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Anionic rearrangements of 4-hydroxycyclohex-2-en-1-ones Wong, Yiu-Fai 1980

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ANIONIC REARRANGEMENTS OF 4-HYDROXYCYCLOHEX-2-EN-1-ONES by YIU-FAI WONG B . S c , The U n i v e r s i t y of Western O n t a r i o , 1977 A THESIS SUBMITTED IN PARTIAL FULFILMENT- OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE 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 September 1980 (Q) Y i u - F a i Wong, 198 0 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of Brit ish Columbia, I agree that the Library shall make i t freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of Chemistry The University of Brit ish Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 September 29, 1980. ABSTRACT The base-induced chemistry of three enone-alcohols, 1,6-di-5 9 cyano-8,9-dimethyl-5-hydroxytricyclo[4.4.0.0 ' ]deca-3,7-dien-2-5 9 one (4_8) , 8 , 9 - d i m e t h y l - 5 - h y d r o x y t r i c y c l o [4 . 4 . 0 . 0 ' ]deca-3,7-dien-2-one (24), and 1,3,4,6,8,9-hexamethyl-5-hydroxytricyclo-5 9 [4.4.0.0 ' ] deca-3,7-dien-2-one (3_) , has been i n v e s t i g a t e d . The i n e r t n e s s of 3_ under the r e a c t i o n c o n d i t i o n s (potassium hydroxide, r e f l u x i n g aqueous dioxane) t h a t converts 1,3,4,6,8,9-hexamethyl-t r i c y c l o [ 4 . 4 . 0 . 0 3 , 1 0 ] d e c - 8 - e n e - 2 , 5 - d i o n e (1) i n t o 1,3,4,6,8,9-3 7 h e x a m e t h y l t r i c y c l o [4 .4 . 0 . 0 ' ] dec-8-ene-2 , 5-dione (2_) i n d i c a t e d t h a t 3_ i s not a major i n t e r m e d i a t e i n such c o n v e r s i o n . R e s t r i c t i o n i n c o n f o r m a t i o n a l isomerism due to the bulky bridgehead methyl groups i s b e l i e v e d to be the main reason f o r p r o h i b i t i n g the r e -arrangement of 3_ to 2_. Under more vig o r o u s r e a c t i o n c o n d i t i o n s (potassium hydride, r e f l u x i n g dimethoxyethane (DME)), however, enone-alcohol 3_ rearranged to g i v e diketone 2_ and twistane d e r i v a -3 8 t i v e 28, 1,3,4,6,8,9-hexamethyltricyclo[4.4.0.0 ' ]dec-9-ene-2,5-dione, which s l o w l y rearranged under the r e a c t i o n c o n d i t i o n to i t s exo-methylene isomer 2_9, 1, 3, 4 , 6, 8-pentamethyl-exo-9-methylene-3 8 t r i c y c l o [ 4 . 4 . 0 . 0 ' ]decane-2,5-dione. When enone-alcohol 24 was t t r e a t e d w i t h KH a t room temperature i n DME, diketone 19_, 8,9-di-3 7 m e t h y l t r i c y c l o [ 4 . 4 . 0 . 0 ' ]dec-8-ene-2,5-dione, was produced. S i m i l a r treatment of enone-alcohol 4_8 with KH a t room temperature i n DME r e s u l t e d i n the formation of 8 , 9 - d i c y a n o - l , 6 - d i m e t h y l t r i -- i i i -c y c l o [4 .4 . 0 . 0 ' ]dec-8-ene-2,5-dione (50). Although diketones 19_ and 5_0 have i d e n t i c a l r i n g s k e l e t o n s , the d i f f e r e n c e i n t h e i r s u b s t i t u e n t p a t t e r n s shows t h a t they are formed by d i f f e r e n t mechanisms. Ring opening of the corresponding a l k o x i d e i s sug-gested as the i n i t i a l step i n a l l three r e a c t i o n s , and the d i v e r g e n t r e s u l t s were e x p l i c a b l e on the b a s i s of the s u b s t i t u e n t -c o n t r o l l e d d i r e c t i o n o f r i n g opening i n a d d i t i o n t o product c o n t r o l through r e s t r i c t i o n of r o t a t i o n o f the i n t e r m e d i a t e s so produced. - i v -TABLE OF CONTENTS Page A b s t r a c t i i Table of Contents i v L i s t of F i g u r e s v i L i s t of Tables and Schemes v i i Acknowledgement v i i i I n t r o d u c t i o n 1 A. Cyclobutanone A n i o n i c Rearrangement 1 1. Homoenolate Anion Pathway 2 2. 1 , 2 - S h i f t Mechanisms 3 (a) A D i r a d i c a l Anion or Carbanion D i s s o c i -ation-Recombination Mechanism 3 (b) A Concerted 1,2-Anionic S h i f t 6 (c) S u c c e s s i v e [2,3] and [1,3] Sigmatropic S h i f t s 10 B. O b j e c t i v e s of Research 21 R e s u l t s and D i s c u s s i o n 23 A. Rearrangement of 1,3,4,6,8,9-Hexamethyl-5-hydroxy-t r i c y c l o [ 4 . 4 . 0 . 0 5 , 9 ] d e c a - 3 , 7 - d i e n - 2 - o n e (3_) 23 B. Rearrangement of 8 , 9 - D i m e t h y l - 5 - h y d r o x y t r i c y c l o -[4.4.0.0 5 , 9]deca-3,7-dien-2-one (2_4) 34 C. Rearrangement of 1,6-Dicyano-8,9-dimethyl-5-h y d r o x y t r i c y c l o [ 4 . 4 . 0 . 0 5 , 9 ] d e c a - 3 , 7 - d i e n - 2 - o n e (48) 39 D. C o n c l u s i o n 46 - v -Table of Contents - cont'd Experimental General Base-Catalyzed Rearrangement Base-Catalyzed Rearrangement Base-Catalyzed Rearrangement Base-Catalyzed Rearrangement B i b l i o g r a p h y Page 48 48 of Enone-Alcohol 3_ 5 0 of Twistane 28_ 5 3 of Enone-Alcohol 2_4 5 4 of Enone-Alcohol 4_8 5 5 57 - v i -LIST OF FIGURES Page F i g u r e 1 T r a n s i t i o n s t a t e s i n [ l , j ] a l k y l m i g r a t i o n . 7 2 T r a n s i t i o n s t a t e of an a n i o n i c [1,2] carbon-to-carbon s h i f t o f an a l k y l group. 8 3 T r a n s i t i o n s t a t e o f a [1,8] a l k y l s h i f t . 9 4 O r b i t a l o v e r l a p diagrams f o r a n i o n i c [2,3] sig m a t r o p i c s h i f t and [1,3] si g m a t r o p i c rearrangement. 11 5 Schematic diagram of o r b i t a l e n e r g i e s and t o p o l o g i e s o f s u p r a f a c i a l 1,3-sigmatropic rearrangement t r a n s i t i o n s t a t e s d e r i v e d by i n t e r a c t i o n of an a l l y l u n i t with a carbon p - o r b i t a l . 13 6 T r a n s i t i o n s t a t e s i n [3,3] si g m a t r o p i c rearrangement. 15 7 A 270-MHz PMR spectrum of twistane 28. 2 5 8 A 270-MHz PMR spectrum of twistane 2_9. . 27 9 A 270-MHz PMR spectrum of diketone 50. 41 - v i i -LIST OF TABLES AND SCHEMES Page Table I C a l c u l a t e d C-H bond energies of CH3OM. 16 I I I s o l a t e d and GC y i e l d s o f the products o b t a i n e d i n the b a s e - c a t a l y z e d r e a r -rangement of enone-alcohol 3_ with r e s -pect to the two bases used. 29 Scheme I 2 II 4 I I I 5 IV 19 V 21 VI 31 VII 33 V I I I 36 IX 38 X 43 - v i i i -ACKNOWLEDGEMENT The author wishes to express h i s deep g r a t i t u d e to Dr. J . R. S c h e f f e r f o r the guidance given throughout the course of t h i s work. Thanks are due to the t e c h n i c a l s t a f f o f the Department of Chemistry f o r t h e i r e x c e l l e n t s e r v i c e s . The f i n a n c i a l support from the U n i v e r s i t y of B r i t i s h Columbia i n the form of a Teaching A s s i s t a n t s h i p i s g r a t e f u l l y acknowledged. - 1 -INTRODUCTION A. Cyclobutanone A n i o n i c Rearrangement I t was the process of t r y i n g to e l u c i d a t e the m e c h a n i s t i c d e t a i l s o f the b a s e - c a t a l y z e d t r a n s f o r m a t i o n of cyclobutanone 1 i n t o the diketone 2_ (eq. (1) ) , t h a t l e d to the s t u d i e s d e s c r i b e d i n t h i s t h e s i s on the base-induced chemistry of the enone-alcohol 3_ owing to the p o s s i b i l i t y t h a t the a l k o x i d e of 3_ was one of the in t e r m e d i a t e s i n v o l v e d i n the c o n v e r s i o n . 