e o e l e c t r o n i c c o n t r o l of the a l k y l a t i o n of the ambident n u c l e o p h i l e i . e . the e n o l a t e anion. A l k y l a t i o n of ion 79. o n carbon r e q u i r e s approach of the e l e c t r o p h i l e p e r p e n d i c u l a r to the plane of the e n o l a t e , whereas oxygen a l k y l a t i o n r e q u i r e s approach i n the plane of the e n o l a t e . Consequently, i n the case of e n o l a t e 7 5 , approach of the a l k y l a t i n g center to the carbanion s i t e i s d i f f i c u l t compared to i t s approach i n the plane to the oxygen s i t e , which r e s u l t s i n the formation of the e n o l ether J76. On the other hand, i n the six-membered r i n g case, carbon a l k y l a t i o n i s s t e r i c a l l y p o s s i b l e s i n c e the e x t r a c h a i n l e n g t h enables a near p e r p e n d i c u l a r approach to the e n o l a t e , r e s u l t i n g i n the p r e f e r e n t i a l formation of cyclohexanone 7 8 . Baldwin has been able to c o r r e l a t e a number of such r e s u l t s i n t o a s e t of e m p i r i c a l r u l e s which may be used to p r e d i c t the r e l a t i v e ease of r i n g forming r e a c t i o n s . In ketone e n o l a t e c y c l i z a t i o n s , an important f a c t o r i s whether the 37 enolate double bond i s e n d o c y c l i c or e x o c y c l i c to the newly formed r i n g . In a d d i t i o n , the nature of h y b r i d i z a t i o n at the carbon center undergoing c y c l i z a t i o n , i . e . t e t r a h e d r a l ( t e t ) , t r i g o n a l ( t r i g ) or d i g o n a l ( d i g ) , appears to p l a y an important r o l e . Hence, equation 16 i l l u s t r a t e s t h a t a 5-exo-tet c y c l i z a -t i o n i s favoured over a 5-endo-trig c y c l i z a t i o n and from equa-t i o n 17, 6-endo-trig i s favoured over 6-exo-tet. The three e m p i r i c a l r u l e s proposed by Baldwin are summarized i n Table IV. The f a i l u r e of compound 7_2 to c y c l i z e to cyclopentanone 7L can be understood i n terms of Baldwin's r u l e s , s i n c e t h i s c y c l i z a t i o n can be c o n s i d e r e d to i n v o l v e an e n d o c y c l i c enolate s i m i l a r to that of ketone 1_4 i n equation 16. At t h i s stage, i t appeared that to form the key i n t e r m e d i -ate 6_9, a s p e c i e s which i s more r e a c t i v e than the very s t a b l e monoanion of g-keto e s t e r s and does not i n v o l v e the l e s s favoured e n d o c y c l i z a t i o n was r e q u i r e d . The enamine 8_0, which can be r e a d i l y prepared from methyl acetoacetate 21 and p y r r o l -48 i d i n e , was found to f u l f i l l these c r i t e r i a H 21 80 38 Table IV. Baldwin's Rules 52 Rule 1: T e t r a h e d r a l Systems a) 3 to 7-Exo-Tet are a l l favoured processes b) 5 to 6-Endo-Tet are d i s f a v o u r e d . Rule 2: T r i g o n a l Systems a) 3 to 7-Exo-Trig are a l l favoured processes b) 3 to 5-Endo-Trig are d i s f a v o u r e d ; 6 to 7-Endo-Trig are favoured. Rule 3: Digonal Systems a) 3 to 4-Exo-Dig are d i s f a v o u r e d p r o c e s s e s ; 5 to 7-Exo-Dig are favoured b) 3 to 7-Endo-Dig are favoured. 39 A g e n e r a l procedure for the a l k y l a t i o n of enaminocar-bonyls at the y p o s i t i o n has been repo r t e d by Yoshimoto e t a l . ^ . For example, a d d i t i o n of n - b u t y l l i t h i u m to a s o l u t i o n of the p y r r o l i d i n e enamine 8_0 of methyl a c e t o a c e t a t e , followed by i n t r o d u c t i o n of methyl i o d i d e or benzyl c h l o r i d e gave the •v-alkylated enamines 81. i n 81 and 73% y i e l d r e s p e c t i v e l y . No evidence f o r e i t h e r a- or G - a l k y l a t e d product c o u l d be d e t e c t e d i n the crude r e a c t i o n product. In a d d i t i o n , t h i s y - a l k y l a t i o n procedure was found to be i n s e n s i t i v e to s u b s t i t u t i o n a t or near the p o s i t i o n of the new carbon-carbon bond, e.g. equation 80 81 18 54 0 1) LDA 2) Mel 0 (18) The a b i l i t y of the anion of enamine 8_0 to r e a c t i n a s i m i l a r f a s h i o n to t h a t of a g-keto e s t e r d i a n i o n p rovided 40 two important advantages. F i r s t l y , the keto group was no longer a v a i l a b l e f o r O - c y c l i z a t i o n , and secondly, the c y c l i z a -t i o n of anion 8_2 c o u l d be c o n s i d e r e d to proceed v i a a 5-exo-c y c l i z a t i o n (equation 19). Such a r i n g forming r e a c t i o n i s 82 favoured a c c o r d i n g to Baldwin's r u l e s , Table IV. To t e s t t h i s h y p o t h e s i s , the p y r r o l i d i n e enamine 8_0 of methyl a c e t o a c e t a t e was t r e a t e d with one e q u i v a l e n t of n - b u t y l -l i t h i u m at -60°C in t e t r a h y d r o f u r a n , f o l l o w e d by the model compound 7fJ. The anion of 8_3 was generated u s i n g one e q u i v a -l e n t of l i t h i u m d i i s o p r o p y l a m i d e , then the r e a c t i o n mixture was allowed to s t i r o v e r n i g h t a t room temperature. On hydro-l y t i c workup, the product obtained was the d e s i r e d c y c l o p e n -48 tanone 71 41 0 1)n-BuLi OMe 2 ) M s O ^ < ^ < c ] fiQ During the course of these i n v e s t i g a t i o n s , M a r t e l and coworkers employed t h i s s t r a t e g y i n the s y n t h e s i s of p r o s t a -g l a n d i n A 2 ^ ° a . The key step i n t h i s study i n v o l v e d the tr e a t -ment of enamine 8_4 with sodium amide to give cyclopentanone 69 a f t e r h y d r o l y s i s . Subsequent experimentation i n our OMe 1) NaNH2 C5H11 84 £9 42 l a b o r a t o r y i l l u s t r a t e d t h a t cyclopentanone 69_ may be prepared d i r e c t l y from the p y r r o l i d i n e enamine 80 of methyl acetoacetate (equation 20). However, e f f o r t s to e f f e c t a more convergent 1) n-BuLi 2) M s O - ^ ^ ^ N ^ C ^ H 5n11 3) 4) LDA H 3 0* 80 69 route to the p r o s t a g l a n d i n s i n v o l v i n g a l k y l a t i o n and c y c l i z a -t i o n of a t e t r a s u b s t i t u t e d enamine (equation 21) were thwarted OMe •x—> o o C5H11 (21) 48 because of d i f f i c u l t i e s i n forming the d e s i r e d enamines . The p r e p a r a t i o n of t e t r a s u b s t i t u t e d enamines are, i n f a c t , known to be d i f f i c u l t due to s t e r i c i n t e r a c t i o n s between the c i s 5 5 s u b s t i t u e n t s on the double bond The problems encountered in c e r t a i n a p p l i c a t i o n s of B-keto e s t e r d i a n i o n s has l e d s e v e r a l r e s e a r c h e r s to consid e r the use of a p r o t e c t e d g-keto e s t e r e q u i v a l e n t . The p r o t e c t e d or hidden g-keto e s t e r should have both the ketone and e s t e r groups t i e d up i n such a way that the d i f f e r e n t i a l r e a c t i v i t y of the a- and Y - P o s l t l o n s i - s maintained, although p r e f e r a b l y the r e a c t i v i t y of the Y - P o s i t i ° n would be dimi n i s h e d r e s u l t i n g in a l e s s r e a c t i v e n u c l e o p h i l e . In a d d i t i o n , the p r o t e c t e d d e r i v a t i v e should be r e a d i l y c l e a v e d back to a g-keto e s t e r f u n c t i o n a l i t y . R e c e n t l y , Chan and Brownbridge have reported the prepara-t i o n and r e a c t i v i t y of a new g-keto e s t e r d i a n i o n e q u i v a l e n t , 5 6 1,3-bis (tr imethylsiloxy)-1-me thoxy buta-1, 3-diene (87) . This compound i s r e a d i l y prepared by t r e a t i n g methyl a c e t o a c e t a t e (21) with b i s ( t r i m e t h y l s i l y l ) acetamide (8_5) to give methyl 3 - t r i m e t h y l s i l o x y c r o t o n a t e (8_6) , followed by ge n e r a t i o n of the anion of 8_6 with l i t h i u m d i i s o p r o p y l a m i d e and quenching with t r i m e t h y l c h l o r o s i l a n e . Judging by i t s NMR spectrum, 87 was A NTMS OTMS OTMS 21 85 1) LDA 2) TMSCl TMSO OMe found to e x i s t as one geometric isomer which was t e n t a t i v e l y assigned as the E-isomer. The s t r u c t u r e of 8_7 was f u r t h e r confirmed by i t s ready h y d r o l y s i s to methyl a c e t o a c e t a t e (21) . The d i f f e r e n c e i n r e a c t i v i t y between 8_7 and d i a n i o n 21_ can be demonstrated by t h e i r r e a c t i o n s with bromine. Due to i t s high r e a c t i v i t y , the d i a n i o n 2_7 r e a c t s with bromine to g i v e a number of p r o d u c t s . On the other hand, 8_7 i s very s e l e c t i v e , r e a c t i n g with one e q u i v a l e n t of bromine to give the Y~brominated product 8_8, and with two e q u i v a l e n t s of bromine to give the a,y-dibromo B-keto e s t e r 89_ (Scheme 4 ) . With other l e s s r e a c t i v e carbon e l e c t r o p h i l e s , a c t i v a t i o n by t i t a n i u m t e t r a c h l o r i d e was necessary to promote r e a c t i o n . For example, M i c h a e l r e a c t i o n of 8_7 with e t h y l a c r y l a t e at -78°C in the presence of t i t a n i u m t e t r a c h l o r i d e gave the c y c l i z e d product 9fJ i n 74% y i e l d 5 * * . OH *COOMe 0 0 II 1 g s H s C H O r ^ ^ ^ O M e TiCl A ^ C O O E t 90 k < ^ C O O E t , T iCl A TMSO OMe 1Br )TMS 2. OH •CcH 6 n 5 Br 87 2Br-0 0 OMe Br Br SI Scheme 4; Selected reactions of 1,3-bis(trimethylsiloxy) " methoxybuta-l,3-diene ( 8 7 ) 5 6 46 The r e a c t i v i t y of 8_7 appears to compliment the chemistry of g-keto e s t e r d i a n i o n s i n s e v e r a l cases, Scheme 4. In a d d i t i o n , 8_7 possesses the u s e f u l f e a t u r e of the generation of a l l i t s chemistry under e i t h e r n e u t r a l or Lewis a c i d c a t a l y z e d c o n d i t i o n s . Chan and Brownbridge have r e c e n t l y 5 7 a p p l i e d t h i s method i n a novel c y c l o a r o m a t i z a t i o n r e a c t i o n (equation 22), as w e l l as i n the simple p r e p a r a t i o n of o x a b i -58 c y c l o r i n g systems (equation 23). The p r e p a r a t i o n of a p r o t e c t e d g-diketone e q u i v a l e n t had been e n t e r t a i n e d e a r l i e r i n our l a b o r a t o r y . In t h i s r e s p e c t , a good candidate appeared to be i s o x a z o l e s e.g. 91.. Isoxazoles are e a s i l y prepared from g-diketones and hydroxylamine hydro-. 59 c h l o r i d e and they can be c l e a v e d back to 3-diketones by h y d r o g e n o l y s i s or h y d r o l y s i s ^ (equation 24). o o H AA * NH2OH-HCl > JkJL 5 6 5 1 i l (24) 0 N D H30+ 0 0 ' C e ^ ^ ^ ^ 2> H 2 ^ H 3 0 + ^ ^ ^ ^ ^ i l SL The g o a l of that e a r l i e r r e s e a r c h was to generate the anion of i s o x a z o l e 91 and r e a c t i t with v a r i o u s e l e c t r o p h i l e s . ° — N Base . Y If E * II O Q S e > J k IL ^ > C 6 H 5 ^ ^ ^ C 6 H 5 - ^ ^ - C 6 H 5 21 92. 93 Since h y d r o l y s i s of the new i s o x a z o l e 93_ would regenerate the 3-diketone system, o v e r a l l , i s o x a z o l e anion 92 would c o r r e -spond to a 1-phenyl-l,3-butanedione d i a n i o n e q u i v a l e n t 50. 48 U n f o r t u n a t e l y , a l l a t t e m p t s t o g e n e r a t e the a n i o n o f i s o x a z o l e 9_1 a t the d e s i r e d C-3 m e t h y l r e s u l t e d i n f a i l u r e . For example, t r e a t m e n t of 9_1 w i t h one e q u i v a l e n t of n - b u t y l -l i t h i u m , f o l l o w e d by d e u t e r i u m o x i d e gave a crude p r o d u c t show-i n g l i t t l e or no d e u t e r a t i o n a t the C-3 m e t h y l and g r e a t e r than f i f t y p e r c e n t d e u t e r i u m i n c o r p o r a t i o n a t C-4 ( e q u a t i o n 2 5 ) . D S i m i l a r l y , use o f two e q u i v a l e n t s o f n - b u t y l l i t h i u m gave g r e a t e r than e i g h t y p e r c e n t d e u t e r i u m i n c o r p o r a t i o n a t C-4, w i t h l i t t l e or no i n c o r p o r a t i o n a t the d e s i r e d C-3 m e t h y l ^ 1 . The g e n e r a l d i f f i c u l t y i n d e p r o t o n a t i n g the C-3 m e t h y l o f 6 2 i s o x a z o l e s has been c o n f i r m e d by the r e p o r t o f Kashima e t a l . t h a t t r e a t m e n t of 3 , 5 - d i m e t h y l i s o x a z o l e (9_4) w i t h sodium amide i n l i q u i d ammonia, f o l l o w e d by a d d i t i o n o f m e t h y l i o d i d e g i v e s a l k y l a t i o n a t the C-5 m e t h y l o n l y . 49 0 — N I 1) NaNH 2 ,NH 3 2) Mel 24 25 In o r d e r t o d i r e c t d e p r o t o n a t i o n and e l e c t r o p h i l i c c a p t u r e t o the d e s i r e d C-3 m e t h y l , the i s o x a z o l e 9_1 was c o n v e r t e d i n t o i t s i s o x a z o l i u m s a l t 96. T h i s was e a s i l y a c c o m p l i s h e d by t r e a t i n g 9_1 w i t h m e t h y l f l u o r o s u l f o n a t e ("Magic M e t h y l " ) i n d i c h l o r o m e t h a n e . The s t r a t e g y i n v o l v e d i n the use of an 0 — N MeS0 3 F S 0 3 F ' 0 N C H 2 C l 2 CcH 6 n 5 91 96 i s o x a z o l i u m s a l t was based upon e a r l i e r work on the c h e m i s t r y o f t h i a m i n e ( 9 7 ) . 97 50 The mechanism of a c t i o n of thiamine (97) was the s u b j e c t of a g r e a t d e a l of re s e a r c h i n the 1950's. In t h i s regard, Breslow found t h a t the thiamine c a t a l y z e d d e c a r b o x y l a t i o n of 6 3 p y r u v i c a c i d (9_8) proceeds by the route i n d i c a t e d i n Scheme 5 - C O Scheme 5; Mechanism f o r thiamine c a t a l y z e d d e c a r b o x y l a t i o n of p y r u v i c a c i d ( 9 8 ) 6 3 51 D e c a r b o x y l a t i o n i s f a c i l i t a t e d by the formation of i n t e r -mediate 9j9, which i s s t a b i l i z e d by both i n d u c t i v e and resonance e f f e c t s . T h i s i n t e r m e d i a t e has a l s o been shown to p a r t i c i p a t e 6 3 i n f u r t h e r r e a c t i o n s i n b i o l o g i c a l systems S i m i l a r l y the c o n v e r s i o n of i s o x a z o l e 9_1 to i t s i s o x a z o l i u m s a l t 9_6 would lead to a c t i v a t i o n of the C-3 methyl. Indeed, d i s s o l u t i o n of i s o x a z o l i u m s a l t 9_6 i n a d i l u t e s o l u t i o n of sodium deuteroxide i n deuterium oxide showed t h a t the C-3 methyl was completely exchanged almost immediately, and no exchange of the C-4 proton c o u l d be d e t e c t e d even a f t e r three hours i n the presence of base. N e v e r t h e l e s s , e f f o r t s to a l k y l a t e the C-3 methyl f a i l e d u s i n g a v a r i e t y of r e a c t i o n c o n d i t i o n s and bases. The p r i n c i p a l problem, i n t h i s a l k y l a t i o n i s b e l i e v e d to be i n the p r o d u c t i o n of w a t e r - s o l u b l e products . These e f f o r t s and those of Kashima e t a l . , d e s c r i b e d e a r l i e r , l e d to con-s i d e r a t i o n of a s i m i l a r system f o r the g e n e r a t i o n of a 3-keto e s t e r d i a n i o n e q u i v a l e n t . I t has long been known that 3-keto e s t e r s r e a c t with hydrox-ylamine to give products which may be formulated as 5-hydrox-y i s o x a z o l e s 100, 4H-isoxazolin-5-ones 101, or 2 H - i s o x a z o l i n -37 5-ones 10_2 . Some c o n t r o v e r s y remained in the l i t e r a t u r e , N 0 N — 0 N 0 100 101 102 52 however, r e l a t i n g to the assignment of s t r u c t u r a l form f o r v a r i o u s R' and R""^'^. T h i s d i s c u s s i o n reappeared from time to time u n t i l 1961, when K a t r i t z k y and Boulton p u b l i s h e d 64 r e p o r t s on the tautomerism of such heteroaromatic compounds In these s t u d i e s , i n f r a r e d and u l t r a v i o l e t spectroscopy, as w e l l as chemical means, were used to deduce the tautomeric makeup of s e v e r a l i s o x a z o l i n - 5 - o n e s . For example, 3,4-dimethyl-5-hydroxyisoxazole (R'=R"=CH3), was found to e x i s t i n aqueous and c h l o r o f o r m s o l u t i o n s and i n the s o l i d s t a t e as the OH form, s t r u c t u r e 100, while 3-phenyl-isoxazolin-5-one (R'=CgH,-, R"=H) e x i s t s as a mixture of the CH and NH forms, s t r u c t u r e s 101 and 102 r e s p e c t i v e l y , i n a r a t i o depending upon the p o l a r i t y of the s o l v e n t . I t was c l e a r t h a t the presence of a c i d i c OH and NH groups i n s t r u c t u r e s 100-102 would not make such compounds s u i t a b l e as B-keto e s t e r d i a n i o n e q u i v a l e n t s . Replacement of OH by OR would, however, almost c e r t a i n l y lead back to the d i f f i c u l t i e s encountered i n the i s o x a z o l e work, i . e . d e p r o t o n a t i o n at C-4 ra t h e r than at the C-3 methyl group. In a d d i t i o n , the presence of an e n o l ether which was s u s c e p t i b l e to h y d r o l y s i s back to the OH form c o u l d pose problems r e g a r d i n g the h a n d l i n g of such a compound. The replacement of NH by NR, on the other hand, would be app e a l i n g f o r two reasons. F i r s t l y , compound 103 would be r e s t r i c t e d to a s i n g l e tautomeric form thereby s i m p l i f y i n g 53 i d e n t i f i c a t i o n , and secondly, the most a c i d i c hydrogen i n com-pound 103 would be expected to r e s i d e on the R' ch a i n by analogy with the B-enamino e s t e r s 104. An advantage of the i s o x a z o l i n - 5 - o n e 103 compared with enamine 104 i s that one of the c i s i n t e r a c t i o n s i n 104 i s now r e p l a c e d by a chemical bond. Two routes have been u t i l i z e d f o r the p r e p a r a t i o n of i s o x a z o l i n - 5 - o n e s of type 103, R^H. The f i r s t of these routes i n v o l v e s the a l k y l a t i o n of i s o x a z o l i n - 5 - o n e s 101. T h i s pro-cedure, however, o f t e n y i e l d s O - a l k y l d e r i v a t i v e s 105 or mix-ture s of N- and O - a l k y l d e r i v a t i v e s , the r e l a t i v e amounts of which depend on the s u b s t i t u e n t s R* and R" and sometimes on 6 5 the reagent employed . N e v e r t h e l e s s , t h i s method has been 103 104 101 103 105 54 used i n the s y n t h e s i s of two i s o x a z o l i n - 5 - o n e n a t u r a l pro-ducts The n a t u r a l occurrence of the i s o x a z o l i n - 5 - o n e r i n g was f i r s t r e c o g n i z e d i n 1969. At t h a t time, V a n P a r i j s a n d cowork-er 7 e r s , while l o o k i n g f o r n u c l e i c a c i d p r e c u r s o r s i n the e l o n -g a t i n g a x i s of pea s e e d l i n g s , found two products with promis-ing u l t r a v i o l e t s p e c t r a and having a-amino a c i d p r o p e r t i e s . These compounds were, i n a d d i t i o n , found to be very s e n s i t i v e to u l t r a v i o l e t i r r a d i a t i o n and d i l u t e a l k a l i . A f t e r comparison of the c h e m i c a l and s p e c t r a l p r o p e r t i e s of the n a t u r a l products with s y n t h e t i c N - s u b s t i t u t e d i s o x a z o l i n - 5 - o n e s , the s t r u c t u r e s of these compounds were e s t a b l i s h e d as 106a and 106b. 106a; R=CH 2CH(NH 2)COOH, R'=R'=H 106b; R= p-D-glucose, R=H, R"=CH2CH(NH2)COOH Subsequently, s i x other i s o x a z o l i n - 5 - o n e n a t u r a l products have been i s o l a t e d and c h a r a c t e r i z e d from pea and sweet pea seed-l i n g s and the chemistry and b i o l o g y of t h i s new c l a s s of p l a n t 6 7 products have been reviewed The s y n t h e s i s of two of these n a t u r a l products by the a l k y l a t i o n of the sodium s a l t 107 of i s o x a z o l i n - 5 - o n e has a l s o 55 6 6 been d e s c r i b e d by these workers . T h e r e f o r e , 2-cyanoethyl-i s o x a z o l i n - 5 - o n e (108) was prepared from the s a l t 107 and a c r y l o n i t r i l e , while the g l u c o s i d e 110 was obtained by r e a c t -ing the s a l t 107 with 2 , 3 , 4 , 6 - t e t r a a c e t y l - a - g l u c o p y r a n o s y l bromide (109) i n dry methanol. The two products were produced, 0 H 108, R=CH 2CH 2CN 110. R= p-D-glucose AcO I Br AcO I Q i 2) H 3 0 + however, i n very low y i e l d s , c a. 1%, and attempts to synthe-s i z e the other n a t u r a l i s o x a z o l i n - 5 - o n e s by t h i s procedure have been u n s u c c e s s f u l . The second route used to prepare i s o x a z o l i n - 5 - o n e s 103, R^H, i n v o l v e s the r e a c t i o n , of N-alkylhydroxylamine with B-keto e s t e r s (equation 26). T h i s procedure p r o v i d e s the d e s i r e d compounds 103 i n good y i e l d without contamination from any O - a l k y l a t e d p r o d u c t s . While both p y r i d i n e and e t h a n o l are s u i t a b l e as s o l v e n t s for these r e a c t i o n s , p y r i d i n e u s u a l l y g i v e s higher y i e l d s of p r o d u c t s . For example, treatment of methyl a c e t o a c e t a t e (21) with N-methylhydroxylamine h y d r o c h l o r i d e (111) i n p y r i d i n e g i v e s 2,3-dimethylisoxazolin-5-one (112) i n 60% y i e l d , while i n e t h a n o l the y i e l d i s 0%, Table V AA0Me' MeNHOH-HO y^,0 H 2 i in in Despite the ready a v a i l a b i l i t y of N - a l k y l a t e d i s o x a z o l i n 5-ones by t h i s method, very l i t t l e work on the chemistry of these compounds has been r e p o r t e d . T h i s l a c k of knowledge concerning i s o x a z o l i n - 5 - o n e chemistry and our i n t e r e s t i n T a b l e V. P r e p a r a t i o n o f 2 - M e t h y l i s o x a z o l i n - 5 - o n e s 103, 1Q3,R=Me Y i e l d s (%) HL HI i n p y r i d i n e i n e t h a n o l C H 3 H 50-60 0 H C H 3 37 21 C H 3 C H 3 78 25 C 6 H 5 H 52 0 H C 6 H 5 89 60 C H 3 C 6 H 5 91 73 C 6 H 5 C H 3 56 5.8 C 6 H 5 C 6 H 5 55 65 d e v e l o p i n g a new B-keto e s t e r d i a n i o n e q u i v a l e n t l e d us to co n s i d e r the study of these compounds. The aims, at the commencement of t h i s work, were to pre pare a number of N - a l k y l i s o x a z o l i n - 5 - o n e s and to examine the generat i o n of the anions of these compounds. Subsequently, an e v a l u a t i o n of the chemistry of the anion of i s o x a z o l i n - 5 -ones as a B-keto e s t e r d i a n i o n e q u i v a l e n t was to be e f f e c t e d 59 RESULTS AND DISCUSSION The study of i s o x a z o l i n - 5 - o n e chemistry began with the s y n t h e s i s of i s o x a z o l i n - 5 - o n e s 112-114• These compounds were chosen because t h e i r anions may be considered to r e p r e s e n t a c y c l i c , c y c l i c , and s u b s t i t u t e d 3-keto e s t e r d i a n i o n e q u i v a -l e n t s r e s p e c t i v e l y (Scheme 6 ) . *N 0 *N 0 0 0 0 cA i l l 0 0 0 0 N J 0 0 0 Scheme 6: Isoxazolin-5-ones as g-keto e s t e r d i a n i o n equ i v a l e n t s 60 The p r e p a r a t i o n of 2,3-dimethylisoxazolin-5-one (112) was accomplished by the r e a c t i o n of methyl acetoacetate (21) with N-methylhydroxylamine h y d r o c h l o r i d e (111) i n p y r i d i n e at 1 0 0 ° C 6 5 . F r a c t i o n a l d i s t i l l a t i o n of the crude r e a c t i o n mixture 0 0 fl 1  • MeNHOH-HCl A A A \ 0 M e 21 111" gave 112 i n 57% y i e l d . The formation of the d e s i r e d product was e v i d e n t from i t s NMR spectrum which d i s p l a y e d three s i n -g l e t s a t 6 2.16 (3H, C-CH 3), 6 3.30 (3H, N-CH 3), and 6 4.93 (1H, C-H). In a d d i t i o n , the i n f r a r e d spectrum of the d i s t i l l e d product showed a b s o r p t i o n s a t 1730 and 1650 cm 1 , t y p i c a l of the i s o x a z o l i n - 5 - o n e r i n g C=0 and C=C s t r e t c h i n g v i b r a t i o n s . These s p e c t r a l data are i n agreement with those r e p o r t e d by De S a r l o e t a l . 6 5 and are i n c l u d e d here f o r subsequent com-p a r i s o n with other more complex i s o x a z o l i n - 5 - o n e s . In the p r e p a r a t i o n of 112, these authors have r e p o r t e d that e x t r a c t i o n o f the dark t a r r y r e s i d u e obtained a f t e r d i s -t i l l a t i o n with l i g r o i n g i v e s a s m a l l amount of 1,3,5-trimethyl-2,4-dicarbomethoxypyrrole ( 1 1 5 ) 6 5 . Although evidence f o r the formation of t h i s compound was apparent from the NMR spectrum of the crude r e a c t i o n mixture, no e f f o r t was made to i s o l a t e 61 t h i s product. M e c h a n i s t i c a l l y , the p y r r o l e 115 may be con-s i d e r e d to a r i s e by the condensation of the i n i t i a l l y formed enamine 116 with unreacted B-keto e s t e r (Scheme 7). Scheme 7: P o s s i b l e mechanism f o r the formation of p y r r o l e 115 The p r e p a r a t i o n of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) was s i m i l a r l y e f f e c t e d by the condensation of e t h y l 2-methyl-ace t o a c e t a t e (117) with N-methylhydroxylamine h y d r o c h l o r i d e 6 4 a (111) i n p y r i d i n e . The NMR spectrum of the d i s t i l l e d 62 0 0 OEt • MeNHOH-HCl 0 117 111 p r o d u c t d i s p l a y e d t h r e e s i n g l e t s a t 6 1.73, 2.10, and 3.17 c o r r e s p o n d i n g t o the C-4, C-3 and N-methyl groups r e s p e c t i v e l y . The f a c i l e s y n t h e s i s o f a f u l l y s u b s t i t u t e d i s o x a z o l i n - 5 - o n e such as 114 may be c o n t r a s t e d w i t h the d i f f i c u l t i e s e n c o u n t e r e d i n the s y n t h e s i s o f t e t r a s u b s t i t u t e d enamines 118 from the c o r r e s p o n d i n g g-keto e s t e r s , as d i s c u s s e d e a r l i e r . The s y n t h e s i s o f 2 - m e t h y l - 3 , 4 - t e t r a m e t h y l e n e i s o x a z o l i n - 5 -one (113) has n o t been r e p o r t e d i n the l i t e r a t u r e . However, i t was a n t i c i p a t e d t h a t t h i s p r o d u c t c o u l d be p r e p a r e d i n a s i m i l a r f a s h i o n t o t h a t o f compounds 112 and 114. A c c o r d i n g l y , m e t h y l 2 - o x o c y c l o h e x a n e c a r b o x y l a t e (6_6) was p r e p a r e d by the 68 method o f Deslongchamps and coworkers ( e q u a t i o n 2 7 ) , and was 63 DNctH, KH 2) (MeO)oCO OMe (27) r e a c t e d with N-methylhydroxylamine h y d r o c h l o r i d e (111) i n p y r i d i n e (equation 28). The product, i s o l a t e d i n 67% y i e l d , 0 0 "NM 0 66 MeNHOH'HCl P y r i d m e > HI (28) HI was shown to be homogeneous by TLC a n a l y s i s , and e x h i b i t e d s p e c t r a l p r o p e r t i e s c o n s i s t e n t with the expected product 113. With these three compounds i n hand, an i n v e s t i g a t i o n of i s o x a z o l i n - 5 - o n e anion g e n e r a t i o n was undertaken. For t h i s purpose, 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) was chosen as the s u b s t r a t e because the d i s t i n c t nature of i t s NMR spectrum would allow ready d e t e r m i n a t i o n of the extent and p o s i t i o n of any d e p r o t o n a t i o n . An e v a l u a t i o n of bases was t h e r e f o r e conducted by t r e a t -ing 114 with one e q u i v a l e n t o f base i n t e t r a h y d r o f u r a n at 0 C, 64 then quenching the r e a c t i o n mixture with iodomethane (equation 29). The r e s u l t s of t h i s study are summarized i n Table VI. o 1) Base ^ I l (29) 0 2) Mel 119 I t i s . p a r t i c u l a r l y noteworthy t h a t n - b u t y l l i t h i u m deprotonates the i s o x a z o l i n - 5 - o n e at -78°C, with no evidence of attack on the c a r b o n y l group of the r i n g . In a d d i t i o n , the r e s u l t i n g anion r e a c t s smoothly at low temperature, i n c o n t r a s t to B-keto e s t e r d i a n i o n a l k y l a t i o n s which proceed o n l y s l o w l y under these c o n d i t i o n s . The s p e c t r a l data f o r the crude r e a c t i o n mixtures from the s u c c e s s f u l a l k y l a t i o n s ( e n t r i e s 2, 4, 7, and 10) i n d i c a t e d t h a t no d i a l k y l a t i o n , O - a l k y l a t i o n or C-4 a l k y l a t i o n had o c c u r r e d . C o n f i r m a t i o n t h a t the condensation had o c c u r r e d a t the C-3 methyl was manifest i n the NMR s p e c t r a o f the p r o d u c t s , which showed a q u a r t e t a t 6 2.45, a t r i p l e t a t 6 1.18, and the absence of the c h a r a c t e r i s t i c C-3 methyl a b s o r p t i o n at <5 2.10 i n the s t a r t i n g m a t e r i a l . The e x c l u s i v e formation of -y-alkylated products from the anions of B-enamino e s t e r s 104 and i s o x a z o l i n - 5 - o n e s 103 appears to be i n c o n t r a s t with the r e c e n t r e s u l t s of Smith and 65 Table VI. E v a l u a t i o n of Bases for Deprotonating 2,3,4-Tri-~ " met h y l i s o x a z o l i n - 5 - o n e (114) ^tJ 0 1) Base 0 2) Mel M 0 119 Entry no. 1 2 3 4 5 6 7 8 9 10 Base NaH LDA MeLi n-BuLi (-78WC) KH ( M e 3 S i ) 2 N L i (Me 3Si) 2NK NaOMe KOMe 69 70 / -t C 6 H 5 71 K C - C 6 H 5 Y i e l d of 119 (%) 0 81 0 74 0 0 79 0 0 71 py a) I s o l a t e d y i e l d s of product 119 66 R ^ N — 0 0 R Me 103 Scarborough on the a l k y l a t i o n of the anions of B-keto e s t e r 72 e n o l e s t e r s . In t h i s study, anions o f the e n o l e t h e r s 120 and 121 were generated u s i n g l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a -h ydrofuran. The r e a c t i o n of these anions with n - p e n t y l i o d i d e and methyl i o d i d e gave products e x h i b i t i n g e x c l u s i v e a - a l k y l a -t i o n (equations 30 and 31). OEt OEt 120 (30) OEt OEt (31) 121 The nature of the a vs y s e l e c t i v i t y i n the a l k y l a t i o n of such systems i s not f u l l y understood. P r e l i m i n a r y extended 73 Huckel c a l c u l a t i o n s r e v e a l , however, t h a t the e l e c t r o n 67 d e n s i t y i s higher on the y-carbon than on the a-carbon i n the anions of B-enamino e s t e r s and i s o x a z o l i n - 5 - o n e s , while i n B - a l k c , x y - a / B - U n s a t u r a t e d e s t e r s , e.g. 120 and 121, the e l e c t r o n d e n s i t y on the a and y p o s i t i o n s appears to be com-parable . With the knowledge t h a t the anion of i s o x a z o l i n - 5 - o n e s may be generated, a s e r i e s of d e u t e r a t i o n experiments were per-formed to determine the degree of anion g e n e r a t i o n f o r a l l three i s o x a z o l i n - 5 - o n e s . For t h i s purpose, l i t h i u m d i i s o -propylamide was used as the base s i n c e i t gave the best r e s u l t s in the a l k y l a t i o n of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114). Treatment of 114 with l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o -furan a t 0°C, f o l l o w e d by quenching the r e a c t i o n mixture with deuterium oxide gave the monodeuterio product 122 i n 78% y i e l d . DLDAJHF, OC 0 2) D20 HA The s t r u c t u r e of 122 was e v i d e n t from i t s s p e c t r a l d a t a . The NMR spectrum of the crude r e a c t i o n mixture r e v e a l e d t h a t the three-proton s i n g l e t at 6 2.10 i n the s t a r t i n g m a t e r i a l had been r e p l a c e d by a broad s i g n a l i n t e g r a t i n g to ca. two pro-tons. In a d d i t i o n , the low r e s o l u t i o n mass spectrum showed a parent mass of 128, which i s c o n s i s t e n t with the formula f o r 68 122. C a r e f u l examination of both the NMR and mass s p e c t r a i n d i c a t e d that deuterium i n c o r p o r a t i o n had occurred to the e x t e n t of 95 ± 5%. De u t e r a t i o n of 2,3-dimethylisoxazolin-5-one (112) was then c a r r i e d out u s i n g l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o -furan at 0°C. I n v e s t i g a t i o n of the NMR spectrum of the crude r e a c t i o n mixture again r e v e a l e d the replacement of the t h r e e -proton s i n g l e t at 6 2.16 with a broad s i g n a l , however,a reduc-t i o n i n i n t e n s i t y of the v i n y l proton was a l s o e v i d e n t . Fur-thermore, the low r e s o l u t i o n mass spectrum of the crude product i n d i c a t e d t h a t s t a r t i n g m a t e r i a l , as w e l l as mono- and d i d e u -t e r i o products were pr e s e n t , i n the r a t i o of 1:2:1. The f a i l u r e of 112 to undergo c l e a n deuterium i n c o r p o r a t i o n at the d e s i r e d y-carbon was a s e r i o u s setback, s i n c e t h i s meant that i t would be i m p r a c t i c a l to use t h i s compound as a methyl ac e t o a c e t a t e d i a n i o n e q u i v a l e n t . The use of a d i f f e r e n t i s o x a z o l i n - 5 - o n e which c o u l d serve i n t h i s c a p a c i t y was t h e r e f o r e c o n s i d e r e d . The most l i k e l y candidate i n t h i s regard was found to be 2,3-dimethy1-4-carboethoxyisoxazolin-5-one (125), s i n c e i t was a n t i c i p a t e d t h at r i n g cleavage accompanied by d e c a r b o x y l a t i o n would regenerate the parent B-keto e s t e r 6 (equation 32). The (32) COOEt 6 s y n t h e s i s of 125 was accomplished i n two steps a c c o r d i n g to equation 33. H2C(C00Et) 1)Mg, EtOH 2 2) CH3COCI MeNHOH-HCL OEt Pyridine 0 COOEt 125 (33) 123 124 A c y l a t i o n o f d i e t h y l malonate (123) with a c e t y l c h l o r i d e 74 a c c o r d i n g to the procedure d e s c r i b e d by T a r b e l l and P r i c e gave d i e t h y l acetylmalonate (124) i n 84% y i e l d . I t i s i n t e r -the y i e l d i n t h i s r e a c t i o n to be 53-55%. The reason f o r the high y i e l d i n t h i s case i s not known, although a l l p h y s i c a l and s p e c t r a l data agree with those r e p o r t e d i n the l i t e r a t u r e 74 for t h i s compound The condensation of d i e t h y l acetylmalonate (124) with N-methylhydroxylamine h y d r o c h l o r i d e (111) i n p y r i d i n e gave the d e s i r e d product 125 i n 72% y i e l d 7 5 . The s t r u c t u r e of 125 was apparent from i t s NMR spectrum which showed three-proton s i n -g l e t s a t 6 2.51 (C-4 methyl) and 6 3.61 (N-methyl), as w e l l as the c h a r a c t e r i s t i c q u a r t e t - t r i p l e t combination due to the c a r -boethoxy group a t 6 4.25 and 6 1.32. In a d d i t i o n , the i n f r a -red spectrum of the product d i s p l a y e d a b s o r p t i o n s at 1750 and e s t i n g to note t h a t these workers and others 64c have rep o r t e d 70 1695 cm 1 a s s i g n a b l e to the e s t e r and i s o x a z o l i n - 5 - o n e C=0 s t r e t c h i n g v i b r a t i o n s . With the p r e p a r a t i o n of 125 i n hand, an i n v e s t i g a t i o n of the degree of anion g e n e r a t i o n was examined. I t was c l e a r , however, that the presence of a carboethoxy group a t C-4 would render the y carbon more a c i d i c than i s o x a z o l i n - 5 - o n e 114. A c c o r d i n g l y , i t was found that treatment of 125 with sodium hydride i n t e t r a h y d r o f u r a n - d i m e t h y l s u l f o x i d e a t 0°C, followed by methyl i o d i d e gave 126 i n 85% y i e l d . C o n f i r m a t i o n that 1) NaH, THF-DMSO ^ Mel a l k y l a t i o n had o c c u r r e d at the d e s i r e d y carbon was secured from the NMR spectrum of the product which e x h i b i t e d a new two-proton q u a r t e t at 6 2.95 and a three-proton t r i p l e t at 6 1.29, both with c o u p l i n g c o n s t a n t s J = 6 Hz, while the c h a r a c t e r i s t i c C-3 methyl a b s o r p t i o n of the s t a r t i n g m a t e r i a l had disappeared. Further evidence for the f o r m u l a t i o n of 126 was provided by the low r e s o l u t i o n mass spectrum of the product which showed a parent peak at 199 m/e and by elemental a n a l y s i s . The f a c i l e a l k y l a t i o n of 125, using sodium hydride as the base, demonstrated t h a t having an e l e c t r o n - w i t h d r a w i n g 71 group a t C-4 does indeed render the y carbon more a c i d i c as expected. For t h i s reason and because the a l k y l a t i o n pro-ceeded i n good y i e l d , the use of 125 as a methyl a c e t o a c e t a t e d i a n i o n e q u i v a l e n t appeared to be a p r a c t i c a l s o l u t i o n to the e a r l i e r problem with i s o x a z o l i n - 5 - o n e 112. The d e u t e r a t i o n of 2-methyl-3,4-tetramethyleneisoxa-zolin-5-one (113) was c a r r i e d out by f i r s t u s i ng one e q u i v a -l e n t of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n , then quenching with deuterium o x i d e . C a r e f u l examination of the low r e s o l u t i o n mass spectrum of the product showed d e u t e r a t i o n had occurred to the ext e n t of 95 ± 5%. With the i n c o r p o r a t i o n s t u d i e s now complete, an i n v e s -t i g a t i o n of the a l k y l a t i o n of i s o x a z o l i n - 5 - o n e anions with simple e l e c t r o p h i l e s was i n i t i a t e d . For t h i s purpose, 114 was chosen f o r a l l subsequent work s i n c e i t was a n t i c i p a t e d t h at s i m i l a r chemistry could be performed on the other systems an a l o g o u s l y . The r e s u l t s of t h i s study with carbon e l e c t r o -p h i l e s (equation 34) are presented i n Table V I I . 