3 S c h e f f e r , Gayler, Zakouras and Dzakpasu c a r r i e d out l a b e l i n g experiments i n order to d i s t i n g u i s h between the m e c h a n i s t i c p o s s i -b i l i t i e s of a double homoenolate anion rearrangement and a formal 1 , 2 - s h i f t , and compound 4_ (X=C2Hj.; Y=Z=CH3) was s y n t h e s i z e d f o r such a purpose. In the event t h a t the base-induced r e a c t i o n i n v o l -ves the intermediacy of homoenolate i o n s , compound 4h should be the ** A l l diagrams r e p r e s e n t racemic mixtures. - 2 -product (Path 2, Scheme I ) , w h i l e i f the c o n v e r s i o n i s an o v e r a l l 1 , 2 - s h i f t , diketone 5 should be formed (Path 1, Scheme I ) . Scheme I (X=C 2H 5, Y=Z=CH3) 1. Homoenolate Anion Pathway The i n t e r a c t i o n between a c a r b o n y l group and a n e g a t i v e l y charged 3-carbon atom r e s u l t s i n the formation of a resonance 2 s t a b i l i z e d homoenolate i o n . An example of a double homoenolate anion involvement i n the rearrangement of 1,4-diketone 6 to 7 ( 3 eq.(2)) has been r e p o r t e d by Yates and B e t t s and the mechanism of the i n t e r c o n v e r s i o n may serve as an a c y c l i c v e r s i o n of t h a t o u t l i n e d i n Scheme I, Path 2. However, by t r e a t i n g cyclobutanone £ under the c o n d i t i o n s which cause the c o n v e r s i o n of 1 i n t o 2, namely potassium hydroxide i n 40% aqueous dioxane s o l u t i o n a t r e f l u x , S c h e f f e r , e t . a l . , 1 found diketone 5_ to be the s o l e product, and thus the intermediacy of homoenolate anions was r u l e d out, f o r - 3 -had they been i n v o l v e d i n the rearrangement, diketone 4h would have been formed i n s t e a d . (2) (B=NaOCH_, 0=C>H_) J b _> j 2. 1,2-Shif t Mechanisms (a) A D i r a d i c a l Anion o r Carbanion D i s s o c i a t i o n - R e c o m b i n a t i o n  Mechanism The l a b e l i n g study thus i n d i c a t e d the e x c l u s i v e occurrence of a 1 , 2 - s h i f t process (Path 1, Scheme I ) . A stepwise process i n v o l v i n g e i t h e r homolytic or h e t e r o l y t i c opening of the f o u r -membered r i n g o f f o l l o w e d by r e c l o s u r e to give 2/_ (Scheme II) , the product diketone e n o l a t e , i s one of the few me c h a n i s t i c pos-s i b i l i t i e s which can b r i n g about the o v e r a l l 1,2-anionic s h i f t . r - 4 -13' 13 Scheme II (l=Homolytic Cleavage, 2 = H e t e r o l y t i c Cleavage) A s i m i l a r d i r a d i c a l a n i o n i c d i s s o c i a t i o n - r e c o m b i n a t i o n me-4 chanism has been suggested by Baldwin and Urban i n the rearrange-ment of l i t h i u m compound 8_ which i s formed by r e d u c i n g 9_ w i t h l i t h i u m i n THF a t -70°C. Anion 8_, on warming to -20°C, a f f o r d s 10 presumably v i a a c o n c e r t e d [2,3] s i g m a t r o p i c s h i f t , whereas 11, and other products, most l i k e l y a r i s e from r e d u c t i o n and c o u p l i n g of r a d i c a l s (Scheme I I I ) . - 5 -9 8 10 D i s s o c i a t i o n - R e c o m b i n a t i o n , H + + > = N + i i Scheme I I I In order to t e s t f o r the intermediacy of d i r a d i c a l anion 12', which would r e s u l t from homolytic opening of 1' (Scheme I I ) , CIDNP 5 (Chemically Induced Dynamic Nuclear P o l a r i z a t i o n ) experiments were c a r r i e d out,"1" and on the grounds t h a t no enhanced a b s o r p t i o n or e m ission resonances were observed under c o n d i t i o n s such t h a t the rearrangement was complete, i t was t e n t a t i v e l y concluded t h a t 12 ' was not an i n t e r m e d i a t e i n the c o n v e r s i o n of l / _ to 2/_. A l s o , the i ntermediacy of carbanion 13', which would be formed by h e t e r o -l y t i c r i n g opening of 2J_ (Scheme I I ) , seems c o n t r a i n d i c a t e d by i t s expected but unobserved p r o t o n a t i o n i n aqueous medium to g i v e e i t h e r the duroquinone-2,3-dimethylbutadiene D i e l s - A l d e r adduct (13) or i t s double bond isomer. - 6 -(b) A Concerted 1,2-Anionic S h i f t An a l t e r n a t i v e c o u l d be a f o r b i d d e n concerted 1,2-anionic rearrangement. A s i g m a t r o p i c r e a c t i o n of the order [ i , j ] i s d e f i n e d by c Woodward and Hoffmann as a m i g r a t i o n of a a-bond f l a n k e d by one or more i r - e l e c t r o n systems, to a new p o s i t i o n whose t e r m i n i are i - 1 and j-1 atoms removed from the o r i g i n a l bonding l o c i , i n an u n c a t a l y z e d i n t r a m o l e c u l a r p r o c e s s . Thus, the well-known Cope rearrangement (eq.(3)) i s a si g m a t r o p i c change of the order [3,3], and the c o n v e r s i o n of 8_[_ to 10' ( e q . ( 4 ) , c f . Scheme III ) may f o l l o w an a n i o n i c [2,3] s i g m a t r o p i c pathway. p 2 1 10' i - l = j - l = 2 , i= j = 3 i - l = l , i=2 j-l=2, j=3 (3) (4) A s i m p l i f i e d e x p l a n a t i o n of the s e l e c t i o n r u l e s f o r [ l , j ] a l k y l m i g r a t i o n s may be given u s i n g the concept of the aromatic 7 8 t r a n s i t i o n s t a t e . ' Thus F i g u r e l a i l l u s t r a t e s the t r a n s i t i o n s t a t e i n a s u p r a f a c i a l s h i f t i n which m i g r a t i n g carbon r e t a i n s i t s c o n f i g u r a t i o n , w h i l e F i g u r e l b i s a p p l i c a b l e to the a n t a r a -f a c i a l s h i f t , a g a i n with r e t e n t i o n a t the m i g r a t i n g c e n t e r . - 7 -(a) (b) (c) Fi g u r e 1 T r a n s i t i o n s t a t e s i n [ l , j ] a l k y l m i g r a t i o n : (a) s u p r a f a c i a l s h i f t (Huckel system) with r e t e n t i o n (b) a n t a r a f a c i a l s h i f t (Mobius system) with r e t e n t i o n (c) s u p r a f a c i a l s h i f t (Mobius system) w i t h i n v e r s i o n In F i g u r e l a there i s continuous o v e r l a p between the p-atomic o r b i t a l of the m i g r a t i n g a l k y l group and the top face of the T T -g system without a phase change and t h i s r e p r e s e n t s a Huckel system, but i n the l a t t e r types o f o v e r l a p (Figure l b and l c ) , a s i g n i n -v e r s i o n occurs i n the p - o r b i t a l a r r a y , which denotes an a n t i - H u c k e l 7 or Mobius system. In g e n e r a l , conjugated systems a s s o c i a t e d with zero or even numbers of nodes are c l a s s i f i e d as of the Huckel type, and those w i t h an odd number of s i g n i n v e r s i o n s are desig n a t e d as of the Mobius type. The Huckel t r a n s i t i o n s t a t e w i l l have aromatic c h a r a c t e r f o r 4n+2 T r - e l e c t r o n systems and a n t i a r o m a t i c c h a r a c t e r f o r 4n i r - e l e c t r o n systems. The o p p o s i t e r e l a t i o n s h i p h olds f o r Mobius t r a n s i t i o n s t a t e s . Hence thermal p e r i c y c l i c r e a c t i o n s with 4n n - e l e c t r o n s w i l l be f a v o r a b l e ("allowed") when the t r a n s i t i o n s t a t e i s of the Mobius type but unfavorable ("forbidden") f o r a Huckel t r a n s i t i o n s t a t e . On the other hand, a thermal process i n which there are 4n+2 p a r t i c i p a t i n g T r - e l e c t r o n s w i l l be f a v o r a b l e i n a Huckel system and not i n a Mobius system. - 8 -F i g u r e 2 T r a n s i t i o n s t a t e of an a n i o n i c [1,2] c a r b o n — t o -carbon s h i f t of an a l k y l group. Turning back to the d i s c u s s i o n of concerted 1,2-anionic a l k y l s h i f t s , i f the Huckel-Mttbius approach i s being c o n s i d e r e d , the c o n v e r s i o n of 1_[_ to 2_[_ ( c f . Scheme I I ) , which i s n e c e s s a r i l y s u p r a f a c i a l w i t h r e t e n t i o n a t the m i g r a t i n g c e n t e r owing to the geometry of the molecule, w i l l have a t r a n s i t i o n s t a t e analogous to F i g u r e 2 t h a t c o n t a i n s 4 Tr-electrons (Huckel system) , and hence should be t h e r m a l l y d i s a l l o w e d . On the other hand, a t r a n -s i t i o n s t a t e s i m i l a r to t h a t of F i g u r e l c , i n which o p p o s i t e faces of the m i g r a t i n g group o r b i t a l are used f o r o v e r l a p (Mttbius) system), would be symmetry allowed. However, such a pathway ( s u p r a f a c i a l s h i f t with i n v e r s i o n o f c o n f i g u r a t i o n ) would l e a d to s e r i o u s s t e r i c d i f f i c u l t i e s . L i k e w i s e , an a n t a r a f a c i a l s h i f t with r e t e n t i o n ( c f . F i g u r e l b ) , which would a l s o be symmetry allowed, i s s t r u c t u r a l l y improbable. Thus t h e r m a l l y induced 1,2-migrations i n c a r b a n i o n i c systems are not expected to be f a v o r a b l e , and a t present, examples o f concerted [1,2] m i g r a t i o n s of a l k y l groups i n carbanions are unknown. A p o s s i b l e example, however, has been 9 o p r o v i d e d by S t a l e y and co-workers. On warming to 0 C the s p i r o -c y c l i c anion 14' (with potassium as the counter i o n i n l i q u i d - 9 -ammonia) undergoes r a p i d rearrangement to d i a n i o n 16' e v i d e n t l y by way o f 15'. The rearrangement o f 14' to 15' w h i l e resembling a [1,2] s i g m a t r o p i c s h i f t may a l s o be looked upon as an allowed [1,8] m i g r a t i o n v i a an aromatic a r r a y (Huckel system) o f nine o r b i t a l s c o n t a i n i n g ten e l e c t r o n s (eq.(5) and F i g u r e 3). F i g u r e 3 T r a n s i t i o n s t a t e of a [1,8] carbon-to-carbon s h i f t . Thus, s t r i c t l y speaking, i n carbanions c o n t a i n i n g o n l y carbon and hydrogen, examples of 1,2-migrations of a l k y l groups a t present are s t i l l unknown. However, u s i n g a molecular o r b i t a l treatment which i n c l u d e s c o n f i g u r a t i o n i n t e r a c t i o n , E p i o t i s and co-workers"'"0 have been ab l e to show t h a t the s t e r e o s e l e c t i v i t y o f 4n T r - e l e c t r o n p e r i c y c l i c processes can be re v e r s e d when p o l a r t r a n s i t i o n s t a t e s ( e l e c t r o n donor-acceptor type) are i n v o l v e d . Thus c o n s i d e r i n g the - 10 -c o n v e r s i o n of l / _ to 2/_ (Scheme II) , as the m i g r a t i o n of an e l e c t r o n -r i c h a l l y l carbanion across an e l e c t r o n - d e f i c i e n t ene-1,4-dione double bond (a p o l a r t r a n s i t i o n s t a t e ) , may make p o s s i b l e the r e -v e r s a l of the s i g m a t r o p i c s t e r e o c h e m i c a l s e l e c t i o n r u l e and b r i n g about the co n c e r t e d s u p r a f a c i a l [1,2] a n i o n i c s h i f t w i t h r e t e n t i o n of c o n f i g u r a t i o n i n the m i g r a t i n g carbon. (c) S u c c e s s i v e [2,3] and [1,3] Sigmatropic S h i f t s The t h i r d and most i n t e r e s t i n g m e c h a n i s t i c p o s s i b i l i t y f o r the c o n v e r s i o n of 1J_ to 2/_ i n v o l v e s the rearrangement of l / _ v i a a symmetry allowed [2,3] s i g m a t r o p i c s h i f t to g i v e e n o l a t e 17' which then f u r t h e r rearranges to e n o l a t e 2/_ through a formal [1,3] s i g m a t r o p i c s h i f t ( e q . ( 6 ) ) . 1' 17' 2' The o r b i t a l diagram a p p l i c a b l e to the [2,3] a n i o n i c s h i f t 4 ( f o r example, see Scheme III) i s shown i n F i g u r e 4a as an a l l y l anion i n t e r a c t i n g w i t h an ethylene fragment. The s u p r a f a c i a l ^ s u p r a f a c i a l o v e r l a p leads to a Huckel type t r a n s i t i o n s t a t e , and as there are s i x p a r t i c i p a t i n g e l e c t r o n s , the t h e r m a l l y induced process i s allowed. On the other hand, as i l l u s t r a t e d i n F i g u r e 4b - 11 -F i g u r e 4 O r b i t a l o v e r l a p diagrams f o r : (a) a n i o n i c [2,3] s i g m a t r o p i c s h i f t and (b) [1,3] s i g m a t r o p i c rearrangement. f o r the [1,3] s u p r a f a c i a l s h i f t w i t h r e t e n t i o n ( t h i s stereochemi-c a l pathway i s e n f o r c e d by the geometry of 1 7 ' ) , the t r a n s i t i o n s t a t e would c o n t a i n 4 i r - e l e c t r o n s i n a Huckel system and hence the thermal process should be d i s a l l o w e d . f s R e t e n t i o n i. - 12 -Berson and co-workers have e x t e n s i v e l y i n v e s t i g a t e d the 1,3-sigmatropic rearrangement i n the b i c y c l o [3.2.0] h e p t e n y l s e r i e s shown i n equations 7 and 8,. which may serve as an example of an o r b i t a l - s y m m e t r y - f o r b i d d e n c o n c e r t e d r e a c t i o n . They have observed t h a t the rearrangement p r e f e r s the allowed pathway ( s u p r a f a c i a l w i t h i n v e r s i o n , eq.