72 Table V I I . A l k y l a t i o n of 2,3,4-Trimethylisoxazolin-5-one (114) With Simple E l e c t r o p h i l e s 1)LDA,THF,0C 0 2) RX V s N 0 Compound I d e n t i f i c a t i o n R-X Y i e l d (%) 127a Mel 81 127b E t I 67 127c n-BuBr 80 127d CH 2=CHCH 2Br 75 127e (CH 3) 2C=CHCH 2Br 75 127f C 6H 5CH 2C1 52 a) Yield of isolated products. 73 0 1U 1) LDAJHF, 0*C ^  0 2) RX R 0 127 ;0 (34) The a l k y l a t i o n of 114 with simple carbon e l e c t r o p h i l e s proceeded smoothly to give the products 127 i n f a i r to good y i e l d . The s t r u c t u r e s of these products were p a r t i c u l a r l y apparent from t h e i r NMR s p e c t r a which a l l showed the absence of the three-proton s i n g l e t a t 6 2.10, c h a r a c t e r i s t i c of the C-3 methyl i n the s t a r t i n g m a t e r i a l . Furthermore, a l l products e x h i b i t e d parent ions i n t h e i r low r e s o l u t i o n mass s p e c t r a , and elemental a n a l y s e s , which were c o n s i s t e n t with t h e i r formulae. The e x t e n s i o n of i s o x a z o l i n - 5 - o n e chemistry to a l d o l and C l a i s e n condensations was a l s o s t u d i e d . Treatment of 114 with l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n at 0°C, followed by benzaldehyde gave the product 128 i n 71% y i e l d . T h i s product N 0 HO 0 0 114 128 74 was found to be homogeneous by TLC a n a l y s i s , and elemental a n a l y s i s of the r e c r y s t a l l i z e d m a t e r i a l was i n agreement with the proposed f o r m u l a t i o n . The molecular weight, determined by mass spectroscopy, i n d i c a t e d the product was a one to one adduct of benzaldehyde and i s o x a z o l i n - 5 - o n e 114, while the i n f r a r e d spectrum of the product showed a b s o r p t i o n s at 3625, 3435, 1733 and 1640 cm 1 i n d i c a t i n g the presence of an a l c o h o l and an i s o x a z o l i n - 5 - o n e r i n g . F i n a l l y , the NMR spectrum of 128 d i s p l a y e d a d o u b l e t a t 6 2.82 due to the a l l y l i c protons at the y carbon, a t r i p l e t a t 6 4.92 due to the b e n z y l i c proton and a s i n g l e t a t 6 7.29 due to the aromatic p r o t o n s . The attempted a l d o l condensation of 114 with a l i p h a t i c aldehydes and ketones was not s u c c e s s f u l . For example, t r e a t -ing the anion of 114 with cyclohexanone gave two spots by TLC a n a l y s i s . One spot was r e a d i l y i d e n t i f i e d as s t a r t i n g m a t e r i a l , while mass s p e c t r o s c o p i c a n a l y s i s of the second spot i s o l a t e d by p r e p a r a t i v e TLC i n d i c a t e d the presence of the cyclohexanone condensation product 129. 129 75 The presence of s i g n i f i c a n t amounts of both s t a r t i n g m a t e r i a l 114 and product 129 i n the above r e a c t i o n suggested that proton t r a n s f e r from cyclohexanone to the i s o x a z o l i n - 5 -one anion was o c c u r r i n g . A l d o l condensation of the anion of cyclohexanone with i t s e l f would t h e r e f o r e account for formation of the product 129. The problem of proton t r a n s f e r i n the a l d o l condensation of i s o x a z o l i n - 5 - o n e s with a l i p h a t i c aldehydes and ketones r e p r e s e n t s a l i m i t a t i o n i n the use of these reagents as d i a n i o n e q u i v a l e n t s . P o s s i b l e s o l u t i o n s to t h i s problem w i l l be d i s -cussed d u r i n g an examination of the r e a c t i o n of i s o x a z o l i n - 5 -one anions with unusual e l e c t r o p h i l e s (pg 80). The a b i l i t y to prepare and p u r i f y the aromatic a l d o l pro-duct 128 may be c o n t r a s t e d with the o b s e r v a t i o n t h a t many 35 B-keto e s t e r aromatic a l d o l products are t h e r m a l l y unstable For example, in the attempted d i s t i l l a t i o n of B-keto e s t e r 130, three products were i d e n t i f i e d by VPC a n a l y s i s . The three components were O-methoxyacetophenone (131) and the two isomers of 4-(2-methoxyphenyl)-pent-3-en-2-one (132). These products may be c o n s i d e r e d to a r i s e v i a a r e t r o - a l d o l and a d e h y d r a t i o n -decarboxymethylation process r e s p e c t i v e l y . 76 T h i s e a r l i e r work had a l s o shown that dehydration of crude 130 with anhydrous hydrogen c h l o r i d e i n c h l o r o f o r m smoothly gave the unsaturated keto e s t e r 133. C a r e f u l examination of the NMR spectrum of the product and comparison with the chemi-c a l s h i f t s of the v i n y l protons i n other s t y r e n e s i n d i c a t e d 35 th a t the isomer r a t i o of the product was 2.3:1, E:Z In the p r e s e n t study, the aromatic a l d o l product 128 was best dehydrated u s i n g the two st e p procedure o u t l i n e d i n equation 35. F i r s t , the a l c o h o l was converted i n t o i t s C H 2 C l 2 , A Y N 0 135 77 corresponding mesylate 134 i n q u a n t i t a t i v e y i e l d by the pro-7 6 cedure of C r o s s l a n d and S e r v i s . Loss of methanesulfonic a c i d was then accomplished by r e f l u x i n g 134 with 1 , 5 - d i a z a b i c y c l o -[1. 3 . (Tj non-5-ene , DBN, (136) i n dichlorome thane . By t h i s 136 method, the r e s u l t i n g styrene 135 was obtained i n 95% y i e l d . The s t r u c t u r e of 135 was e v i d e n t from i t s i n f r a r e d spec-trum which showed the l o s s of the c h a r a c t e r i s t i c mesylate S-0 s t r e t c h i n g v i b r a t i o n a t 1370 cm 1 i n the s t a r t i n g m a t e r i a l . In a d d i t i o n , both the molecular weight d e r i v e d from the mass spectrum and elemental a n a l y s i s were c o n s i s t e n t with the pro-posed f o r m u l a t i o n . C a r e f u l examination of the high f i e l d (100 MHz) NMR spec-trum of the product r e v e a l e d the expected three-proton s i n g l e t s at 6 1.98 and 6 3.24, as w e l l as a m u l t i p l e t at 6 7.36-7.66 corresp o n d i n g to the aromatic p r o t o n s . The two v i n y l protons appeared as an AB q u a r t e t with a c o u p l i n g constant J = 16 Hz. From the i n t e g r a t i o n of t h i s spectrum i t was apparent that the product 135 c o n s i s t e d of only one g e o m e t r i c a l isomer, which from the c o u p l i n g c o n s t a n t was assigned the trans or E-geo-77 . . . metry 135 . The formation of a s i n g l e isomer i n t h i s r e a c t i o n 78 J O 135 0 probably r e f l e c t s the s t e r i c r e p u l s i o n between the benzene r i n g and the h e t e r o c y c l i c r i n g i n the t r a n s i t i o n s t a t e f o r e l i m i n a t i o n . T h i s may be i l l u s t r a t e d by c o n s i d e r i n g Newman p r o j e c t i o n s 134a and 134b f o r the trans e l i m i n a t i o n of H and OMs. The gauche i n t e r a c t i o n between C^Hj. and Het i n 134b d e s t a b i l i z e s t h i s c o n f o r m a t i o n and t h e r e f o r e e l i m i n a t i o n p r o -ceeds v i a 134a t o g i v e the ob s e r v e d E-isomer. An i n v e s t i g a t i o n o f the C l a i s e n c o n d e n s a t i o n o f i s o x a -z o l i n - 5 - o n e a n i o n s was n e x t attempted by t r e a t i n g the a n i o n of 114 w i t h m e t h y l benzoate ( e q u a t i o n 3 6 ) . The s t r u c t u r e of H H OMs 134a OMs 134b 79 1) L D A . T H F , 0°C 2) C 6 H 5 C O O M e c 6 H 5 0 0 0 0 (36) 137 137 was c l e a r from i t s NMR spectrum which showed a broad m u l t i -p l e t of s i g n a l s from 5 7.47-8.06 due to the aromatic protons, and a two-proton s i n g l e t at 6 4.21, which was assigned to the methylene protons at the y carbon. The low and high r e s o l u -t i o n mass s p e c t r a were c o n s i s t e n t with the proposed s t r u c t u r e and the i n f r a r e d spectrum d i s p l a y e d a new c a r b o n y l a b s o r p t i o n at 1700 cm - 1. An attempt to prepare 137 by the a c y l a t i o n of 114 with benzoyl c h l o r i d e (138) proved to be f u t i l e and i n s t e a d gave N,N-diisopropylbenzamide (139). T h i s product c l e a r l y a r i s e s by a c y l a t i o n of the conjugate a c i d of the amide base (equa-t i o n 37). The C l a i s e n condensations of 114 with a l i p h a t i c a c i d • C 6 H 5 C O N : (37) 138 139 80 c h l o r i d e s and e s t e r s were a l s o u n s u c c e s s f u l . I t appeared that proton t r a n s f e r from the a l i p h a t i c e s t e r s to the anion of 114 was again hampering the success of t h i s r e a c t i o n , s i n c e sub-s t a n t i a l amounts of s t a r t i n g m a t e r i a l were recovered. The next f a c e t of i s o x a z o l i n - 5 - o n e chemistry which was examined may be c l a s s i f i e d as r e a c t i o n s with unusual e l e c t r o -p h i l e s (equation 38). The r e s u l t s of t h i s study are summarized in Table V I I I . The bromination of B-keto e s t e r d i a n i o n s has been found 78 to y i e l d a p l e t h o r a of products . However, t r e a t i n g the anion of 114 with bromine at -78°C gave the y-bromo i s o x a z o l i n -5-one 140a i n 41% y i e l d . The s t r u c t u r e of 140a was e s t a b l i s h e d on the b a s i s of i t s NMR spectrum which d i s p l a y e d a two-proton s i n g l e t a t 6 4.08 due to the y methylene protons. A d d i t i o n a l 81 Table V I I I . Reaction of 2,3,4-Trimethylisoxazolin-5-one (114) With Unusual E l e c t r o p h i l e s > — ? 1) LP A, THF, 0°C ^ — 0 A ^ y ^ o 2) E X E \ A ^ Y ^ O HA m Compound a I d e n t i f i c a t i o n E X Y i e l d (%) 140a Br Br 41 140b C 6 H 5 S e C 1 6 1 140c ( C H 3 ) 3 S i C l 64 140d C 6 H 5 S S C 6 H 5 7 1 140e CH 3OOCCH 2 Br 58 140f BrCH 0CH 0CH 9 Br 16 a) Yie l d of isolated products. 82 support f o r the formation of 140a was provided by both low and high r e s o l u t i o n mass measurements. One s t r a t e g y i n the p r e p a r a t i o n of the bromide 140a was to convert t h i s compound i n t o i t s phosphonium s a l t 141, for use as a W i t t i g reagent 79 The condensation of 141 with Br • (C6H5)P — > ( C 6 H 5 ) 3 R UOQ a l i p h a t i c aldehydes and ketones would then, i n t u r n , provide the unsaturated i s o x a z o l i n - 5 - o n e s 142 which c o u l d not be pre-pared v i a an a l d o l condensation r o u t e , as d i s c u s s e d e a r l i e r . ( C 6 H 5 L P 1) Base 0 2) RCOR' R 0 1AZ The f e a s i b i l i t y of t h i s p l a n , however, appeared to be somewhat impaired by the rather poor y i e l d obtained i n the bromination of the anion of 114. Since t h i s was o n l y the f i r s t s tep i n the scheme, an a l t e r n a t e pathway f o r the prepar-a t i o n of 140a was c o n s i d e r e d . 83 I t has long been known that a l l y l i c and b e n z y l i c p o s i t i o n s are s u s c e p t i b l e to f r e e r a d i c a l h a l o g e n a t i o n s . For example, 3-methyl.thiophene (143) r e a c t s with N-bromosuccinimide in r e f l u x i n g carbon t e t r a c h l o r i d e c o n t a i n i n g a c a t a l y t i c amount of benzoyl peroxide to give 3-bromomethylthiophene (144) i n 3 8 70-80% y i e l d . I t t h e r e f o r e seemed l i k e l y t h a t s i m i l a r chemistry might be performed on i s o x a z o l i n - 5 - o n e s . Treatment of 114 with one e q u i v a l e n t of N-bromosuccinimide and a c a t a l y t i c amount of benzoyl peroxide i n r e f l u x i n g carbon t e t r a c h l o r i d e gave 140a i n 76% y i e l d . The crude r e a c t i o n CH 2 Br 1A3 1AA N-Br (C6H5C0-0-)2 C C L , A ^ N 0 0 11A 1A0a product was then d i s s o l v e d i n t e t r a h y d r o f u r a n and t r e a t e d with t r i p h e n y l p h o s p h i n e . Almost immediately a f l o c c u l e n t , white s o l i d p r e c i p i t a t e d . F i l t r a t i o n of the s o l i d , f o l l o w e d by r e c r y s t a l l i z a t i o n from ether-methanol gave 141 as s m a l l , c o l o u r l e s s c r y s t a l s , mp 245-246°,in 69% o v e r a l l y i e l d from 114. Br 0 140a 0 • (C 6 H 5 LP 0 141 The s t r u c t u r e of 141 was e v i d e n t from i t s NMR spectrum which showed a d o u b l e t a t 6 5.40, assigned to the y methylene protons, with a l a r g e c o u p l i n g constant J = 16 Hz due'to c o u p l i n g with 3 1 P . In a d d i t i o n , the C-4 methyl at 6 1.18 was 77 a l s o s p l i t by phosphorus with a c o u p l i n g c o n s t a n t J = 3 Hz Further proof f o r the f o r m u l a t i o n of 141 was provided by e l e -mental a n a l y s i s . The W i t t i g r e a c t i o n of 14_1 with ben za ldehyde was f i r s t i n v e s t i g a t e d i n order to provide some c o r r e l a t i o n with the e a r l i e r work on a l d o l condensations. T h e r e f o r e , treatment of 141 with one e q u i v a l e n t of sodium hydride i n t e t r a h y d r o f u r a n -dimethyl s u l f o x i d e , f o l l o w e d by a d d i t i o n of benzaldehyde gave 135 i n 58% y i e l d . The product obtained i n t h i s f a s h i o n was Br ' N 0 N 0 V 135 P N a H , THF-DMSiD 2 ) C 6 H 5 C H 0 , A C g H 5 141 i d e n t i c a l i n a l l r e s p e c t s to the compound prepared e a r l i e r . In p a r t i c u l a r the NMR spectrum of the product once again con-firmed the p r e f e r e n t i a l formation of the E-isomer. To demonstrate that the W i t t i g r e a c t i o n c o u l d a l s o be a p p l i e d to a l i p h a t i c aldehydes, 141 was t r e a t e d with sodium hydride i n t e t r a h y d r o f u r a n - d i m e t h y l s u l f o x i d e , f o l l o w e d by hexanal. P r e p a r a t i v e TLC of the crude r e a c t i o n mixture gave the unsaturated i s o x a z o l i n - 5 - o n e 145 i n 64% y i e l d . The product 145 was c h a r a c t e r i z e d by a parent ion at 209 m/e i n the low r e s o l u t i o n mass spectrum as w e l l as by a high r e s o l u t i o n mass measurement. The NMR spectrum of the product r e v e a l e d the expected v i n y l protons at 6 5.88-6.48 as w e l l as two s i n g l e t s f o r both the N-methyl and C-methyl s i g n a l s . The NMR data suggests t h a t both double bond isomers are formed i n the r e a c t i o n , i n a r a t i o of 3:1. Although i t i s not c l e a r which isomer predominates i n t h i s r e a c t i o n , i t appears l i k e l y t h a t the E-isomer should again p r e v a i l on s t e r i c grounds. The W i t t i g r e a c t i o n of 141 with a l i p h a t i c ketones was attempted, however condensations with both cyclohexanone and acetone r e s u l t e d i n o n l y recovered s t a r t i n g m a t e r i a l . Since 141 145 86 ald e h y d e s r e a c t e d w i t h 141 o n l y i n r e f l u x i n g t e t r a h y d r o f u r a n , p o s s i b l y the use of a h i g h e r b o i l i n g s o l v e n t may be more a p p r o p r i a t e t o c o n d e n s a t i o n s i n v o l v i n g k e t o n e s . The p r e p a r a t i o n o f compounds 140b and 140d was n e x t examined f o r two r e a s o n s . F i r s t , e a r l i e r work had shown the analogous r e a c t i o n s w i t h B-keto e s t e r d i a n i o n s t o be d i f f i -78 c u l t . S e c o n d l y , the use o f the p h e n y l t h i o and p h e n y l s e l e n o 8 0 groups as h a n d l e s f o r the f o r m a t i o n of o l e f i n s was e n t e r -t a i n e d . T h i s s t r a t e g y i s o u t l i n e d i n e q u a t i o n 39. T h e r e f o r e , E= C 6 H 5 S or C 6 H 5 S e a l k y l a t i o n o f compounds 140b or 140d w i t h an a l k y l h a l i d e , f o l l o w e d by o x i d a t i o n t o the c o r r e s p o n d i n g s u l f o x i d e or s e l e n o x i d e and e l i m i n a t i o n would g i v e the d e s i r e d u n s a t u r a t e d i s o x a z o l i n - 5 - o n e s . The p r e p a r a t i o n o f 140b and 140d was a c h i e v e d by the a l k y l a t i o n of 114 w i t h p h e n y l s e l e n e n y l c h l o r i d e and d i p h e n y l d i s u l f i d e r e s p e c t i v e l y . The s t r u c t u r e of the p r o d u c t s thus obtained was secured from t h e i r NMR s p e c t r a which d i s p l a y e d a two-proton s i n g l e t at 6 3.66 f o r 140b and at <5 3.78 f o r 140d, which was assigned to the Y - I T i e t h y l e n e protons. Further more, the molecular f o r m u l a t i o n d e r i v e d from both the high r e s o l u t i o n mass s p e c t r a and the elemental analyses were con-s i s t e n t with assignment of these s t r u c t u r e s . Having demon-s t r a t e d t h a t these compounds may be r e a d i l y prepared and that the anion of 114 r e a c t s smoothly with carbon e l e c t r o p h i l e s , the pathways represented by equation 39 are p o t e n t i a l routes to unsaturated i s o x a z o l i n - 5 - o n e s . The reasoning behind the e x t e n s i v e i n v e s t i g a t i o n of the s y n t h e s i s of these unsaturated i s o x a z o l i n - 5 - o n e s was based 81 upon the e a r l i e r work of Nazarov and Zavyalow . In t h e i r study, these workers were able to demonstrate the u t i l i t y of e t h y l 3-oxo-4-pentenoate (146) i n a Robinson a n n e l a t i o n pro-c e s s . In p a r t i c u l a r , the r e a c t i o n of an e n o l a t e with methyl v i n y l ketone had been c o n s i d e r a b l y improved by r e p l a c i n g the l a t t e r component with 146, known as the Nazarov reagent (equa t i o n 40) . 88 0 -OEt + 0 0 0 COOEt OEt (40) Wider a p p l i c a t i o n of both 146 and s u b s t i t u t e d e t h y l 3-oxo-4-pentenoates has, however, been g r e a t l y hampered by t h e i r l i m i t e d a c c e s s i b i l i t y . The c l a s s i c a l s y n t h e s i s of 146, f o r example, proceeded i n on l y 7-9% o v e r a l l y i e l d 81 (Scheme 8) S e v e r a l approaches have been d e s c r i b e d for 89 Scheme 8: C l a s s i c a l preparation of Nazarov reagent 146 90 the p r e p a r a t i o n of 14 6 and s u b s t i t u t e d d e r i v a t i v e s t h e r e o f , 8 2 but a l l s u f f e r from a l a c k of g e n e r a l i t y . T h i s problem l e d to the s y n t h e s i s of unsaturated i s o x a z o l i n - 5 - o n e s , s i n c e i t was hoped that r i n g cleavage of these d e r i v a t i v e s would pro-vide the d e s i r e d Nazarov reagents (equation 41). OEt (41) During the course of t h i s r e s e a r c h , two new approaches to the s y n t h e s i s of s u b s t i t u t e d Nazarov reagents have appeared in the l i t e r a t u r e . The key f e a t u r e i n these s t u d i e s i n v o l v e s the p r e p a r a t i o n of a Y " " P h ° s P h o r Y l a t e c 3 B-keto e s t e r , as out-g o g 4 l i n e d i n equations 42 and 43 . The W i t t i g - t y p e condensation B r , 0 0 U NQH F F M [J )Et 2) (EtO)2P(0)"Na+ 1 2 3) H30* 0 0 0 Et (42) 147 Br N 0 (C6H5)2POEt Et (C6H5) (43) 148 91 of 147 or 148 with aromatic and a l i p h a t i c aldehydes and ketones has been found to proceed i n very good y i e l d s . For example, the r e a c t i o n of 148 with two e q u i v a l e n t s o f sodium hydride i n tetrahydrofuran-hexamethylphosphoramide, f o l l o w e d by c y c l o -84 hexanone gave 149 i n 85% y i e l d , „ L l , § ? f 1)2NaH,THF-HMPA [ l . j} H Next an i n v e s t i g a t i o n of the r e a c t i o n of 114 with c h l o r o -t r i m e t h y l s i l a n e was undertaken. The i n t e r e s t i n t h i s process stemmed from a n t i c i p a t i o n t h a t the product formed might be the O - a l k y l a t e d compound 150 (equation 44). T h i s e x p e c t a t i o n was based on the knowledge that upon quenching a ketone e n o l a t e with c h l o r o t r i m e t h y l s i l a n e , O - s i l y l a t e d products are 38 formed e x c l u s i v e l y (equation 45). The O - s i l y l a t e d product 148 149 114 150 5 92 150 might then r e a c t with v a r i o u s e l e c t r o p h i l e s i n the p r e -CfZ C O sence of Lewis a c i d s to g i v e products of type 140 (equa-t i o n 46) . A c c o r d i n g l y , treatment of 114 with one e q u i v a l e n t of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n , followed by c h l o r o t r i m e t h y l s i l a n e gave a s i n g l e product by TLC a n a l y s i s . The s t r u c t u r e of t h i s product was apparent from i t s NMR spec-trum which showed s i n g l e t s a t 6 0.31 (9H, ( C H 3 ) 3 S i ) , 6 1.89 (3H, C=C-CH 3), 6 2.09 (2H, C H 2 S i ) , and 6 3.32 (3H, N-CH3) and an absence of any v i n y l p rotons. C l e a r l y , the C - s i l y l a t e d compound 140c was formed i n pr e f e r e n c e to the d e s i r e d 0 - s i l y l -ated product 150. Further evidence f o r the formation of 93 compound 140c was provided by the s t r o n g C-Si s t r e t c h i n g v i b r a t i o n i n the i n f r a r e d a t 1253 cm ^. The p o s s i b i l i t y t h a t 150 was indeed formed i n the r e a c -t i o n but was h y d r o l y z e d d u r i n g workup was c o n s i d e r e d . However, when a s m a l l amount of the crude r e a c t i o n was evaporated w i t h -out workup and an NMR spectrum taken, no evidence f o r any v i n y l protons was found. The reason f o r e x c l u s i v e C - s i l y l a t i o n i n t h i s r e a c t i o n i s not w e l l understood, however t h i s compound does appear to have p o t e n t i a l i n p r e p a r i n g unsaturated i s o x a z o l i n - 5 - o n e s by a 8 5 Peterson o l e f i n a t i o n route (equation 47). 94 The f i n a l aspect of the r e a c t i o n of i s o x a z o l i n - 5 - o n e s with unusual e l e c t r o p h i l e s which was i n v e s t i g a t e d i n v o l v e d the r e a c t i o n of 114 with d i f u n c t i o n a l e l e c t r o p h i l e s . The r e a c t i o n of the d i a n i o n of methyl a c e t o a c e t a t e with methyl bromoacetate 7 had e a r l i e r been found to y i e l d a complex mixture of products (equation 48). The a l k y l a t i o n of the anion of 114 with methyl 0 0 * BrCHUCOOMe Me L Mixture of (48) Products bromoacetate was found to g i v e the e s t e r 140e i n 58% y i e l d , uncontaminated by any a c y l a t e d products. The s t r u c t u r e of 1) LDA, THF 0 2) BrCH2C00Me> M e 0 0 C KOe 140e was e v i d e n t from i t s NMR spectrum which showed a t h r e e -proton s i n g l e t at 6 3.74 assigned to the carbomethoxy protons and a f o u r - p r o t o n m u l t i p l e t a t 6 2.50-2.92 due to the adjacent methylene pro t o n s . Further evidence for formula 140e was provided by both low and high r e s o l u t i o n mass measurements. The a l k y l a t i o n of 114 with 1,3-dibromopropane was a l s o s t u d i e d . P r e p a r a t i v e TLC of the crude r e a c t i o n mixture gave the d e s i r e d bromide 140f, however, i n only 16% y i e l d . 1) LDA, THF :Q 2) B r ( C H 2 ) 3 B r > B r . C o n f i r m a t i o n f o r the formation of 140f was obtained from i t s low r e s o l u t i o n mass spectrum which e x h i b i t e d parent ions at 249 and 247 m/e, and from i t s NMR spectrum which showed a t r i p l e t at 6 3.46 (2H, CE^Br), another t r i p l e t at 6 2.51 (2H, CH 2-Het) , and a m u l t i p l e t a t 6 1.6-2.1 (4H, CH2CH"2) . An attempt to prepare a cyclobutane r i n g was made by t r e a t i n g 114 with two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e , f o l l o w e d by one e q u i v a l e n t of 1,3-dibromopropane (equation 49) N 0 T I D 2LDA,THF A ^ A ^ O 2) B r t C H ^ B r * 1U (49) TLC a n a l y s i s of the crude r e a c t i o n mixture d i s c l o s e d two spots which were subsequently i d e n t i f i e d as the bromide 140f and the alkene 127d. 96 1)2LDA,THF^  0 2) BKCH2)^Br KOf IH 127d Having examined the r e a c t i o n of 114 w i t h some u n u s u a l e l e c t r o p h i l e s , t h e r e remained o n l y one o t h e r f u n c t i o n a l i t y t o be s t u d i e d . R e s u l t s s e c u r e d e a r l i e r i n our l a b o r a t o r y 5 1 had shown t h a t the r e a c t i o n o f B-keto e s t e r d i a n i o n s w i t h e p o x i d e s proceeded smoothly t o g i v e a l c o h o l s . In p a r t i c u l a r , t r e a t i n g the d i a n i o n TT_ w i t h p r o p y l e n e o x i d e gave the secondary a l c o h o l 152 e x c l u s i v e l y ( e q u a t i o n 5 0 ) . However, the B _ k e t o e s t e r 0 0 Me • A/ 0 0 OMe (50) OH 27 152 a l c o h o l s were found t o be v e r y s e n s i t i v e t o a c i d and a f f o r d e d the c y c l i c f u r y l i d e n e s , e.g. 153, under m i l d a c i d c o n d i t i o n s ( e q u a t i o n 51) 0 0 51 The use o f an i s o x a z o l i n - 5 - o n e r i n g t o CHCOOMe (51) 152 153 97 prevent such c y c l i z a t i o n was obvious, and t h e r e f o r e the a l k y l a -t i o n of 114 with epoxides was examined. Treatment of the anion of 114 with ethylene oxide gave the a l c o h o l 154 i n 30% y i e l d . The s t r u c t u r e of 154 was 1) LDA,THF 2) A IH 154 apparent from i t s i n f r a r e d spectrum which d i s p l a y e d an 0-H s t r e t c h i n g v i b r a t i o n a t 3400 cm - 1. Furthermore, both NMR and mass s p e c t r a l analyses were c o n s i s t e n t with the assigned s t r u c t u r e . A s i m i l a r r e a c t i o n o f 114 with propylene oxide gave the a l c o h o l 155, t h i s time i n 41% y i e l d . The a l c o h o l 155 was again U L D A J H F , 0 2) A/ 0 15& OH c h a r a c t e r i z e d by an O-H s t r e t c h i n g v i b r a t i o n i n i t s i n f r a r e d spectrum. In a d d i t i o n , the d i r e c t i o n of epoxide opening was secured from the NMR spectrum of the product, which showed a do u b l e t at 6 1.40 due to the t e r m i n a l methyl of the s i d e c h a i n T h i s concluded the study of the chemistry of the anion of i s o x a z o l i n - 5 - o n e s and c o n s i d e r a t i o n was now given to the cleavage of these h e t e r o c y c l i c r i n g s . One of the e a r l i e s t s t u d i e s of the cleavage of N - s u b s t i -tuted isoxazolin-5-ones,was r e p o r t e d by U l r i c h e t a l . i n 75a 1962 . In t h i s work i t was found t h a t C-3 u n s u b s t i t u t e d N-methylisoxazolin-5-ones undergo a remarkably f a c i l e r i n g opening i n d i l u t e base. For example, when compound 156 was added to 5% sodium hydroxide or aqueous sodium carbonate, an immediate exothermic r e a c t i o n o c c u r r e d and carboethoxymethyl-75a acetamide (157) was obtained i n 54% y i e l d . The key element of t h i s r e a c t i o n i s the a v a i l a b i l i t y of a proton at the 3-posi t i o n of the h e t e r o c y c l e . For example, treatment of 2,3-dimethyl-4-carboethoxyisoxazolin-5-one (125) with 5% sodium hydroxide s o l u t i o n gave on l y recovered s t a r t i n g m a t e r i a l a f t e r f i f t e e n minutes. In a d d i t i o n , i f the r e a c t i o n mixture was l e f t o v e r n i g h t , only e s t e r h y d r o l y s i s occurred to give 2,3-dime t h y l - 4 - c a r b o x y i s o x a z o l i n - 5 - o n e ( 1 5 8 ) ^ 5 a . 0 COOEt 156 15Z 99 N 0 NaOH,H2CL 0 0 COOEt 125 158 The o b s e r v a t i o n t h a t C-3 u n s u b s t i t u t e d N - m e t h y l i s o x a z o l i n -5-ones are r e a d i l y h ydrolyzed by a l k a l i n e s o l u t i o n s was a l s o 8 6 made by De S a r l o and Renzi . In t h e i r study, however, these workers were able to demonstrate t h a t 3 - s u b s t i t u t e d compounds a l s o undergo r i n g opening on prolonged h e a t i n g with d i l u t e sodium hydroxide with the formation of ketones (equation 52). Since a l l i s o x a z o l i n - 5 - o n e s prepared i n t h i s t h e s i s were C-3 s u b s t i t u t e d , i t was c l e a r t h at base h y d r o l y s i s c o u l d not be used to regenerate the B-keto e s t e r s or t h e i r e q u i v a l e n t s . The cleavage of N-methylisoxazolin-5-ones by a d i f f e r e n t procedure has a l s o been r e p o r t e d by De S a r l o e t a l . * ' 5 . In (52) 100 t h i s study, these workers showed t h a t the hydrogenation of N-methylisoxazolin-5-ones i n anhydrous a l c o h o l with Raney n i c k e l as c a t a l y s t gave secondary amines. T h i s r e a c t i o n i n v o l v e s the a b s o r p t i o n of two moles of hydrogen and the l o s s of carbon d i o x i d e (equation 53). In a d d i t i o n , when the R "NjJ 0 H 2 -CO-I, R 159 Me R • R 160b H 2 Me\ /H (53) V R R hydrogenation was performed i n 95% a l c o h o l , with p a l l a d i u m black as c a t a l y s t , compound 159 absorbed o n l y one mole of 65 hydrogen and gave ketone 161 . In t h i s case, the i n t e r -mediate methylimine 160b was hydrolyzed before f u r t h e r reduc-t i o n t r a n s p i r e d . These r e s u l t s demonstrated that the N-0 bond 101 i n the i s o x a z o l i n - 5 - o n e r i n g may be c l e a v e d , however, the i n t e r m e d i a t e s underwent f u r t h e r r e a c t i o n s to y i e l d products which were not of d i r e c t use i n the present study. The s t r a t e g y i n v o l v e d i n the i n v e s t i g a t i o n of the c l e a v -age of i s o x a z o l i n - 5 - o n e s i n t h i s t h e s i s was based upon a c t i v a -t i o n of the h e t e r o c y c l i c r i n g by formation of an i s o x a z o l i n - 5 -one s a l t . P r e v i o u s work i n our l a b o r a t o r y had shown that i s o x a z o l i u m s a l t s 9j5 c o u l d be r e a d i l y prepared by t r e a t i n g i s o x a z o l e s with methyl f l u o r o s u l f o n a t e , as d i s c u s s e d e a r l i e r ^ 1 (equation 54). In the formation of an i s o x a z o l i n - 5 - o n e s a l t S 0 3 F " + 9 N MeOSOoF 9 C 6 H A A -c^clT C 6 H 5 A A «*) 51 26 102 by t h i s procedure, two p o s s i b l e products c o u l d be obtained (equation 55), however, i t was f e l t t h a t both c o u l d be con-ve r t e d i n t o g-keto e s t e r s . Treatment of 114 with methyl f l u o r o s u l f o n a t e i n carbon t e t r a c h l o r i d e gave no evidence f o r any s a l t formation even when the s o l u t i o n was r e f l u x e d f o r long p e r i o d s . T h i s was s u r p r i s i n g not onl y because i s o x a z o l i u m s a l t formation i s so f a c i l e (equation 54), but a l s o because methyl f l u o r o s u l f o n a t e + 8 7 i s r e p o r t e d l y the s t r o n g e s t source of Me known 0 •> No Reaction N e v e r t h e l e s s , a l k y l a t i o n s with other powerful e l e c t r o p h i l i c reagents were a l s o attempted. However, treatment of 114 with g e i t h e r d i m e t h y l s u l f a t e or t r i e t h y l o x o n i u m t e t r a f l u o r o b o r a t e gave on l y recovered s t a r t i n g m a t e r i a l . The f a i l u r e of the 103 l a t t e r r e a g e n t i n t h i s r e a c t i o n may be c o n t r a s t e d w i t h i t s 3 8 f a c i l e c o n v e r s i o n o f amides i n t o i m i no e s t e r s a l t s ( e q u a t i o n 56) . C6H5CONEt2 • Et30+BFA" C6 H5 NEto • BF/ (56) With the s u c c e s s o f our i n i t i a l s t r a t e g y of u s i n g i s o x a -z o l i n - 5 - o n e s now i n doubt, c o n s i d e r a t i o n was g i v e n t o two o t h e r c l e a v a g e r e a c t i o n s . The f i r s t approach would r e q u i r e a method t o h y d r o g e n o l y z e the N-0 bond o f the i s o x a z o l i n - 5 - o n e r i n g under m i l d c o n d i t i o n s so t h a t the enamino a c i d i n t e r m e d i a t e c o u l d be i s o l a t e d and c o n v e r t e d t o i t s e s t e r , then h y d r o l y z e d t o the B-keto e s t e r ( e q u a t i o n 5 7 ) . The second p o s s i b i l i t y 0 NHMe DChhNo R ^ Y 2 ) H2° R-0 (57) OMe would be t o reduce the c a r b o n y l group of the i s o x a z o l i n - 5 - o n e r i n g i n t o a l a c t o l - l i k e compound, which c o u l d then e i t h e r be h y d r o l y z e d and o x i d i z e d t o the B-keto e s t e r or h y d r o l y z e d d i r e c t l y t o a B-keto aldehyde ( e q u a t i o n 5 8 ) . 104 Many reagents are known to e f f e c t N-0 bond hydrogenoly-3 8 s i s . The nature of the d e s i r e d t r a n s f o r m a t i o n r e q u i r e d , however, that a mil d and s p e c i f i c method be used which would leav e carbon-carbon double bonds and c a r b o n y l groups i n t a c t . R ecently, Keck and coworkers have r e p o r t e d a new and e f f i c i e n t 89 method f o r the r e d u c t i v e cleavage of N-0 bonds . In t h i s procedure, i t was found t h a t simple exposure of the s u b s t r a t e s 105 t o e x c e s s aluminum amalgam i n aqueous t e t r a h y d r o f u r a n r e s u l t e d i n a l m o s t q u a n t i t a t i v e y i e l d s o f N-0 h y d r o g e n o l y s i s . In a d d i -t i o n , under these m i l d c o n d i t i o n s , c a r bon-carbon double bonds, amide c a r b o n y l g r o u p s , and a c i d l a b i l e f u n c t i o n a l i t i e s were found t o s u r v i v e . For example, r e d u c t i o n o f 162 was e f f e c t e d i n 95% y i e l d by t h i s method ( e q u a t i o n 5 9 ) . The a p p l i c a t i o n o f t h i s method i n the p r e s e n t s t u d y t o the r e d u c t i o n of i s o x a z o l i n - 5 - o n e s , however, l e d o n l y t o the r e c o v e r y o f s t a r t i n g m a t e r i a l . C o n s i d e r a t i o n was t h e r e f o r e g i v e n t o the use o f 6% sodium amalgam, which i s r e p o r t e d l y a 89 s t r o n g e r r e d u c i n g agent than aluminum amalgam . However, i n the r e a c t i o n o f 114 w i t h 6% sodium amalgam i n e t h a n o l c o n t a i n -i n g d i s o d i u m hydrogen phosphate as a b u f f e r , o n l y s t a r t i n g mate-r i a l c o u l d be d e t e c t e d even upon p r o l o n g e d exposure ( e q u a t i o n 60) . OH (59) No Reaction (60) H i 106 In f a c t , a l l attempts i n t h i s study to hydrogenolyze the N-O 38 bond i n i s o x a z o l i n - 5 - o n e s by u s i n g z i n c and ammonium c h l o r i d e 90 91 s u l f u r a t e d sodium borohydride , diborane , and t i t a n i u m 92 t e t r a c h l o r i d e - d i i s o b u t y l a l u m i n u m hydride (1:3) proved to be f u t i l e . The p o s s i b i l i t y of regen e r a t i n g 3-keto aldehydes or B-keto e s t e r s by r e d u c t i o n of the c a r b o n y l group i n i s o x a z o l i n -5-ones, as o u t l i n e d e a r l i e r (equation 58), was t h e r e f o r e examined. Many reagents are known to e f f e c t the r e d u c t i o n o f carbon-oxygen double bonds and much i s known of the f u n c t i o n a l group 93 s e l e c t i v i t y e x h i b i t e d by these reagents . The uniqueness of the i s o x a z o l i n - 5 - o n e c a r b o n y l group would, however, undoubt-e d l y r e q u i r e t h a t a r a t h e r s e l e c t i v e reducing agent be found. In these s t u d i e s , 2-methyl-3,4-tetramethyleneisoxazolin-5-one (113) was chosen as the s u b s t r a t e because r e d u c t i o n and indeed o v e r r e d u c t i o n of the compound would provide l e s s v o l a t i l e p r o -ducts than the other simple i s o x a z o l i n - 5 - o n e s . m A c c o r d i n g l y , compound 113 was t r e a t e d with a v a r i e t y of reducing agents and the r e a c t i o n s followed by TLC and NMR a n a l y s i s . In the case of sodium borohydride, sodium 107 bis(methoxyethoxy)aluminum h y d r i d e , l i t h i u m t r i - t - b u t o x y -aluminum h y d r i d e , l i t h i u m t r i - s - b u t y l a l u m i n u m h y d r i d e , and borane-methyl s u l f i d e complex, no evidence f o r any r e d u c t i o n was apparent even upon prolonged exposure to excess reducing agent. The r e d u c t i o n of 113 with l i t h i u m aluminum h y d r i d e , on the other hand, i n v a r i a b l y gave overreduced products c o r r e s -ponding to 1,2 and 1,4-reduction of the i s o x a z o l i n - 5 - o n e . The problem of s e l e c t i v i t y i n the 1,2 vs 1,4-reduction of a , B-unsaturated ketones has been addressed by Masamune and 94 coworkers . In t h i s study, a remarkable s o l v e n t dependence was observed i n the r e d u c t i o n of unsaturated ketone 163 with l i t h i u m aluminum h y d r i d e . In a d d i t i o n , the use of d i i s o b u t y l -aluminum hydride to e f f e c t almost e x c l u s i v e 1,2-reduction was e s p e c i a l l y noteworthy (Table I X ) . The a p p l i c a t i o n of these r e s u l t s i n the presen t study has shown t h a t the r e d u c t i o n of 113 with l i t h i u m aluminum hydride g i v e s mixtures of products whether conducted i n ether or t e t r a -h y drofuran. However, i n the r e d u c t i o n of 113 with d i i s o b u t y l -aluminum hydride some i n t e r e s t i n g r e s u l t s have been o b t a i n e d . 0 163 108 Table IX. The Reduction of Unsaturated Ketone 163 With Various Reducing Agents"'* H 'OH LAH, . l E t 2 0 , 25 C* LAH, THF, 0 UC NaBH 4, EtOH, 78°C A1H 3, THF, 0 C i.Bu 2AlH, C g H 6 , 0 C 13 0 0 86 98 28 100 0 10 0 26 0 100 4 1 * recovered 23% s t a r t i n g m a t e r i a l 109 Treatment of 113 with one e q u i v a l e n t of d i i s o b u t y l a l u m i n u m hydride i n ether a t room temperature gave on l y mixtures of pro-d u c t s . R e p e t i t i o n of t h i s r e a c t i o n at -23°C(dry ice-carbon t e t r a c h l o r i d e bath), however, r e v e a l e d that a new product was formed along with unreacted s t a r t i n g m a t e r i a l . T h i s r e s u l t was c l e a r by NMR a n a l y s i s which showed the presence of a new N-methyl a b s o r p t i o n a t 6 2.84 as w e l l as the c o r r e s p o n d i n g s i g n a l of the s t a r t i n g m a t e r i a l at <5 3.11, i n a r a t i o of 1:1. In order to d r i v e t h i s r e a c t i o n to completion, compound 113 was t r e a t e d with two e q u i v a l e n t s of d i i s o b u t y l a l u m i n u m hydride a t -23°C i n e t h e r . The product thus obtained was char-a c t e r i z e d by i t s NMR spectrum which d i s p l a y e d a s i n g l e t at 6 2.84 and the c o l l a p s e of the c y c l o h e x y l protons to a m u l t i -p l e t a t 6 1.33-2.00 (cf 6 1.70-1.90 (4H) and 6 2.14-2.45 (4H) i n s t a r t i n g m a t e r i a l ) . The i n f r a r e d spectrum of the product showed a c a r b o n y l a b s o r p t i o n a t 1735 cm 1 and the absence of an O-H s t r e t c h i n g v i b r a t i o n . F i n a l l y , the low r e s o l u t i o n mass spectrum d i s p l a y e d a parent ion a t 155 m/e and a base peak at 111 m/e c o r r e s p o n d i n g to the l o s s of carbon d i o x i d e . On the b a s i s of these r e s u l t s and the molecular formula d e r i v e d from high r e s o l u t i o n mass measurement, the s t r u c t u r e of the product was assigned as 164. The product 164 may be viewed as a r i s i n g — 0 1M 110 from a c o n j u g a t e a d d i t i o n o f h y d r i d e i o n a t carbon 3 o f 113. The s u s c e p t i b i l i t y o f i s o x a z o l i n - 5 - o n e s t o n u c l e o p h i l i c a t t a c k a t carbon 3 had been suggested p r e v i o u s l y i n the h y d r o l y t i c c l e a v a g e o f i s o x a z o l i n - 5 - o n e s ^ . I l l CONCLUSIONS The p r e p a r a t i o n of a number of i s o x a z o l i n - 5 - o n e s has been d e s c r i b e d and anion g e n e r a t i o n of these compounds i n v e s t i g a t e d . The r e a c t i v i t y of these anions appears to p a r a l l e l those of 8-enamino e s t e r s i n t h a t e x c l u s i v e y - a l k y l a t i o n o c c u r s . The r e a c t i o n s of i s o x a z o l i n - 5 - o n e anions with simple c a r -bon e l e c t r o p h i l e s proceed i n f a i r to good y i e l d s , while a l d o l and C l a i s e n condensations are l i m i t e d to aromatic aldehydes and e s t e r s . The dehydration of the r e s u l t i n g aromatic a l d o l products p r o v i d e s unsaturated i s o x a z o l i n - 5 - o n e s i n e x c e l l e n t y i e l d s . The geometry of the new double bond i n these compounds was predominantly t r a n s . The a l k y l a t i o n of the anion of i s o x a z o l i n - 5 - o n e s with some unusual e l e c t r o p h i l e s was a l s o conducted, s i n c e the analogous r e a c t i o n s with B-keto e s t e r d i a n i o n s cannot be e f f e c t e d . In p a r t i c u l a r , the r e a c t i o n with bromine proceeds i n o n l y f a i r y i e l d , while d i r e c t N-bromosuccinimide bromination gave the d e s i r e d y-bromo product i n good y i e l d . Conversion of t h i s compound i n t o i t s corresponding W i t t i g reagent and condensation with benzaldehyde and hexanol provided a second route to unsaturated i s o x a z o l i n - 5 - o n e s . The r e a c t i o n s of i s o x a z o l i n - 5 - o n e anions with epoxides appear to p a r a l l e l those of B-keto e s t e r d i a n i o n s , however the r e s u l t i n g products are more s t a b l e to a c i d . In a d d i t i o n , the s e l e c t i v i t y observed i n the r e a c t i o n of these anions with 112 d i f u n c t i o n a l e l e c t r o p h i l e s a l s o p r o v i d e s some advantages over the use o f B-keto e s t e r d i a n i o n s . The c l e a v a g e o f i s o x a z o l i n - 5 - o n e s has been found t o be e x t r e m e l y p r o b l e m a t i c a l . V a r i o u s approaches i n v o l v i n g i s o x a -z o l i n - 5 - o n e s a l t f o r m a t i o n , n i t r o g e n - o x y g e n h y d r o g e n o l y s i s , and c a r b o n y l r e d u c t i o n have n o t proven s u c c e s s f u l t o d a t e . In p a r t i c u l a r , the r e a c t i o n of i s o x a z o l i n - 5 - o n e s w i t h d i i s o b u t y l -aluminum h y d r i d e has been found t o i n v o l v e i n i t i a l 1,4-reduc-t i o n , f o l l o w e d by f u r t h e r r e d u c t i o n s . The c l e a v a g e o f i s o x a z o l i n - 5 - o n e s t o k e t o n e s , amides, and s e condary amines has been r e p o r t e d i n the l i t e r a t u r e and the p r e s e n t methodology s h o u l d prove u s e f u l i n e x t e n d i n g t h i s c h e m i s t r y . However, the use o f i s o x a z o l i n - 5 - o n e a n i o n s as B-keto e s t e r d i a n i o n e q u i v a l e n t s r e q u i r e s t h a t f u r t h e r s t u d y i n v o l v i n g new approaches be conducted on the c l e a v a g e o f these h e t e r o c y c l i c r i n g s . 113 EXPERIMENTAL SECTION Unless otherwise s p e c i f i e d the f o l l o w i n g are i m p l i e d . A l l temperatures are s t a t e d i n degrees C e n t i g r a d e . M e l t i n g p o i n t s were determined on a K o f l e r hot stage microscope and are uncor-r e c t e d . Kugelrohr d i s t i l l a t i o n s were performed by means of a Buchi Kugelrohr thermostat. I n f r a r e d s p e c t r a were recorded in c h l o r o f o r m s o l u t i o n on Perkin-Elmer Model 700 or 710B spec-trophotometers, and were c a l i b r a t e d with the 1601 cm 1 band of p o l y s t y r e n e . Proton n u c l e a r magnetic resonance s p e c t r a were recorded on V a r i a n A s s o c i a t e d Model T-60, HA-100, or XL-100 spectrometers. Chemical s h i f t s are r e p o r t e d on the 6-scale, with d e u t e r o c h l o r o f o r m as s o l v e n t and t e t r a m e t h y l s i l a n e as an i n t e r n a l standard. The m u l t i p l i c i t y , c o u p l i n g c o n s t a n t s ( i f o b s e r v a b l e ) , and i n t e g r a t e d peak area are i n d i c a t e d i n paren-theses a f t e r each s i g n a l . Low r e s o l u t i o n mass s p e c t r a were recorded on an A t l a s CH-4B mass spectrometer, and high r e s o l u -t i o n mass measurements were obtained u s i n g an AEI MS-9 or MS-50 mass spectrometer. A l l instruments were operated a t an i o n i z -ing p o t e n t i a l of 70 eV. Observed metastable peaks (m*) are given i n the r e p o r t e d mass s p e c t r a , and c a l c u l a t e d values f o r the metastable peak r e s u l t i n g from the fragmentation process parentheses a f t e r the m* v a l u e s . High pressure l i q u i d chromatography was performed on a Waters A s s o c i a t e s l i q u i d 2 1 114 chromatograph u s i n g a r a d i a l pak s i l i c a g e l column and a v a r i -able wavelength u l t r a v i o l e t d e t e c t o r . Elemental analyses were performed by Mr. Peter Borda, M i c r o a n a l y s i s L a b o r a t o r y , U n i -v e r s i t y of B r i t i s h Columbia, Vancouver B.C. S i l i c a g e l P F254+366 s u P P l i e < 3 by E. Merck was used f o r both a n a l y t i c a l and p r e p a r a t i v e t h i n l a y e r chromatography (TLC), while 100-200 mesh ASTM was employed for column chromatography. F l a s h chromatography was performed u s i n g S i l i c a Gel 60, 230-400 mesh ASTM, s u p p l i e d by E. Merck. V i s u a l i z a t i o n of spots or bands on TLC p l a t e s was accomplished by u l t r a v i o l e t l i g h t and/or i o d i n e vapour s t a i n i n g . A l l s o l v e n t systems are expressed i n r a t i o s by volume ( v / v ) . Vapour-phase chromatographic analyses (VPC) were conducted on a Hewlett-Packard Model 5830-A chroma-tograph u s i n g 6 f t x 1/8 inch columns of 3% OV-17 or 3% OV-101. Dry e t h y l e ther and t e t r a h y d r o f u r a n were obtained by d i s -t i l l a t i o n from l i t h i u m aluminum h y d r i d e . Dichloromethane was d r i e d by d i s t i l l i n g from phosphorus pentoxide. Anhydrous hexamethylphosphoramide was obtained by r e f l u x i n g over barium oxide, f o l l o w e d by d i s t i l l a t i o n under reduced pressure and storage over a c t i v a t e d 4A molecular s i e v e s . P y r i d i n e and d i i s o -propylamine were d i s t i l l e d from potassium hydroxide and then s t o r e d over potassium hydroxide. M e t h y l l i t h i u m i n ether and n - b u t y l l i t h i u m i n hexane were obtained from A l d r i c h Chemical Company, Inc. The a l k y l l i t h i u m s o l u t i o n s were 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 a 1.0 M 115 s o l u t i o n of t - b u t y l a l c o h o l in benzene using 1,10-phenanthroline 95 . . . as i n d i c a t o r . Sodium hydride (from A l f a D i v i s i o n , Ventron Corporation) was weighed as a 50% d i s p e r s i o n i n m i n e r a l o i l and was washed with dry t e t r a h y d r o f u r a n to remove the o i l p r i o r to use. A l l other reagents and s o l v e n t s were e i t h e r of reagent grade and used d i r e c t l y , or p u r i f i e d a c c o r d i n g to l i t e r a t u r e p r o c e d u r e s ^ . F i n a l l y a l l r e a c t i o n s were run under a dry n i t r o -gen or argon atmosphere. 116 Methyl 2-Oxocyclohexanecarboxylate (118) A 500-mL three-necked round bottom f l a s k equipped with a r e f l u x condenser, p r e s s u r e - e q u a l i z e d a d d i t i o n f unnel and a n i t r o g e n i n l e t was charged with sodium hydride (22.5 g; 0.47 mole) and dry t e t r a h y d r o f u r a n (120 mL). Dimethyl carbonate (33.8 g; 0.38 mole) was added i n one p o r t i o n and the suspension was heated to r e f l u x with constant s t i r r i n g . A s o l u t i o n of cyclohexanone (14.7 g; 0.15 mole) i n anhydrous t e t r a h y d r o f u r a n (40 mL) was added dropwise through the a d d i t i o n f unnel and potassium hydride (ca.100 mg, 24.5% i n o i l ) was introduced to i n i t i a t e the r e a c t i o n . The a d d i t i o n of cyclohexanone was con-tinued over a p e r i o d of 1 hour, then the r e a c t i o n mixture was maintained a t r e f l u x f o r an a d d i t i o n a l 0.5 hour. On workup, the mixture was cooled i n an i c e bath, quenched with 5% h y d r o c h l o r i c a c i d (150 mL) and poured onto b r i n e (100 mL). The aqueous phase was e x t r a c t e d with c h l o r o f o r m (4 x 100 mL) and the combined o r g a n i c l a y e r s washed with b r i n e , d r i e d over anhydrous mag-nesium s u l f a t e and concentrated under reduced p r e s s u r e . Vacuum d i s t i l l a t i o n of the crude product gave 20.3 g (87%) of 118 as a c o l o u r l e s s l i q u i d : bp 63-64°/1.4 t o r r ( l i t . 6 8 bp 68°/0.8 t o r r ) ; IR 1765, 1735 cm - 1, 1680 and 1640 cm - 1; NMR 6 1.4-2.5 (m,8H),3.3 (m, = 0.2H, due to the keto form), 3.70 (s, 3H), 12.1 (s, = 0.8H, due to the e n o l form); mass spectrum m/e ( r e l i n t e n s i t y ) 156 (62), 125 (25), 124 (100), 68 (33) and 55 (34). 117 2-Methyl-3,4-teframethyleneisoxazolin-5-one (113) A 100-mL three-necked round bottom f l a s k equipped with a r e f l u x condenser, n i t r o g e n i n l e t and a rubber septum was charged with N-methylhydroxylamine h y d r o c h l o r i d e (10 g; 0.12 mole) and dry p y r i d i n e (55 mL). Methyl 2-cyclohexanonecarboxylate (118) (15.6 g; 0.10 mole) was introduced v i a s y r i n g e i n one p o r t i o n and the r e a c t i o n mixture was heated on an o i l bath at 100° f o r 8 hours. On workup, the mixture was cooled to room temperature and the p y r i d i n e was removed under reduced p r e s s u r e . The residue was t r e a t e d with s a t u r a t e d aqueous potassium carbonate u n t i l s l i g h t l y a l k a l i n e , then e x t r a c t e d with ether (3 x 100 mL) and d r i e d over anhydrous magnesium s u l f a t e . The e t h e r e a l s o l u -t i o n was c o n c e n t r a t e d under reduced p r e s s u r e , and the r e s i d u e was d i s t i l l e d under vacuum g i v i n g 10.4 g (67%) of a c o l o u r l e s s o i l : bp 122-124°/0.2 t o r r ; IR 1738 and 1640 cm - 1; NMR 6 1.7-1.9 (m, 4H), 2.14-2.45 (m, 4H), 3.11 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 154 (11), 153 (100), 152 (25), 127 (15), 125 (86), and 96 (15). A n a l . C a l c d for CgH-^NO^ C, 62.73; H, 7.24; N, 9.14. Found: C, 62.58; H, 7.41; N, 9.00. 2,3-Dimethylisoxazolin-5-one (112) The procedure used i n the p r e p a r a t i o n of 113 was f o l l o w e d , s t a r t i n g from N-methylhydroxylamine h y d r o c h l o r i d e (5.20 g; 118 61.9 mmole), e t h y l a c e t o a c e t a t e (20.6 g; 155 mmole) and dry p y r i d i n e (35 mL). F r a c t i o n a l d i s t i l l a t i o n of the crude product gave 5.20 g (74%) of 112 as a c o l o u r l e s s o i l : bp 82-84°/0.05 t o r r ( l i t . 6 5 bp 88-89°/0.2 t o r r ) ; IR 1725 and 1645 cm" 1; NMR 6 2.16 (s, 3H), 3.30 (s, 3H) , and 4.93 (s, IH), mass spectrum m/e ( r e l i n t e n s i t y ) 113 (100), 96 (7) and 57 (31). 2,3, 4 - T r i m e t h y l i s o x a z o l i n - 5 - o n e (114 ) The procedure used in the p r e p a r a t i o n of 113 was followed u s i n g N-methylhydroxylamine h y d r o c h l o r i d e (10 g; 0.12 mole), e t h y l 2-methylacetoacetate (13.2 g; 0.10 mole) and anhydrous p y r i d i n e (50 mL). The crude product was f r a c t i o n a l l y d i s t i l l e d to y i e l d 8.7 g (69%) of 114 as a c o l o u r l e s s o i l , which s o l i d i -f i e d on c o o l i n g : bp 127-129°/5.0 t o r r , mp 39-40° ( l i t . 6 4 a mp 39-40°); IR 1720 and 1640 cm - 1; NMR 6 1.73 (s, 3H), 2.10 (s, 3H), and 3.17 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 127 (100), 98 (7) and 56 (17) . A n a l . C a l c d f o r CgH 9N0 2: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.48; H, 7.24; N, 11.00. 119 Base Dependency S t u d i e s o f Isoxazolin-5-one Anion Generation  2,4-Dimethyl-3-ethylisoxazolin-5-one (127a) a) V i a l i t h i u m d i i s o p r o p y l a m i d e A s o l u t i o n of d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole) i n dry t e t r a h y d r o f u r a n (10 mL) was prepared i n a 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber spetum. The f l a s k was cooled to 0° i n an i c e water bath and n - b u t y l l i t h i u m as a 1.0 M s o l u t i o n i n hexane (1.57 mL; 1.47 mmole) was added dropwise. The c o l o u r l e s s to pale yellow s o l u t i o n was s t i r r e d for 10 minutes and 2 , 3 , 4 - t r i -m e t h y l i s o x a z o l i n - 5 - o n e (114) (200 mg; 1.57 mmole) i n t e t r a -hydrofuran (3 mL) was introduced slowly v i a s y r i n g e . Upon s t i r -r i n g f o r an a d d i t i o n a l 15 minutes, methyl i o d i d e (199 mg; 1.57 mmole) was added and the r e a c t i o n mixture allowed to stand f o r a f i n a l 10 minutes to complete the r e a c t i o n . D i l u t e hydro-c h l o r i c a c i d (5 mL) was added and the r e a c t i o n was e x t r a c t e d with ether (3 x 10 mL). The combined o r g a n i c e x t r a c t s were then washed with water (5 mL) and d r i e d over anhydrous magne-sium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 127a as an amber o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , 3:1 e t h y l ether-chloroform) to give 180 mg (81%) of 127a: Rf 0.40; bp (Kugelrohr d i s t i l l a -t i o n ) 80-82°/1.3 t o r r ; IR 1722 and 1635 cm - 1; NMR 6 1.18 ( t , 3H, J = 7 Hz), 1.74 (s, 3H), 2.45 (q, 2H, J = 7 Hz), and 3.14 120 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 141 (100), 112 (16), and 70 (22) . A n a l . C a l c d f o r C^H^NC^: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.30; H, 7.86; N, 9.96. b) V i a n.-butyllithium A 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum was charged with a s o l u t i o n of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) (204 mg; 1.61 mmole) i n dry t e t r a h y d r o f u r a n (10 mL). The f l a s k was coo l e d to -78° i n a dry ice-acetone bath and n - b u t y l l i t h i u m as a 1.56 M s o l u t i o n i n hexane (1.20 mL; 1.87 mmole) was added dropwise. Upon complete a d d i t i o n the r e a c t i o n mixture was s t i r r e d f o r 1 hour at -78°. Methyl i o d i d e (365 mg; 2.57 mmole) was then i n t r o d u c e d in one p o r t i o n and the r e a c t i o n allowed to warm to room temperature over 4 hours. Workup and p u r i f i c a t i o n as above gave 165 mg (73%) of 127a as a c o l o u r l e s s o i l with 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 to those reported e a r l i e r . c) V i a potassium b i s ( t r i m e t h y l s i l y l ) a m i d e 7 0 Potassium hydride as a 20.6% d i s p e r s i o n i n m i n e r a l o i l (367 mg; 1.88 mmole) was weighed i n t o a 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum, and dry t e t r a h y d r o f u r a n (10 mL) was d i s t i l l e d d i r e c t l y i n t o the r e a c t i o n f l a s k . The suspension was cooled to 121 0° i n an i c e water bath, 1,1,1,3,3,3-hexamethyldisilazane (303 mg; 1.88 mmole) was slowly added and the r e a c t i o n mixture was allowed to stand f o r 45 minutes to ensure complete formation of the amide base. A s o l u t i o n of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) (200 mg; 1.57 mmole) in t e t r a h y d r o f u r a n (3 mL) was then added dropwise v i a s y r i n g e and the r e a c t i o n was s t i r r e d f o r 1 hour. I n t r o d u c t i o n of methyl i o d i d e (199 mg; 1.57 mmole), f o l -lowed by s t i r r i n g f o r an a d d i t i o n a l 1.25 hour completed the reac-t i o n . Workup and p u r i f i c a t i o n as above gave 175 mg (79%) of 127a as a c o l o u r l e s s o i l with 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 to those r e p o r t e d e a r l i e r . A l k y l a t i o n of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) General procedure A s o l u t i o n of d i i s o p r o p y l a m i n e (1.2 e q u i v a l e n t s ) i n dry t e t r a h y d r o f u r a n (10 mL) was prepared i n a 25-mL two-necked round bottom f l a s k . The f l a s k was f i t t e d with a n i t r o g e n i n l e t and a rubber septum, c o o l e d to 0° i n an i c e water bath, and n - b u t y l l i t h i u m as a s o l u t i o n i n hexane (1.1 e q u i v a l e n t ) was added dropwise. The c o l o u r l e s s to pale yellow s o l u t i o n was s t i r r e d f o r 15 minutes to ensure complete base formation and a s o l u t i o n of 114 (1.0 e q u i v a l e n t ) i n anhydrous t e t r a h y d r o f u r a n (3 mL) was introduced v i a s y r i n g e . Upon s t i r r i n g f o r 30 min-u t e s , the a l k y l a t i n g agent (1.0 e q u i v a l e n t ) was added and the 122 r e a c t i o n mixture was then allowed to stand u n t i l s t a r t i n g m a t e r i a l was consumed as judged by TLC. D i l u t e h y d r o c h l o r i c a c i d (5 mL) was added and the r e a c t i o n mixture e x t r a c t e d with ether (3 x 10 mL). The combined e x t r a c t s were washed with water (5 mL) and d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether under reduced pressure gave the crude a l k y l a t e d p r o d u c t s . D e u t e r a t i o n S t u d i e s a) 2 , 3 , 4 - T r i m e t h y l i s o x a z o l i n - 5 - o n e - d i (122) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure for a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (159 mg; 1.57 mmole), n - b u t y l l i t h i u m as a 1.26 M s o l u t i o n i n hexane (1.25 mL; 1.57 mmole), 114 (181 mg; 1.43 mmole) and excess deuterium oxide (1 mL). The r e s u l t i n g mixture was allowed to stand f o r 10 minutes, then ether (10 mL) and deuterium oxide (3 mL) were added. The o r g a n i c l a y e r was separated, washed with deuterium oxide (2 mL) then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 122 as an amber o i l : NMR 6 1.73 (s, 3H), 2.07 (bs, 2.OH) and 3.17 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 129 (12), 128 (100), 99 (11) and 57 (20). Mass s p e c t r a l and proton nuclear mag-n e t i c resonance a n a l y s i s i n d i c a t e d product was 95 ± 5% d-^. 123 2,3-Dimethylisoxazolin-5-one-di T h i s compound was prepared by a procedure analogous to that o f compound 122 u s i n g d i i s o p r o p y l a m i n e (288 mg; 2.85 mmole), n - b u t y l l i t h i u m as a 1.20 M s o l u t i o n i n hexane (2.43 mL; 2.85 mmole), 112 (270 mg; 2.39 mmole) and deuterium oxide (1 mL). Workup as above gave an amber o i l : NMR 6 2.10 (bs, * 2.4H), 3.27 (s, 3H) and 4.93 (s, = 0.6H); mass spectrum m/e ( r e l i n t e n s i t y ) i n d i c a t e d 28% d D , 48% d 1 and 24% d 2 . 2-Methyl-3,4-te f r a m e t h y l e n e i s o x a z o l i n - 5 - o n e - d i The r e a c t i o n was c a r r i e d out a c c o r d i n g to the procedure d e s c r i b e d f o r the p r e p a r a t i o n of 122, u s i n g d i i s o p r o p y l a m i n e (131 mg; 1.42 mmole), n - b u t y l l i t h i u m as a 1.42 M s o l u t i o n i n hexane (1.00 mL; 1.42 mmole), 113 (200 mg; 1.29 mmole) and deuterium oxide (1 mL). The r e s u l t i n g mixture was allowed to stand f o r 15 minutes, then worked up as u s u a l to give a y e l -low o i l : mass spectrum m/e ( r e l i n t e n s i t y ) 154 (100) , 126 (68) and 97 (12). 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 s product i s 95 ± 5% d 1 . D i e t h y l acetylmalonate( 124) A 500-mL three-necked round bottom f l a s k equipped with a mechanical s t i r r e r , r e f l u x condenser f i t t e d with a c a l c i u m c h l o r i d e d r y i n g tube, and a p r e s s u r e - e q u a l i z e d dropping f u n n e l 124 was charged with magnesium t u r n i n g s (5.4 g; 0.22 mole). Dry e t h a n o l (5 mL) and carbon t e t r a c h l o r i d e (0.5 mL) were added to i n i t i a t e the r e a c t i o n and a f t e r s e v e r a l minutes anhydrous ether (175 mL) was added c a u t i o u s l y with constant s t i r r i n g . A s o l u -t i o n of d i e t h y l malonate (35.2 g; 0.22 mole), e t h a n o l (20 mL) and ether (25 mL) was added dropwise through the a d d i t i o n fun-n e l a t such a r a t e t h a t r a p i d b o i l i n g was maintained, and the r e a c t i o n mixture was then allowed to r e f l u x f o r an a d d i t i o n a l 3.0 hours. A s o l u t i o n of a c e t y l c h l o r i d e (17.3 g; 0.22 mole) i n ether (25 mL) was added dropwise over 15 minutes and the r e a c t i o n mixture was r e f l u x e d u n t i l i t became t o o v i s c o u s to s t i r . The r e s u l t a n t suspension was cooled in an i c e water bath and d i l u t e s u l f u r i c a c i d added u n t i l a l l the s o l i d s had d i s -s o l v e d . The e t h e r e a l l a y e r was separated and the aqueous l a y e r f u r t h e r e x t r a c t e d with ether (1 x 75 mL). The combined or g a n i c l a y e r s were washed with water, d r i e d over anhydrous magnesium s u l f a t e and then concentrated under reduced pressure l e a v i n g a p a l e y e l l o w l i q u i d . D i s t i l l a t i o n under water a s p i r a t o r p r e s -sure gave 37.3 g (84%) of 124 as a c o l o u r l e s s l i q u i d : bp 127-128°/20 t o r r ( l i t . 7 3 bp 110-115°/13 t o r r ) ; IR 3410, 1720, 1645 and 1610 cm" 1; NMR 6 1.30 ( t , 6H, J = 6 Hz), 2.17 (s, - 1.75H), 2.30 (s, * 1.25H), 3.27 ( s , ^ 0 . 5 H ) , 4 . 2 0 ( l , 4 H , J = 6 Hz), and 15.0 (s, ^ 0.5H); mass spectrumm/e ( r e l i n t e n s i t y ) 202 (0.7), 160 (8), 133 (59), 115 (100) and 88 (24). 125 2,3-Dimethy1-4-carbe thoxyisoxazolin-5-one 125 N-methylhydroxylamine h y d r o c h l o r i d e (0.50 g; 6.0 mmole) and d i e t h y l acetylmalonate 124 (1.0 g; 5.0 mmole) were i n t r o -duced i n t o a 25-mL two-necked round bottom f l a s k . The f l a s k was f i t t e d with a n i t r o g e n i n l e t and a rubber septum, and dry p y r i d i n e (7 mL) was added v i a s y r i n g e . The r e a c t i o n mixture was heated on an o i l bath a t 80° f o r 7 hours, then c o o l e d to room temperature. P y r i d i n e was removed under reduced pressure and the re s i d u e was t r e a t e d with s a t u r a t e d aqueous potassium carbonate u n t i l s l i g h t l y a l k a l i n e . The aqueous s o l u t i o n was then e x t r a c t e d with ether (3 x 50 mL) and d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether under reduced p r e s -sure, f o l l o w e d by r e c r y s t a l l i z a t i o n from methanol gave 0.551 g (72%) of 125 as white c r y s t a l s : mp 137-138° ( l i t . 