(7)) by a f a c t o r of ten over the s t e r i c a l l y more f a v o r a b l e f o r b i d d e n one ( s u p r a f a c i a l w i t h r e t e n t i o n , eq.(8)) when R^=H and R^=CE^. As the s t e r i c d i f f i c u l t i e s o f the * allowed r e a c t i o n are i n c r e a s e d by r e q u i r i n g the methyl group r a t h e r than the hydrogen (R^=CH^, R2=H) to pass between the m i g r a t i n g carbon and the r i n g ( e q . ( 7 ) ) , the f o r b i d d e n path (R^=CH^, R 2 = H ' eq.(8)) i s p r e f e r r e d by a s i m i l a r f a c t o r . Berson's i n t e r p r e t a t i o n i s t h a t even the f o r b i d d e n process i n t h i s i n s t a n c e i s c o n c e r t e d and the o v e r l a p between the f r o n t lobe of the m i g r a t i n g carbon and the bonding a l l y l o r b i t a l ip^ (Figure 5a) s t r o n g l y s t a b i l i z e s the f o r b i d d e n c o n c e r t e d t r a n s i t i o n s t a t e r e l a t i v e to the non-concerted one, f o r example, a d i r a d i c a l mechanism (Figure 5b), and such i n t e r a c t i o n together w i t h the o v e r l a p between the m i g r a t i n g p - o r b i t a l and the s u p r a f a c i a l lobe of the c e n t r a l carbon atom of the a l l y l i c framework which r e i n f o r c e s the e f f e c t may thereby permit v i o l a t i o n s of the Woodward-Hoffmann r u l e s . - 13 -Non-i n t e r a c t i n g 8 ^3-^ 2 -1 I (a) P ^ 2 1 _L 1 I, (b) F i g u r e 5 Schematic diagram of o r b i t a l e nergies and t o p o l o g i e s o f s u p r a f a c i a l 1,3-sigmatropic rearrangement t r a n s i t i o n s t a t e s d e r i v e d by i n t e r a c t i o n of an a l l y l u n i t w i t h a carbon p - o r b i t a l . (a) Forbidden 2s+2s and (b) d i r a d i c a l t r a n s i t i o n s t a t e s . Formal [1,3] rearrangement i s a l s o observed i n the s e a l e d tube p y r o l y s i s of diketone 18_ (e q . ( 9 ) ) , and compound 19_ i s ob-12 t a m e d i n 6 2% y i e l d . However, evidence does not a l l o w a d e c i -s i o n to be made between concerted and d i r a d i c a l mechanisms. In a d d i t i o n , g e n e r a t i o n of 18' from 18_ under the t y p i c a l b a s i c c o n d i t i o n s ( i . e . KOH i n r e f l u x i n g aqueous dioxane) g i v e s n e a r l y q u a n t i t a t i v e y i e l d s of 19_ (eq. (10) ) . The c o n v e r s i o n of 1_8 to 19 does not occur under otherwise i d e n t i c a l c o n d i t i o n s i n the absence of base. The f a c i l e c o n v e r s i o n o f 18' i n t o 19' thus appears to r e p r e s e n t a n i o n i c a c c e l e r a t i o n of a f o r b i d d e n (subjacent o r b i t a l controlled"'"''") 1, 3-sigmatropic rearrangement. - 14 -18' 19' A n i o n i c a c c e l e r a t i o n of allowed s i g m a t r o p i c rearrangements has r e c e n t l y a t t r a c t e d much a t t e n t i o n . One e a r l y example was pro-13 v i d e d by Evans and Golob who s t u d i e d the [3,3] s i g m a t r o p i c rearrangement of diene a l k o x i d e 2_0 ( e q . ( l l ) ) . S u p r a f a c i a l - s u p r a -f a c i a l [3,3] s i g m a t r o p i c rearrangement i s t h e r m a l l y allowed s i n c e the t r a n s i t i o n s t a t e i n v o l v e s 6 i r - e l e c t r o n s i n a Huckel a r r a y of p - o r b i t a l s ( Figure 6), but the o b s e r v a t i o n t h a t 20a - (M=K) r e a r -1 2 ranged a t approximately 10 times the r a t e o f the co r r e s p o n d i n g a l c o h o l 20b i s s t a r t l i n g . In a l a t e r i n v e s t i g a t i o n , Evans and co-14 workers e s t a b l i s h e d t h a t t h i s alkoxide-promoted r a t e a c c e l e r a t i o n i s g e n e r a l i z a b l e t o other systems (eq.(12)). (11) 20 a, M=K,Na,Li 21 b, M=H - 15 -(a) (b) F i g u r e 6 T r a n s i t i o n s t a t e s i n [3,3] s i g m a t r o p i c rearrangement: (a) c h a i r c o n f i g u r a t i o n and (b) boat c o n f i g u r a t i o n . X=H,OCH , q 6 5 R=H,CH3 (12) In a d d i t i o n , r e c e n t r e l a t e d o b s e r v a t i o n s have been made on the a c c e l e r a t i o n o f [1,3] s i g m a t r o p i c rearrangements. An example was 15 p r o v i d e d by Wilson and co-workers and i s shown i n equation 13. They observed t h a t rearrangement of 2 2 i s much f a s t e r w i t h a - 16 -potassium c o u n t e r i o n than with sodium; i n f a c t such a trend, K> Na>Li, i s a l s o seen i n the [3,3] s i g m a t r o p i c s h i f t o f 2_0 ( c f . eq. ( 1 1 ) ) . These r e a c t i o n s are a l s o a c c e l e r a t e d by complexing 13 15 agents such as 18-crown-6 or 15-crown-5. ' R a t i o n a l i z a t i o n o f t h i s counter i o n e f f e c t was pro v i d e d i n 16 a r e c e n t t h e o r e t i c a l study by Goddard and co-workers. They c a l c u l a t e d the carbon-hydrogen bond e n e r g i e s f o r methanol, sodium methoxide, potassium methoxide, and the methoxide anion (Table I ) , by employing ab i n i t i o g e n e r a l i z e d valence bond and c o n f i g u r a t i o n i n t e r a c t i o n methods. Experimental AEnergy 91.8+1.2 0 -10.1 -11.7 -16.5 Table I C a l c u l a t e d C-H Bond En e r g i e s (kcal/mol) o f CH-OM. C a l c u l a t e d H-CH2OH 90.7 H-CH2ONa 80.6 H-CH20K 79.0 H-CH20~ 74.2 On the b a s i s o f the c a l c u l a t e d numbers, i t can be seen t h a t the C-H bond i s weakened by 10 to 12 kcal/mol on going from methanol to the a l k a l i methoxides, and by 17 kcal/mol on going to the anion. Goddard e x p l a i n s these d i f f e r e n c e s by n o t i n g t h a t i n the case o f hydroxymethyl r a d i c a l (eq.(15)) the oxygen p-ir lone p a i r can o v e r l a p with the carbon r a d i c a l o r b i t a l to form a weak t h r e e - e l e c t r o n bond. From the experimental C-H bond energi e s of ethane (98 kcal/mol) and methanol (92 kcal/mol) , t h i s Tr-bond i s - 17 -(14) (15) (16) estimated to be worth about 6 kcal/mol. Thus the d e l o c a l i z a t i o n of e l e c t r o n s weakens the C-H bond by 6 kcal/mol on going from ethane to methanol. By the same token, the d e l o c a l i z a t i o n of e l e c t r o n s lowers the C-H bond energies of methoxides (eq.