7 4 mp 138°); IR 1750 and 1690 cm - 1; NMR 6 1.32 ( t , 3H, J = 6 Hz), 2.51 (s, 3H), 3.61 (s, 3H) and 4.25 (q, 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 185 (31), 140 (100) and 67 (35). 2-Methy1-3-ethy1-4-carbethoxyisoxazolin-5-one (126) A 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum was charged with sodium hydride (58 mg; 1.20 mmole) and dry t e t r a h y d r o f u r a n (12 mL). The f l a s k was then c o o l e d t o 0° i n an i c e water bath and a s o l u t i o n of 125 (185 mg; 1.00 mmole) i n 1:1 126 t e t r a h y d r o f u r a n - d i m e t h y l s u l f o x i d e (3 mL) was added dropwise. The r e a c t i o n mixture was allowed to stand f o r 20 minutes, then methyl i o d i d e (14 2 mg; 1.00 mmole) was introduced and the s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l 2 hours. Ether (10 mL) and water (5 mL) were added and the o r g a n i c l a y e r separated. The aqueous s o l u t i o n was f u r t h e r e x t r a c t e d with ether ( 2 x 5 mL) and the combined o r g a n i c l a y e r s d r i e d over anhydrous mag-nesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 126 as a yellow o i l . P u r i f i c a t i o n by column chromatography on s i l i c a g e l (100-200 mesh) u s i n g petroleum e t h e r - e t h y l ace-tate mixtures gave 169 mg (85%) of 126 as a white s o l i d : mp 62-63°; bp (Kugelrohr d i s t i l l a t i o n ) 137-140°/0.15 t o r r ; IR 1765, 1750 and 1650 cm" 1; NMR 6 1.13-1.43 (m, 6H), 2.90 (q, 2H, J = 7 Hz), 3.60 (s, 3H) and 4.23 (q, 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 199 (42), 153 (100), 152 (24), 117-118 (m*,^ 5^- = 117.6), 82 (12) and 81 (13). A n a l . C a l c d f o r C 9 H 1 3 N 0 4 : C, 54.26; H, 6.57, N, 7.03. Found: C, 54.11; H, 6.40; N, 7.04. 2,4-Dimethy1-3-propylisoxazolin-5-one (127b) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure fo r a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole) n - b u t y l l i t h i u m as a 1.56 M s o l u t i o n i n hexane (1.12 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole), and e t h y l i o d i d e (245 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d for 30 127 minutes, then workup gave 195 mg of crude 127b as an amber o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l with e t h e r - c h l o r o f o r m (2:1) gave 163 mg (67%) of 127b as a c o l o u r -l e s s o i l : Rf = 0.40; bp (Kugelrohr d i s t i l l a t i o n ) 87-90°/1.4 t o r r ; IR 1722 and 1625 cm" 1; NMR 6 1.04 ( t , 3H, J = 7.5 Hz), 1.55-1.80 (m, 2H), 1.82 (s, 3H), 2.48 ( t , 2H, J = 7.5 Hz), and 3.21 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 155 (100), 127 (79), 104 ( m * , ^ 3 - = 104.1), and 98 (23). A n a l . C a l c d f o r CgH^NC^: C, 61.91; H, 8.44; N, 9.03. Found: C, 61.99; H, 8.29; N, 9.26. 2,4-Dimethyl-3-pentylisoxazolin-5-one (127c) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l -l i t h i u m as a 1.6 M s o l u t i o n i n hexane (1.10 mL, 1.74 mmole), 114 (200 mg; 1.57 mmole) and n - b u t y l bromide (215 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 3 hours, then workup gave crude 127c as an amber o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l with e t h y l e t h e r - c h l o r o f o r m (3:1) gave 230 mg (80%) of 127c as a c o l o u r l e s s o i l : Rf 0.60; bp (Kugelrohr d i s t i l l a t i o n ) 93-95°/1.2 t o r r ; IR 1722 and 1630 cm - 1; NMR 6 0.88 ( t , 3H, J = 7 Hz), 1.23-1.65 (m, 6H), 1.72 (s, 3H), 2.39 ( t , 2H, J = 7 Hz) and 3.12 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 183 (42), 141 (10), 140 (33), 128 (10), 127 (100), 99 (11) and 98 (24). 128 A n a l . C a l c d f o r C l f JH 1 7N0 2: C, 65.54; H, 9.35; N, 7.64. Found: C, 65.24; H, 9.44; N, 7.50. 2,4-Dimethyl-3-(3'-butenyl)isoxazolin-5-one (127d) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g d i i s o p r o p y l a m i n e (174 mg; 1.56 mmole), n - b u t y l -l i t h i u m as a 1.56 M s o l u t i o n i n hexane (1.10 mL; 1.72 mmole), 114 (198 mg; 1.56 mmole) and 3-bromo-l-propene (189 mg; 1.56 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 10 minutes, then worked up to give 127d as a ye l l o w o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , 3:1 ether-chloroform) to give 195 mg (75%) of 127d as a c o l o u r l e s s o i l : Rf 0.50; bp (Kugelrohr d i s t i l l a t i o n ) 92-95°/1.5 t o r r ; IR 1725 and 1632 cm" 1; NMR 6 1.88 (s, 3H), 2.20-2.66 (m, 4H), 3.21 (s, 3H), 5.01-5.24 (m, 2H) and 5.64-6.01 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 167 (100), 166 (7), 127 (13), 125 (29), 96 (22), and 81 (40). A n a l . C a l c d f o r CgH^NC^: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.38; H, 7.80; N, 8.61. 2,4-Dime t h y l - 3 - ( 4 1 me thyl-3'-penteny1)isoxazolin-5-one (127e) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l -l i t h i u m as a.1.6 M s o l u t i o n i n hexane (1.10 mL, 1.74 mmole), 129 114 (200 mg; 1.57 mmole) and 3-methyl-l-bromo-2-butene (233 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 10 minutes, then worked up to g i v e 127e as a y e l l o w o i l . The crude pro-duct was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , 3:1 e t h e r -chloroform) to g i v e 230 mg (75%) o f 127e as a c o l o u r l e s s o i l : Rf 0.65; bp (Kugelrohr d i s t i l l a t i o n ) 93-95°/1.4 t o r r ; IR 1722 and 1629 cm" 1; NMR 6 1.57 (s, 3H), 1.67 (s, 3H), 1.74 (s, 3H), 2.14-2.54 (m, 4H), 3.15 (s, 3H) and 5.08 ( t , IH, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 195 (49), 136 (24), 127 (100), and 69 (71). A n a l . C a l c d f o r C-^H^NG^: C ' 67.66; H f 8.78; N, 7.17. Found: C, 67.79; H, 8.96; N, 7.17. 2,4-Dimethyl-3-(2'-phenethyl)isoxazolin-5-one (127f) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l -l i t h i u m as a 1.56 M s o l u t i o n i n hexane (1.12 mL, 1.74 mmole), 114 (200 mg; 1.57 mmole) and b e n z y l c h l o r i d e (199 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 3 hours, then workup gave crude 127f as a y e l l o w o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l with e t h e r - c h l o r o f o r m (3:1) gave 179 mg (52%) of 127f as a c o l o u r l e s s o i l : Rf 0.40; bp (Kugelrohr d i s t i l l a t i o n ) 127-130°/2.3 t o r r ; IR 1722 and 1630 cm" 1; NMR 6 1.55 (s, 3H), 2.59-2.94 (m, 4H), 3.00 (s, 3H), 130 and 7.04-7.36 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 217 (100), 105 (29) and 91 (98). A n a l . C a l c d for C 1 3 H 1 5 N 0 2 : C, 71.87; H, 6.96; N, 6.45. Found: C, 71.91; H, 6.92; N, 6.46. 2, 4-Dimethy1-3-(2'-hydroxyphenethyl)isoxazolin-5-one (128) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g d i isopropylamine (176 mg; 1.7.4 mmole), n - b u t y l -l i t h i u m as a 1.6 M s o l u t i o n i n hexane (1.09 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole) and benzaldehyde (167 mg; 1.57 mmole). The r e s u l t i n g mixture was allowed to stand f o r 1.5 hours, then worked up to give 128 as a yellow o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l u s i n g e t h e r - e t h y l acetate (5:1), f o l l o w e d by c r y s t a l l i z a t i o n from ether gave 260 mg (71%) of 128 as c o l o u r l e s s c r y s t a l s : Rf 0.35; mp 92-94°; IR 3625, 3435, 1733 and 1640 cm - 1; NMR 6 1.57 (s, 3H), 2.80 (d, 2H, J = 6.5 Hz), 3.16 (s, 4H), 4.92 ( t , 2H, J = 6.5 Hz) and 7.29 (s, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 233 (100), 127 (100), 107 (96), 81 (36), 79 (48), 55 (23), and 53 (23). A n a l . C a l c d f o r c i 3 H i 5 N 0 3 : c> 66.94; H, 6.48; N, 6.00. Found: C, 66.87; H, 6.47; N, 6.01. 131 2,4-Dimethy1-3-(2'-mesyloxyphenethyl)isoxazolin-5-one (134) A s o l u t i o n of compound 128 (133 mg; 0.57 mmole) i n dry t e t r a h y d r o f u r a n (10 mL) was prepared i n a 25-mL two-necked round bottom f l a s k . The f l a s k was f i t t e d with a n i t r o g e n i n l e t and stoppered with a rubber septum, then cooled to 0° i n an i c e water bath. T r i e t h y l a m i n e (87 mg; 0.86 mmole) was added and upon standing f o r 15 minutes, methanesulfonyl c h l o r i d e (78 mg; 0.68 mmole) was i n t r o d u c e d dropwise. The r e a c t i o n mixture was s t i r r e d f o r 1 hour then worked up to give 134 as a pale yellow o i l . The o i l c r y s t a l l i z e d on standing and the r e s u l t i n g c r y s t a l s were washed with ether ( 3 x 5 mL), then d r i e d under vacuum g i v i n g 168 mg (95%) of 134 as a n a l y t i c a l l y pure c o l o u r -l e s s c r y s t a l s : mp 94-95°; IR 1730, 1640 and 1370 cm - 1; NMR 6 1.51 (s, 3H), 2.80 (s, 3H), 3.21 (s, 3H), 3.08-3.35 (m, 2H), 5.70 ( t , IH, J = 7 Hz) and 7.42 (s, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) ' 311 (16), 215 (100), 170 (29), 156 (22), 141 (46), 128 (39) and 115 (23) . A n a l . C a l c d for c i 4 H i 7 N 0 5 S : c » 54.01; H, 5.50; N, 4.50. Found: C, 53.91; H, 5.47; N, 4.44. 2,4-Dimethy1-3-(2'-phenylethenyl)isoxazolin-5-one (135) A 25-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and a n i t r o g e n i n l e t was charged with 134 (330 mg; 1.06 mmole) and anhydrous dichloromethane (15 mL). 132 1, 5-Diazabicyclo[4.3.0]non-5-ene (199 mg ; 1.60 mmole) was then introduced and the r e a c t i o n mixture was r e f l u x e d f o r 4 hours. The r e a c t i o n was c o o l e d to room temperature and 5% h y d r o c h l o r i c a c i d (5 mL) was added. The o r g a n i c phase was separated, washed with water (10 mL) and b r i n e (10 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s -sure gave 13 5 as a yellow o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l u s i n g e t h e r - e t h y l a c e t a t e (1:1) gave 217 mg (95%) of 135 as a c o l o u r l e s s o i l which c r y s t a l l i z e d on s t a n d i n g : Rf 0.85; bp (Kugelrohr d i s t i l l a t i o n ) 120-122°/0.18 t o r r ; mp 46-47°; IR 1730 and 1650 cm - 1; NMR 6 1.98 (s, 3H), 3.24 (s, 3H), 7.01 (q, 2H, J = 16 Hz), and 7.36-7.66 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 215 (100), 170 (17), 156 (14), 141 (14), 129 (15) and 105 (14). A n a l . C a l c d f o r C 1 3 H 1 3 N 0 2 : C, 72.54; H, 6.09; N, 6.51. Found: C, 72.58; H, 6.14; N, 6.41. 2,4-Dimethy1-3-benzoyImethylisoxazolin-5-one (137) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure u s i n g d i i s o p r o p y l a m i n e (352 mg; 3.48 mmole), n - b u t y l -l i t h i u m as a 1.57 M s o l u t i o n i n hexane (2.23 mL; 3.48 mmole), 114 (200 mg; 1.57 mmole) and methyl benzoate (214 mg; 1.57 mmole). The r e s u l t i n g mixture was allowed to stand f o r 5 hours, then worked up to g i v e 137 as an amber o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , 5:1 133 e t h e r - e t h y l acetate) to g i v e 207 mg (57%) of 137 as a white s o l i d : Rf = 0.40; mp 77.5-78.5°; IR 1735, 1700 and 1642 cm - 1; NMR 6 1.80 (s, 3H), 3.24 (s, 3H), 4.21 (s, 2H), 7.47-7.69 (m, 3H) and 7.96-8.06 (m, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 231 (9), 122 (46), 105 (100) and 77 (46). High R e s o l u t i o n Mass Measurement C a l c d f o r C ^ 2 H i 3 N 0 2 : 231.0895. Found: 231.0894. 2,4-Dimethy1-3-bromomethylisoxazolin-5-one (140a) Procedure A T h i s compound was prepared by a m o d i f i c a t i o n of the ge n e r a l procedure. The anion of 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 -one (114) was prepared as u s u a l a t 0° u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.16 M s o l u t i o n i n hexane (1.50 mL; 1.74 mmole) and 114 (200 mg; 1.57 mmole). The r e a c t i o n mixture was then c o o l e d to -78° in a dry ice-acetone bath and bromine (251 mg« 1.57 mmole) was introduced dropwise. The r e s u l t i n g mixture was allowed to stand f o r 10 minutes, then worked up as us u a l to give 140a as an amber o i l . P re-p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l using e t h e r -e t h y l a c e t a t e (2:1) gave 133 mg (41%) of 140a as a pa l e yellow o i l : Rf 0.50; IR 1740 and 1645 cm - 1; NMR <5 1.81 (s, 3H) , 3.23 (s, 3H), and 4.08 (s, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 207 (100), 205 (100), 126 (68), 81 (93), and 53 (98). 134 High R e s o l u t i o n Mass Measurement Calc d f o r CgHglS^Br: 206.9719, 204.9739. Found: 206.9714, 204.9734. 2,4-Dimethyl-3-bromomethylisoxazolin-5-one (140a) Procedure B A 25-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and a n i t r o g e n i n l e t was charged with N-bromosuccini-mide (28 0 mg; 1.57 mmole), 114 (200 mg; 1.57 mmole) and dry carbon t e - t r a c h l o r i d e (10 mL) . A few c r y s t a l s of benzoyl peroxide (ca. 10 mg) was then added and the r e a c t i o n mixture was r e f l u x e d f o r 2 hours. On workup, the s o l u t i o n was co o l e d to room tempera-ture and water (5 mL) added. The o r g a n i c phase was separated, washed with b r i n e (5 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 345 mg (76%) of 140a as a ye l l o w o i l , which 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 as those r e p o r t e d above. 2 , 4-Dime t h y l - 3 - (phenylselenenylme t h y l ) i s o x a z o l i n - 5 - o n e (140b) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l k y l a t i o n u s i n g d i i s p p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.57 M s o l u t i o n i n hexane (1.11 mL\ 1.74 mmole), 114 (200 mg; 1.57 mmole), and p h e n y l s e l e n e n y l c h l o r i d e (307 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d for 1.5 hours, then worked up to a f f o r d 140b as an amber o i l . 135 P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l with e t h e r -e t h y l a c e t a t e (1:1) gave 271 mg (61%) of 140b as a white s o l i d : Rf 0.75; mp 69-70°; bp (Kugelrohr d i s t i l l a t i o n ) 110-112°/0.06 t o r r ; IR 1730 and 1625 cm" 1; NMR 6 1.40 (s, 3H), 3.12 (s, 3H), 3.66 (s, 2H), and 7.06-7.57 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 284 (11), 283 (68), 282 (5), 281 (36), 280 (14), 279 (14), 202 (18), 125 (68) and 81 (100). A n a l . C a l c d f o r C 1 2 H 1 3 N 0 2 S e : C, 51.07; H, 4.64; N, 4.97. Found: C, 51.26, H, 4.65; N, 4.97. 2 , 4-Dime t h y l - 3 - (tr i m e t h y l s i l y l m e t h y l ) i s o x a z o l i n - 5 - o n e (140c) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (1.10 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole) and t r i m e t h y l c h l o r o s i l a n e (171 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 15 minutes, then worked up to g i v e 140c as a ye l l o w o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , 1:1 e t h e r -e t h y l acetate) to g i v e 200 mg (64%) of 140c as a c o l o u r l e s s o i l : Rf 0.70; bp (Kugelrohr d i s t i l l a t i o n ) 97-99°/1.6 t o r r ; IR 1720, 1620 and 1253 cm" 1; NMR 6 0.31 (s, 9H), 1.89 (s, 3H), 2.09 (s, 2H) and 3.32 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 199 (100), 184 (43), 156 (39), 127 (89), 96 (54) and 73 (100). High R e s o l u t i o n Mass Measurement C a l c d f o r CgH^NC^Si: 199.1029. Found: 199.1035. 136 2,4-Dimethyl-3-(phenylthiomethyl)isoxazolin-5-one (140d) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.45 M s o l u t i o n i n hexane (1.20 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole) and d i p h e n y l d i s u l f i d e (342 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d for 2 hours, then worked up to g i v e 140d as a yellow o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l , et h e r ) to gi v e 262 mg (71%) of 140d as a white s o l i d : Rf 0.40; mp 62-63°; bp (Kugelrohr d i s t i l l a t i o n ) 132-135°/0.1 t o r r ; IR 1725 and 1640 cm - 1; NMR <$ 1.46 (s, 3H), 3.22 (s, 3H), 3.78 (s, 2H), and 7.32-7.56 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 235 (100) , 127 (17), 126 (87) and 67-68 (m*, - ^ j ^ = 67.6). High R e s o l u t i o n Mass Measurement C a l c d f o r C ^ 2 H i 3 N 0 2 S ; 235.0667. Found: 235.0667. 2,4-Dimethy1-3-(3'-methylpropionate)isoxazolin-5-one (140e) Th i s compound was prepared by the m o d i f i c a t i o n of the g e n e r a l procedure d e s c r i b e d f o r compound 140a, u s i n g d i i s o p r o p y l -amine (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.45 M s o l u t i o n i n hexane (1.20 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole) and methyl bromoacetate (240 mg; 1.57 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 2 hours, then worked up to g i v e 140e as a y e l -low o i l . The crude product was p u r i f i e d by p r e p a r a t i v e TLC 137 ( s i l i c a g e l , ether) to give 178 mg (57%) of 140e as a c o l o u r l e s s o i l : Rf 0.40; bp (Kugelrohr d i s t i l l a t i o n ) 92-95°/0.10 t o r r ; IR 1740 and 1650 cm - 1; NMR <S 1.83 (s, 3H), 2.50-2.92 (m, 4H), 3.24 (s, 3H) and 3.74 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 199 (100), 168 (37), 140 (31), 127 (78), 112 (29), and 96 (25). High R e s o l u t i o n Mass Measurement C a l c d f o r C^H^NO^: 199.0845. Found: 199.0845. 2,4-Dimethyl-3-(4'-bromobutyl)isoxazolin-5-one (14Of) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.34 M s o l u t i o n i n hexane (1.30 mL« 1.74 mmole), 114 (200 mg; 1.57 mmole) and 1,3-dibromopropane (317 mg; 1.57 mmole). The r e s u l t i n g mixture was allowed to stand fo r 1 hour, then worked up to gi v e 140f as a yel l o w o i l . Pre-p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l using ether as s o l v e n t gave 60 mg (16%) of 140f as a c o l o u r l e s s o i l : Rf 0.40; bp (Kugelrohr d i s t i l l a t i o n ) 120-122°/0.25 t o r r ; IR 1728 and 1645 cm" 1; NMR 6 1.81 (s, 3H), .1.60-2.10 (m, 4H), 2.51 ( t , 2H, J = 7 Hz), 3.24 (s, 3H) and 3.46 ( t , 2H, J = 5 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 249 (37), 247 (36), 168 (100), 153 (82), 140 (44), 124 (40), 114-115 (m*, ^ y - = 114.3), 113-114 ( m*'T4ir = 1 1 3 - 4 ) ' 9 6 <57>' 5 5 < 5°)' a n d 5 3 ( 6 7 ) * High R e s o l u t i o n Mass Measurement C a l c d f o r CgH^NG^Br: 249.0187, 247.0208. Found: 249.0186, 247.0211. 138 2 ,4-Dime thy 1-3 -me thy l t r ipheny iphosphon iumisoxazolin-5-one bromide  (141) A 25-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and n i t r o g e n i n l e t was charged with t r i p h e n y l p h o s p h i n e (412 mg; 1.57 mmole) and dry t e t r a h y d r o f u r a n (10 mL). A s o l u -t i o n of the crude 140a i n t e t r a h y d r o f u r a n (3 mL) was added i n one p o r t i o n and then the r e a c t i o n mixture was allowed to r e f l u x f o r 3 hours. The r e s u l t i n g p r e c i p i t a t e was c o l l e c t e d , and washed with ether ( 3 x 5 mL) to g i v e 141 as a white powder. R e c r y s t a l -l i z a t i o n from ether-methanol gave 507 mg (69% o v e r a l l from 114) of 141 as s m a l l white c r y s t a l s : mp 245-246°; IR (KBr) 1735, 1635 and 1590 cm" 1; NMR ((CD 3) 2SO) <5 1.18 (d, 3H, J = 3 Hz), 3.00 (s, 3H), 5.40 (dd,2H, J = 16 Hz) and 7.66-7.97 (m, 15H). A n a l . C a l c d f o r C 2 4 H 2 3 N 0 2 P B r : C, 61.55, H, 4.95; N, 2.99. Found: C, 61.33; H, 5.00; N, 3.11. 2,4-D ime t h y i - 3 - ( 2 ' - p h e n y l e t h e n y l ) i s o x a z o l i n - 5 - o n e (135) A suspension of sodium hydride (31 mg; 0.64 mmole) in dry t e t r a h y d r o f u r a n (12 mL) was prepared i n a 25-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and a n i t r o g e n i n l e t . A s o l u t i o n of 141 (300 mg; 0.64 mmole) i n anhydrous d i m e t h y l s u l f o x i d e (3 mL) was then added dropwise and the s o l u -t i o n allowed to stand f o r 15 minutes. I n t r o d u c t i o n of benzalde-hyde (68 mg? 0.64 mmole), fo l l o w e d by h e a t i n g to r e f l u x 139 f o r 1.5 hours completed the r e a c t i o n . Workup and p u r i f i c a t i o n gave 79 mg (58%) of 135 as a c o l o u r l e s s o i l with i d e n t i c a l spec-t r a l p r o p e r t i e s as those r e p o r t e d e a r l i e r (pg. 131). 2,4-Dimethyl-3-(1'-heptenyl)isoxazolin-5-one (145) T h i s compound was prepared by the same procedure d e s c r i b e d for 135, u s i n g 141 (300 mg; 0.64 mmole), sodium hydride (31 mg; 0.64 mmole) and hexanal (64 mg; 0.64 mmole). The r e s u l t i n g mix-ture was r e f l u x e d f o r 4 hours, then worked up to give 145 as a y e l l o w s o l i d . P r e p a r a t i v e TLC of the crude m a t e r i a l on s i l i c a g e l u s i n g ether-petroleum ether (1:1) gave 86 mg (64%) of 145 as a pale yellow o i l : Rf 0.35; IR 1725, 1660, 1625 and 1615 cm - 1; NMR 6 1.20-1.60 (m, 9H), 1.86 (s, 3H), 2.1-2.4 (m, 2H), 3.17 (s, 3H) and 6.00-6.35 (m, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 209 (67), 166 (27), 153 (17) and 138 (100). High R e s o l u t i o n Mass Measurement C a l c d f o r C ^ 2 H i 9 N 0 2 : 209.1416. Found: 209.1413. 2,4-Dimethyl-3-(3'-hydroxybutyl)isoxazolin-5-one (154) T h i s compound was prepared a c c o r d i n g t o the g e n e r a l p r o -cedure f o r a l k y l a t i o n u s ing d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.09 M s o l u t i o n i n hexane (1.60 mL; 1.74 mmole), 114 (200 mg; 1.57 mmole) and propylene oxide (911 mg; 15.7 mmole). The r e s u l t i n g mixture was allowed t o stand f o r 3 140 hours, then worked up to g i v e 154 as a yel l o w o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l using ether as s o l v e n t gave 118 mg (41%) of 154 as a c o l o u r l e s s o i l : Rf 0.15; bp (Kugelrohr d i s t i l l a t i o n ) 107-110°/0.15 t o r r ; IR 3430, 1730 and 1635 cm - 1; NMR 5 1.40 (d, 3H, J = 6 Hz), 1.58-1.89 (m, 2H), 1.89 (s, 3H), 1.96 (bs, IH), 2.61 ( t , 2H, J = 7 Hz), 3.25 (s, 3H) and 3.75-3.94 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 185 (25), 158 (11), 142 (44), 112 (28) and 96 (100). High R e s o l u t i o n Mass Measurement C a l c d f o r C^H^NO^: 185.1051. Found: 185.1049. 2 , 4-Dime t h y l - 3 - (3 ' -hydroxypropyl) i s o x a z o l i n - 5 - o n e (lj>5_) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l k y l a t i o n u s i n g d i i s o p r o p y l a m i n e (176 mg; 1.74 mmole), n - b u t y l l i t h i u m as a 1.43 M s o l u t i o n i n hexane (1.22 mL#* 1.74 mmole), 114 (200 mg; 1.57 mmole) and eth y l e n e oxide (690 mg; 15.7 mmole). The r e s u l t i n g mixture was s t i r r e d f o r 2.5 hours, then worked up to g i v e 155 as a yellow o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l u s i n g e t h e r - e t h y l a c e t a t e (1:1) gave 81 mg (30%) of 155 as a c o l o u r l e s s o i l : Rf 0.40; IR 3450, 1725 and 1640 cm - 1; NMR 6 1.78 (s, 3H), 1.76-1.92 (m, 3H), 2.62 ( t , 2H, J = 7 Hz), 3.24 (s, 3H) and 3.70 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 171 (37), 127 (100), and 98 (25). High R e s o l u t i o n Mass Measurement Calcd f o r CgH^2 N 03 : 171.0895. Found: 171.0894. 141 Dihydro-2-methy1-3,4-tetramethyleneisoxazolin-5-one (164) A 100-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum was charged with a s o l u t i o n of 113 (1.53 g; 10.0 mmole) i n ether (50 mL). The f l a s k was c o o l e d to -23° i n a dry ice-ca r b o n t e t r a c h l o r i d e bath and d i i s o b u t y l a l u m i n u m hydride as a 1.0 M s o l u t i o n i n hexane (20.0 mL; 20.0 mmole) was added dropwise. The r e s u l t i n g mixture was s t i r r e d f o r 6 hours, then 5% h y d r o c h l o r i c a c i d (30 mL) was i n t r o d u c e d , and the s o l u t i o n was allowed to s t i r f o r an a d d i -t i o n a l hour. The o r g a n i c phase was separated, washed with water and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . The e t h e r e a l s o l u t i o n was co n c e n t r a t e d and the re s i d u e d i s t i l l e d to giv e 1.19 g (77%) of 164 as a c o l o u r l e s s o i l : bp (Kugelrohr d i s t i l l a t i o n ) 80-82°/0.15 t o r r ; IR 1730 and 1635 cm - 1; NMR 6 1.30-2.00 (m, 10H), 2.90 (m, IH), 2.75 (s, 3H), and 3.13 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 155 (35), 138 (14), 112 (100), 109 (21), 81 (51), 68 (35), and 67 (41). High R e s o l u t i o n Mass Measurement C a l c d f o r CgH-j^NC^: 155.0946. Found: 155.0941. 142 SECTION II LACTONE SYNTHESIS VIA B-KETO ESTER DIANION ALKYLATION INTRODUCTION The s y n t h e s i s of medium and l a r g e r i n g s or m a c r o c y c l i c l a c t o n e s has been an o b j e c t of i n t e r e s t to o r g a n i c chemists for over f i f t y y e a r s . T h i s i n t e r e s t stemmed from the d i s c o v e r y 97 by Kerschbaum of the presence of pentadecanolide ( e x a l t o l i d e ) (165) and A 7-hexadecanolide (ambrettolide) (166) i n the vege-t a b l e musk o i l s of a n g e l i c a r o o t and ambrette seed r e s p e c t i v e l y . ( C H 2 ) 8 . C=0 ( C H 2 ) 5 ^ 166 As a r e s u l t , there ensued vigorous e f f o r t s to uncover s y n t h e t i c routes to these and other r e l a t e d compounds, prompted not o n l y by the c h a l l e n g e o f p r e p a r i n g the novel m a c r o c y c l i c l a c -tones but a l s o by t h e i r importance i n the fragrance i n d u s t r y . S e v e r a l p r e p a r a t i v e techniques were developed to form these 143 l a r g e r i n g s , g e n e r a l l y i n v o l v i n g c y c l i z a t i o n of b i f u n c t i o n a l 98 p r e c u r s o r s under high d i l u t i o n c o n d i t i o n s The next major development in t h i s area occurred i n 1950 9 9 with the r e p o r t by Brockmann and Henkel of the i s o l a t i o n of the f i r s t m a c r o c y l i c a n t i b i o t i c , picromycin (167), from an Actinomyces c u l t u r e . Soon af t e r w a r d s , the i s o l a t i o n from 167 Streptomyces c u l t u r e s of s e v e r a l other a n t i b i o t i c s which appeared to be r e l a t e d i n s t r u c t u r e and a c t i v i t y to picromycin (167) was r e p o r t e d 1 0 0 . The e l e g a n t execution of c l a s s i c a l chemical degradations l e d to the e l u c i d a t i o n of the gross s t r u c t u r e s of methymycin ( 1 6 8 ) 1 0 1 , erythromycin A ( 1 6 9 ) 1 0 2 and B ( 1 7 0 ) 1 0 3 , and magnamycin A ( 1 7 1 ) 1 0 4 . The term 'macrolide' 144 mycaminosyl 145 was o r i g i n a l l y coined to r e p r e s e n t t h i s new c l a s s of a n t i b i -o t i c s 1 0 4 3 , which are c h a r a c t e r i z e d by a l a r g e lactone r i n g c o n t a i n i n g few double bonds, and one or more sugar r e s i d u e s . However, as the number of n a t u r a l l y o c c u r r i n g m a c r o c y c l i c com-pounds has i n c r e a s e d , the term 'macrolide' has g r a d u a l l y found use i n a broader context encompassing a l l n a t u r a l products with a l a r g e l a c t o n e r i n g . The i s o l a t i o n of these novel compounds and demonstration of t h e i r c l i n i c a l importance has r e s u l t e d i n tremendous i n t e r e s t i n the t o t a l s y n t h e s i s of m a c r o l i d e s . N e v e r t h e l e s s , e a r l y e f f o r t s were hampered by the need to d e v i s e new methods for the i n t r o d u c t i o n of c h i r a l c e n t e r s i n t o an a l i p h a t i c moiety and methods for the c o n s t r u c t i o n of l a r g e - s i z e d l a c t o n e s . S o l u t i o n s to both problems have been forthcoming i n the p a s t ten y e a r s , and t h i s has r e s u l t e d i n the t o t a l s y n t h e s i s of a number of macrolide a n t i b i o t i c s ^ 8 ' 1 0 5 . In p a r t i c u l a r , s e v e r a l approaches to the formation of l a r g e - s i z e d l a c t o n e s have been r e p o r t e d and these w i l l now be reviewed. A. S y n t h e s i s of m a c r o c y c l i c l a c t o n e s v i a ( j j-halocarboxylic  a c i d s T h i s approach provided the f i r s t , and one of the most d i r e c t , syntheses of simple m a c r o l i d e s such as e x a l t o l i d e 98 (165) and a m b r e t t o l i d e (166) . C y c l i z a t i o n of the c o r r e s -ponding w-bromo- or i o d o - a l k a n o i c a c i d s 172 c o u l d be e f f e c t e d 146 by h e a t i n g with s i l v e r oxide or by slow a d d i t i o n (e.g. 6.6 mmole/day/liter of s o l v e n t ) of the h a l o a c i d to a s o l v e n t con-t a i n i n g potassium carbonate or potassium hydroxide (equation 61). By t h i s method, 10 to 18-membered l a c t o n e s could be 122, X=Br or I 98 obtained i n f a i r to good y i e l d s The c y c l i z a t i o n of such open, long c h a i n p r e c u r s o r s r e p r e -sents the g u i d i n g p r i n c i p l e behind many of the newly developed methods for macrolide formation. While c o n c e p t u a l l y simple, however, two problems a r i s e d u r i n g the employment of such p r o -cedures. F i r s t , r i n g c l o s u r e of a long c h a i n p r e c u r s o r i s unfavourable on entropy grounds due to the l o s s of entropy a s s o c i a t e d with b r i n g i n g i t s two ends together. Secondly, i n t e r m o l e c u l a r r a t h e r than i n t r a m o l e c u l a r c y c l i z a t i o n o f t e n o c c u r s . Many of the new s y n t h e t i c methods for macrolide forma-t i o n p r o v i d e s o l u t i o n s to one or both of these problems. I 147 B. Sy n t h e s i s of m a c r o c y c l i c l a c t o n e s v i a co-hydroxycar b o x y l i c  a c i d s i) By d i r e c t e s t e r i f i c a t i o n The most d i r e c t route to m a c r o c y c l i c lactones, as repo r t e d by S t o l l and Rouve , i n v o l v e s the i n t r a m o l e c u l a r e s t e r i f i c a -t i o n of ( j j-hydroxyalkanoic a c i d s 173. In t h i s study the use of d i l u t e S o l u t i o n s (e.g. 0.0002-0.0008 M) and c a t a l y s t s such as benzenesulf on i c or jo-toluenesulf o n i c a c i d were found to be e s s e n t i a l (equation 62). 173. The s y n t h e s i s of l a c t o n e s with as many as twenty-four r i n g atoms has been r e p o r t e d , with y i e l d s ranging from c a. 1% f o r the case of nonanolide (174) to 87% f o r e x a l t o l i d e ( 1 6 5 ) 1 0 6 . 148 0 174 165 N e v e r t h e l e s s , t h i s procedure i s cumbersome and the product i s contaminated with dimers, t r i m e r s , and polymers. A r e c e n t v a r i -a t i o n has been r e p o r t e d by S c o t t and N a p l e s 1 ^ 7 , who have e f f e c t e d the d i r e c t l a c t o n i z a t i o n of o j-hydroxy a c i d s i n improved y i e l d s by u s i n g boron t r i f l u o r i d e e t h e r a t e i n the presence of u n f u n c t i o n a l i z e d p o l y s t y r e n e beads as c a t a l y s t . i i ) By t r a n s e s t e r i f i c a t i o n T h i s approach i n v o l v e s the p r e p a r a t i o n of m a c r o c y l i c l a c -tones by the i n t e r n a l t r a n s e s t e r i f i c a t i o n of oo-hydroxy e s t e r s 175 (equation 63). An e a r l y a d a p t a t i o n of t h i s procedure was (63) 175 149 re p o r t e d by H i l l and C a r o t h e r s x u o , who found t h a t p y r o l y s i s of l i n e a r p o l y e s t e r s 176 under vacuum at c a . 270°C, i n the p r e -sence of a c a t a l y s t , r e s u l t e d i n the d i s t i l l a t i o n of monomeric and d i m e r i c products obtained v i a e s t e r exchange (equation 64). 0 - f t — 0 0 —0 ft - 0 - =0 (64) 1Z£ P y r o l y s i s of l i n e a r p o l y e s t e r s of to-hydroxyalkanoic a c i d s 176 i n t h i s manner gave l a c t o n e s with 11 to 17-membered r i n g s i n y i e l d s ranging from a t r a c e (14-membered) to 90% (15-membered), 109 Subsequent work by S t o l l and B o l l e has shown that gas phase p y r o l y s i s of the e s t e r s 177 generates pentadecanolide (165) i n y i e l d s of c a . 50%. The authors have p o s t u l a t e d forma-t i o n and subsequent d e p o l y m e r i z a t i o n of p o l y e s t e r s on the cata-, _ . ... .. 108 l y s t s u r f a c e i n t h i s r e a c t i o n Ti0 2 or HC00-(CH 2 ) 1 7 C00R 7 J- > L 14 Z r 0 2 , A 17Za,R=H b,R=Me 16£ 150 Recent v a r i a t i o n s of these procedures have found a p p l i c a -t i o n in the s y n t h e s i s o f m a c r o c y c l i c musk lactones 1''' 0. How-ever, the use of t h i s method i n the s y n t h e s i s of complex macro-l i d e s appears to be preclude d by the high r e a c t i o n temperatures which c o u l d a l t e r many of the f u n c t i o n a l groups on the la c t o n e r i n g . The d i r e c t l a c t o n i z a t i o n of w-hydroxyesters i n s o l u t i o n using sodium a l k o x i d e s has a l s o been r e p o r t e d 1 1 1 . For example, the c y c l i z a t i o n of hydroxy methyl e s t e r 178 to the zearalenone p r e c u r s o r 179 has been accomplished i n low y i e l d by t r e a t i n g 178 with a d i l u t e toluene s o l u t i o n of sodium t-amylate i n t-amyl a l c o h o l 1 1 1 . The by-product methanol was c o n t i n u o u s l y removed by d i s t i l l a t i o n to d r i v e the r e a c t i o n to completion. 