(16)) by about 17 kcal/mol compared to t h a t of ethane. The f u r t h e r lowering of energy can be understood on the assumption t h a t the major e f -f e c t i n r e p l a c i n g hydrogen atom with an a l k a l i atom i s to i n c r e a s e the amount of charge t r a n s f e r r e d from M to the r e s i d u a l o r g a n i c fragment v i a the two-center, t h r e e - e l e c t r o n bond. In the extreme case of the "naked" anion, such an e f f e c t i s even more important due to the complete charge t r a n s f e r . - 18 -The t h e o r e t i c a l s t u d i e s on the e f f e c t of v a r i o u s o x y - s u b s t i -tuents (-0H, -ONa, -OK, -0 ) on the s t r e n g t h of adjacent C-H bonds d i s c u s s e d above h e l p to e x p l a i n the e f f e c t s t h a t these groups 15 13 e x e r t on c e r t a i n [1,3] and [3,3] s i g m a t r o p i c rearrangements ( c f . e q s . ( 1 1 ) , ( 1 3 ) ) . In these rearrangements, a carbon-carbon bond adjacent to the carbon-oxygen bond i s broken (eqs.(17),(18)) and t h a t may be c l o s e l y r e l a t e d to the model pr o v i d e d by Goddard and co-workers (eq.(19)). [3,3] MO (17) MCT^ R, [1,3] MO R, (18) H M0-CH2 + H (19) Turning back to the d i s c u s s i o n of the c o n v e r s i o n of 18' to 19' (Scheme IV, c f . e q . ( l O ) ) , i t i s not unreasonable to suggest, i n view of Goddard's work, t h a t t h i s r e a c t i o n r e p r e s e n t s v i n y l o -gous a n i o n i c a c c e l e r a t i o n of a d i s a l l o w e d s i g m a t r o p i c rearrange-ment. An i n t r i g u i n g a l t e r n a t i v e to the d i r e c t c o n v e r s i o n o f 18' to 19' i n v o l v e s i n i t i a l t r a n s f o r m a t i o n of 18' to 24' ( a l s o a - 19 -Scheme IV d i s a l l o w e d 1 , 3 - s h i f t ) f o l l o w e d by the c o n v e r s i o n of 24' to 19'. This l a t t e r t r a n s f o r m a t i o n i s of course an example of the alkoxy-Cope or alkoxy [3,3] s i g m a t r o p i c rearrangement (cf.eqs.(11),(17)) d i s c u s s e d i n d e t a i l p r e v i o u s l y . In f a c t the c o n v e r s i o n of n e u t r a l 24 to 19_ (eq. (20)) c o u l d be brought about by s e a l e d tube thermo-l y s i s a t 200°C f o r 5 hr, w i t h a 70% y i e l d of 1 9 . 1 2 (20) (21) 3 2 0 13 - 20 -S i m i l a r l y , t h e r m o l y s i s of enone-alcohol 3_ a t 280 C f o r 2 hr i n a s e a l e d tube a f f o r d e d diketone 2_ (53%) together w i t h the duroquinone-2,3-dimethylbutadiene D i e l s - A l d e r adduct (13_, 20%) ( e q . ( 2 1 ) ) . 1 2 The t r a n s f o r m a t i o n s of 2_4 to 19_ and 3 to 2 are the formal r e s u l t s o f allowed [3,3] s u p r a f a c i a l s h i f t s . However non-concerted mechanisms cannot be r u l e d out, p a r t i c u l a r l y i n view of the remoteness of the ends of the 1,5-diene system i n 2A_ and 3_. Form-a t i o n of the D i e l s - A l d e r adduct 13_ i n the themolysis of 3_ may be i n t e r p r e t e d as an example of an oxy-retro-ene r e a c t i o n (eq.(22)), which i s q u i t e common f o r y/^-unsaturated a l c o h o l s , and an example 17 i s shown i n e q u a t i o n 23. (22) (23) - 21 -B. O b j e c t i v e s of Research On the b a s i s of the i n f o r m a t i o n gathered thus f a r , the me-chanism o f the b a s e - c a t a l y z e d c o n v e r s i o n o f cyclobutanone 1 i n t o diketone 2_ ( e q . ( l ) ) very l i k e l y i n v o l v e s rearrangement v i a an i n i t i a l [2,3] s i g m a t r o p i c pathway (Scheme V, c f . e q . ( 6 ) ) . z 27 26 - 22 -In a key experiment, S c h e f f e r and co-workers"1" showed t h a t while (X=Y=CH3, Z=H) rearranges r e a d i l y to give 5_^_ (X=Y=CH3, Z=H) , the c o r r e s p o n d i n g dihydro compound 2_7, which i s i n c a p a b l e of [2,3] s h i f t , does not rearrange under the t y p i c a l b a s i c r e a c t -i o n c o n d i t i o n s (Scheme V ) . The hydrogenation o f the double bond may a l s o a f f e c t the concerted 1 , 2 - s h i f t pathway s i n c e t h i s w i l l c o n s t i t u t e a l e s s p o l a r t r a n s i t i o n s t a t e by r e d u c i n g the e l e c t r o n a v a i l a b i l i t y of the donor and hence w i l l make the r e v e r s a l of the s i g m a t r o p i c s t e r e o c h e m i c a l s e l e c t i o n r u l e l e s s probable."'" 0 The b a s i c q u e s t i o n t h i s t h e s i s was designed to answer was whether a l k o x i d e 26' was an o b l i g a t o r y i n t e r m e d i a t e i n the c y c l o -butanone rearrangement. That i s , does 5_^_ a r i s e d i r e c t l y from 25' or i s the sequence 25' to 26' to 5_[_ followed? (See Scheme V.) Thus f o r the i n t e r e s t i n g chemistry t h a t w i l l c e r t a i n l y be pro-v i d e d by the enone-alcohol 2_6_ and a l s o i n order to g a i n more knowledge about the mechanism of the cyclobutanone rearrangement, the base-induced chemistry of s e v e r a l enone-alcohols was examined. Reasons f o r the c h o i c e of a p a r t i c u l a r enone-alcohol and i t s p r e p a r a t i o n are g i v e n i n the R e s u l t s and D i s c u s s i o n s e c t i o n . - 23 -RESULTS AND DISCUSSION A. Rearrangement of Hexamethyl Enone-Alcohol 3_ With the hope of understanding the base-induced cyclobutanone rearrangement ( e q . ( l ) ) i n g r e a t e r d e t a i l as d i s c u s s e d i n the In-t r o d u c t i o n s e c t i o n , a study of the base-induced chemistry of hexa-methyl enone-alcohol 3_ under the same r e a c t i o n c o n d i t i o n s was undertaken. The c h o i c e of 3_ as the f i r s t enone-alcohol to be i n v e s t i g a t e d i s obvious s i n c e i t corresponds to the " n a t u r a l " C2.6 H22°2 s Y s t e m of 1_ and 2_. P r e p a r a t i o n of 3_ was c a r r i e d out by i r r a d i a t i o n (X> 340 nm) of the duroquinone-2,3-dimethylbutadiene D i e l s - A l d e r add-u c t (1_3) i n a c e t o n i t r i l e a c c o r d i n g to the procedure of S c h e f f e r 12 and co-workers. Two compounds, 3_ and 1 ( r a t i o 4:1), are formed i n a t o t a l y i e l d of 80% (eq.(24)). The product r a t i o i s s o l v e n t dependent, and i n methanol or dioxane-water mixtures, the diketone 2 i s a l s o formed as a minor photo-product. Enone-alcohol 3_ c o u l d e a s i l y be separated from 1, by r e c r y s t a l l i z a t i o n from n-hexane. (24) 13 3 1 - 24 -With the e x p e c t a t i o n of c o n v e r t i n g enone-alcohol 3_ i n t o d i -ketone 2_ under the t y p i c a l b a s i c c o n d i t i o n (KOH i n r e f l u x i n g aqu-eous) dioxane) , we were somewhat s u r p r i s e d to f i n d t h a t there was e s s e n t i a l l y no r e a c t i o n a f t e r 24 hours. T h i s r e s u l t suggests t h a t enone-alcohol 3_ i s not a major i n t e r m e d i a t e i n the rearrangement of 1 to 2 ( e q . ( l ) ) . Under more vigo r o u s r e a c t i o n c o n d i t i o n s , how-ever, treatment of 3_ w i t h potassium t e r t - b u t o x i d e i n anhydrous dioxane a t r e f l u x f o r 52 hours a f f o r d e d a mixture of three products (eq.