178 179 151 i i i ) By c a r b o x y l i c a c i d a c t i v a t i o n The d e s i r e t o p e r f o r m c y c l i z a t i o n s , such as t h a t o f 178 t o 179 i l l u s t r a t e d above, u s i n g l e s s f o r c i n g c o n d i t i o n s l e d t o the c o n s i d e r a t i o n o f methods t o a c t i v a t e the c a r b o x y l i c a c i d . In t h i s p r o c e d u r e , the i n t r a m o l e c u l a r a t t a c k o f the f r e e h y d r o x y l f u n c t i o n a l i t y on the newly a c t i v a t e d c a r b o x y l i c a c i d under s u i t -a b l e d i l u t i o n o c c u r s under r e l a t i v e l y m i l d c o n d i t i o n s . The l a c ton i z a t i o n o f o j-hydroxy a c i d s 173 has been a c h i e v e d , i n t h i s manner, by t h e i r r e a c t i o n w i t h p h o s g e n e - t r i e t h y l a m i n e or w i t h t r i f l u o r o a c e t i c a n h y d r i d e through the f o r m a t i o n o f mixed a n h y d r i d e s 180 ( e q u a t i o n 6 5 ) . For example, t r e a t m e n t of the hydroxy a c i d 181 w i t h t r i f l u o r o a c e t i c a n h y d r i d e , f o l l o w e d by boron t r i b r o m i d e t o c l e a v e the a.r.yl e t h e r s , gave z e a r a l e n o n e 112 (18 2) i n v a r y i n g y i e l d 152 MeO 181 1) (CF3CO)20 0 2) BBr 3 HO' )H 0' ;0 182 ;0 An a l t e r n a t e method f o r the a c t i v a t i o n of c a r b o x y l i c a c i d s i n v o l v e s t h e i r c o n v e r s i o n to N - a c y l i m i d a z o l i d e s 184 by t r e a t -113 ment with N fN'-carbonyldiimidazole (18 3) Re c e n t l y , Masamune 183 184 and coworkers have shown t h a t N - a c y l i m i d a z o l i d e s 184 may a l s o be prepared from phenyl or 2 , 2 , 2 - t r i f l u o r o e t h y l e s t e r s by t h e i r r e a c t i o n with N - t r i m e t h y l s i l y l i m i d a z o l e (185) i n the presence of 114 a c a t a l y t i c amount of sodium phenoxide (equation 66). 153 RCOOR' • T M S - N N C 6 H 5 QNa RCO-H' (66) 185 R= Aryl , alkyl or cycloalkyl R= C 6 H 5 or C F 3 C H 2 The c y c l i z a t i o n of a c y l i m i d a z o l i d e s 184 has been e f f e c t e d i n d i l u t e s o l u t i o n by t h e i r treatment with a c a t a l y t i c amount of base. For example, the r e a c t i o n of i m i d a z o l i d e 186 with a c a t a l y t i c amount of sodium t-amylate gave the t r i d e c a n o l i d e 1 8 7 1 1 5 . 1-AmONa r" ^ 0 — > • OCOCH3 0^0 18£ Carboxyl a c t i v a t i o n v i a i m i d a z o l i d e formation has a l s o been employed by C o l v i n e t a l . 1 1 6 i n t h e i r s y n t h e s i s of pyreno-phor i n (189). T h i s a n t i f u n g a l and c y t o s t a t i c d i l a c t o n e was 154 prepared by the c y c l i z a t i o n of i m i d a z o l i d e 188 with a c a t a l y t i c amount of 1, 5 - d i a z a b i c y c l o Q . 3 . <5] non-5-ene (DBN) i n d i l u t e s o l u t i o n , f o l l o w e d by h y d r o l y s i s of the d i t h i o k e t a l s . 1) DBN 2) NCS,AgN03 188 An analogous l a c t o n i z a t i o n of o j-hydroxy a c i d s has been accomplished by c a r b o x y l a c t i v a t i o n with 1-methy1-2-chloropyri-dinium i o d i d e (190) i n the presence of t r i e t h y l a m i n e (equation 67) 1 1 7 . T h i s r e a c t i o n proceeds v i a formation of the p y r i d i n i u m 192 155 intermediate 191, f o l l o w e d by n u c l e o p h i l i c attack of the h y d r o x y l f u n c t i o n to g i v e the l a c t o n e and the 2-pyridone 192. Lactones with up to s i x t e e n members have been prepared i n t h i s f a s h i o n i n r e f l u x i n g dichloromethane or a c e t o n i t r i l e . 118 R e c e n t l y , B a r t l e t t and Green have reported the use of t h i s procedure i n t h e i r s y n t h e s i s of b r e f e l d i n A (196). The slow a d d i t i o n of hydroxy a c i d 193 and t r i e t h y l a m i n e to a r e f l u x -ing s o l u t i o n of l - m e t h y l - 2 - c h l o r o p y r i d i n i u m t e t r a f l u o r o b o r a t e (194) i n 3:1 d i c h l o r o m e t h a n e - a c e t o n i t r i l e gave compound 19 5 in 37% y i e l d as a mixture of C-15 epimers. Reduction of the ketone f u n c t i o n with sodium borohydride, followed by h y d r o l y s i s of the methoxymethyl ether with t r i f l u o r o a c e t i c a c i d gave b r e f e l d i n A (196). H 196 156 iv) By h y d r o x y l a c t i v a t i o n A new s t r a t e g y f o r the r i n g c l o s u r e of to-hydroxy a c i d s has 119 been r e p o r t e d by K u r i h a r a e t a l . , wherein the h y d r o x y l f u n c t i o n i s a c t i v a t e d and the c a r b o x y l a t e anion a c t s as the n u c l e o p h i l e . In t h i s method, the r e a c t i o n of the hydroxy a c i d with t r i p h e n y l p h o s p h i n e and d i e t h y l a z o d i c a r b o x y l a t e a t room temperature e f f e c t s r i n g c l o s u r e v i a the alkoxyphosphonium c a r b o x y l a t e 197. T h i s procedure has been a p p l i e d by White and CCH 2OH COOH • EtOOC-N=N-COOEf (C 6 H 5 ) 3 P (^J=0+ R 3 P 0 " 197 C H 2 - 0 - P R 3 00"'' >(Et00C-NH-h coworkers i n t h e i r s y n t h e s i s of v e r m i c u l i n e (199) . C y c l i z a -t i o n of the hydroxy a c i d 198 with t r i p h e n y l p h o s p h i n e and d i e t h y l a z o d i c a r b o x y l a t e provided v e r m i c u l i n e (199) in 15% y i e l d . 157 HOOC 198 ( E t 0 0 C - N ^ 9 ^> 0: (C 6 H 5 ) 3 P 0' 199 A s i m i l a r approach has a l s o been r e p o r t e d i n the s y n t h e s i s 121 of pyrenophorin (189) by G e r l a c h e t a l . . In t h i s case, the hydroxy a c i d 200 was dim e r i z e d u s i n g t r i p h e n y l p h o s p h i n e and d i e t h y l a z o d i c a r b o x y l a t e . H y d r o l y s i s of the k e t a l p r o t e c t i n g groups then gave pyrenophorin (189). 1) (Et00C-N±o ° ° H (C 6 H 5 ) 3 P J 2) p_-TsOH Me 2C0 2QD. 158 v) By a c t i v a t i o n of both the c a r b o x y l and hy d r o x y l groups T h i s s t r a t e g y arose from the b e l i e f t h a t simultaneous a c t i v a t i o n of both the c a r b o x y l and hy d r o x y l groups would per-mit r a p i d c y c l i z a t i o n under even milder c o n d i t i o n s , thereby p r o v i d i n g access to complex, p o l y f u n c t i o n a l l a c t o n e s . Corey 122 and N i c o l a o u e n v i s i o n e d t h a t one way to e f f e c t such "double a c t i v a t i o n " would be to u t i l i z e an a p p r o p r i a t e c a r b o x y l i c a c i d d e r i v a t i v e which would favour proton t r a n s f e r from the hydroxyl group to the c a r b o x y l i c a c i d oxygen. T h i s idea i s i l l u s t r a t e d f o r the case of 2 - p y r i d i n e t h i o l e s t e r s 202 i n Scheme 9. The 201 202 M H 205 204 201 Scheme 9; Lactone formation v i a double a c t i v a t i o n u s i n g 2 - p y r i d i n e t h i o l e s t e r s . 159 key element - o f i t h i s scheme i n v o l v e s the p a r t i c i p a t i o n o f the b a s i c n i t r o g e n of the p y r i d i n e nucleus i n the proton t r a n s f e r from the hydroxyl group to c a r b o n y l oxygen in 202. C y c l i z a -t i o n of the d i p o l a r i n t e r m e d i a t e 203 to 204 i s f a c i l i t a t e d by an e l e c t r o s t a t i c a t t r a c t i o n , and p r o v i d e s the d e s i r e d l a c t o n e with concomitant e l i m i n a t i o n of 2 - p y r i d t h i o n e 205. The use of high d i l u t i o n techniques i s c l e a r l y a requirement, s i n c e a comparable path may a l s o be f e a s i b l e with two molecules of 202 r e a c t i n g i n t e r m o l e c u l a r l y . A c c o r d i n g l y , the 2 - p y r i d i n e t h i o l e s t e r s 202 were prepared 123 by the method developed by Mukaiyama , employing d i ( 2 - p y r i d y l ) d i s u l f i d e (201) i n the presence of t r i p h e n y l p h o s p h i n e . The r e s u l t i n g t h i o l e s t e r s were then heated i n xylene under high d i l u t i o n c o n d i t i o n s and gave the c o r r e s p o n d i n g l a c t o n e s 207 i n f a i r t o good y i e l d together with v a r y i n g amounts of macro-c y c l i c d i l a c t o n e s 208 (Table X). 206 207 208 In a subsequent study , evidence f o r the "double a c t i v a -t i o n " mechanism proposed i n Scheme 9 was o b t a i n e d . Thus, the 160 Table X. C y c l i z a t i o n of 2 - P y r i d i n e t h i o l E s t e r s of w-Hydroxy-c a r b o x y l i c A c i d s 1 2 5 •OH 1)(C 6H 5) 3P 1 ( C H ^ O O H 2 ) X y l e n e t L X^J (fjl / - ^ o ^cocv 206 2GZ 00C 208 n S o l v e n t 207 208 I s o l a t e d - I s o l a t e d Y i e l d (%) Y i e l d (%) 5 benzene 71 7 7 xylene 8 41 10 xylene 47 30 11 xylene 66 7 12 xylene 68 6 14 xylene 80 5 161 r a t e of c y c l i z a t i o n of 16-hydroxyhexadecanoic a c i d t h i o l e s t e r 209a to hexadecanolide (210) i n r e f l u x i n g benzene was not found to be i n f l u e n c e d by the a d d i t i o n of t r i p h e n y l p h o s p h i n e , t r i p h e n y l p h o s p h i n e o x i d e , t r i e t h y l a m i n e , triamylamine, 2 - p y r i d -thione or a c e t i c a c i d . These r e s u l t s i n d i c a t e d t h a t the c y c l i -z a t i o n was not c a t a l y z e d by a c i d , base, or any of the con-taminants p r e s e n t in the r e a c t i o n mixture. Furthermore, the H O ( C H 2 ) 1 5 C O S - ^ N (CH 2) 1 5 C=0 209a t h i o l e s t e r s 2fJ9b.and 209c.which cannot form hydrogen bonded i n t e r m e d i a t e s were found n o t t o c y c l i z e on h e a t i n g . HO(CH 2) 1 5COS HO(CH2)15COS 209b 209c The u t i l i t y o f 2 - p y r i d i n e t h i o l e s t e r s i n the s y n t h e s i s o f m a c r o c y c l i c l a c t o n e s has been demonstrated by Corey and coworkers who, i n r e c e n t y e a r s , have succeeded i n the synthe-,105b,127 s i s of s e v e r a l complex macrolides" For example, i n 162 the s y n t h e s i s of z e a r a l e n o n e (182), the key l a c t o n i z a t i o n was ac c o m p l i s h e d by f i r s t t r e a t i n g t h e hydroxy a c i d 211 w i t h d i ( 2 - p y r i d y l ) d i s u l f i d e i n the p r e s ence o f t r i p h e n y l p h o s p h i n e , then h e a t i n g the r e s u l t i n g t h i o l e s t e r i n d i l u t e benzene. H y d r o l y s i s o f the k e t a l and t e t r a h y d r o p y r a n y l e t h e r p r o t e c t i n g 122 groups gave z e a r a l e n o n e (18 2) i n 75% y i e l d o v e r a l l In an e f f o r t t o maximize the e f f i c i e n c y of c y c l i z a t i o n by the double a c t i v a t i o n method, the use o f a number o f o t h e r 126 h e t e r o c y c l i c d i s u l f i d e s was a l s o i n v e s t i g a t e d . D i s u l f i d e s 212-214 were found t o be l e s s e f f e c t i v e i n promoting c y c l i z a t i o n than the d i - 2 - p y r i d y l d e r i v a t i v e . On the o t h e r hand, use of 212a;X=NMe,R = H 213 2K b ;X=0 , R = H C ; X = S , R=H d ; X = S , R=N0 2 163 the i m i d a z o l y l d i s u l f i d e 215 was shown t o e x h i b i t e x c e p t i o n a l p r o m i s e , s i n c e l a c t o n i z a t i o n e m ploying t h i s r e a g e n t c o u l d be e f f e c t e d v e r y r a p i d l y even a t room t e m p e r a t u r e . For example, when 215, t r i p h e n y l p h o s p h i n e , and 16-hydroxyhexadecanoic a c i d were a l l o w e d t o r e a c t i n benzene s o l u t i o n , the f o r m a t i o n of h e x a d e c a n o l i d e (210) c o u l d be d e t e c t e d by VPC a n a l y s i s a f t e r 12 6 o n l y ten m i n u t e s , i n y i e l d s o f 20-37% ( e q u a t i o n 68) However, subsequent t o t h i s p e r i o d no f u r t h e r l a c t o n e f o r m a t i o n o c c u r r e d e i t h e r upon p r o l o n g e d exposure or h e a t i n g . These low y i e l d s were l a t e r found t o be due t o c o m p e t i t i v e f o r m a t i o n o f N - a c y l d e r i v a t i v e 216 a t the expense o f the r e q u i r e d S - a c y l d e r i v a t i v e 217, and t h i s r e s u l t s uggested the use o f a sub-s t i t u t e d i m i d a z o l e r i n g which would h i n d e r f o r m a t i o n of 216. (68) 215 I \ COR 216 211 164 Indeed, the d i s u l f i d e s 218 and 219, i n which a t - b u t y l group i s s t r a t e g i c a l l y p l a c e d to suppress N - a c y l a t i o n , were found to be s u p e r i o r to a l l reagents f o r the formation of simple l a c t o n e s from u)-hydroxy a c i d s . For example, the c y c l i z a t i o n of 16-hydroxyhexadecanoic a c i d to hexadecanolide (210), c f . equation 126 68, was accomplished i n 96% y i e l d by t h i s method 218 219 R e c e n t l y , Corey and coworkers have r e p o r t e d the a p p l i c a t i o n 127 of t h i s procedure i n the s y n t h e s i s of e r y t h r o n o l i d e A (220) 128 and B (221) . The key l a c t o n i z a t i o n step was performed using the c o r r e s p o n d i n g hydroxy a c i d s , d i s u l f i d e 219 and t r i p h e n y l -phosphine, by h e a t i n g i n a d i l u t e toluene s o l u t i o n and gave the m a c r o c y c l i c l a c t o n e s i n 30 and 50% y i e l d r e s p e c t i v e l y . 0 0 H o Y [ O H 165 A m o d i f i c a t i o n of the Corey double a c t i v a t i o n method i s 129 due to G e r l a c h and Thalmann , who found that s i l v e r ion (AgC10 4 or AgBF^) a c t i v a t e s 2 - p y r i d i n e t h i o l e s t e r s by complexa-t i o n as shown in 222. The a c t i v a t e d w-hydroxyalkanoic a c i d s 222 undergo f a c i l e c y c l i z a t i o n at room temperature i n benzene s o l u t i o n . T h i s m o d i f i c a t i o n has found a p p l i c a t i o n s i n the 130 s y n t h e s i s of a number of m a c r o c y c l i c l a c t o n e s . For example, in the s y n t h e s i s of the p l a n t growth i n h i b i t o r l a s i o d i p l o d i n (224), c y c l i z a t i o n of the hydroxy t h i o l e s t e r 223 was accom-p l i s h e d u s i n g s i l v e r p e r c h l o r a t e i n a d i l u t e a c e t o n i t r i l e s o l u -t i o n . H y d r o g e n o l y s i s of the b e n z y l ether gave l a s i o d i p l o d i n (224) i n g r e a t e r than 50% y i e l d o v e r a l l 1 3 0 0 . 222a 222b OMe OH OMe 0 C 6 H 5 C H 2 0 C H 3 C N , A > 2)H 2 ,Pd-C 1)AgCl0A HO 221 22k 166 A s i m i l a r approach has a l s o been r e p o r t e d by Masamune and 131 coworkers , i n v o l v i n g t - b u t y l t h i o l and b e n z e n e t h i o l e s t e r s of w-hydroxy a c i d s , and mercuric t r i f l u o r o a c e t a t e or methane-s u l f o n a t e as c a t a l y s t s . The t h i o l e s t e r s 228 c o u l d be p r e -pared from the c o r r e s p o n d i n g a c i d c h l o r i d e s by r e a c t i o n with t h a l l o u s t h i o l a t e s 2 2 5 1 3 1 a ' b or by treatment with d i e t h y l phos-phor o c h l o r i d a t e (226), f o l l o w e d by r e a c t i o n with the t h i o l a t e s a l t 225 (equation 6 9 ) 1 3 2 . A l t e r n a t i v e l y , the t h i o l e s t e r s 228 c o u l d be prepared v i a t h i o l y s i s of the corresponding a c y l i m i d a z o l e s 227 (equation 7 0 ) 1 1 3 ' 1 3 1 c . C y c l i z a t i o n of the > RCOCl RCOOH / RCOSR (69) , 228 (EtO)2POCl 226 > RC00P0(0Et)2 RSTl 22£ RSH ^ RCOSR (70) RCOOH ^ RCO.-N \ = l 227 228 r e s u l t i n g t h i o l under very m i l d e s t e r s with cond i t i o n s . mercury s a l t s f u r n i s h e d l a c t o n e s Subsequent s t u d i e s have r e v e a l e d 167 the m e t a l - c a t a l y z e d l a c t o n i z a t i o n p r oceeds p r i m a r i l y through c o o r d i n a t i o n of the a l c o h o l and the s u l f u r t o the m e t a l (equa-The u t i l i t y o f t h i s t e c h n i q u e has been demonstrated i n the 131 s y n t h e s i s o f methymycin (173) by Masamune and cowor k e r s The key c y c l i z a t i o n s t e p was e f f e c t e d by exposure o f the hydroxy t h i o l e s t e r 229 t o m e r c u r i c t r i f l u o r o a c e t a t e i n a c e t o n i t r i l e and gave, a f t e r removal o f the t - b u t y l d i m e t h y l s i l y l p r o t e c t i n g group, m e t h y n o l i d e (173, R=H) i n 20-30% y i e l d . t i o n 71) 131b (71) 0 0 H C H 3 C N 1Z1 168 A p o s s i b l e disadvantage to t h i s procedure l i e s i n the e T e c t r o p h i l i c i t y of mercury (II) toward r e a c t i v e alkenes. How-ever, i n most cases the r e a c t i v i t y of mercury (II) toward s u l f u r exceeds i t s r e a c t i v i t y toward o r d i n a r y or e l e c t r o n d e f i c i e n t double bonds, and o n l y i n the attempted c y c l i z a t i o n of cytochalasan-B s e c o - a c i d 230 was t h i s problem found to be d e t r i m e n t a l to a s u c c e s s f u l l a c t o n i z a t i o n . N e v e r t h e l e s s , t r e a t i n g the t h i o l e s t e r 230 with s i l v e r t r i f l u o r o a c e t a t e , a c c o r d i n g to the procedure of G e r l a c h d e s c r i b e d e a r l i e r , gave c y t o c h a l a s i n - B (2^ ) as d e s i r e d 1 0 5 a . v i ) By cleavage of carbon-carbon double bonds The concept of c l e a v i n g b i c y c l i c compounds to c r e a t e l a r g e r i n g s has been a p p l i e d with some success to the s y n t h e s i s of simple m a c r o c y c l i c l a c t o n e s . In t h i s r e s p e c t , the o x i d a t i v e cleavage of b i c y c l i c e n o l e t h e r s with the double bond at the r i n g f u s i o n has proven to be very v a l u a b l e , s i n c e t h i s r e a c t i o n 169 generates a l a r g e r i n g and a l a c t o n e f u n c t i o n a l i t y i n a s i n g l e step (equation 72). These o x i d a t i o n s may be performed using (CH2)n 2'm [0] 0 ( 7 2 ) 0 m-chloroperbenzoic a c i d , chromic a c i d , hydrogen peroxide or 133 ozone T h i s procedure has been a p p l i e d i n the s y n t h e s i s of a number of medium and l a r g e r i n g keto l a c t o n e s . For example, o x i d a t i o n o f 231 with m-chloroperbenzoic a c i d gave the keto l a c -134 tone 232 i n s a t i s f a c t o r y y i e l d . R e c e n t l y , Wakamatsu e t mCPBA C H 2 C l 2 231 232 a l . have d e s c r i b e d the s y n t h e s i s of d i p l o d i a l i d e C (235) by a s l i g h t m o d i f i c a t i o n of t h i s r o u t e . Lead t e t r a a c e t a t e o x i d a t i o n of the b i c y c l i c d i o l 233 gave the keto l a c t o n e 234 170 i n n e a r l y q u a n t i t a t i v e y i e l d , which was then converted i n t o d i p l o d i a l i d e C (235) by a s e r i e s of s t e p s . v i i ) By i n t r a m o l e c u l a r carbon-carbon bond formation The p r e p a r a t i o n of m a c r o c y c l i c l a c t o n e s by i n t r a m o l e c u l a r carbon-carbon bond formation has r e c e n t l y commanded a gr e a t d e a l of a t t e n t i o n . T h i s i n t e r e s t has p a r t i a l l y a r i s e n out of recog-n i t i o n of the many methods a v a i l a b l e to e f f e c t such bond forma-t i o n s . More important, however, was the r e a l i z a t i o n t h a t the p r e p a r a t i o n of l a c t o n e s v i a carbon-carbon bond formation p o t e n t i a l l y o f f e r s a g r e a t e r degree of f l e x i b i l i t y i n s y n t h e t i c design than c o n v e n t i o n a l l a c t o n i z a t i o n r o u t e s . For example, a convergent scheme may be employed i n which the a l c o h o l and a c i d p o r t i o n s are s y n t h e s i z e d independently, p r i o r to e s t e r i f i c a t i o n and f i n a l r i n g c l o s u r e . A c c o r d i n g l y , a number of procedures have been developed and these w i l l now be reviewed. 171 The f i r s t approach i n v o l v e s the i n t r a m o l e c u l a r a l k y l a t i o n of an a c t i v a t e d p h e n y l t h i o compound. T h i s procedure has been 136-138 used by T s u j i and coworkers i n the s y n t h e s i s of a number of simple m a c r o c y c l i c l a c t o n e s . For example, i n the s y n t h e s i s of r e c i f e i o l i d e (237) the key r i n g c l o s u r e was accomplished by slow a d d i t i o n of the p h e n y l t h i o i o d i d e 236 to a s o l u t i o n of potassium b i s ( t r i m e t h y l s i l y l ) a m i d e i n t e t r a h y d r o f u r a n . Raney n i c k e l r e d u c t i o n of the p h e n y l t h i o group gave r e c i f e i o l i d e (237) 136 in 60% y i e l d o v e r a l l 1) KN(TMS)2 THF 5 SC5H5 2) Ra-Ni 236 0 ^ 0 221 A c o n c e p t u a l l y s i m i l a r approach has been d e s c r i b e d by 137 • T r o s t and Verhoeven . In t h i s study, the i n t r a m o l e c u l a r r e a c t i o n of s t a b i l i z e d anions with a l l y l i c a c e t a t e s c a t a l y z e d by palladium(0) complexes was found to give medium- and large-s i z e d l a c t o n e s under mild c o n d i t i o n s and i n good y i e l d s (equa-t i o n 73). M e c h a n i s t i c a l l y , the r e a c t i o n i s b e l i e v e d to proceed 172 o=c PdLA 9> 0= E = Electron withdrawing group L = Neutral ligand e.g. (C 6H 5) 3P (73) v i a an i n i t i a l d i s s o c i a t i o n o f the p a l l a d i u m ( 0 ) c a t a l y s t , f o l l o w e d by f o r m a t i o n o f an a l l y l - p a l l a d i u m IT-complex 238 . C y c l i z a t i o n o f t h i s a c t i v a t e d i n t e r m e d i a t e p r o v i d e s a n - o l e f i n complex 239, which s u b s e q u e n t l y d i s s o c i a t e s t o g i v e the l a c t o n e and r e g e n e r a t e d c a t a l y s t (Scheme 1 0 ) 1 3 9 b . W h i l e c y c l i z a t i o n o f PdL Pdl_2 * 2L Pdl_2 OAc 238 PdL Scheme 10 239 Mechanism proposed f o r p a l l a d i u m - c a t a l y z e d c y c l i z a -t i o n s l 3 9 b . 173 238 may t h e o r e t i c a l l y be e f f e c t e d at the p o s i t i o n s denoted as a and b i n 238 , e x c l u s i v e carbon-carbon bond formation at p o s i t i o n a was found in a l l cases. T h i s i s p a r t i c u l a r l y noteworthy i n the case of e x c l u s i v e eight-membered r i n g f o r m a t i o n , s i n c e forma-t i o n of a six-membered r i n g i s u s u a l l y h i g h l y favoured. The source of t h i s r e g i o s e l e c t i v i t y i n these c y c l i z a t i o n s i s not w e l l understood. The a p p l i c a t i o n of t h i s procedure to the s y n t h e s i s of example, in the s y n t h e s i s of r e c i f e i o l i d e (237) , the key r i n g forming r e a c t i o n was performed by t r e a t i n g the a l l y l i c acetate 240 with sodium h y d r i d e , then s l o w l y adding the r e s u l t i n g anion to a c a t a l y t i c amount of t e t r a k i s ( t r i p h e n y l p h o s p h i n e ) p a l l a d i u m -(0) i n r e f l u x i n g t e t r a h y d r o f u r a n . E s t e r h y d r o l y s i s , decar-b o x y l a t i o n , and subsequent sodium amalgam r e d u c t i o n of the s u l -140 fone gave r e c i f e i o l i d e (237) i n 63% y i e l d o v e r a l l s e v e r a l m a c r o c y c l i c l a c t o n e s has a l s o been r e p o r t e d 139b For MeOOC AcO 0 ((C 6H 5) 3P) / tPd^ 2) Me^N* OAc" 3) Na/Hg 1) NaH, THF 0 240 237 174 An a l t e r n a t e method f o r l a c t o n e s i n v o l v e s the use of t i o n 1 4 1 (equation 74). T h i s the c o n s t r u c t i o n of m a c r o c y c l i c an i n t r a m o l e c u l a r W i t t i g r e a c -approach has r e c e n t l y been 0 " — C H O Base / ° ^ ~ > H 0-d _ b o s e ^ 0 = C SH (74) PO(OR)- Solvent \ ^ y\\ demonstrated by the groups of S t o r k 1 4 z and Nicolaou""" 4 J i n the s y n t h e s i s of 13 to 18-membered l a c t o n e s i n y i e l d s of 45-70%. For example, treatment of the aldehydophosphonate 241 with sodium hydride i n dimethoxyethane under high d i l u t i o n c o n d i -] 42 t i o n s gave 242 i n 70% y i e l d . 175 C. The p r e s e n t approach The a v a i l a b i l i t y of new methods f o r the c o n s t r u c t i o n of l a r g e r i n g l a c t o n e s has r e s u l t e d i n the s u c c e s s f u l s y n t h e s i s of a number of n a t u r a l m a c r o c y c l i c l a c t o n e s . Most of the surveyed procedures, however, s u f f e r from a v a r i e t y of d i s a d -vantages which prevent t h e i r g e n e r a l use. These problems are most commonly low y i e l d s , dimer f o r m a t i o n , and requirements f o r high temperatures, r e a c t i v e reagents or c a t a l y s t s , and par-t i c u l a r l y high d i l u t i o n c o n d i t i o n s . The search f o r procedures which might circumvent these d i f f i c u l t i e s , t h e r e f o r e , remains at the f o r e f r o n t o f o r g a n i c s y n t h e s i s . For a number of y e a r s , our l a b o r a t o r y has e x p l o r e d the p o s s i b i l i t y t h a t l a r g e r i n g s may be c o n v e n i e n t l y prepared u s i n g 3-keto e s t e r d i a n i o n c h e m i s t r y . E a r l y e f f o r t s had shown that a l k y l a t i o n of the d i a n i o n 2_7 of methyl a c e t o a c e t a t e with l , n -dibromoalkanes g i v e s a mixture of the bromide 243 and b i s a l k y -l a t e d product 244, with no evidence f o r any c y c l i c product (except n=3). N e v e r t h e l e s s , the c y c l i z a t i o n of bromides 243 (CH 2 ) n (CH 2 k 27 m 2hk 176 (n=4 or 5) c o u l d be e f f e c t e d by t r e a t m e n t w i t h one e q u i v a l e n t of sodium methoxide i n methanol a t r e f l u x ( e q u a t i o n 7 5 ) . 0 0 0 0 OMe NaOMe (CH2)n I Br MeOH,A A ^ N T ^ O M e 241 C y c l i z a t i o n o f the d i a n i o n o f 243 (n=4 or 5) was a l s o attempted and t h i s r e s u l t e d i n the f o r m a t i o n o f c y c l i c B - k e t o e s t e r s 245. 0 0 0 0 (CH 2) n I Br OMe 1)NaH,THF (CH2)n 2) LDA > V 2A1 2A5. The e x t e n s i o n o f these methods t o the p r e p a r a t i o n o f l a r g e 144 r i n g s , however, proved t o be f u t i l e R e c e n t l y , Yonemitsu and coworkers have r e p o r t e d a v e r -145 s a t i l e new method f o r the p r e p a r a t i o n o f B - k e t o e s t e r s T h i s p r o c e s s i n v o l v e s the a c y l a t i o n o f Meldrum's a c i d 177 ( 2 4 6 ) X 4 P , 2 , 2 - d i m e t h y l - 1 , 3 - d i o x a n e - 4 , 6 - d i o n e , w i t h a c i d c h l o r i d e s t o i n i t i a l l y p r o v i d e the a c y l Meldrums' a c i d s 247. A l c o h o l y s i s of these d e r i v a t i v e s then a f f o r d s B - k e t o e s t e r s , acetone and carbon d i o x i d e through n u c l e o p h i l i c a t t a c k on the e s t e r c a r -145 b o n y l group ( e q u a t i o n 76) A number of B - k e t o e s t e r s were p r e p a r e d i n t h i s s t u d y i n y i e l d s r a n g i n g from 69-92% and the u t i l i t y o f t h i s method has a l s o been demonstrated i n i t s a p p l i -c a t i o n i n n a t u r a l p r o d u c t s y n t h e s i s 1 4 7 ' 1 4 ^ . Our i n t e r e s t i n t h i s p r o c e s s was s t i m u l a t e d by the r e a l i -z a t i o n t h a t a l c o h o l y s i s o f the a c y l Meldrum's a c i d 247 w i t h a l , n - h y d r o x y h a l i d e 248 would p r o v i d e a B - k e t o e s t e r h a l i d e 249 i d e a l l y s u i t e d f o r r i n g c l o s u r e v i a the d i a n i o n method (Scheme 11 ) . 178 Scheme 11; Proposed plan for m a c r o c y c l i c 8-keto l a c t o n e f o r m a t i o n . T h i s s t r a t e g y f o r m a c r o c y c l i c l a c t o n e formation would be a t t r a c t i v e f o r s e v e r a l reasons. F i r s t , the p r e p a r a t i o n of the a l c o h o l and a c y l Meldrum's a c i d p o r t i o n s independently would allow a convergent approach to the s y n t h e s i s of a m a c r o c y c l i c l a c t o n e . Secondly, while the i n t e r m o l e c u l a r a l k y l a t i o n of 6-keto e s t e r d i a n i o n s g e n e r a l l y occurs r a p i d l y , the i n t r a m o l e -c u l a r e q u i v a l e n t under a p p r o p r i a t e c o n d i t i o n s may be even f a s t e r thereby circumventing the need f o r high d i l u t i o n c o n d i -t i o n s . T h i r d l y , the presence of a 6-keto e s t e r moiety in the c y c l i z e d product would permit f u r t h e r e l a b o r a t i o n of the macro-c y c l i c l a c t o n e r i n g . 179 The aim of t h i s study was to examine the f e a s i b i l i t y of f i r s t p r e p a r i n g B-keto e s t e r h a l i d e s 249 using the chemistry 14 5 developed by Yonemitsu and coworkers , then c y c l i z i n g these compounds to medium- and l a r g e - r i n g B-keto l a c t o n e s using B-keto e s t e r d i a n i o n c h e m i s t r y . An i n v e s t i g a t i o n of the e f f e c t s of r e a c t i o n c o n d i t i o n s and l e a v i n g groups on these c y c l i z a t i o n s would be conducted with a view towards e s t a b l i s h i n g the scope and l i m i t a t i o n s of t h i s p r o c e s s . F i n a l l y , the a p p l i c a t i o n of t h i s procedure to the s y n t h e s i s of simple m a c r o c y c l i c B-keto l a c t o n e s was to be s t u d i e d . 180 RESULTS AND DISCUSSION A c c o r d i n g l y , our i n v e s t i g a t i o n began with the s y n t h e s i s of Meldtum's a c i d (246) , 2,2-dimethyl-l,3-dioxane-4,6-dione, by 14 6 the procedure o r i g i n a l l y d e s c r i b e d by Meldrum i n 1908. Treatment of malonic a c i d (250) with a c e t i c anhydride, acetone and s u l f u r i c a c i d i n the c o l d gave 246 i n 58% y i e l d . The C H 2 ( C O O H ) 2 • Me2C0 A f f > " " " Q ^ 0 250 246 s t r u c t u r e of 246 was e v i d e n t from i t s NMR spectrum which showed a two-proton s i n g l e t at <S 3.57 and a s i x - p r o t o n s i n g l e t at 6 1.78, while i t s i n f r a r e d spectrum d i s p l a y e d a s t r o n g C=0 s t r e t c h i n g v i b r a t i o n a t 1755 cm 1 . Furthermore, the mass spec-trum of the product e x h i b i t e d a parent ion at 144 m/e and a st r o n g peak a t 100 m/e due to the l o s s of carbon d i o x i d e . I t i s i n t e r e s t i n g to note t h a t the o r i g i n a l s t r u c t u r e 146 proposed by Meldrum was a c t u a l l y t h a t of 3 - l a c t o n i c a c i d 251. T h i s view was based on the o b s e r v a t i o n t h a t t i t r a t i o n experiments i n d i c a t e d t h a t the product was a monobasic a c i d , and hence Meldrum concluded t h a t one of the c a r b o x y l groups of malonic a c i d must remain i n t a c t . T h i s s t r u c t u r a l assignment 181 •COOH A 0 251 remained i n the l i t e r a t u r e f o r over f o r t y y e a r s , before Davidson and Bernhard demonstrated t h a t the product has s t r u c -149 ture 246 . The strong a c i d i t y e x h i b i t e d by Meldrum's a c i d (246), pK 5.1, may be a t t r i b u t e d to the str o n g resonance a s t a b i l i z a t i o n a s s o c i a t e d with the planar 1,3-dioxane-4,6-dione r i n g 252. a c e t y l Meldrum's a c i d 253 i n 85% y i e l d . The formation of 253 0 2 5 2 Meldrum's a c i d (246) was a c y l a t e d with a c e t y l c h l o r i d e 14 5 and two e q u i v a l e n t s of p y r i d i n e i n dichloromethane to give 182 M e . .OH 0. •0 1) 2Pyridine .0 C H 2 C l 2 2) MeCOCl 246 253 was c l e a r from the NMR spectrum of the product which showed a s i x - p r o t o n s i n g l e t a t 6 1.75, a three-proton s i n g l e t a t 6 2.67, and a one-proton s i n g l e t a t 6 15.0. The product was f u r t h e r c h a r a c t e r i z e d by i t s i n f r a r e d spectrum, which d i s p l a y e d absorp-t i o n s a t 1740 c m - 1 (C=0 s t r e t c h ) and 1665 c m - 1 (C=C s t r e t c h ) , and elemental a n a l y s i s , which was c o n s i s t e n t with the proposed f o r m u l a t i o n . The f e a s i b i l i t y of p r e p a r i n g 8-keto e s t e r h a l i d e s 255 through a l c o h o l y s i s of a c e t y l Meldrum's a c i d 253 was next 145 examined. Employing a m o d i f i c a t i o n of Yonemitsu's procedure , i t was found that t r e a t i n g 1.2 e q u i v a l e n t s of 253 with one e q u i v a l e n t of a h a l o a l c o h o l 254 i n t e t r a h y d r o f u r a n at r e f l u x gave the d e s i r e d B-keto e s t e r h a l i d e s 255 i n very good y i e l d . The r e s u l t s of t h i s p r e l i m i n a r y study are summarized in Table XI. The f a c i l e p r e p a r a t i o n of B-keto e s t e r c h l o r i d e 255d i s 183 Table XI. P r e l i m i n a r y Study of the P r e p a r a t i o n of B-Keto E s t e r H a l i d e s Compound I d e n t i f i c a t i o n n 254 R X Y i e l d 255* a 2 H Br 68 b 3 H Br 80 c 4 H C l 1 5 0 79 d 5 CH 3 c i 1 5 1 85 Y i e l d s of 255 r e f e r to y i e l d s of d i s t i l l e d 1 184 -OH 0* ;0 2 5 2 254 / R \ ) H 0 0 T H F A X C C H ^ " 255. *R e s p e c i a l l y noteworthy s i n c e i t p r o v i d e s an e x c e l l e n t intermedi-135 ate f o r the s y n t h e s i s of (±)-diplodialide C (235) , v i a c y c l i z a t i o n and subsequent r e d u c t i o n of the ketone f u n c t i o n -a l i t y . 