(25)). The 2:28:29 r a t i o was approximately 2:1:1. Column t-BuOK Dioxane A (25) 28 29 chromatography on s i l i c a g e l u s i n g 4% e t h y l a c e t a t e - t o l u e n e as s o l v e n t separated 2_9 from the other two products. F u r t h e r separa-t i o n of 2_8 from 2_ was achieved by adding n-hexane to the mixture and c e n t r i f u g a t i o n . Compound 2_, which was p u r i f i e d by p r e p a r a t i v e g l p c , was r e a d i l y shown to be the 5,5-diketone by comparison of i t s i n f r a r e d and n.m.r. s p e c t r a w i t h those of an a u t h e n t i c sample. The s t r u c t u r e s of the other two products, 2_8 and 2_9, which were u l t i m a t e l y shown to have the i n t e r e s t i n g twistane ( t r i c y c l o -3 8 [4.4.0.0 ' ]decane) carbon s k e l e t o n , were assigned i n p a r t on the - 25 -b a s i s o f t h e i r s p e c t r a . In a d d i t i o n to having the same mass (246) as t h a t of the s t a r t i n g m a t e r i a l 3_, both 2_8 and 2_9_ show str o n g peaks a t 1710 cm and 1720 cm-"*" i n t h e i r i n f r a r e d s p e c t r a i n d i -c a t i n g the presence of c a r b o n y l f u n c t i o n a l i t y i n a six-membered r i n g . F u r t h e r support f o r the s t r u c t u r e o f 2_8 i s s u p p l i e d by i t s n.m.r. spectrum (Figure 7) which shows the C(10) v i n y l hydrogen F i g u r e 7 A 270-MHz PMR spectrum of 1,3,4,6,8,9-hexamethyl-3 8 ' t r i c y c l o [ 4 . 4 . 0 . 0 ' ]dec-9-ene-2,5-dione (28). as the lowest s i g n a l a t 6 5.24 and a d i s t i n c t q u a r t e t a t 6 2.61 (J=7Hz), which i s due to the C(4) methine c o u p l i n g w i t h the three - 26 -methyl protons. Correspondingly, one of the methyl s i g n a l s i s s p l i t by the C(4) hydrogen i n t o a doublet a t 6 0.92 w i t h the same c o u p l i n g constant (7Hz) . Furthermore, a v i n y l methyl s i g n a l i s observed a t 6 1.8 5 which corresponds to the C(9) methyl group, and two doublets (J=13Hz) a t 5 1.81 and 1.36, each having an i n t e g r a t i o n of one proton, are due to the g e m i n a l l y coupled C(7) methylenes. One other p i e c e o f data, the enhanced e x t i n c t i o n * c o e f f i c i e n t of 370 f o r the n-^ir t r a n s i t i o n a t 287 nm observed i n the u l t r a v i o l e t spectrum of 2_8_, which i n d i c a t e s the presence of 18 a 3,y-unsaturated ketone, i s c o n s i s t e n t w i t h the a s s i g n e d * s t r u c t u r e . In c o n t r a s t , compound 29_ d i s p l a y s a "normal" n-Hr uv spectrum (285 nm, e 80). F u r t h e r i n f o r m a t i o n f o r the s t r u c t u r e of 2_9 i s p r o v i d e d by comparing i t s n.m.r. spectrum (Figure 8) w i t h t h a t of 2_8 (Figure 7) . The major d i f f e r e n c e s between the two are the disappearance of the v i n y l methyl s i g n a l and the presence of t e r m i n a l o l e f i n i c p roton s i g n a l s a t 6 4.87 and 4.78. These exo-methylenes are coupled to one of the C(10) hydrogens (J=3Hz) through a l l y l i c c o u p l i n g and c o r r e s p o n d i n g l y t h i s C(10) proton s i g n a l shows up as a doublet of t r i p l e t s (J=15Hz and 3Hz) c e n t r e d a t 8 2.78. The other C(10) proton s i g n a l i s observed as a d o u b l e t a t 6 2.04 w i t h a geminal c o u p l i n g c o n s t a n t of 15 Hz. The broadening of the exo-methylene s i g n a l s may be due to geminal c o u p l i n g between the two t e r m i n a l o l e f i n i c hydrogens. Again the C(4) methine appears as a q u a r t e t (J=7Hz), though not p e r f e c t l y c l e a r , a t 6 2.71, and the corresponding methyl doublet (J=7Hz) - 27 -F i g u r e 8 A 2 70-MHz PMR spectrum of 1, 3 , 4,6,8-pentamethyl-3 8 exo-9-methylene-tricyclo[4.4.0.0 ' ]decane-2,5-dione (29_) . appears a t 6 0.92. The C(7) methylenes show up as an AB q u a r t e t (J=14Hz) a t 6 1.90-1.75. Since on the b a s i s of the s p e c t r a l data alone i t was not 100% c e r t a i n t h a t 2_9 i s the r i g h t s t r u c t u r e , a s i n g l e c r y s t a l of 2_9, which was r e c r y s t a l l i z e d from n-hexane, was submitted f o r an X-ray c r y s t a l s t r u c t u r e a n a l y s i s . The s t r u c t u r e determin-a t i o n was performed by P r o f e s s o r J . T r o t t e r and Dr. T. J . Green-19 hough of t h i s department whom the author wishes to thank. The - 28 -r e s u l t s of the a n a l y s i s confirmed the s t r u c t u r e 29_ as drawn. When enone-alcohol 3_ was t r e a t e d w i t h potassium h y d r i d e i n r e f l u x i n g dimethoxyethane (DME) f o r 4 hours, a mixture of the same three compounds, 2_, 2_8_ and 29_, was obtained but i n a d i f f e r -ent r a t i o and i n a much b e t t e r o v e r a l l i s o l a t e d y i e l d . i n compar-i s o n w i t h the use of potassium t e r t - b u t o x i d e as base i n dioxane. The improvement i n y i e l d may be accounted f o r by the much s h o r t e r r e a c t i o n time (4 hr vs 5 2 hr) and the lower r e a c t i o n temperature (the b o i l i n g p o i n t of DME i s 84°C w h i l e the b o i l i n g p o i n t o f dioxane i s 101°C). In the case of potassium h y d r i d e , the i n i t i a l p roton removal i s made i r r e v e r s i b l e by the l i b e r a t i o n o f hydrogen gas (eq.(26)) and the formation of the a l k o x i d e i s b e l i e v e d to be 20 q u a n t i t a t i v e . The use of potassium t-butoxide, however, can only b r i n g about an e q u i l i b r i u m r e a c t i o n w i t h the formation of a l k o x i d e i o n (eq.(27)) probably i n l e s s than one hundred percent. R-O-H + KH > R-0~K + + H2 (g) ( 2 6 ) R-O-H + KOC(CH 3) 3 ^ ^ R-0"l<+ + HOC(CH 3) 3 (27) I f the potassium i o n does a c c e l e r a t e the rearrangement ( c f . the counter i o n e f f e c t i n I n t r o d u c t i o n S e c t i o n ) , the r e l a t i v e l y low c o n c e n t r a t i o n of a l k o x i d e may account f o r the longer r e a c t i o n time observed i n the case of potassium t - b u t o x i d e . Furthermore, the e n o l a t e s of the rearrangement products can be protonated by - 29 -the t - b u t a n o l p r e s e n t i n the r e a c t i o n mixture to form ketones which might r e a c t f u r t h e r to g i v e condensation and/or decomposit-i o n p roducts. Condensation r e a c t i o n s may be minimized when potas-sium h y d r i d e i s used as the base, s i n c e without any pro t o n source, a l l of the products w i l l be i n the en o l a t e form and cannot r e a c t with each o t h e r . T h i s i s c o n s i s t e n t with the b e t t e r o v e r a l l i s o l -ated y i e l d o b t a i n e d w i t h potassium h y d r i d e . The i s o l a t e d y i e l d s and the r a t i o s from gas chromatography f o r the three rearrangement products are summarized i n Table I I . 3_ 2 28 29 KOtBu % I s o l a t e d Y i e l d 0 13 7 5 i n Dioxane % GC Y i e l d 3 47 28 20 KH % I s o l a t e d Y i e l d 5 5 58 1 i n DME % GC Y i e l d 12 10 77 1 Table I I I s o l a t e d and GC y i e l d s (%) of the rearrangement products w i t h r e s p e c t to the two bases used. R e f e r r i n g once more to the mechanism of the b a s e - c a t a l y z e d rearrangement of cyclobutanone 1 ( e q . ( l ) ) , i t can be concluded t h a t i n s p i t e of the f a c t t h a t the a l k o x i d e of 3_ does rearrange to g i v e some diketone 2, the r e s u l t s i n d i c a t e t h a t t h i s a l k o x i d e i s probably not a major i n t e r m e d i a t e i n the c o n v e r s i o n o f 1_ to 2 s i n c e n e i t h e r 2_8 nor 29_ i s observed i n t h i s r e a c t i o n . T h i s p o i n t w i l l be d i s c u s s e d i n more d e t a i l l a t e r i n the t h e s i s . In the mean-time, we t u r n to the formation of the two i n t e r e s t i n g twistane d e r i v a t i v e s 28 and 29. - 30 -The f i r s t s y n t h e s i s of twistane (30) was r e a l i z e d by Whit-l o c k v i a the i n t e r n a l c y c l i z a t i o n of an a p p r o p r i a t e b i c y c l o [ 2 . 2 . 2 ] 30 system i n 1962 (eq.(28)). In c o n t r a s t to i t s isomer adamantane (31), which i s made up of c h a i r cyclohexane r i n g s and i s h i g h l y symmetrical, twistane (30) i s dissymmetric and i s composed e x c l u -s i v e l y of t w i s t - b o a t cyclohexane r i n g s and e x i s t s i n two e n a n t i o -meric forms 30a and 30b. T h i s c h i r a l system i s c o n s i d e r e d to be a v a l u a b l e model i n s t u d i e s of c h i r o p t i c a l p r o p e r t i e s of t w i s t - b o a t 22 s t r u c t u r e s . Moreover, twistane can be rearranged smoothly to 23 adamantane on treatment with aluminium c h l o r i d e . E f f e c t i v e 31 30a 30b - 31 -'O 32 R 33 R=NH2, CHCH 3NH 2 methods f o r s y n t h e s i z i n g twistane compounds have been sought and developed by many r e s e a r c h groups s i n c e some of these d e r i v a t i v e s are r e p o r t e d to be b i o l o g i c a l l y a c t i v e . For i n s t a n c e , the 4-keto 24 d e r i v a t i v e of twistane 3_2 i s r e p o r t e d to be an a n t i f u n g a l and a n t i b a c t e r i a l agent, and the t r i c y c l i c amines 3_3 have been shown 2' to possess a n t i v i r a l a c t i v i t y a g a i n s t i n f l u e n z a A and A' i n mice. Thus the b a s e - c a t a l y z e d rearrangement of enone-alcohol 3_, which forms the twistane d e r i v a t i v e s 28_ and 29_, i s unusual and i s worthy o f f u r t h e r i n v e s t i g a t i o n . In c o n s i d e r i n g the mechanism, the formation of diketone 2_ and twistane 2_8_ may be e x p l a i n e d by r i n g opening of a l k o x i d e 3_[_ to the a l l y l anion 13' and r e c l o s u r e v i a i n t e r n a l M i c h a e l a d d i t i o n 28 3' 28' **0 Bonding 2 13' 2' Scheme VI - 32 -as i n d i c a t e d (Scheme VI) . Once formed, compound 2_8 s l o w l y r e a r -ranges under the r e a c t i o n c o n d i t i o n to i t s exo-methylene isomer 29, p o s s i b l y by an enolate/homoenolate d i a n i o n pathway (eq.(29)). (29) 28' 29 T h i s i n t e r c o n v e r s i o n was v e r i f i e d by t r e a t i n g twistane 2_8 w i t h excess potassium h y d r i d e i n dimethoxyethane. A f t e r r e f l u x i n g f o r 9 hours, about 10% of 28_ was converted i n t o 2_9, and t h i s r a t i o was time independent. S i m i l a r treatment of twistane 29 w i t h potassium h y d r i d e l e d o n l y to polymeric m a t e r i a l . Diketone 2_ was found to be s t a b l e under the r e a c t i o n c o n d i t i o n s . An example of g e n e r a t i o n of homoenolate anions i n ketones 2 6 with e n o l i c (a) protons has been p r o v i d e d by Nickon e t a l . At 250°C i n KO-t-Bu/t-BuOH f o r 52 hours, exo-isocamphanone (34) con-v e r t s i n t o i t s endo epimer 35_ and to camphor (3_6) v i a a common in t e r m e d i a t e homoenolate i o n 37' (Scheme V I I ) . A f t e r 52 hours, the 34:35:36 r a t i o was 42:36:22. - 33 -C 2 - C 6 Cleavage Scheme VII Besides the r i n g o p e n i n g - r e c l o s u r e pathway, the c o n v e r s i o n of 3_ to 2_8 may a l s o be viewed as o c c u r i n g v i a a v i n y l o g o u s a c y l o i n 27 rearrangement (eq.(30)). (30) 3' 28' 38 OH OH R OH 39 (31) - 34 -The t r a n s f o r m a t i o n o f 4 - s u b s t i t u t e d 4-hydroxycyclohexa-2,5-d i e n - l - o n e s (3_8) i n t o 2 - s u b s t i t u t e d hydroquinones (39_) upon 2 8 treatment with base (eq.(31)) has been known f o r some time. While t h i s t r a n s f o r m a t i o n , which may be termed a v i n y l o g o u s a c y l o i n rearrangement, presumably owes i t s d r i v i n g f o r c e t o the product a r o m a t i c i t y i t g a i n s , the c o n v e r s i o n of 3_, a 4-hydroxy-cyclohexenone d e r i v a t i v e , i n t o 2_8_ upon treatment with potassium hy d r i d e may r e p r e s e n t a nonaromatic v e r s i o n of t h i s rearrangement. B. Rearrangement of Dimethyl Enone-Alcohol 24 In order to examine whether or not the c o n v e r s i o n o f enone-a l c o h o l s i n t o twistane d e r i v a t i v e s i s a g e n e r a l process, another enone-alcohol 2_4, which d i f f e r s from 3_ i n having hydrogen atoms r a t h e r than methyl groups a t the 1,3,4 and 6 p o s i t i o n s , was cho-sen f o r study. I r r a d i a t i o n of the benzoquinone-2,3-dimethylbuta-diene D i e l s - A l d e r adduct (4_0) f o l l o w i n g the procedure o f S c h e f f e r 12 e t a l . u s i n g l i g h t o f X>340 nm i n benzene f o l l o w e d by column chromatography on s i l i c a g e l a f f o r d e d compound 18_ and enone-alco-h o l 24_ i n i s o l a t e d y i e l d s of 35 and 22% r e s p e c t i v e l y , and diketone 19 was p r e s e n t i n o n l y t r a c e amount. In t e r t - b u t y l a l c o h o l however, the major product (80% y i e l d ) was 19_, while 1_8 and 2_4 were pres e n t 12 i n a combined y i e l d o f l e s s than 5% (eq.