0 0 255d 1) 2Base 2) [ H - ] The r e a c t i o n of 253 with 4 - c h l o r o - l - b u t a n o l (254c) 150 was t y p i c a l of these a l c o h o l y s i s r e a c t i o n s , i n that i t gave a s i n g l e d i s t i l l a b l e p roduct. T h i s product was found to be homogeneous by TLC a n a l y s i s and elemental a n a l y s i s of the d i s t i l l e d mate-r i a l was i n f u l l agreement with the proposed formula. Further evidence for: the s t r u c t u r e 255c was provided by the i n f r a r e d spectrum of the product which showed ab s o r p t i o n s at 1745 and 1720 cm 1 , t y p i c a l of a B-keto e s t e r , and i t s NMR spectrum which e x h i b i t e d a three-proton s i n g l e t at 6 2.26 (CH^CO), a two-proton s i n g l e t at 6 3.43 (COCH^COO), and two-proton t r i p l e t s at 6 3.50 (CH 2C1) and 6 4.13 (COOCH_2) . The c y c l i z a t i o n of these B-keto e s t e r h a l i d e s v i a d i a n i o n formation was next s t u d i e d . The a d d i t i o n of B-keto e s t e r bromide 255b to a s o l u t i o n of two e q u i v a l e n t s of l i t h i u m d i i s o -propylamide i n t e t r a h y d r o f u r a n gave a s i n g l e product by TLC a n a l y s i s . T h i s product was c h a r a c t e r i z e d by i t s i n f r a r e d spec-trum which showed the t y p i c a l B-keto e s t e r a b s o r p t i o n s at 1742 and 1715 cm 1 as w e l l as an ab s o r p t i o n at 1650 cm 1 due to a C=C s t r e t c h i n g v i b r a t i o n . In a d d i t i o n , the NMR spectrum of the product d i s p l a y e d resonances a t 6 1.24 (s, 3H), 3.45 (s, 2H) , and 5.00-6.17 (m, 3H). On the b a s i s of t h i s s p e c t r a l data and f u r t h e r evidence s u p p l i e d by mass spectroscopy and elemental a n a l y s i s , the s t r u c t u r e of the product was assigned as the o l e f i n i c B-keto e s t e r 257. T h i s was subsequently confirmed by an independent s y n t h e s i s u s i n g a c e t y l Meldrum's a c i d 253 and 2 - p r o p e n - l - o l (256) (equation 77). 186 The f o r m a l l y analogous r e a c t i o n of B-keto e s t e r c h l o r i d e s 255c and 255d with two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n , however, gave o n l y unreacted s t a r t i n g m a t e r i a l even upon prolonged exposure. C o n f i r m a t i o n of d i a n i o n formation was obtained by the a d d i t i o n of one e q u i v a l e n t of methyl i o d i d e to a s o l u t i o n of the d i a n i o n of 255c, which gave the y - a l k y l a t e d product 258 i n 75% y i e l d . Evidence t h a t 187 0 0 Cl 1) 2LDA, THF 2) Mel 255c 25£ a l k y l a t i o n had indeed occurred a t the Y * * c a r k ° n was manifest in the NMR spectrum of the product which showed a q u a r t e t a t 6 2.56, a t r i p l e t at 6 1.09, and the absence of a three-proton s i n g l e t a t 6 2.26 due to the Y - m e t n y l protons i n the s t a r t i n g m a t e r i a l . The molecular weight d e r i v e d from the low r e s o l u t i o n mass spectrum of the product, and elemental a n a l y s i s p rovided f u r t h e r evidence f o r the formation of compound 258. With the q u e s t i o n of d i a n i o n formation no longer i n doubt, i t appeared l i k e l y t h a t the d i f f i c u l t y encountered was l i n k e d to the use of c h l o r i d e s as l e a v i n g groups. One method to s o l v e t h i s problem would be to use a more p o l a r s o l v e n t such as hexa-methylphosphoramide, which i s known to a c t i v a t e carbanions 152 through s o l v a t i o n of t h e i r metal counter ions . The a d d i t i o n of c h l o r i d e 255d in tetrahydrofuran-hexamethylphosphoramide to a s o l u t i o n of two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e under a v a r i e t y of c o n d i t i o n s , however, gave mixtures of products a r i s i n g from e l i m i n a t i o n and d i m e r i z a t i o n p r o c e s s e s . 188 A second s o l u t i o n was to convert these c h l o r i d e s i n t o b e t t e r l e a v i n g groups such as bromides or i o d i d e s . A c c o r d i n g l y , the treatment of 8-keto e s t e r c h l o r ide 255c with sodium i o d i d e i n r e f l u x i n g acetone gave the i o d i d e 259 i n 90% y i e l d . Evidence for the h a l i d e exchange was obtained from the NMR spectrum of the product which showed a new t r i p l e t a t 6 3.18 (CH^I) and the absence of a t r i p l e t at 6 3.50 (CH^Cl) c h a r a c t e r i s t i c of the s t a r t i n g m a t e r i a l . Furthermore, the molecular weight d e r i v e d from the low r e s o l u t i o n mass spectrum of the product was c o n s i s t e n t with the formation of the i o d i d e 259. The attempted c y c l i z a t i o n of i o d i d e 259 proved to be f u t i l e under a v a r i e t y of c o n d i t i o n s . Instead a predominance of 260 r e s u l t i n g from an e l i m i n a t i o n process was found i n a l l cases. T h i s c o n c l u s i o n was d e r i v e d from NMR a n a l y s i s of the crude r e a c t i o n m i x t ures. A study of molecular models r e v e a l e d that 255c 259 189 the f o r m a t i o n o f e i g h t t o eleven-membered B-keto l a c t o n e s v i a i n t r a m o l e c u l a r d i a n i o n a l k y l a t i o n w ould be v e r y d i f f i c u l t . The p r o b l e m i n t h e s e c y c l i z a t i o n s a p p e a r s t o a r i s e f r o m the need o f the l o n g c h a i n h a l i d e t o span f i v e s u c c e s s i v e p l a n a r sp c e n -t e r s i n o r d e r t o promote the B-keto e s t e r d i a n i o n a l k y l a t i o n ( e q u a t i o n 7 8 ) . C a r e f u l a n a l y s i s i n d i c a t e d t h i s t o be p o s s i b l e 190 o n l y i n cases where the c h a i n l e n g t h , n, was g r e a t e r than or equal to seven carbons. The formation of o l e f i n i c r a t h e r than d i m e r i c products (equation 79) i n the attempted c y c l i z a t i o n of B-keto e s t e r h a l i d e s 255b and 255c suggested that p o s s i b l y the l o s s of H-X was o c c u r r i n g i n t r a m o l e c u l a r l y with the d i a n i o n i t s e l f a c t i n g as the base (equation 80). T h i s r e s u l t may r e f l e c t the r i g i d 0 0 0 0 (79) 0 0 -HX (80) g e o m e t r i c a l requirements f o r the S N2 r e a c t i o n . In p a r t i c u -l a r , the need f o r a back s i d e approach to w i t h i n 1.5-2.0 R may 191 be c o n t r a s t e d with the r e l a t i v e l y loose t r a n s i t i o n s t a t e r e q u i r e -153 ments suggested f o r i n t r a m o l e c u l a r proton t r a n s f e r In order to v e r i f y t h a t c y c l i z a t i o n would indeed occur with g-keto e s t e r h a l i d e s of a p p r o p r i a t e chain l e n g t h and to d e t e r -mine e x a c t l y a t what p o i n t e l i m i n a t i o n becomes c o m p e t i t i v e with c y c l i z a t i o n , the p r e p a r a t i o n of a s e r i e s of g-keto e s t e r bromides 262, n = 5 - l l , was under taken (Table X I I ) . The 0 0 • B r (CH 2 ) n 0H ™F > AAo-(CH 2 ) n Br 253 261 262. bromoalcohol 261g was obtained commercially, while 261b-f were prepared by continuous e x t r a c t i o n of the product from a heated s o l u t i o n of the corresponding d i o l s 263 i n 48% hydrogen bro-m i d e 1 5 5 - " 1 " 6 0 . The bromoalcohol 261a was c o n v e n i e n t l y prepared H 0 ( C H 2 ) n 0 H 4 8 % "^-Solvent > H 0 ( C H 2 , n B r 263 261 i n two s t e p s . F i r s t , cleavage of tetrahydropyran 264 with a c e t y l bromide and a c a t a l y t i c amount of z i n c c h l o r i d e to give 134 154 the bromoacetate 265 , then h y d r o l y s i s of the e s t e r 192 Table X I I . P r e p a r a t i o n of Long Chain B-Keto Est e r Bromides. Compound I d e n t i f i c a t i o n 261 n Y i e l d of 262* (%) a c134,154 D 74 b ,155 b 86 c ?156 84 d 8157 86 e 9158 95 f 1 0 1 5 9 92 g l l 1 6 0 85 * I s o l a t e d y i e l d s . 193 0 MeC00(cw m ^ 264 265 261 a The bromoalcohols 261 a l l e x h i b i t e d s p e c t r a l p r o p e r t i e s which were i n accordance with t h e i r proposed s t r u c t u r e s . For example, the NMR spectrum of 6-bromo-l-hexanol 261b showed two-proton t r i p l e t s a t 6 3. 62 (CH^OH) and 6 3.44 (CFj^Br) as w e l l as a one-proton s i n g l e t at 6 2.32 (CH2OH) which exchanged with deuterium o x i d e . The i n f r a r e d spectrum of the product d i s -p layed 0-H s t r e t c h i n g v i b r a t i o n s at 3620 and 3450 cm ^, while i t s low r e s o l u t i o n mass spectrum contained the expected p a i r of parent ions at 164 and 162 m/e with r e l a t i v e i n t e n s i t i e s of 1:1. The a l c o h o l y s i s of a c e t y l Meldrum's a c i d 253 with bromo-a l c o h o l s 261 proceeded smoothly to g i v e the d e s i r e d B-keto e s t e r bromides 262 i n e x c e l l e n t y i e l d s (Table X I I ) . A study of the c y c l i z a t i o n of these compounds was t h e r e f o r e i n i t i a t e d by f i r s t examining the i n t r a m o l e c u l a r a l k y l a t i o n of B-keto e s t e r bromide 262g to give the sixteen-membered B-keto lactone 266g. 194 B r ( C H 2 ) 1 l -262g 2LDA THF 0 0 2£&g Care fu l NMR ana lys is of the crude react ion product obtained from the addi t ion of the bromide 262g to a so lut ion containing two equivalents of l i th ium di isopropylamide in tetrahydrofuran revealed the presence of two new compounds in addi t ion to some unreacted s ta r t ing mate r ia l . The major product appeared to be the desired c y c l i c B-keto lactone 266g as in fer red by the pre -sence of a new t r i p l e t at 6 2.56 (2H, CH2COCH2COO) and the reduced in tens i ty of the Y - m e t n Y l protons of the s t a r t i n g mate-r i a l . The minor product consisted of a very small amount of the B-keto ester o l e f i n 267g. In an attempt to dr ive th is 2£Zg react ion to complet ion, the dianion was s t i r r e d for longer per iods; however again some s t a r t i n g mater ia l was recovered. 195 The use of excess l i t h i u m d i i s o p r o p y l a m i d e , on the other hand, gave a crude r e a c t i o n product which appeared to be devoid of s t a r t i n g m a t e r i a l . The p u r i f i c a t i o n of the c y c l i c B-keto la c t o n e 266g obtained from the r e a c t i o n of B-keto e s t e r bromide 262g with excess l i t h i u m d i i s o p r o p y l a m i d e was found to be very prob-•: l e m a t i c a l . E f f o r t s to u t i l i z e TLC, for example, were hampered by the d i f f i c u l t i e s encountered in v i s u a l i z i n g the TLC s p o t s . Vapour phase chromatographic (VPC) a n a l y s i s i n d i c a t e d the p r e -sence of two major products i n a r a t i o of 5:1. However, subsequent s t u d i e s u s i n g VPC-mass spectrometry, VPC c o l l e c t i o n and NMR r e v e a l e d t h a t the product decomposes under the VPC c o n d i t i o n s . F i n a l l y , attempts to d i s t i l l the crude r e a c t i o n product gave o n l y mixtures of compounds 266g and 267g in very poor y i e l d s . These r e s u l t s suggested t h a t an i n v e s t i g a t i o n of r e a c t i o n c o n d i t i o n s l e a d i n g to c l e a n e r , product formation should be e f f e c t e d . The f i r s t approach s t u d i e d was the e f f e c t of s o l v e n t on the a l k y l a t i o n p r o c e s s . In the p r e s e n t case, i t was f e l t t h a t the a d d i t i o n of p o l a r s o l v e n t s such as hexamethylphosphoramide would render the Y " c a r ' : , a n : L O n more n u c l e o p h i l i c and hence i n c r e a s e the r e l a t i v e p r o p o r t i o n of c y c l i z a t i o n versus e l i m i n a -t i o n . The r e a c t i o n of the B-keto e s t e r bromide 262g with two to three e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a -hydrofuran-hexamethylphosphoramide, however, r e s u l t e d only i n 196 i n c r e a s e d formation of the o l e f i n i c product 267g at the expense of the c y c l i c g-keto l a c t o n e 266g. T h i s o b s e r v a t i o n suggested the need to d e a c t i v a t e the g-keto e s t e r d i a n i o n to achieve more s e l e c t i v e g-keto l a c t o n e 266g for m a t i o n . One method to deac-t i v a t e the d i a n i o n would be to employ a l e s s p o l a r s o l v e n t s y s -tem and t h e r e f o r e the r e a c t i o n was repeated using ether as s o l v e n t . Under these c o n d i t i o n s , however, the d i a n i o n a l k y l a -t i o n was found to be very slow and i n e v i t a b l y l a r g e amounts of s t a r t i n g m a t e r i a l were reco v e r e d . S i m i l a r l y , when hexanes were used as s o l v e n t only unreacted 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 . A s o l v e n t which i s i n t e r m e d i a t e between ether and t e t r a h y d r o -furan i n terms of p o l a r i t y was a l s o t e s t e d . However, use of 1,2-dimethoxyethane as s o l v e n t gave mixtures of c y c l i c and o l e f i n i c p r o d u c t s . A second p o s s i b l e method to accentuate the d i f f e r e n c e between the a l k y l a t i o n and e l i m i n a t i o n p r o c e s s e s would i n v o l v e the employment of low temperatures. The g-keto e s t e r h a l i d e 262g was t h e r e f o r e added to s o l u t i o n s of two to three e q u i v a l e n t s 197 of l i t h i u m d i i s o p r o p y l a m i d e a t v a r i o u s temperatures ranging from 0°C to -98°C. Under c o n d i t i o n s where the r e a c t i o n was run i n i t s e n t i r e t y a t low temperature, on l y s t a r t i n g m a t e r i a l could be r e c o v e r e d . On the other hand, when the r e a c t i o n was i n i t i a t e d a t low temperature and allowed to warm to room tem-pe r a t u r e over s e v e r a l hours, the crude r e a c t i o n product i n e v i -t a b l y showed evidence on l y f o r the g-keto l a c t o n e 266g and unreacted s t a r t i n g m a t e r i a l . The use of up to four e q u i v a l e n t s of base f a i l e d to d r i v e t h i s r e a c t i o n to completion. Never-t h e l e s s , these r e s u l t s a t l e a s t suggested t h a t m o d i f i c a t i o n of the d i a n i o n r e a c t i v i t y was the key to the p r e f e r e n t i a l forma-t i o n of c y c l i c p r o d u c t s . An a l t e r n a t e approach to the m o d i f i c a t i o n of g-keto e s t e r d i a n i o n r e a c t i v i t y was based on p r e v i o u s work conducted on the e f f e c t of metal counter ion on the r a t e of a l k y l a t i o n of ketone 3 8 e n o l a t e s . In g e n e r a l , i t has been found t h a t the r a t e of r e a c t i o n of metal e n o l a t e s i s i n c r e a s e d s u b s t a n t i a l l y as the metal c a t i o n i s changed from l i t h i u m to sodium to potassium. T h i s trend r e f l e c t s the degree of c o v a l e n t c h a r a c t e r of these metal e n o l a t e s , i n t h a t the more c o v a l e n t the i n t e r a c t i o n , the slower i s the r a t e of r e a c t i o n . The rate of a l k y l a t i o n may be r e t a r d e d even f u r t h e r by the use of z i n c and magnesium e n o l a t e s which tend to form even more t i g h t ion p a i r s . These metal e n o l a t e s can be used only with h i g h l y r e a c t i v e a l k y l a t i n g 4. 38 agents 198 T h i s work suggested t h a t the r e a c t i v i t y o f a B-keto e s t e r d i a n i o n may be enhanced by f o r m a t i o n of the d i p o t a s s i u m d i a n i o n , w h i l e i t s r e a c t i v i t y may be m o d i f i e d by the a d d i t i o n o f z i n c or magnesium s a l t s . In o r d e r t o t e s t t h i s h y p o t h e s i s , an e x a m i n a t i o n o f the e f f e c t of c o u n t e r i o n on the i n t r a m o l e c u l a r a l k y l a t i o n o f the B-keto e s t e r h a l i d e 262g was c o n d u c t e d . p r e p a r e d u s i n g p o t a s s i u m h y d r i d e as base. However a l l a t t e m p t s t o g e n e r a t e the d i p o t a s s i u m s a l t u s i n g p o t a s s i u m b i s ( t r i m e t h y l -70 s i l y l ) a m i d e (269) and p o t a s s i u m d i p h e n y l 2 - p y r i d y I m e t h i d e 71 (270) p r o v e d f u t i l e . R e c e n t l y , P i e r r e and cowo r k e r s have 2£Zg The g e n e r a t i o n of the d i p o t a s s i u m s a l t 268, M1=M2=K, was f i r s t attempted. The monopotassium anion of 262g was e a s i l y 269 270 199 d e s c r i b e d the m e t a l l a t i o n of a s e r i e s of weak a c i d s by potas-161 sium hydride i n the presence of 2.2.2 cryptand 271" / \ For 271 example, the d e p r o t o n a t i o n of diphenylmethane (272), pK 33.4, and triphenylmethane (273) , pK = 31.5, was r e a d i l y accomplished a under these c o n d i t i o n s , while i n the absence of the cryptand no d e p r o t o n a t i o n c o u l d be observed. These authors suggested 272 213 t h a t the strong b a s i c i t y e x h i b i t e d by potassium hydride i n the presence of 2.2.2 cryptand 271 a r i s e s from a c t i v a t i o n of the 161 c r y s t a l s u r f a c e of the potassium hydride by the cryptand. . 200 The f a c i l e d e p r o t o n a t i o n of diphenylmethane (272) with potassium hydride and cryptand 271 appeared to o f f e r some pro-mise f o r the s u c c e s s f u l g e n e r a t i o n of a d i p o t a s s i u m B-keto e s t e r d i a n i o n . However, t r e a t i n g the 3-keto e s t e r bromide 262g with two e q u i v a l e n t s of both potassium hydride and the cryptand 271 i n t e t r a h y d r o f u r a n gave on l y s t a r t i n g m a t e r i a l . Evidence t h a t no d i a n i o n was formed under these c o n d i t i o n s was obtained from the recovery of unreacted s t a r t i n g m a t e r i a l upon quenching the r e a c t i o n mixture with methyl i o d i d e . With the a v a i l a b i l i t y of a s t r o n g potassium base capable of g e n e r a t i n g a B-keto e s t e r d i a n i o n now i n doubt, a r e t u r n to the o r i g i n a l plan of moderating d i a n i o n r e a c t i v i t y through the formation of more c o v a l e n t l y l i n k e d metal e n o l a t e s was examined. Although the d i r e c t p r e p a r a t i o n of z i n c e n o l a t e s i s o f t e n very d i f f i c u l t , an i n d i r e c t approach i n v o l v i n g the formation of the l i t h i u m e n o l a t e and a d d i t i o n of an anhydrous z i n c s a l t p r o v i d e s 162 convenient access to these e n o l a t e s . A c c o r d i n g l y , the g-keto e s t e r bromide 262g ,was t r e a t e d with two to three e q u i v -a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e to generate the d i a n i o n , and then one e q u i v a l e n t of anhydrous z i n c c h l o r i d e was added. A copious p r e c i p i t a t e formed almost immediately, which f a i l e d to d i s s o l v e d u r i n g the course of the r e a c t i o n . H y d r o l y t i c workup of the r e a c t i o n mixture r e s u l t e d in the d i s s o l u t i o n of the p r e c i p i t a t e and the recovery of s t a r t i n g m a t e r i a l . T h i s out-come was found to be independent of the time of r e a c t i o n as w e l l 201 as the amount of l i t h i u m d i i s o p r o p y l a m i d e used, and suggested that the observed p r e c i p i t a t e may c o n s i s t of a very s t a b l e z i n c c h e l a t e 274. In an attempt to moderate the B-keto e s t e r d i a n i o n r e a c -t i v i t y to a l e s s e r e x t e n t , an i n v e s t i g a t i o n of the e f f e c t of copper (I) s a l t s on the a l k y l a t i o n process was conducted. The reasoning behind t h i s approach was based on the known tendency of copper (I) s a l t s to moderate the r e a c t i v i t y of o r g a n o l i t h i u m 163 reagents i n t h e i r r e a c t i o n s with a c i d c h l o r i d e s (equation 81) RLi RCOCl 0.5 Cul RLi RCOR (81) Mixture of products 202 G e n e r a t i o n o f the d i a n i o n of B - k e t o e s t e r h a l i d e 262g as u s u a l , f o l l o w e d by the a d d i t i o n o f copper (I) s a l t s such as copper i o d i d e 1 6 3 , copper b r o m i d e - d i m e t h y l s u l f i d e c o m p l e x 1 6 4 , m e t h y l -c o p p e r 1 6 5 , and t r i - n - b u t y l p h o s p h i n e - c o p p e r i o d i d e c o m p l e x 1 6 6 , however, i n v a r i a b l y gave m i x t u r e s o f s t a r t i n g m a t e r i a l , and p r o d u c t s d e r i v e d from c y c l i z a t i o n and e l i m i n a t i o n p r o c e s s e s . An a l t e r n a t e approach which does n o t i n v o l v e the d i a n i o n d i r e c t l y d e a l s w i t h the e f f e c t o f l e a v i n g group on the compe-t i t i o n between a l k y l a t i o n and e l i m i n a t i o n r e a c t i o n s . S e v e r a l y e a r s ago, Bumgardner a d d r e s s e d a s i m i l a r problem i n a r e p o r t c f the e f f e c t o f l e a v i n g group on the mode o f r e a c t i o n of 3 - p h e n y l p r o p y l d e r i v a t i v e s 275 w i t h sodium amide i n l i q u i d 167 ammonia ( e q u a t i o n 8 2 ) . In t h i s s t u d y , i t was found t h a t ^ C 6 H 5 C H 2 C H = C H 2 C 6 H 5 C H 2 C H 2 C H 2 X (82) 275 when the l e a v i n g group was bromide, e l i m i n a t i o n p r e d o m i n a t e d , w h i l e when X=C1, a m i x t u r e o f c y c l i z a t i o n and e l i m i n a t i o n was o b s e r v e d . More n o t e w o r t h y , however, was the o b s e r v a t i o n t h a t 203 the use of t o s y l a t e and trimethylammonium l e a v i n g groups gave o n l y c y c l o p r o p a n e f o r m a t i o n . The d i r e c t a p p l i c a t i o n o f these r e s u l t s t o the p r e s e n t s t u d y was hampered by the a b i l i t y of l i t h i u m d i i s o p r o p y l a m i d e t o d e p r o t o n a t e a t o s y l a t e group and by the d i f f i c u l t y o f p r e -p a r i n g a B-keto e s t e r trimethylammonium s a l t 276. The problem posed by t o s y l a t e d e p r o t o n a t i o n was e a s i l y s o l v e d by u t i l i z i n g the b e n z e n e s u l f o n a t e 277, w h i l e a second c a n d i d a t e f o r c y c l i z a -t i o n was deemed t o be the p h e n y t h i o B-keto e s t e r 278. 0 0 0 C 6 H 5 S 0 2 0 ( C H 2 ) 1 ( ) C e H g S f C H ^ H 277 278 The s y n t h e s i s o f the b e n z e n e s u l f o n a t e 277 i s o u t l i n e d i n Scheme 12. The s y n t h e s i s o f 277 was i n i t i a t e d by the 204 AcOH, H 2 S O / 279 H O ( C H 2 ) l 0 O S O 2 C 6 H 5 282 0 0 AA-H 2 0 HCl MeOH , THF,A ( C H 2 ) l 0 O S O 2 C 6 H 5 211 A c O ( C H 2 ) 1 Q O H 280 C 6 H 5 S 0 2 C I P y r i d i n e A c O ( C H 2 ) 1 Q O S 0 2 C 6 H 5 281 Scheme 12: P r e p a r a t i o n o f B-keto e s t e r b e n z e n e s u l f o n a t e 277. p r e p a r a t i o n o f 1 0 - a c e t o x y - l - d e c a n o l (280) from 1 , 1 0 - d e c a n e d i o l (279) i n 66% y i e l d by the pr o c e d u r e d e s c r i b e d by B a b l e r and 168 Coghlan . The r e s u l t i n g a c e t o x y a l c o h o l 280 was then c o n -v e r t e d i n t o the a c e t o x y b e n z e n e s u l f o n a t e 281 i n 80% y i e l d u s i n g b e n z e n e s u l f o n y l c h l o r i d e and p y r i d i n e . The p r o d u c t 281 was c h a r a c t e r i z e d by i t s NMR spectrum which e x h i b i t e d resonance a t 6 2.03 ( s , 3H, CH 3COO), 4.00 205 ( t , 4H, CH 2OAc + CH 2OS0 2C 6H 5) , 7.33-7.90 (m, 5H, a r o m a t i c ) , and 1.20-1.70 (m, 16H, hydrocarbon). The i n f r a r e d spectrum of the product d i s p l a y e d a st r o n g C=0 s t r e t c h i n g v i b r a t i o n at 1725 cm" , while i t s low r e s o l u t i o n mass spectrum showed a weak parent ion a t 356 m/e, which i s c o n s i s t e n t with the proposed composition. S e l e c t i v e h y d r o l y s i s of the acetoxy benzenesulfonate 281 was r e a d i l y accomplished by s e v e r a l methods, the most con-v e n i e n t of which i n v o l v e d the use of h y d r o c h l o r i c a c i d i n methanol. By t h i s method, the hydroxy benzenesulfonate 282 was prepared i n 72% y i e l d . Evidence f o r the s e l e c t i v e h y d r o l y s i s of the acetate group was secured from the NMR spectrum of the product which e x h i b i t e d t r i p l e t s at 6 3.57 (CH_2OH) and 6 4 .00 (CH 2OS0 2C 6H 5) , a m u l t i -p l e t a t 6 7.18-7.90 due to the aromatic protons, as w e l l as the absence of a three-proton s i n g l e t at 6 2.03, c h a r a c t e r i s t i c of the a c e t a t e group i n the s t a r t i n g m a t e r i a l . Furthermore, the i n f r a r e d spectrum of the product d i s p l a y e d O-H s t r e t c h i n g v i b r a t i o n s a t 3625 and 3450 cm - 1, and the absence of any c a r -bonyl a b s o r p t i o n s . The p r e p a r a t i o n of the B-keto e s t e r benzenesulfonate 277 was completed by the a l c o h o l y s i s of a c e t y l Meldrum's a c i d 253 with the a l c o h o l 282. The r e s u l t a n t product was obtained 206 T H F , A H O ( C H 2 ) 1 0 O S 0 2 C 6 H 5 ' 253 282 0 0 AA, C 6 H 5 S 0 2 0 ( C H 2 ) , 0 -277 i n 86% y i e l d and e x h i b i t e d s p e c t r a l d a t a i n f u l l a ccordance w i t h the a s s i g n e d s t r u c t u r e . The p r e p a r a t i o n of p h e n y l t h i o B-keto e s t e r 278 was con -v e n i e n t l y c a r r i e d o u t i n two s t e p s as o u t l i n e d i n Scheme 13. ' , 2NaH, T H F H0(CH,)„Br — > H 0 ( C H 2 ) 1 1 S C 6 H 5 2Mg C 6 H 5 S H 281 -OH 6 ^ -THF'A 0 0 ( C ^ ^ S C S H B 278 Scheme 13: P r e p a r a t i o n o f p h e n y l t h i o B-keto e s t e r 278. In the f i r s t s t e p , the c o m m e r c i a l l y a v a i l a b l e 11-bromoundecanol ( 2 6 1 g ) 1 6 0 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 sodium h y d r i d e , 207 f o l l o w e d by one e q u i v a l e n t of t h i o p h e n o l . The product 283, obtained i n 83% y i e l d , was homogeneous by TLC a n a l y s i s . The i n f r a r e d spectrum of the product had a b s o r p t i o n s a t 3620 and 3460 cm \ t y p i c a l of an a l c o h o l , and i t s NMR spectrum e x h i b i t e d t r i p l e t s a t 6 3.64 (CH2OH) and 6 2.92 (CH 2SC 6H 5), and a m u l t i -p l e t a t 6 7.10-7.40 due to the aromatic p r o t o n s . The s y n t h e s i s of B-keto e s t e r s u l f i d e 278 was completed by the a l c o h o l y s i s of a c e t y l Meldrum's a c i d 253 with the h y d r o x y s u l f i d e 283. The product obtained i n 76% y i e l d again e x h i b i t e d s p e c t r a l data i n f u l l accordance with the proposed s t r u c t u r e . With the B-keto e s t e r s u l f i d e 278 and B-keto e s t e r benzenesulfonate 277 now i n hand, a study of the c y c l i z a t i o n of these compounds was conducted. Treatment of the B-keto e s t e r benzenesulfonate 277 with two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n at 0°C was found to give a mixture of s t a r t i n g m a t e r i a l and the c y c l i z e d product 266f. A l l attempts to d r i v e t h i s r e a c t i o n 277 266f 208 to completion u s i n g longer r e a c t i o n times, higher temperatures, more base, and a l t e r n a t e s o l v e n t systems, however, proved to be f u t i l e . In p a r t i c u l a r , the use of three or more e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n a t room temper-ature l e d to the apparent formation of the a l c o h o l 284 v i a cleavage of the benzenesulfonate group. 0 0 xx, C 6H 5SO 2O(CH 2) 1 0  277 3LDA THF HO(CH2)10" 284 The attempted c y c l i z a t i o n of the g-keto e s t e r s u l f i d e 278 to the sixteen-membered B-keto l a c t o n e 266g was a l s o unsuccess-f u l . For example, the r e a c t i o n of s u l f i d e 278 with three e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e gave only unreacted s t a r t i n g m a t e r i a l . T h i s r e s u l t may be c o n t r a s t e d with the work 0 0 x x C 5H 5S(CH 2) 1 1 31-DA^THF^ • (CH^ m 2m 209 o f J u l i a and c o w o r k e r s 1 " on the e f f e c t o f l e a v i n g group on the i n t r a m o l e c u l a r a l k y l a t i o n o f a l k e n e 28J5 t o c y c l o p r o p a n e 2 8 6 . In t h i s s t u d y , i t was found t h a t c y c l i z a t i o n was b e s t performed and e l i m i n a t i o n was m i n i m i z e d when the l e a v i n g group X=CgH^S was used. The l a c k o f s u c c e s s e n c o u n t e r e d i n the attempt t o o p t i -mize the c o n d i t i o n s f o r 8-keto e s t e r d i a n i o n c y c l i z a t i o n l e d t o a r e e v a l u a t i o n o f the o r i g i n a l p r o c e d u r e found t o e f f e c t B-keto l a c t o n e f o r m a t i o n (3LDA, THF, 0°->-R.T.). In p a r t i c u l a r , the development o f a method t o p u r i f y the r e s u l t i n g p r o d u c t on a p r e p a r a t i v e s c a l e was t o be a c r u c i a l p a r t of t h i s r e i n v e s t i -g a t i o n . E a r l i e r e f f o r t s had shown the p u r i f i c a t i o n o f B-keto l a c -tone 266g by TLC, VPC, and d i s t i l l a t i o n t o be d i f f i c u l t . A t e c h n i q u e which has r e c e n t l y shown a g r e a t d e a l o f promise i n 210 the s e p a r a t i o n o f o r g a n i c compounds i n v o l v e s the use o f h i g h 170 p r e s s u r e l i q u i d chromatography (HPLC) . In the p r e s e n t c a s e , the p u r i f i c a t i o n o f B-keto l a c t o n e 266g on a s m a l l s c a l e was found t o be r e a d i l y a c c o m p l i s h e d u s i n g an a n a l y t i c a l h i g h p r e s -sure l i q u i d chromatograph equipped w i t h a v a r i a b l e w avelength u l t r a v i o l e t d e t e c t o r . S u b s e q u e n t l y , by u s i n g HPLC t o f o l l o w the r e a c t i o n , the b e s t c o n d i t i o n s f o r c y c l i z a t i o n were d e t e r -mined t o i n v o l v e the dr o p w i s e a d d i t i o n o f B-keto e s t e r bromide 262g t o a s o l u t i o n c o n t a i n i n g t h r e e e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n (0.03 M s o l u t i o n ) . Under these c o n d i t i o n s , the f o r m a t i o n o f e l i m i n a t e d p r o d u c t 267g was m i n i m i z e d t o l e s s than f i v e p e r c e n t . 0 0 Br(CH 2) l 1 " 2£2g 3 L D A , T H F r 0 ° - > R T ^ r - ( C H 2 ) 9 267g The p u r i f i c a t i o n o f the sixteen-membered B-keto l a c t o n e 266g on a l a r g e s c a l e was a c c o m p l i s h e d u s i n g a p r e p a r a t o r y h i g h p r e s s u r e l i q u i d chromatograph. The p r o d u c t , o b t a i n e d i n 49% p u r i f i e d y i e l d , was c h a r a c t e r i z e d by its.NMR spectrum which d i s p l a y e d s i g n a l s a t 6 4.22 ( t , 2H, COOCH_2) , 3.46 ( s , 2H, C0CH 2C00), 2.56 ( t , 2H, CH 2CO), and 1.20-1.80 (m, 20H, 211 hydrocarbon). The i n f r a r e d spectrum of the product showed ab s o r p t i o n s a t 1735 and 1710 cm ^, t y p i c a l of a 8-keto e s t e r , while i t s low r e s o l u t i o n mass spectrum e x h i b i t e d the expected parent ion a t 254 m/e, and no i n d i c a t i o n of any higher mole-c u l a r weight fragments corr e s p o n d i n g to dimer fo r m a t i o n . The absence of dimer was f u r t h e r i m p l i e d by the s i m i l a r s u b l i m a t i o n temperatures observed f o r the B-keto l a c t o n e 266g and commer-c i a l e x a l t o l i d e 287. R e c e n t l y , S t i l l and coworkers have rep o r t e d the develop-ment of a new chromatographic technique f o r p r e p a r a t i v e separa-t i o n s with moderate r e s o l u t i o n 1 7 1 . T h i s technique i s c a l l e d f l a s h chromatography and i s b a s i c a l l y a form of a i r p r e s s u r e d r i v e n column chromatography which has been optimized f o r par-t i c u l a r l y r a p i d s e p a r a t i o n s . For example, the s e p a r a t i o n of d i a s t e r e o m e r i c a l c o h o l s 288 and 289 (ARf=0.09 i n 5% e t h y l a cetate-petroleum ether) on a one gram s c a l e was e a s i l y achieved with o n l y one mixed f r a c t i o n (65 mg) i n seven minutes. 212 OH n B u 3 S n ' " nBu 288 H B U 3 S 1 V ' ' 289 The a p p l i c a t i o n of t h i s technique to the p u r i f i c a t i o n of B-keto la c t o n e 2 66g was found to be very s a t i s f a c t o r y , p r o v i d i n g the d e s i r e d product i n s i m i l a r y i e l d to t h a t obtained u s i n g HPLC. The p u r i f i c a t i o n u s i n g f l a s h chromatography, however, proceeded f a r more q u i c k l y and r e q u i r e d much l e s s s o l v e n t . With both the methodology and technology now a v a i l a b l e , the s y s t e m a t i c study of the c y c l i z a t i o n of B-keto e s t e r bromide 262, n = 5 - l l , was conducted. The r e s u l t s of t h i s study are summarized i n Table X I I I , with the products a l l being p u r i f i e d u s i n g f l a s h chromatography 1 7" 1". The products obtained from the 0 0 Br (CH 2 ) n 262 0 0 3LDA, THF 0°—* RT 0 0 (CH 2)n 266 (CH2)nZ2 267 c y c l i z a t i o n o f B-keto e s t e r bromides 262f and 262e e x h i b i t e d s p e c t r a l d a t a s i m i l a r t o t h a t o f the sixteen-membered B-keto l a c t o n e s 266g d i s c u s s e d e a r l i e r . 213 Table X I I I . Attempted C y c l i z a t i o n of B-Keto E s t e r Bromides 262, n = 5 - l l . 0 0 A A ^ C H 2 ) n ^ 267 S t a r t i n g 262 Product(s) %* M a t e r i a l n 266 267 262g 11 49 f 10 45 e 9 43 d 8 41 c 7 57 b 6 45 a 5 41 * I s o l a t e d y i e l d s . The NMR s p e c t r a of the crude r e a c -t i o n mixtures suggest r e l a t i v e l y c l e a n product forma-t i o n and t h e r e f o r e the moderate y i e l d s probably r e f l e c t l o s s e s i n c u r r e d d u r i n g p u r i f i c a t i o n . 214 The attempted c y c l i z a t i o n of B-keto e s t e r bromide 262c was t y p i c a l of the r e a c t i o n s which gave e l i m i n a t i o n . The pro-duct, p u r i f i e d by f l a s h chromatography, was homogeneous by TLC a n a l y s i s , and elemental a n a l y s i s of the d i s t i l l e d m a t e r i a l was in agreement with the proposed formula. The i n f r a r e d spectrum of the product showed a b s o r p t i o n s at 1745 and 1715 cm ^, while i t s low r e s o l u t i o n mass spectrum e x h i b i t e d the expected parent ion a t 198 m/e. Evidence t h a t e l i m i n a t i o n had occu r r e d was .manifest i n the NMR spectrum of the product, which showed m u l t i p l e t s a t 6 5.64-6.04 and 6 4.92-5.10 i n t e g r a t i n g to a t o t a l of three protons, which were assigned to the protons of the t e r m i n a l o l e f i n i c group. The presence of a three-proton s i n g l e t a t <5 2.28 and a two-proton s i n g l e t a t 6 3.46, which are t y p i c a l of an a c e t o -a c e t a t e group (CH3COCH_2COOR) provided f u r t h e r support f o r the formation of an e l i m i n a t i o n product. An examination of the r e s u l t s i n Table XIII shows t h a t i n t r a m o l e c u l a r a l k y l a t i o n predominates only i n the p r e p a r a t i o n of f o u r t e e n to sixteen-membered B-keto l a c t o n e s . The observa-t i o n of c y c l i z a t i o n when the c h a i n l e n g t h n=9, and e l i m i n a t i o n when n=8 demonstrates the importance of ch a i n length on the c y c l i z a t i o n of B-keto e s t e r bromides v i a d i a n i o n f o r m a t i o n . Molecular model s t u d i e s r e v e a l the p o s s i b i l i t y of forming a twelve-membered r i n g and the l i k e l i h o o d of p r e p a r i n g l a r g e r r i n g s . The r a t i o n a l e behind the f a i l u r e of B-keto e s t e r 215 bromides 262c and 262d to c y c l i z e i s not w e l l understood, how-ever, i t might r e f l e c t the r i g i d t r a n s i t i o n s t a t e requirements f o r the S N2 r e a c t i o n , as d i s c u s s e d e a r l i e r (pg 190). An a l t e r n a t e s t r a t e g y f o r the p r e p a r a t i o n of l a r g e r i n g B-keto l a c t o n e s u s i n g Meldrum"s a c i d d e r i v a t i v e s was a l s o examined. In t h i s approach, the key c y c l i z a t i o n step i n v o l v e s l a c t o n i z a t i o n through i n t r a m o l e c u l a r a l c o h o l y s i s of an a c y l Meldrum's a c i d d e r i v a t i v e (equation 83). The f e a s i b i l i t y of 290 (83) 266 t h i s s t r a t e g y was examined by p r e p a r i n g the hydroxy a c y l Meldrum's a c i d 295 a c c o r d i n g to the route o u t l i n e d i n Scheme 14. 216 iBuMe 9 SiCl , i • I H O K H ^ C O O H imidazole * ^ S i - O ( C H 2 ) 1 0 C O O S i - f 221 DMF Q 1) Im 2CO ^ - ( C H 2 ) 9 O S i — | -nBu^NF THF 222 NaOH H 2 0 - | - S i - O ( C H 2 ) 1 0 C O O H m 0 HO ^ - ( C H 2 ) 9 0 H 295 Scheme 14: P r e p a r a t i o n of hydroxy a c y l Meldrum's a c i d 295, The s y n t h e s i s of the a l c o h o l 295 was i n i t i a t e d by conver-s i o n of the commercially a v a i l a b l e 11-hydroxyundecanoic a c i d ( 2 9 1 ) 1 7 2 i n t o the s i l y l e s t e r 292 i n 95% y i e l d u s i n g t - b u t y l -173 d i m e t h y l c h l o r o s i l a n e and imidazole i n dimethylformamide The r e s u l t i n g e s t e r 292 was then h y d r o l y z e d to the a c i d 293 i n 97% y i e l d u s i n g aqueous sodium hydroxide. 217 The product 293 was c h a r a c t e r i z e d by i t s NMR spectrum which showed s i n g l e t s a t 6 0.00 and 6 0.86, t y p i c a l of a t - b u t y l d i -m e t h y l s i l y l group, t r i p l e t s a t 6 2.34 (CH2COO) and 6 3.58 (CH 2OSi), as w e l l as a broad s i g n a l a t 6 10.13 (COOH) which exchanged upon the a d d i t i o n of deuterium o x i d e . The i n f r a r e d spectrum of the product d i s p l a y e d a strong a b s o r p t i o n a t 1718 cm 1 and a weak, broad s i g n a l a t 3550-2550 cm ^, which are t y p i c a l of C=0 and 0-H s t r e t c h i n g v i b r a t i o n s of a c a r b o x y l i c a c i d . F i n a l l y , both the molecular weight d e r i v e d from the low r e s o l u t i o n mass spectrum of the product and elemental a n a l y s i s of the d i s t i l l e d m a t e r i a l were c o n s i s t e n t with the formation of the a c i d 293 . The c o n v e r s i o n of the a c i d 293 i n t o i t s corre s p o n d i n g a c y l h a l i d e was next c o n s i d e r e d . Recently Ryan and coworkers 148 have r e p o r t e d the a c y l a t i o n of Meldrum's a c i d (246) with an . . . . 113 a c y l i m i d a z o l e d e r i v a t i v e 296 . A c y l i m i d a z o l e s are g e n e r a l l y 231 218 much more e a s i l y prepared than a c y l h a l i d e s and o f f e r the a d d i t i o n a l advantage that the r e a c t i o n by-products, carbon d i o x i d e and i m i d a z o l e , are compatible with the next step i n the sequence. T h i s suggests t h a t the c o n v e r s i o n of the a c i d 293 i n t o the a c y l Meldrum's a c i d 294 may be performed i n one s t e p . Treatment of the a c i d 293 with one e q u i v a l e n t of N ,N' -113 c a r b o n y l d i i m i d a z o l e (298) i n dichloromethane , f o l l o w e d by the a d d i t i o n of t h i s r e a c t i o n mixture to a dichloromethane s o l u t i o n c o n t a i n i n g the anion 300 of Meldrum's a c i d provided the d e s i r e d a c y l a t e d product 294 i n 94% crude y i e l d . Evidence , I CH7Cl2 , I -f-Si-0(CH2)10COOH ^ 1 L> -|-Si-0(CH2)10COIm WN4-2C0 298 299 (CH2)9OSi-{-294 f o r the formation of 294 was secured from the NMR spectrum of the product which showed t r i p l e t s at 6 3 .47 (2H, CH_2OSi) and OH 6 2.90 (2H, C=C-CH 2), s i n g l e t s a t 5 1.81 (6H, ( C H 3 ) 2 C ) , 6 0.97 (9H, ( C H 3 ) 3 C - S i ) , and 6 0.10 (6H, ( C H 3 ) 2 S i ) , as w e l l as 219 a broad m u l t i p l e t a t 6 1.27-1.83 (16H, hydrocarbon). Further support was p r o v i d e d by the i n f r a r e d spectrum of the product which d i s p l a y e d strong a b s o r p t i o n s at 1730, 1635 and 835 cm 1 which are c h a r a c t e r i s t i c of C=0, C=C, S i - 0 s t r e t c h i n g v i b r a t i o n s r e s p e c t i v e l y . The s y n t h e s i s of the a l c o h o l 295 was completed by cleavage of the s i l y l ether i n compound 294 u s i n g tetra-n-butylammonium f l u o r i d e 1 7 4 i n t e t r a h y d r o f u r a n 1 7 3 . The cleavage of the s i l y l ether group was e v i d e n t from the i n f r a r e d spectrum of the p r o -duct which d i s p l a y e d a broad O-H a b s o r p t i o n a t 3400 cm 1 and the absence of a str o n g S i - 0 s t r e t c h i n g v i b r a t i o n at 835 cm 1 i n the s t a r t i n g m a t e r i a l . In a d d i t i o n , the NMR spectrum of the crude product was a l s o c o n s i s t e n t with the l o s s of the t - b u t y l -d i m e t h y l s i l y l group from the s t a r t i n g m a t e r i a l . The f i n a l s t e p i n the p r e p a r a t i o n of the fourteen-membered B-keto l a c t o n e 266e i n v o l v e d the i n t r a m o l e c u l a r a l c o h o l y s i s o f the hydroxy a c y l Meldrum's a c i d 295. The major concern i n (CH 2 ) 9 0H THF A 2 2 5 266e 220 t h i s c y c l i z a t i o n p r o c e s s was t o a v o i d any i n t e r m o l e c u l a r r e a c -t i o n s which c o u l d l e a d t o dimer f o r m a t i o n . I t t h e r e f o r e appeared r e a s o n a b l e t h a t the use o f h i g h d i l u t i o n c o n d i t i o n s would be r e q u i r e d . A c c o r d i n g l y , the a l c o h o l 295 was added v e r y s l o w l y over f i v e hours t o a r e f l u x i n g t e t r a h y d r o f u r a n s o l u t i o n . The p r o d u c t was p u r i f i e d by f l a s h chromatography and was found t o be i d e n t i c a l i n a l l r e s p e c t s t o the fourteen-membered B - k e t o l a c t o n e 266e p r e p a r e d v i a the d i a n i o n method. The o v e r a l l 0 0 H O ( C H 2 ) 1 0 C O O H 291 y i e l d of l a c t o n e 266e from the hydroxy a c i d 291 was 25%. 221 CONCLUSIONS The p r e p a r a t i o n of a s e r i e s of B-keto e s t e r h a l i d e s 262 has been d e s c r i b e d and the c y c l i z a t i o n of the d i a n i o n of these B-keto e s t e r s i n v e s t i g a t e d . The major product obtained when 0 0 AA„ Br(CH 2 ) n ' 262 0 0 Br(CH 2 ) n ' 0 0 the c h a i n l e n g t h n<5, was found to be of type 267 corresponding to the e l i m i n a t i o n of H-X. 0 0 A X •(CH2)n-2-267 The c y c l i z a t i o n of B-keto e s t e r bromide 262g, n = l l , u s i n g three e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e gave predominantly the d e s i r e d sixteen-membered B-keto l a c t o n e 266g, p l u s a s m a l l amount of 267g. Attempts to improve the s e l e c t i v i t y i n t h i s 222 r e a c t i o n by v a r y i n g the s o l v e n t systems, c o u n t e r i o n s , and temperature were u n s u c c e s s f u l . The p r e p a r a t i o n of B-keto e s t e r s 277 and 278 was con d u c t e d i n an e f f o r t t o d e t e r m i n e the p o s s i b l e e f f e c t s o f l e a v i n g groups on the c y c l i z a t i o n p r o c e s s . The attempted c y c l i z a t i o n of these 0 0 0 0 C 6 H 5 S 0 2 0 ( C H 2 ) 1 0 ^ C 6 H 5 S ( C H 2 ) n  277 278 B-keto e s t e r s , however, p r o v i d e d o n l y u n r e a c t e d s t a r t i n g m a t e r i a l or u n d e s i r e d s i d e p r o d u c t s . The p r e p a r a t i o n o f B-keto l a c t o n e s 266 was s u b s e q u e n t l y found t o be b e s t performed by dr o p w i s e a d d i t i o n o f a B-keto e s t e r bromide 262 t o a s o l u t i o n c o n t a i n i n g t h r e e e q u i v a l e n t s o f l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n . In p a r t i c u l a r , under these c o n d i t i o n s the f o r m a t i o n o f B-keto e s t e r o l e f i n s 267 was found t o be m i n i m i z e d . The a p p l i c a t i o n o f t h i s p r o -cedure towards the c y c l i z a t i o n o f B-keto e s t e r bromides 262, n = 5 - l l , has shown t h a t B-keto l a c t o n e p r e d o m i n a t e s when the c h a i n l e n g t h n = 9 - l l , w h i l e e l i m i n a t i o n p r e v a i l s when n<8. T h i s t r e n d appears t o r e f l e c t t he g e o m e t r i c c o n s t r a i n t i n 223 c y c l i z a t i o n of the planar B-keto e s t e r d i a n i o n and.the impor-tance of chain l e n g t h i n overcoming t h i s c o n s t r a i n t . Many of the macrolide a n t i b i o t i c s have been found to possess l a c t o n e s c o n t a i n i n g f o u r t e e n or more members. The con-s t r u c t i o n of such r i n g s v i a carbon-carbon bond fo r m a t i o n , as d i s c u s s e d e a r l i e r , p r e s e n t s s e v e r a l advantages over that of the c l a s s i c a l l a c t o n i z a t i o n r o u t e . Most important, however, i s the a b i l i t y t o employ a convergent approach i n v o l v i n g independent s y n t h e s i s of the a l c o h o l and a c i d p o r t i o n s before c y c l i z a t i o n i s e f f e c t e d . The p r e p a r a t i o n of the m a c r o c y c l i c r i n g v i a d i a n i o n a l k y l a t i o n a l s o allows t h i s convergent approach to be taken. In a d d i t i o n , t h i s method o f f e r s the advantages that high d i l u t i o n c o n d i t i o n s can be avoided i n the c y c l i z a t i o n step and t h a t the presence of a B-keto l a c t o n e f u n c t i o n a l i t y i n the product should allow f u r t h e r e l a b o r a t i o n of the r i n g . F i n a l l y , a second approach to the s y n t h e s i s of l a r g e r i n g B-keto l a c t o n e s was a l s o i n v e s t i g a t e d . T h i s procedure i n v o l v e s the i n t r a m o l e c u l a r a l c o h o l y s i s of an a c y l Meldrum's a c i d 290. 224 T h i s s t r a t e g y was s u c c e s s f u l l y employed i n the s y n t h e s i s of the fourteen-membered B-keto l a c t o n e 266e, and appears to o f f e r p o t e n t i a l f o r the p r e p a r a t i o n of B-keto l a c t o n e s where the d i a n i o n procedure i s u n s a t i s f a c t o r y . 225 EXPERIMENTAL SECTION General: See page 113. 2,2-Dimethyl-1,3-dioxane-4,6-dione (246) A 250-mL Erlenmeyer c o n t a i n i n g a l a r g e magnetic s t i r r i n g bar was charged with malonic a c i d (52 g; 0.50 mole) and a c e t i c j anhydride (60 mL; 0.60 mole). To the r e s u l t i n g suspension was added con c e n t r a t e d s u l f u r i c a c i d (1.5 mL) with c o n s t a n t s t i r r i n g and most of the malonic a c i d d i s s o l v e d with spontaneous c o o l i n g . Acetone (40 mL; 0.55 mole) was then i n t r o d u c e d s l o w l y while c o o l i n g to 20-25° and the r e a c t i o n mixture was allowed to stand i n the f r i d g e o v e r n i g h t . The r e s u l t a n t c r y s t a l s were f i l t e r e d by s u c t i o n , washed with i c e water (3 x 75 mL), then allowed to a i r d r y . The r e s u l t i n g white s o l i d was d i s s o l v e d i n acetone (110 mL), f i l t e r e d to remove any u n d i s s o l v e d m a t e r i a l , then d i l u t e d with water (220 mL). F i l t r a t i o n gave a f l o c c u l e n t white s o l i d which was d r i e d i n a vacuum d e s s i c a t o r over phos-phorus pentoxide, wt 35 g ( 4 9 % ) : mp 93-94° ( l i t . 1 4 6 94-95° d e c ) ; IR 1790 and 1755 cm" 1; NMR 6 1.78 (s, 6H), 3.57 (s, 2H) ; mass spectrum m/e ( r e l i n t e n s i t y ) 144 ( 1 ) , 129 (100), 100 ( 8 8 ) , 72 ( 2 0 ) , 69 ( 7 2 ) , 61 ( 4 0 ) , 59 ( 3 5 ) , and 58 ( 3 4 ) . 226 5-(1'-Hydroxye thylidene)-2, 2-dimethyl-1,3-dioxane-4,6-dione (253) A 250-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum was charged with 246 (10.0 g; 69.4 mmole) and dry dichloromethane (150 mL). The s o l u t i o n was then c o o l e d to 0° i n an i c e water bath and dry p y r i d i n e (10.99 g; 139 mmole) was added i n one p o r t i o n . Upon s t i r r i n g f o r 10 minutes, a c e t y l c h l o r i d e (6.0 g; 76 mmole) was i n t r o d u c e d dropwise and the r e a c t i o n mixture was allowed to stand at 0° f o r 1 hour, then a t room temperature f o r 1 hour. The dichloromethane, s o l u t i o n was washed with 5% h y d r o c h l o r i c a c i d (2 x 25 mL), water (2 x 50 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s -sure f o l l o w e d by r e c r y s t a l l i z a t i o n from e t h y l ether gave 10.5g (81%) of 253 as a pale y e l l o w s o l i d . An a n a l y t i c a l sample was prepared by s u b l i m a t i o n (60°/0.35 t o r r ) and had the f o l l o w i n g p r o p e r t i e s : mp 83.5-84.5°; IR 1740 and 1665 cm - 1; NMR 6 1.75 (s, 6H), 2.67 (s, 3H), 15.0 (bs, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 186 (47), 171 (17), 128 (100), 111 (16), 85 (36), 84 (55) and 69 (36). A n a l . C a l c d f o r CgH^C^: C, 51.61; H, 5.41. Found: C, 51.82; H, 5.22. 227 4 - C h l o r o - l - b u t a n o l (254c) A 250-mL three-necked round bottom f l a s k equipped with a r e f l u x condenser, mechanical s t i r r e r and a p r e s s u r e - e q u a l i z i n g dropping f u n n e l was charged with 1,4-butanediol (20 g; 0.22 mole) and dry p y r i d i n e (17.6g; 0.22 mole). The f l a s k was p l a c e d i n a water bath maintained a t 55° and t h i o n y l c h l o r i d e (26.4 g; 0.22 mole) was added dropwise over 1 hour. The temper-ature of the water bath was then r a i s e d to 80° f o r 1 hour as s u l f u r d i o x i d e was vented down the d r a i n by means of a rubber hose. On workup, the r e a c t i o n mixture was c o o l e d and e x t r a c t e d with ether (3 x 100 mL). The e t h e r e a l e x t r a c t s were washed with 5% h y d r o c h l o r i c a c i d (50 mL), water (50 mL), b r i n e (50 mL), then d r i e d over anhydrous magnesium s u l f a t e . The s o l v e n t was removed under reduced p r e s s u r e and the r e s i d u e f r a c t i o n a l l y d i s -t i l l e d to g i v e 8.7 g,. (36%) of 254c as a c o l o u r l e s s l i q u i d ; bp 67-69°/5.0 t o r r ( l i t . 1 5 0 84-85°/16 t o r r ) ; IR 3620, 3450 and 2950 cm - 1; NMR 6 1.70-2.00 (m, 4H), 2.65 (s, IH), and 3.43-3.72 (m, 4H); mass spectrum m/e ( r e l i n t e n s i t y ) 108 (1), 92 (14), 90 (59), 71 (100), 62 (23), 57 (13), 55 (78) and 29 (13). 6-Chloro-2-hexanone A o n e - l i t e r two-necked round bottom f l a s k equipped with a l a r g e magnetic s t i r r i n g bar and an a d d i t i o n f u n n e l was charged with a s o l u t i o n of sodium h y p o c h l o r i t e i n water (400 mL of a 5% s o l u t i o n ) . The f l a s k was c o o l e d to 0° i n an i c e water bath 228 and 1-methylcyclopentanol (10 g; 0.10 mole) in carbon t e t r a -c h l o r i d e (2.0 mL) added dropwise. Upon complete a d d i t i o n , a s o l u t i o n of g l a c i a l a c e t i c a c i d (40 mL) i n carbon t e t r a c h l o r i d e (5 mL),was introduced and the r e a c t i o n mixture v i g o r o u s l y s t i r r e d f o r 5h hours. The separated g r e e n i s h - y e l l o w carbon t e t r a c h l o r i d e L l a y e r w a s combined with carbon t e t r a c h l o r i d e e x t r a c t s of the aqueous phase (3 x 10 mL), then washed with a s a t u r a t e d sodium carbonate s o l u t i o n (2 x 10 mL) and d r i e d over anhydrous magnesium s u l f a t e . Removal of the d r y i n g agent by f i l t r a t i o n l e f t 1 - m e t h y l c y c l o p e n t y l h y p o c h l o r i t e i n carbon t e t r a c h l o r i d e s o l u t i o n , ready f o r the rearrangement s t e p . The carbon t e t r a c h l o r i d e s o l u t i o n was r e f l u x e d for 1% hours then the s o l v e n t removed under reduced p r e s s u r e . Excess s a t u r a t e d aqueous sodium b i s u l f i t e was added and the r e s u l t i n g a d d i t i o n compound was washed with ether (25 mL) then decomposed with warm aqueous sodium carbonate s o l u t i o n . The aqueous l a y e r was e x t r a c t e d with ether (2 x 50 mL) and the e t h e r e a l s o l u t i o n d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s s u r e f o l l o w e d by vacuum d i s t i l l a t i o n gave 4.0 g (30%) of 6-chloro-2-hexanone as a c o l o u r l e s s l i q u i d : bp 64-66°/3.8 t o r r ( l i t . 1 5 1 a 52.5-54°/2.3 t o r r ) ; IR 1710 cm - 1; NMR 6 1.60-1.90 (m, 4H), 2.16 (s, 3H), 2.48 ( t , 2H, J = 7 Hz), and 3.52 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 136 (0.25), 134 (0.75), 118 (6), 99 (13), 98 (46), 71 (21), 58 (100) and 55 (58). 229 6-Chloro-2-hexanol (254d) A 50-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and a g l a s s stopper was charged with 6-chloro-2-hexanone (4.0 g; 30 mmole) and e t h a n o l (25 mL). The f l a s k was c o o l e d to 0° i n an i c e water bath and sodium borohydride (1.13 g; 30 mmole) was added s l o w l y i n p o r t i o n s . Upon complete a d d i t i o n , the i c e bath was removed and the r e a c t i o n mixture was allowed to stand f o r Ah hours a t room temperature. On workup, the e t h a n o l was removed under reduced pressure and 5% hydro-c h l o r i c a c i d s o l u t i o n was added c a u t i o u s l y to the r e s i d u e . The aqueous s o l u t i o n was then e x t r a c t e d with ether (4 x 25 mL) and the combined o r g a n i c e x t r a c t s were washed with water (20 mL), and b r i n e (20 mL). The e t h e r e a l s o l u t i o n was d r i e d over anhydrous magnesium s u l f a t e then the s o l v e n t was removed under reduced p r e s s u r e l e a v i n g 254d as a y e l l o w l i q u i d . Vacuum d i s -t i l l a t i o n o f the crude m a t e r i a l gave 2.8 g (70%) of 254d as a c o l o u r l e s s l i q u i d : bp 78-79°/2.3 t o r r ( l i t . 1 5 1 b 58°/l.l t o r r ) ; IR 3620 and 3470 cm" 1; NMR 6 1.17 (d, 3H, J = 6 Hz), 1.30-1.90 (m, 6H), 2.07 (s, IH, exchanged with D 2 0 ) , 3.50 ( t , 2H, J = 7 Hz), and 3.50-3.90 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 136 (1), 123 (28), 121 (100), 102 (17), 85 (56), 67 (53), 57 (48) , 56 (46) and 55 (100) . 230 General procedure f o r the a l c o h o l y s i s of 252. A 50-mL si n g l e - n e c k e d round bottom f l a s k equipped with a r e f l u x condenser f i t t e d with a n i t r o g e n i n l e t was charged with 253 (1.2 e q u i v a l e n t ) , the a p p r o p r i a t e a l c o h o l (1.0 e q u i v a l e n t ) and dry t e t r a h y d r o f u r a n (25 mL). The r e a c t i o n mixture was heated to r e f l u x f o r 4 hours, then c o o l e d to room temperature and t r a n s f e r r e d to a s e p a r a t o r y f u n n e l c o n t a i n i n g 50 mL of e t h e r . The s o l u t i o n was washed with s a t u r a t e d sodium bicarbonate s o l u t i o n (1 x 15 mL), water (1 x 15 mL) and b r i n e (1 x 10 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave the crude g-keto e s t e r s . (2 '-Bromo-1 '-ethyl) -3-oxobutanoate (,2,55a) T h i s compound was prepared according to the g e n e r a l pro-cedure u s i n g 253 (3.6 g; 19.4 mmole) and 2-bromoethanol (1.99 g; 16.0 mmole). D i s t i l l a t i o n of the crude m a t e r i a l gave 2.27 g (67%) of 255a as a c o l o u r l e s s l i q u i d : bp 62-64°/0.18 t o r r ; IR 1755 and 1725 cm" 1; NMR 6 2.27 (s, 3H), 3.46 (s, 2H), 3.48 ( t , 2H, J = 6 Hz) and 4.40 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 210 (19), 208 (19), 168 (30), 166 (29), 129 (52), 109 (100), 107 (100) and 102 (59). A n a l . C a l c d f o r CgHgO^r: C, 34.47; H, 4.34. Found: C, 34.66; H, 4.29. 231 (3'-Bromo-1'-propyl)-3-oxobutanoate (25 5b) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure u s i n g 253 (1.20 g; 6.45 mmole) and 3-bromo-l-propanol (742 mg; 5.34 mmole). Vacuum d i s t i l l a t i o n of the crude m a t e r i a l gave 953 mg (80%) of 255b as a c o l o u r l e s s l i q u i d : bp 80-82°/ 0.40 t o r r ; IR 1745, 1720 and 1663 cm - 1; NMR 6 2.27 (s, 3H), 1.93-2.36 (in, 2H) , 3.43 ( t , 2H, J = 6 Hz), 3.43 (s, 2H) and 4.25 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 224 (32), 222 (32), 206 (24), 204 (24), 187-188 (m*, = 187.5), 189-190 (M*,2~f = 189 .5), 182 (78), 180 (78), 143 (100), 123 (48), 122 (77), 121 (48), 120 (78), 103 (73), 102 (53) and 101 (35). A n a l . C a l c d f o r C ^ ^ B r : C, 37.69; H, 4.97. Found: C, 37.65; H, 5.10. (4 ' - C h l o r o - l ' - b u t y l ) -3-oxobutanoate ( ? ^ c ) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r a l c o h o l y s i s u s i n g 253 (3. 60 g; 19.2 mmole) and 254c (1.72 g; 1.6.0 mmole). Vacuum d i s t i l l a t i o n of the crude mate-r i a l gave 2.44 g (79%) of 255c as a c o l o u r l e s s l i q u i d : bp 87-88°/0.18 t o r r ; IR 1745 and 1720 cm - 1; NMR <S 1.70-1.90 (m, 4H), 2.26 (s, 3H), 3.43 (s, 2H), 3.50 ( t , 2H, J = 5.5 Hz) and 4.13 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 194 (9), 192 (18), 157 (12), 152 (11), 150 (33), 116 (17), 115 (23), 103 (100) , and 102 (53) . 232 A n a l . C a l c d f o r CgH^O^Cl: C, 49 .88 ; H, 6.80. Found: C, 49.82; H, 6.91. (6'-Chloro-2'-hexyl)-3-oxobutanoate (255d) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (4.62 g; 2.48 mmole) and 254d (2.80 g; 2.06 mmole). Vacuum d i s t i l l a t i o n of the crude mate-r i a l gave 3.82 g (85%) of 255d as a c o l o u r l e s s l i q u i d : bp 96-98°/0.20 t o r r ; IR 1740 and 1715 cm - 1; NMR 6 1.27 (d, 3H, J = 6 Hz), 1.40-2.00 (m, 6H), 2.23 (s, 3H), 3.41 (s, 2H), 3.48 ( t , 2H, J = 6 Hz) and 4.77-5.07 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 222 (0.70), 220 (2), 118 (58), 103 (74), and 85 (100) . A n a l . C a l c d f o r C ^ H ^ C ^ C l : C, 54.42; H, 7.76. Found: C, 54.44; H, 7.79. (2'-Propen-l'-yl)-3-oxobutanoate (257) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r a l c o h o l y s i s u s i n g 253 (2.40 g; 12.9 mmole) and 2- p r o p e n e - l - o l (624 mg; 10.8 mmole). Vacuum d i s t i l l a t i o n o f the crude m a t e r i a l gave 1.37 g (90%) of 257 as a c o l o u r l e s s l i q u i d : bp 71-72°/25 t o r r ; IR 1742, 1715 and 1650 cm - 1; NMR 6 2.24 (s, 3H), 3.45 (s, 2H) , 4.57 (d, 2H, J = 5 Hz) and 233 5.00-6.17 (m, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 142 (9), 100 (15), 84 (100) and 58 (100). A n a l . C a l c d f o r C ^ g C ^ : C, 59.14; H, 7.09. Found: C, 59.24; H, 7.16. Attempted c y c l i z a t i o n of (3'-bromo-1'-propyl)-3-oxobutanoate  (255b) A s o l u t i o n of d i i s o p r o p y l a m i n e (222 mg; 2.20 mmole) i n dry t e t r a h y d r o f u r a n (12 mL) was prepared i n a 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum. The f l a s k was cooled to 0° i n an i c e water bath and n - b u t y l l i t h i u m as a 1.43 M s o l u t i o n i n hexane (1.55 mL; 2.20 mmole) was added dropwise. The c o l o u r l e s s to pale y e l l o w s o l u t i o n was s t i r r e d f o r 10 minutes and a s o l u t i o n of 255b (223 mg ; 1.00 mmole) i n t e t r a h y d r o f u r a n (3 mL) was i n t r o d u c e d . The r e a c t i o n mixture was allowed to s t i r f o r 30 minutes, then water (3 mL) and ether (5 mL) were added. The o r g a n i c phase was separated, washed with water ( 2 x 5 mL) and b r i n e (5 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , f o l l o w e d by p u r i f i c a t i o n gave 82.5 mg (58%) of a p a l e y e l l o w o i l which e x h i b i t e d 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 those r e p o r t e d above f o r compound 257. 234 (4'-Chloro-1'-butyl)-3-oxopentanoate (258) A 25-mL two-necked round bottom f l a s k equipped with a n i t r o g e n i n l e t and stoppered with a rubber septum was charged with d i i s o p r o p y l a m i n e (223 mg; 2.. 2.0 mmole) and dry t e t r a h y d r o -furan (12 mL). The f l a s k was co o l e d to 0° i n an i c e water bath and n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (1.38 mL; 2.20 mmole) was added dropwise. The c o l o u r l e s s to pale y e l l o w s o l u -t i o n was then allowed to s t i r f o r 15 minutes to ensure complete formation of the base. A s o l u t i o n of 255c (19 3 mg; 1.00mmole) in dry t e t r a h y d r o f u r a n (3 mL) was introduced and upon s t i r r i n g f o r an a d d i t i o n a l 30 minutes the r e a c t i o n mixture was quenched with methyl i o d i d e (143 mg; l.QOmmole). On workup, the s o l u t i o n was t r e a t e d with 5% h y d r o c h l o r i c a c i d s o l u t i o n u n t i l a c i d i c then d i l u t e d with ether (25 mL). The e t h e r e a l l a y e r was sepa r a t e d , washed with water (10 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s -sure gave 258 as a y e l l o w o i l . P r e p a r a t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l u s i n g c h l o r o f o r m as s o l v e n t gave 155 mg (75%) of 2 58 as a c o l o u r l e s s l i q u i d : Rf 0.41; bp (Kugelrohr d i s t i l l a t i o n ) 70-72°/0.13 t o r r ; IR 1745 and 1718 cm - 1; NMR 6 1.09 ( t , 3H, J = 7 Hz), 1.85 (m, 4H), 2.56 ( q ? 2H, J = 7 Hz), 3.46 (s, 2H), 3.58 ( t , 2H, J = 6 Hz), and 4.20 ( t , 2H, J = 6 Hz); 235 mass spectrum m/e ( r e l i n t e n s i t y ) 208 (3), 206 (7), 171 (5), 116 (8), 98 (15), 93 (37) and 91 (100). A n a l . C a l c d f o r C g H ^ C ^ C l : C, 52.30; H, 7.32. Found: C, 52.30; H, 7.39. (4'-Iodo-1'-butyl)-3-oxobutanoate (259) A 100-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and a n i t r o g e n i n l e t was charged with 255c (1.93 g; 10.0 mmole), sodium i o d i d e (6.0 g; 40.0 mmole) and acetone (50 mL). The r e a c t i o n mixture was heated to r e f l u x f o r 20 hours then c o o l e d to room temperature. The acetone was removed under reduced pressure and e t h e r (50 mL) added. The e t h e r e a l s o l u t i o n was washed with water (3 x 20 mL) and b r i n e (20 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t gave 259 as a y e l l o w l i q u i d . D i s t i l l a t i o n of the crude m a t e r i a l a f f o r d e d 2.56 g (90%) of 259 as a c o l o u r l e s s l i q u i d : bp 96-100°/0.25 t o r r ; IR 1740 and 1720 cm - 1; NMR 6 1.77-1.92 (m, 4H), 2.25 (s, 3H), 3.18 ( t , 2H, J = 7 Hz), 3.43 (s, 2H), and 4.12 ( t , 2H, J = 5 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 284 (2), 183 (70), 157 (82), 103 (75) and 85 (100). High R e s o l u t i o n Mass Measurement C a l c d f o r CgH^O^I: 283.9910. Found: 283.9902. 236 5-Acetoxy-l-broinopentane (265) A 50-mL two-necked round bottom f l a s k equipped with a r e f l u x condenser and a n i t r o g e n i n l e t was charged with anhydrous z i n c c h l o r i d e (ca. 20 mg) and tetrahydropyran (8.61 g; 0.10 mole). The f l a s k was then c o o l e d to 0° i n an i c e water bath and a c e t y l bromide (7.99 g; 0.065 mole) was i n t r o d u c e d dropwise. Upon complete a d d i t i o n , the r e a c t i o n mixture was allowed to stand f o r 0.5 hour at 0°, then warmed to room temperature over 1 hour and r e f l u x e d f o r 2 hours. The s o l u t i o n was cooled and d i l u t e d with c h l o r o f o r m (100 mL). The o r g a n i c l a y e r was washed with water (20 mL), s a t u r a t e d sodium bicarbonate s o l u t i o n (20 mL), water (20 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure followed by vacuum d i s t i l l a t i o n of the crude m a t e r i a l gave 11.0 g (88%) of 265 as a c o l o u r l e s s l i q u i d : bp 89-91°/4.5 t o r r ( l i t . 1 3 3 106-107°/ 12 t o r r ) ; IR 1720 cm - 1; NMR 6 1.53-2.10 (m, 6H), 2.03 (s, 3H), 3.37 ( t , 2H, J = 7 Hz) and 4.03 ( t , 2H, J = 6 Hz); mass spec-trum m/e ( r e l i n t e n s i t y ) 210 (0.5), 208 (0.5), 150 (35), 148 (35), 73 (18), 69 (100), 68 (28) and 61 (45). 5-Bromo-l-pentanol (261a) A s o l u t i o n of 265 (10.8 g; 0.052 mole) i n dry methanol (150 mL) was prepared i n a 250-mL si n g l e - n e c k e d round bottom f l a s k equipped with a n i t r o g e n i n l e t . Anhydrous potassium c a r -bonate (16 g; 0.116 mole) was then added i n p o r t i o n s and the 237 r e s u l t i n g suspension was s t i r r e d v i g o r o u s l y f o r 4 hours a t room temperature. D i l u t e h y d r o c h l o r i c a c i d was added u n t i l the mix-ture became a c i d i c and the s o l u t i o n was e x t r a c t e d with e t h y l a c e t a t e (3 x 100 mL). The combined o r g a n i c e x t r a c t s were washed with water (50 mL) and b r i n e (50 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s s u r e , f o l l o w e d by vacuum d i s t i l l a t i o n of the crude m a t e r i a l gave 5.71 g (66%) of 261a as a c o l o u r l e s s l i q u i d : bp 53-56°/0.20 t o r r ( l i t . 1 5 4 75-76°/0.5 t o r r ) ; IR 3620 and 3400 cm - 1; NMR 6 1.30-2.03 (m, 6H), 2.50 (s, IH, exchanged with D 2 0 ) , 3.40 ( t , 2H, J = 6 Hz) and 3.60 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 168 (0.1), 166 (0.1), 150 (4), 148 (4), 137 (5), 135 (5), 122 (1), 120 (1), 109 (2), 107 (2), 88 (2), 86 (2), 70 (9), 69 (100), 68 (16), 57 (10), 56 (13) and 55 (26). (5'-Bromo-1'-pentyl)-3-oxobutanoate (262a) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r a l c o h o l y s i s u s i n g 253 (2.23 g; 12.0 mmole) and 261a (1.67 g; 10.0 mmole). Vacuum d i s t i l l a t i o n of the crude m a t e r i a l gave 1.87 g (74%) of 262a as a c o l o u r l e s s l i q u i d : bp 98-99°/ 0.2 t o r r ; IR 1740, 1720 and 1660 cm" 1; NMR 6 1.50-2.00 (m, 6H), 2.27 (s, 3H), 3.40 ( t , 2H, J = 7 Hz), 3.45 (s, 2H), and 4.13 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 252 (0.6), 238 250 ( 0 . 6 ) , 210 ( 0 . 3 ) , 208 ( 0 . 3 ) , 171 ( 1 ) , 150 ( 7 ) , 148 ( 1 0 ) , 103 ( 3 8 ) , 85 ( 3 3 ) , and 69 (100). H i g h R e s o l u t i o n Mass Measurement C a l c d f o r CgH^^O^Br: 252.0184, 250.0205. Found: 252.0175, 250.0205. G e n e r a l p r o c e d u r e f o r the p r e p a r a t i o n o f ( l , n ) b r o m o a l c o h o l s  (n=6-10) from ( l , n ) - d i o l s A s o l u t i o n o f the d i o l i n 48% HBr was p l a c e d i n a 100-mL l i q u i d - l i q u i d e x t r a c t o r . The s o l u t i o n was then heated i n an o i l b a t h w h i l e b e i n g c o n t i n u o u s l y e x t r a c t e d w i t h an a p p r o p r i a t e s o l v e n t . On workup, the s o l u t i o n was c o o l e d and the o r g a n i c l a y e r s e p a r a t e d , washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u -t i o n , w a t e r , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced p r e s s u r e gave the crude b r o m o a l c o h o l s , which were f u r t h e r p u r i f i e d by vacuum d i s t i l l a -t i o n . 6-Bromo-l-hexanol (2J51fcO 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 the g e n e r a l p r o -cedure f o r b r o m o a l c o h o l f o r m a t i o n u s i n g 1 , 6 - h e x a n e d i o l (6.00 g; 50.9 mmole) and 48% h y d r o c h l o r i c a c i d (12 mL). The s o l u t i o n was he a t e d t o 75-80° and the e x t r a c t i o n was c o n t i n u e d f o r 39 hours u s i n g t o l u e n e (50 mL) as s o l v e n t . D i s t i l l a t i o n of the crude p r o d u c t gave 5.16 g (56%) of 261b as a c o l o u r l e s s l i q u i d : bp 59-62°/0.10 t o r r ( l i t . 1 5 5 105-106°/5.0 t o r r ) ; IR 3620 and 239 3450; NMR 6 1.30-2.00 (m, 8H), 2.27 (s, IH, exchanged with D 2 0 ) , 3.43 ( t , 2H, J = 7 Hz) and 3.63 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 164 (6), 162 (6), 136 (14), 134 (14), 83 (63), 32 (16) and 55 (100). 7- Bromo-l-heptanol (261c) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r bromoalcohol formation u s i n g 1,7-heptanediol (7.0 g; 53.0 mmole) and 48% hydrobromic a c i d (36 mL). The s o l u t i o n was heated to 75-80° and the e x t r a c t i o n was continued f o r 16 hours u s i n g toluene (100 mL) as s o l v e n t . D i s t i l l a t i o n of the crude product gave 4.85 g (47%) of 261c as a c o l o u r l e s s l i q u i d : bp 107-108°/4.0 t o r r ( l i t . 1 5 6 lll-112°/4 t o r r ) ; IR 3640 and 3450 cm - 1; NMR 6 1.30-2.00 (m, 10H), 3.02 (s, IH, exchanged with D 2 0 ) , 3.37 ( t , 2H, J = 6 Hz) and 3.60 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 195 (1), 193 (1), 150 (24), 148 (24), 97 (22), 69 (48), 68 (20) and 55 (100). 8- Bromo-l-octanol (2 6Id) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r bromoalcohol formation u s i n g 1,8-octanediol (6.0 g; 41.2 mmole) and 48% hydrobromic a c i d (6 mL). The s o l u t i o n was heated to 90° and the e x t r a c t i o n was continued f o r 72 hours using toluene (100 mL)as s o l v e n t . The crude m a t e r i a l was d i s -t i l l e d and gave 3.86 g (45%) of 26Id as a c o l o u r l e s s l i q u i d : 240 bp 95-100°/0.27 t o r r ( l i t . 1 5 7 bp 77-78°/0.01 t o r r ) ; IR 3620 and 3450; NMR 6 1.10-2.00 (m, 12H), 2.08 (s, IH, exchanged with D 2 0 ) , 3.40 ( t , 2H, J = 7 Hz) and 3.58 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 192 (3), 190 (3), 164 (14), 162 (14), 150 (14), 148 (14), 111 (11), 82 (38), 69 (80), 68 (34), 67 (14), 56 (20), and 55 (100). 9-Bromo-l-nonanol (261e) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r bromoalcohol formation u s i n g 1,9-nonanediol (6.0 g; 37.4 mmole) and 48% hydrobromic a c i d (8 mL). The s o l u t i o n was heated to 90° and the e x t r a c t i o n was continued f o r 72 hours u s i n g toluene (100 mL) as s o l v e n t . The crude m a t e r i a l was d i s -t i l l e d and gave 3.19 g (38%) of 261e as a c o l o u r l e s s l i q u i d : bp 92-94°/0.06 t o r r ( l i t . 1 5 8 bp 97-100°/0.06 t o r r ) ; IR 3630 and 3450; NMR 6 1.27-2.00 (m, 14H), 2.00 (s, IH, exchanged with D 2 0 ) , 3.35 ( t , 2H, J = 7 Hz), and 3.57 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 206 (1), 204 (1), 169 (3), 167 (3), 150 (11), 148 (11), 137 (35), 135 (35), 97 (43), 69 (80), 68 (20), 57 (13), 56 (16), and 55 (100). 10-Bromo-l-decanol (261f) T h i s compound was prepared a c c o r d i n g t o the g e n e r a l pro-cedure f o r bromoalcohol formation u s i n g 1,10-decanediol (6.0 g; 34.4 mmole) and 48% hydrobromic a c i d (27 mL). The s o l u t i o n was 241 heated to 90-95° and the e x t r a c t i o n was continued f o r 65 hours using petroleum e t h e r , bp 100-115°, (100 mL) as s o l v e n t . Vacuum d i s t i l l a t i o n gave 5.33 g (65%) of 261f as a c o l o u r l e s s l i q u i d : bp 115-117°/0.30 t o r r ( l i t . 1 5 9 166-169°/10 t o r r ) ; IR 3625 and 3445 cm" 1; NMR 6 1.33-2.00 (m, 16H), 3.10 (s, IH, exchanged with D 2 0 ) , 3.37 ( t , 2H, J = 7 Hz) and 3.58 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 220 (1), 218 (1), 192 (3), 190 (3), 164 (6), 162 (6), 150 (28), 148 (.28), 137 (16), 135 (16), 97 (26), 69 (90), 68 (25), 57 (20), 56 (20) and 55 (100). (6'-Bromo-1*-hexyl)-3-oxobutanoate (262b) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (2.47 g; 13.3, mmole) and 261b (2.00 g; 11.1 mmole). S o l v e n t removal gave 2.53 g (86%) of crude 262b as a y e l l o w l i q u i d which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC on s i l i c a g e l u s i n g 3:1 ether-petroleum ether and gave 262b as a c o l o u r l e s s l i q u i d : Rf 0.75; bp (Kugelrohr d i s t i l l a t i o n ) 97-100°/ 0.12 t o r r ; IR 1740 and 1718 cm" 1; NMR 6 1.30-1.96 (m, 8H), 2.28 (s, 3H), 3.44 ( t , 2H, J = 7 Hz), 3.48 (s, 2H), and 4.18 ( t , 2H, J = 6.5 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 266 (0.1), 264 (0.1), 164 (3), 162 (3), 103 (100), 85 (44), 83 (81), and 55 (73). A n a l . C a l c d f o r C 1 Q H 1 7 0 3 B r : C, 45.30; H, 6.46. Found: C, 45.82; H, 6.70. 242 High R e s o l u t i o n Mass Measurement Calc d f o r C^gH^O^Br: 266.0341. Found: 266.0346. (7'-Bromo-1'-heptyl)-3-oxobutanoate (262c) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (1.92 g; 10.30 mmole) and 261c (1.67 g; 8.56 mmole). S o l v e n t removal gave 2.02 g (84%) of crude 262c as a pale y e l l o w l i q u i d which was homogeneous by TLC. A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC on s i l i c a g e l u s i n g ether as s o l v e n t and gave 262c as a c o l o u r l e s s l i q u i d : Rf 0.81; bp (Kugelrohr d i s t i l l a t i o n ) 120-125°/0.50 t o r r ; IR 1735 and 1710 cm - 1; NMR 6 1.30-1.98 (m, 10H), 2.30 (s, 3H), 3 a-4 4 ( t , 2H, J = 7 Hz), 3.49 (s, 2H) , and 4.18 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 280 (<0.1), 2.78 (<0.1), 188 (2), 186 (2), 150 (4), 148 (4), 137 (1), 135 (1), 103 (100), 97 (42), 85 (30), 69 (20) and 55 (70). A n a l . C a l c d f o r c 1 1 H 1 9 ° 3 B r : C ' 47.32; H, 6.86. Found: C, 4 7.42; H, 6.77. (8'-Bromo-1•-octyl)-3-oxobutanoate (262d) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (1.07 g; 5.74 mmole) and 26Id (1.0 g; 4.78 mmole). Eva p o r a t i o n of the s o l v e n t gave 1.20 g (86%) of crude 262d as a y e l l o w l i q u i d which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e 243 TLC on s i l i c a g e l u s i n g 3:1 ether-petroleum ether and gave 262d as a c o l o u r l e s s l i q u i d : Rf 0.77; bp (Kugelrohr d i s t i l l a t i o n ) 115-118°/0.40 t o r r ; IR 1740 and 1713 cm" 1; NMR 6 1.14-1.97 (m, 12H) , 2.28 (s, 3H), 3.43 ( t , 2H, J = 7 Hz), 3.47 (s, 2H), and 4.17 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 294 (0.2), 292 (0.2), 213 (3), 192 (4), 190 (4), 164 (4), 162 (4), 150 (7), 148 (7), 137 (4), 135 (4), 111 (18), 103 (100), 85 (19), 69 (35), and 55 (21). A n a l . C a l c d f o r C 1 2 H 2 1 0 3 B r : C, 49.07; H, 7.38. Found: C, 49.29; H, 7.35. (9 1-Bromo-1 1-nonyl)-3-oxobutanoate (262e) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (1.0 g; 5.38 mmole) and 261e (1.0 g; 4.48 mmole). Ev a p o r a t i o n of the s o l v e n t gave 1.21 g (88%) of crude 262e as a y e l l o w l i q u i d , which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC on s i l i c a g e l u s i n g 3:1 ether-petroleum ether and gave 262e as a c o l o u r l e s s l i q u i d : Rf 0.78; bp (Kugelrohr d i s t i l l a -t i o n ) 110-113°/0.12 t o r r ; IR 1735 and 1710 cm" 1; NMR 6 1.30-1.96 (m, 14H), 2.27 (s, 3H), 3.42 ( t , 2H, J = 7 Hz), 3.46 (s, 2H) and 4.16 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 308 (0.1), 306 (0.1), 150 (1), 148 (1), 137 (1), 135 (1), 103 (100), 85 (18), 83 (9), 69 (21), and 55 (19). 244 High R e s o l u t i o n Mass Measurement C a l c d f o r c ^ 3 H 2 3 ° 3 B r : 308.0812, 306.0830. Found: 308.0814, 306.0832. (10'-Bromo-1'-decyl)-3-oxobutanoate (262f) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (2.0 g; 11.1 mmole) and 261f (2.0 g; 9.0 mmole). Removal of the s o l v e n t gave 2.49 g(92%) of crude 262f as a yellow o i l , which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC u s i n g 3:1 e t h e r -petroleum ether and gave 262f as a c o l o u r l e s s l i q u i d : Rf 0.79; bp (Kugelrohr d i s t i l l a t i o n ) 120-125°/0.12 t o r r ; IR 1740 and 1715 cm - 1; NMR 6 1.30-1.96 (m, 16H), 2.29 (s, 3H), 3.46 ( t , 2H, J = 7 Hz), 3.48 (s, 2H), and 4.17 ( t , 2H, J = 7 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 322 (0.1), 320 (0.1), 192 (13), 190 (14), 164 (36), 162 (34), 150 (67), 148 (68), 137 (44), 135 (46), 103 (100), 85 (88), 69 (99), 57 (72), 56 (82), 55 (100) and 54 (65) . A n a l . C a l c d f o r C 1 4 H 2 5 0 3 B r : C, 52.34; H, 7.84. Found: C, 52.75; H, 8.09. (11'-Bromo-1'-undecyl)-3-oxobutanoate (262g) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (1.78 g; 9.57 mmole) and 11-b r o m o - l - u n d e c a n o l 1 6 0 (2.00 g; 7.97 mmole). Workup as u s u a l gave 2.26 g (85%) of crude 262g as a y e l l o w l i q u i d , which was 245 homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC using c h l o r o f o r m as s o l v e n t and gave 262g as a c o l o u r l e s s l i q u i d : Rf 0.40; bp (Kugelrohr d i s t i l l a t i o n ) 135-140°/0.13 t o r r ; IR 1740 and 1715 cm" 1; NMR 6 1.25-1.95 (m, 18H) , 2.28 (s, 3H), 3.43 ( t , 2H, J = 7 Hz), 3.45 (s, 2H), and 4.15 (t , 2H, J = 6.5 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 336 (2), 334 (2), 318 (3), 316 (3), 255 (14), 164 (26), 162 (26), 150 (40), 148 (40), 85 (100) and 69 (100). A n a l . C a l c d f o r C 1 5 H 2 7 0 3 B r : C, 53.73; H, 8.12. Found: C, 53.92; H, 8.08. General procedure f o r the attempted c y c l i z a t i o n of B-keto  e s t e r s 262a-g A s o l u t i o n of d i i s o p r o p y l a m i n e (three e q u i v a l e n t s ) i n dry t e t r a h y d r o f u r a n was prepared i n a 200-mL two-necked round bottom f l a s k equipped with a p r e s s u r e - e q u a l i z i n g dropping f u n -n e l and a n i t r o g e n i n l e t . The f l a s k was c o o l e d to 0° i n an i c e water bath and n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (three e q u i v a l e n t s ) was added dropwise. The c o l o u r l e s s to pale y e l l o w s o l u t i o n was s t i r r e d f o r 10 minutes and a s o l u t i o n of the B-keto e s t e r bromide (one e q u i v a l e n t ) i n t e t r a h y d r o f u r a n was added dropwise. The r e a c t i o n mixture was then s t i r r e d f o r 5 hours and the s o l u t i o n was slowly allowed to warm to room temperature over t h i s p e r i o d . On workup, water and ether were added, and the or g a n i c phase was separate d . The or g a n i c 246 e x t r a c t was washed with water, b r i n e , then d r i e d over anhydrous magnesium., s u l f a t e . Removal of the s o l v e n t under reduced p r e s -sure gave the crude p r o d u c t s . (4'-Penten-l'-yl)-3-oxobutanoate (267a) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r c y c l i z a t i o n u s ing d i i s o p r o p y l a m i n e (1.52 g; 15.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (9.38 mL; 15.0 mmole), and 262a (1.27 g; 5.00 mmole). P u r i f i c a t i o n by column chromatography u s i n g c h l o r o f o r m as e l u e n t gave 353 mg (41%) of 267a as a c o l o u r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a -t i o n ) 40-42°/0.20 t o r r ; IR 1742, 1720 and 1645 cm" 1; NMR 6 1.63-2.19 (m, 4H), 2.28 (s, 3H), 3.46 (s, 2H), 4.19 ( t , 2H, J = 7 Hz), 4.97-5.16 (m, IH), and 5.64-7.03 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 170 (6), 103 (5), 85 (30), 69 (21), 68 (100) and 67 (35). A n a l . C a l c d f o r C gH 1 4C> 3: C, 63.51; H, 8.29. Found: C, 63.65; H, 8.30. (5'-Hexen-l'-yl)-3-oxobutanoate (267b) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.50 mL; 12.0 mmole), and 262b (1.06 g; 4.0 mmole). P u r i f i c a t i o n by f l a s h chromatography u s i n g petroleum e t h e r - e t h y l acetate (9:1) 247 as e l u e n t gave 331 mg (45%) of 267b as a c o l o u r l e s s l i q u i d : bp 40-45°/0.20 t o r r ; IR 1735, 1718 and 1645 cm - 1; NMR 6 1.26-1.80 (m, 4H), 1.92-2.20 (m, 2H), 2.28 (s, 3H), 3.46 (s, 2H), 4.18 (t , 2H, J = 6 Hz), 4.93-5.12 (m, 2H), and 5.64-7.04 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 184 (0.3), 137 (8), 103 (10), 85 (43), 82 (100), 67 (59), 56 (44) and 55 (85). A n a l . C a l c d f o r C 1 0 H i 6 O 3 : C, 65.19; H, 8.75. Found: C, 65.36; H, 8.90. (6'-Hepten-1'-yl)-3-oxobutanoate (267c) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.50 mL; 12.0 mmole), and 262c (1.12 g; 4.00 mmole). F l a s h chromatog-raphy of the crude m a t e r i a l u s i n g petroleum e t h e r - e t h y l acetate (9:1) as e l u e n t gave 457 mg (57%) of 267c as a c o l o u r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 45-48°/0.23 t o r r ; IR 1735, 1718 and 1635 cm" 1; NMR 6 1.26-1.80 (m, 6H), 1.94-2.12 (m, 2H) , 2.28 (s, 3H) , 3.45 (s, 2H) , 4.16 ( t , 2H, J = 6 Hz), 4.92-5.09 (m, 2H), and 5.63-7.03 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 198 (0.1), 102 (72), 96 (63), 85 (67), 81 (41), 69 (25), 68 (59), 67 (69), 56 (28), 55 (100), and 54 (74). A n a l . C a l c d f o r C ^ H ^ C ^ : C, 66.64; H, 9.15. Found: C, 66.71; H, 9.25. 248 (7'-Octen-l'-yl)-3-oxobutanoate (267d) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.5 mL; 12.0 mmole), and 262d (1.17 g; 4.0 mmole). F l a s h chromatog-raphy of the crude m a t e r i a l u s i n g petroleum e t h e r - e t h y l acetate (9:1) as e l u e n t gave 348 mg (41%) of 267d as a c o l o u r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 60-63°/0.4 t o r r ; IR 1740, 1718, and 1650 cm" 1; NMR 6 1.26-1.85 (m, 8H), 1.93-2.10 (m, 2H), 2.28 (s, 3H), 3.46 (s, 2H), 4.17 ( t , 2H, J = 6 Hz), 4.93-5.10 (m, 2H), and 5.66-7.04 (m, IH); mass spectrum m/e ( r e l i n t e n -s i t y ) 212 (0.1), 103 (87), 95 (20), 85 (87), 82 (50), 81 (58), 69 (100), 68 (84), 67 (80), 66 (11), 56 (79) and 55 (100). A n a l . C a l c d f o r C 1 2 H 2 0 ° 3 : C, 67.89; H, 9.50. Found: C, 67.94; H, 9.55. 3 - O x o t r i d e c a n o l i d e (266e) T h i s compound was prepared a c c o r d i n g t o the g e n e r a l p r o -cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.5 mL; 12.0 mmole), and 262e (1.23 g; 4.0 mmole). P u r i f i c a t i o n by f l a s h chromatography u s i n g petroleum e t h e r - e t h y l acetate (9:1) as e l u e n t gave 389 mg (43%) of 266e as a c o l o u r l e s s s e m i - s o l i d : s u b l i m a t i o n temperature 103-105°/0.18 t o r r ; IR 1750 and 1725 cm - 1; NMR 6 1.25-1.81 (m, 16H), 2.61 ( t , 2H, J = 7 Hz), 3.44 249 (s, 2H) , and 4.24 ( t , 2H, J = 5 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 226 (8), 208 (6), 124 (23), 103 (25), 82 (36), 69 (46), 67 (29), 56 (23), and 55 (100). A n a l . C a l c d f o r C 1 3 H 2 2 ° 3 : C, 68.99; H, 9.80. Found: C, 68.78; H, 9.8 4. 3-0xotetradecanolide (266f) T h i s compound was prepared a c c o r d i n g to the g e n e r a l p r o -cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.5 mL; 12.0 mmole), and 262f (1.28 g; 4.0 mmole). P u r i f i c a t i o n by f l a s h chromatography u s i n g petroleum e t h e r - e t h y l a c e t a t e (9:1) as e l u e n t gave 432 mg (45%) of 266f as a c o l o u r l e s s semi-s o l i d : bp (Kugelrohr d i s t i l l a t i o n ) 85-88°/0.l0 t o r r ; IR 1742 and 1718 cm" 1; NMR 6 1.20-1.82 (m, 18H), 2.57 ( t , 2H, J = 7 Hz), 3.46 (s, 2H), and 4.22 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n s i t y ) 240 (1), 148 (17), 103 (19), 96 (24), 83 (19), 82 (31), 81 (20), 69 (33), 68 (28), 67 (27), 56 (14), 55 (100) and 54 (17). A n a l . C a l c d f o r C 1 4 H 2 4 ° 3 : C ' 6 9 - 9 6 ' H ' 10.07. Found: C, 70.00; H, 10.14. 3-0xopentadecanolide (266g) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r c y c l i z a t i o n u s i n g d i i s o p r o p y l a m i n e (1.21 g; 12.0 250 mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n i n hexane (7.5 mL; 12.0 mmole), and 262g (1.34 g; 4.0 mmole). F l a s h chromatog-raphy of the crude product u s i n g petroleum e t h e r - e t h y l a c e t a t e (7:1) as e l u e n t gave 498 mg (49%) of 266g as a c o l o u r l e s s semi-s o l i d : s u b l i m a t i o n temperature 110-113°/0.25 t o r r ; IR 1735 and 1710 cm" 1; NMR 6 1.20-1.80 (m, 20H), 2.56 ( t , 2H, J = 6.5 Hz), 3.46 (s, 2H), and 4.22 ( t , 2H, J = 5 Hz); mass spectrum m/e o o c 2 ( r e l i n t e n s i t y ) 254 (26), 236 (22), 219-220 (m*, 4 j ~ - = 219.3), 152 (55), 103 (100), 95 (68), and 55 (91). A n a l . C a l c d f o r C 1 5 H 2 g 0 3 : C, 70.83; H, 10.30. Found: C, 70.65; H, 10.17. 10-Acetoxy-l-decanol ( 2 8 0 ) 1 6 8 A s o l u t i o n o f 1,10-decanediol (3.91 g; 22.5 mmole) i n g l a c i a l a c e t i c a c i d (135 mL) was prepared i n a 500-mL l i q u i d -l i q u i d e x t r a c t o r . The s o l u t i o n was d i l u t e d with water (180 mL), then c o n c e n t r a t e d s u l f u r i c a c i d (0.5 mL) added and the r e s u l t i n g mixture e x t r a c t e d c o n t i n u o u s l y with 1:1 hexane-cyclohexane (250 mL) over 40 hours. The e x t r a c t i n g s o l v e n t was c o o l e d , f i l t e r e d to remove unreacted 1,10-decanediol, then d r i e d over anhydrous potassium carbonate. Removal of the s o l v e n t under reduced p r e s s u r e f o l l o w e d by vacuum d i s t i l l a t i o n gave 3.24 g (66%) of 28 0 as a c o l o u r l e s s l i q u i d : bp 118-120°/0.40 t o r r ; IR 3630, 3460, and 1725 cm" 1; NMR 6 1.20-1.83 (m, 16H), 2.02 (s, 3H), 2.40 (s, IH, exchanges with DjO), 3.57 ( t , 2H, J = 6 251 Hz), and 4.00 ( t , 2H, J = 6 Hz); mass spectrum m/e ( r e l i n t e n -s i t y ) 216 (2.5), 186 (10), 126 (24), 110 (32), 109 (23), 97 (22), 96 (58), 95 (50), 83 (39), 82 (97), 81 (61), 69 (61), 68 (96), 67 (73), 57 (23), 56 (30), 55 (100), and 54 (53). 1-(10'-Acetoxydecyl)benzenesulfonate (281) A s o l u t i o n of 280 (500 mg; 2.31 mmole) i n anhydrous p y r i -dine (7 mL) was prepared i n a 25-mL sin g l e - n e c k e d round bottom f l a s k equipped with a n i t r o g e n i n l e t . The f l a s k was cooled to 0° i n an i c e water bath and b e n z e n e s u l f o n y l c h l o r i d e (491 mg; 2.78 mmole) was i n t r o d u c e d dropwise. Upon complete a d d i t i o n , the f l a s k was p l a c e d i n the f r i d g e o v e r n i g h t . Water (15 mL) and ether (20 mL) were added and the o r g a n i c l a y e r was sepa-r a t e d . The o r g a n i c phase was washed with d i l u t e h y d r o c h l o r i c a c i d (4 x 15 mL), water (15 mL), and b r i n e (15 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 281 as a y e l l o w l i q u i d . P r e p a r a t i v e TLC of the crude m a t e r i a l on s i l i c a g e l using c h l o r o f o r m as s o l -vent gave 663 mg (80%) of 281 as a c o l o u r l e s s l i q u i d : Rf 0.44; bp (Kugelrohr d i s t i l l a t i o n ) 180-185°/0.20 t o r r ; IR 1725 cm - 1; NMR 6 1.20-1.70 (m, 16H), 2.03 (s, 3H), 4.00 ( t , 4H, J = 7 Hz) and 7.33-7.90 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 356 (0.8), 313 (0.8), 159 (16), 141 (17), 138 (96), 110 (46), 109 (16), 96 (62), 95 (42), 83 (32), 82 (91), 81 (52), 77 (83), 69 (51), 68 (80), 67 (58), 56 (17), 55 (100), and 54 (52). 252 A n a l . C a l c d f o r C l g H 2 g S 0 5 : C, 60.65; H, 7.92; S, 8.99. Found: C, 60.36; H, 8.00; S, 8.81. 1-(10'-Hydroxydecyl)benzenesulfonate (282) A s o l u t i o n of 281 (700 mg; 19.7 mmole) i n dry methanol (25 mL) was prepared i n a 50-mL sin g l e - n e c k e d round bottom f l a s k equipped with a n i t r o g e n i n l e t . Concentrated h y d r o c h l o r i c a c i d (2 mL) was introduced and s t i r r i n g was continued f o r 3.5 hours at room temperature. On workup, the methanol was removed under reduced p r e s s u r e and the r e s i d u e was d i l u t e d with ether (25 mL). The ether s o l u t i o n was washed with water (2 x 15 mL) and b r i n e (15 mL), then d r i e d over anhydrous magnesium s u l f a t e . E v a p o r a t i o n of the s o l v e n t gave 282 as a y e l l o w o i l . P repara-t i v e TLC of t h i s crude m a t e r i a l on s i l i c a g e l u s i n g 1:1 c h l o r o -form-ether gave 446 mg (72%) of 28 2 as a c o l o u r l e s s o i l : Rf 0.48; bp (Kugelrohr d i s t i l l a t i o n ) 180-185°/0.20 t o r r ; IR 3625 and 3450 cm - 1; NMR 6 1.20-1.83 (m, 16H), 1.83 (s, IH, exchanged with D 2 0 ) , 3.57 ( t , 2H, J = 6 Hz), 4.00 ( t , 2H, J = 6 Hz), and 7.18-7.90 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 314 (3), 284 (4), 159 (94), 141 (26), 138 (64), 126 (53), 110 (46), 98 (29), 97 (26), 96 (46), 95 (36), 83 (39), 82 (85), 81 (46), 77 (87), 70 (28), 69 (56), 68 (78), 67 (58), 57 (21), 56 (37), 55 (100), 54 (45), and 51 (21). A n a l . C a l c d f o r C l g H 2 6 0 4 S : C, 61.12; H, 8.33, S, 10.20. Found: C, 61.20; H, 8.17; S, 10.02. 253 (10'-Benzenesulfonoxy-1'-decyl)-3-oxobutanoate (277) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (1.14 g; 6.13 mmole) and 282 (1.675 g; 5.11 mmole). Removal of the s o l v e n t gave 1.75 g (80%) of''28 4 as a y e l l o w l i q u i d , which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC on s i l i c a g e l u s i n g 1:1 e t h e r - c h l o r o f o r m and gave 277 as a c o l o u r -l e s s l i q u i d : Rf 0.66, IR 1740, 1718 and 1660 cm - 1; NMR 6 1.10-1.83 (m, 16H), 2.23 (s, 3H), 3.40 (s, 2H), 4.00 ( t , 2H, J = 7 Hz), 4.07 ( t , 2H, J = 6 Hz) and 7.33-7.87 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 398 (0.7), 380 (0.9), 356 (1), 159 (10), 138 (100), 110 (34), 97 (19), 96 (47), 95 (27), 85 (36), 83 (48), 82 (64), 81 (35), 77 (54), 69 (53), 68 ( 5 l ) , 67 (38), 56 (11), 55 (93) , and 54 (29). A n a l . C a l c d f o r C 2 0 H 3 0 S O 6 : C ' 6 0 * 2 8 '" H ' 7 « 5 9 ' " s> 8.05. Found: C, 60.68; H, 7.70; S, 7.79. 11-Phenythio-l-undecanol (283) A 100-mL two-necked round bottom f l a s k ' e q u i p p e d with a p r e s s u r e - e q u a l i z i n g a d d i t i o n f u n n e l and a n i t r o g e n i n l e t was charged with sodium hydride (960 mg; 20.0 mmole) and dry t e t r a -hydrofuran (40 mL). The f l a s k was cooled to 0° i n an i c e water bath and t h i o p h e n o l (1.10 g; 10.0 mmole) added dropwise. The r e a c t i o n mixture was allowed to stand f o r 15 minutes, then 11-bromo-l-undecanol 2 6 1 g 1 6 0 (2.51 g; 10.0 mmole) i n 254 t e t r a h y d r o f u r a n (10 mL) was i n t r o d u c e d and the s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l 18 hours a t room temperature. D i l u t e h y d r o c h l o r i c a c i d (20 mL) and ether (100 mL) were added, and the o r g a n i c l a y e r s e p a r a t e d . The o r g a n i c phase was washed with s a t u r a t e d sodium bicar b o n a t e s o l u t i o n (20 mL), water (25 mL) and b r i n e (25 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t under reduced pressure gave 2.31g (83%) of 28 3 as a white s o l i d . An a n a l y t i c a l sample was obtained by prepara-t i v e TLC on s i l i c a g e l u s i n g c h l o r o f o r m - e t h e r (1:1) and a f f o r d e d 283 as a white s o l i d : Rf 0.55; mp 66-67°; IR 3620, 3460, and 1590 cm" 1; NMR 6 1.20-1.66 (m, 18H), 1.43 (s, IH, exchanged with D 2 0 ) , 2.87 ( t , 2H, J = 7 Hz), 3.57 ( t , 2H, J = 6 Hz), and 7.00-7.25 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 281 (8), 280 (50), 123 (21), 110 (100), 69 (16), and 55 (45). A n a l . C a l c d f o r C 1 7 H 2 g S O : C, 72.80; H, 10.06; S, 11.43. Found: C, 73.01; H, 10.21; S, 11.55. (11'-Phenylthio-l'-undecyl)-3-oxobutanoate (278) T h i s compound was prepared a c c o r d i n g to the g e n e r a l pro-cedure f o r a l c o h o l y s i s u s i n g 253 (839 mg; 4.51 mmole) and 283 (1.00 g; 3.57 mmole). Workup gave 992 mg (76%) of 278 as a y e l l o w l i q u i d which was homogeneous by TLC a n a l y s i s . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e TLC on s i l i c a g e l u s i n g c h l o r o f o r m as s o l v e n t and gave 278 as a c o l o u r l e s s l i q u i d which c r y s t a l l i z e d on s t a n d i n g ; Rf 0.36; mp 29-30°; bp (Kugelrohr 255 d i s t i l l a t i o n ) 175-180°/0.20 t o r r ; IR 1735, 1715, 1655, and 1590 cm" 1; NMR <5 1.20-1.80 (m, 18H), 2.25 (s, 3H), 2.89 ( t , 2H, J = 7 Hz), 3.43 (s, 2H), 4.14 ( t , 2H, J = 6 Hz), and 7.10-7.40 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 365 (12), 364 (50), 280 (34), 123 (34), 110 (100), 103 (23), 85 (20), 83 (20), 69 (34), and 55 (67). A n a l . C a l c d f o r C 2 1 H 3 2 S ° 3 : C, 69.19; H, 8.93; S, 8.80. Found: C, 69.36; H, 8.75; S, 8.59. t - B u t y l d i m e t h y l s i l y l 1 1 - t - b u t y l d i m e t h y l s i l o x y u n d e c a n o a t e (292) A 50-mL s i n g l e - n e c k round bottom f l a s k equipped with a 172 n i t r o g e n i n l e t was charged with 11-hydroxyundecanoic a c i d (1.52 g; 7.50 mmole), t - b u t y l d i m e t h y l c h l o r o s i l a n e (2.70 g; 18.0 mmole), imid a z o l e (2.55 g; 37.5 mmole), and dimethylformamide (15 mL). The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 72 hours, then water (15 mL) and ether (15 mL), were added. The o r g a n i c l a y e r was separated, and the aqueous l a y e r was f u r t h e r e x t r a c t e d with ether (2 x 20 mL). The combined o r g a n i c e x t r a c t s were washed with water (15 mL), b r i n e (15 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , f o l l o w e d by vacuum d i s t i l l a t i o n gave 3.06 g (95%) of 292 as a c o l o u r l e s s l i q u i d : bp 154-156°/0.20 t o r r ; IR 1710 and 835 cm" 1; NMR 6 0.00 (s, 6H), 0.20 (s, 6H), 0.86 (s, 9H), 0.90 (s, 9H), 1.10-1.69 (m, 16H), 2.28 ( t , 2H, J = 7 Hz), and 3.54 ( t , 2H, J = 6 Hz); mass spec-trum m/e ( r e l i n t e n s i t y ) 430 (1), 415 (10), 373 (100), 357 256 (49), 241 (35), 149 (36), 147 (32), 83 (20), 81 (13), 75 (97), 73 (94) , and 55 (23). A n a l . C a l c d f o r C 2 3 H 5 0 O 3 S i 2 : C, 64.12; H, 11.70. Found: C, 64.34; H, 11.60. 1 1 - t - B u t y l d i m e t h y l s i l o x y u n d e c a n o i c a c i d (293) A 50-mL s i n g l e - n e c k round bottom f l a s k was charged with 292 (3.13 g; 7.28 mmole) and 10% sodium hydroxide s o l u t i o n (25 mL). The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 4 hours, then was a c i d i f i e d with d i l u t e h y d r o c h l o r i c a c i d . The aqueous l a y e r was e x t r a c t e d with e t h y l a c e t a t e (3 x 20 mL) and the o r g a n i c e x t r a c t s were washed with water (15 mL), b r i n e (15 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t f o l l o w e d by vacuum d i s t i l l a t i o n gave 2.23 g (97%) of 293 as a t h i c k , c o l o u r l e s s o i l : bp 148-150°/0.10 t o r r ; IR 3550-2550, 1718, and 845 cm" 1; NMR 6 0.00 (s, 6H), 0.86 (s, 9H), 1.20-1.72 (m, 16H), 2.34 ( t , 2H, J = 7 Hz), 3.58 ( t , 2H, J = 6 Hz), and 10.13 (bs, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 316 (1), 24] 2 283 (8), 259 (20), 241 (100), 224-225 (m*, = 224.3), 149 (6), 83 (14), 81 (11), 75 (29), 73 (25), and 55 (20). A n a l . C a l c d f o r C 1 7 H 3 6 0 3 S i : C, 64.50; H, 11.46. Found: C, 64.57; H, 11.35. 257 5 - (11' -t:-Bu t y l d i m e t h y l s i l o x y - 1 ' -hydroxyundecylidene)-2,2-dimethy1-1,3-dioxane-4,6-dione (294) A 50-ml s i n g l e - n e c k round bottom f l a s k was charged with 293 (1.74 g; 4.18 mmole) and dichloromethane (30 mL). N,N-Car-b o n y l d i i m i d a z o l e (981 mg; 6.05 mmole) was added i n p o r t i o n s and the r e a c t i o n mixture was s t i r r e d u n t i l gas e v o l u t i o n ceased. A 100-mL s i n g l e - n e c k round bottom f l a s k was charged with Meldrum's a c i d (246) (1.13 g; 6.07 mmole) and dichloromethane (40 mL). P y r i d i n e (1.07 g; 13.5 mmole) was int r o d u c e d i n a s i n g l e por-t i o n and the r e a c t i o n mixture was s t i r r e d f o r 1 hour. The con-t e n t s of the f i r s t f l a s k was then s y r i n g e d i n t o the second f l a s k and the combined r e a c t i o n mixture s t i r r e d f o r an a d d i t i o n a l 14 hours. On workup, the dichloromethane s o l u t i o n was washed with d i l u t e h y d r o c h l o r i c a c i d , water, b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t gave 1.45 g (78%) of 294 as a y e l l o w s e m i - s o l i d : IR 1730, 1635, and 835 cm 1 ; NMR 6 0.10 (s, 6H), 0.97 (s, 9H), 1.27-1.83 (m, 16H), 1.81 (s, 6H), 2.90 ( t , 2H, J = 7 Hz), and 3.47 ( t , 2H, J = 6 Hz). 5-(11'-Hydroxy-1'-hydroxyundecylidene)-2,2-dimethyl-1,3-dioxane- 4,6-dione (295) A 100-mL s i n g l e - n e c k round bottom f l a s k equipped with a n i t r o g e n i n l e t was charged with 294 (1.25 g; 2.83 mmole), t e t r a -n-butylammonium f l u o r i d e (1.85 g; 7.07 mmole), and dry t e t r a -hydrofuran (50 mL). The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 3.5 258 hours, then 5% h y d r o c h l o r i c a c i d (15 mL) and ether (25 mL) were added. The o r g a n i c l a y e r was separated, washed with water (10 mL) and b r i n e (10 mL), then d r i e d over anhydrous magnesium s u l -f a t e . Removal of the s o l v e n t gave 8 66 mg (98%) of 295 as a y e l l o w o i l : IR 3400, 1735 and 1635 cm - 1; NMR 6 1.20-1.65 (m, 16H), 1.73 (s, 6H), 2.90 ( t , 2H, J = 7 Hz), 3.53 ( t , 2H, J = 6 Hz), and 3.56 (bs, 2H, exchanged with D 2 0 ) ; mass spectrum m/e ( r e l i n t e n s i t y ) 311 (0.1), 269 (6), 211 (12), 126 (12), 100 (14), 98 (15), 86 (31), 84 (48), 77 (40), 75 (100), 72 (43), 71 (40), 67 (30), 61 (59), 58 (82), 56 (24), and 55 (25). High R e s o l u t i o n Mass Measurement C a l c d f o r 0^^270 , . (M +-OH): 311.18 58. Found: 311.18 58. 3 - O x o t r i d e c a n o l i d e (266e) To a 200-ml two-necked round bottom f l a s k equipped with a p r e s s u r e - e q u a l i z i n g dropping f u n n e l and a n i t r o g e n i n l e t was added t e t r a h y d r o f u r a n (100 mL). The s o l v e n t was heated to r e f l u x and a s o l u t i o n of 295 (8 50 mg; 2.73 mmole) i n t e t r a h y d r o -furan (20 mL) was added dropwise over 5 hours. The r e a c t i o n mix-ture was allowed to c o o l and e t h e r (75 mL) was i n t r o d u c e d . The o r g a n i c phase was washed with s a t u r a t e d sodium bicarbonate (2 x 25 mL), water (2 x 25 mL), b r i n e (25 mL), then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , f o l l o w e d by p u r i f i c a t i o n v i a f l a s h chromatography u s i n g petroleum e t h e r -e t h y l a c e t a t e (9:1) gave 213 mg (35%) o f 266e as a p a l e s e m i - s o l i d w i t h 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 as r e p o r t e d e a r l i e r (pg 248) . 260 BIBLIOGRAPHY 1. a) E . J . Corey, R.L. Danheiser, S. Chandrasekaran, P. S i r e t , G. Keck, and J.-L. Gras, J . Am. Chem. Soc., 100, 8031 (1978) . b) E . J . Corey, R.L. Danheiser, S. Chandrasekaran, G.E. 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Nakamura, S y n t h e s i s , 602 (1976). SPECTRAL APPENDIX 273 274 275 •—i CO z UJ I— z ° '—' o _ i n d 122. D.O I 1 50.0 100.0 150.0 200.0 M/E 250.0 300.0 350.0 400.0 450.0 276 M 00 279 282 283 R E L A T I V E INTENSITY 0.0 25.0 50.0 15.0 100.0 00 00 292 MICROMETERS Um) FREQUENCY (CM'I RELATIVE IN' 25.0 50.0 _J I RELATIVE INTENSITY 0.0 25.0 50.0 75.0 100.0 to o o u> o 0 0 AA- 306 0-(CH2)6Br 262b l±J > (X 0 0 0-(CH2)9Br 2£2e 309 cc _ l a 50.0 100.0 'I ' ' 150.0 200.0 M/E I 1 • 250.0 300.0 MICROMETERS (om) 350.0 400.0 450.0 1600 1200 2400 2000 1800 I6O0 1400 FREQUENCY (CM') 1200 1000 311 315 0 0 AA„. ( C H 2 ) 6 C H = C H 2 ma CKrsi RELATIVE INTENSITT 0.3 25.0 50.0 75.0 100.0 J 1 I I I U) co 

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