(32)). (32) 40 18 24 19 - 35 -When the dimethyl enone-alcohol 2_4 was t r e a t e d w i t h potas-sium h y d r i d e , and s t i r r e d f o r two hours a t room temperature i n dimethoxyethane, g l p c a n a l y s i s showed o n l y one v o l a t i l e product, the s t r u c t u r e of which was r e a d i l y i d e n t i f i e d as t h a t of 19_ (eq. :(33)) by comparison of i t s i n f r a r e d and n.m.r. s p e c t r a with those 12 of an a u t h e n t i c sample. Thus, the formation of twistane d e r i v a -t i v e s from base-induced rearrangements of enone-alcohols i s not a g e n e r a l process. Furthermore, w h i l e i t i s c o n c e i v a b l e t h a t compound 3_ c o u l d r e a c t v i a a concerted v i n y l o g o u s a c y l o i n r e a r -rangement mechanism ( c f . eq. (30) ) to g i v e 2_8 whereas 24_ would not r e a c t s i m i l a r l y , t h i s does not appear l o g i c a l , and we p r e f e r to e x p l a i n both s e t s of r e s u l t s on the b a s i s of the r i n g opening-r e c l o s u r e mechanism of Scheme VI. The assumption i s made t h a t immediately f o l l o w i n g the c l e a v -age of bond a of a l k o x i d e 26', the a l l y l anion e x i s t s mainly i n t w i s t conformation 41' (Scheme VIII) which can c l o s e d i r e c t l y to form twistane compound or i s o m e r i z e to conformation 43' v i a r i n g f l i p p i n g , and then c l o s e to g i v e d i k e t o n e . By i n s p e c t i o n of mole-c u l a r models, the formation of diketone i s o n l y p o s s i b l e from -conformation 43' , and s i m i l a r l y , the formation of twistane can (33) 24 19 - 36 -R R R 3 Bond a •0 Cleavage 1 1 \ h »3 / o 26' 41' 43' o Twistane 42' Diketone Scheme V I I I (R 1=CH 3) only be achieved from conformation 41' due to the geometry of the system. The r i n g c l o s u r e o f 43' to g i v e diketone should be more 29 f a v o r a b l e s i n c e a c c o r d i n g to Sc h l e y e r and co-workers, the t r i -3 8 cyclo[4.4.0.0 ' ]decane r i n g system of twistane possesses a 3 7 gr e a t e r s t r a i n energy than the t r i c y c l o [ 4 . 4 . 0 . 0 ' ]decane r i n g system of diketo n e . Moreover, bonding i n 41' occurs between atoms which are not o n l y f u r t h e r apart but more h i g h l y s u b s t i t u t e d (R^= CH^) than i n the case of 43'. Since the c o n f o r m a t i o n a l isomerism of 41' to 43' i n v o l v e s r o t a t i o n through an e c l i p s e d bridgehead R 2 group arrangement 42', the s i z e o f the R 2 groups t h e r e f o r e p l a y s an important r o l e i n governing the r a t e of c o n f o r m a t i o n a l e q u i l i -b r a t i o n between 41' and 43'. We suggest t h a t when R~ i s equal to - 37 -hydrogen, c o n f o r m a t i o n a l isomerism between 41' and 43' i s f a s t i n comparison w i t h the r a t e s of c l o s u r e o f 41' to twistane and 43' to diketone, and as a r e s u l t , the twistane/diketone product r a t i o w i l l be governed by the d i f f e r e n c e i n the a c t i v a t i o n e n e r g i e s f o r the two r i n g c l o s u r e processes (Curtin-Hammett p r i n c i p l e ) . 3 0 Since the a c t i v a t i o n energy f o r the formation of diketone should be lower than t h a t o f twistane (vide supra) , diketone 19_ (see eq. (33) ) i s observed as the onl y product. When R 2 ' i s equal to methyl however, the e q u i l i b r a t i o n o f 41' and 43' i s b e l i e v e d to be slower than the r a t e o f c l o s u r e due to the unfavorable arrangement 42', and i n t h i s case the product r a t i o w i l l depend on the r e l a t i v e 31 conformer p o p u l a t i o n s . Thus, a f t e r the cleavage o f bond a (see Scheme V I I I ) , twistane w i l l be formed v i a the i n i t i a l l y produced conformer 41' b e f o r e 41' can i s o m e r i z e to 43' to an a p p r e c i a b l e e x t e n t . T h i s p r e d i c t i o n i s again i n agreement wi t h r e s u l t s observed e x p e r i m e n t a l l y t h a t the r a t i o o f twistane 2_8 to diketone 2_ was about 8 to 1 i n r e f l u x i n g dimethoxyethane ( b o i l i n g p o i n t 84°C), and was about 1 ( i n c l u d i n g twistane 29) to 1 i n r e f l u x i n g dioxane which has a b o i l i n g p o i n t o f 101°C. That i s to say, a t a higher r e a c t i o n temperature, the c o n v e r s i o n o f conformer 41' to 43' i s somewhat a c c e l e r a t e d , and the comparatively favored r i n g c l o s u r e o f 4 3' to g i v e 2_ may e x p l a i n the l a r g e r amount o f diketone being produced. S i m i l a r methyl group e c l i p s i n g e f f e c t s have been observed by S c h e f f e r and co-workers i n the photochemical s t u d i e s o f the 2,3- 3 dimethylbutadiene-duroquinone D i e l s - A l d e r adduct "(13, Scheme IX) . - 38 -46 45 Scheme IX On the b a s i s t h a t the i n i t i a l l y formed d i r a d i c a l i n t e r m e d i a t e 44, from 3-hydrogen a b s t r a c t i o n by c a r b o n y l oxygen, e x i s t s mainly i n the same t w i s t conformation as the p r e c u r s o r 13_, t h i s i n t e r -mediate i s i d e a l l y s e t up to undergo C ( l ) to C(6) bonding to y i e l d 33 enone-alcohol 3_. X-Ray c r y s t a l l o g r a p h y shows t h a t the p r e f e r r e d conformation of 13_ i s i n f a c t as drawn. However, the formation o f photoproducts of s t r u c t u r e s 17_ and 2_ (see eq.(6)) r e q u i r e s con-f o r m a t i o n a l isomerism of 44_ to 4_5 and 4_6, r e s p e c t i v e l y , each of which i n v o l v e s e i t h e r formation o f , or r o t a t i o n through, an - 39 -e c l i p s e d bridgehead methyl group arrangement. Thus, by the same reaso n i n g p r e v i o u s l y d i s c u s s e d , i t i s not s u r p r i s i n g to f i n d t h a t p h o t o l y s i s o f D i e l s - A l d e r adduct 13_ g i v e s enone-alcohol 3_ and 32 only t r a c e s , i f any, of the compounds of s t r u c t u r e s 1_7 and 2_. C. Rearrangement o f Dicyano-Dimethyl Enone-Alcohol 48 32 I t has a l s o been observed by S c h e f f e r e t a l . t h a t when D i e l s - A l d e r adduct 47 was i r r a d i a t e d a t A>340 nm i n 10% (volume by volume) b e n z e n e - t e r t - b u t a n o l s o l u t i o n , d icyano-dimethyl enone-a l c o h o l 4_8 was formed (eq.(34)), and the y i e l d was about 50%. Thus a p p a r e n t l y bridgehead cyano groups e x e r t the same i n f l u e n c e as methyl groups i n r e s t r i c t i n g c o n f o r m a t i o n a l isomerism i n t h i s photo-rearrangement. CN O h v A>340 nm O (34) CN b 47 48 CN •CN KH 48 (35) DME 49 50 - 40 -In o r d e r to compare the behavior of the dicyano-dimethyl compound 4_8 wi t h t h a t of the hexamethyl compound 3_ i n the base-c a t a l y z e d rearrangement, enone-alcohol 4_8 was t r e a t e d s i m i l a r l y w i t h potassium h y d r i d e i n dimethoxyethane s o l u t i o n . A f t e r s t i r -r i n g a t room temperature f o r 5 to 6 hours, g l p c a n a l y s i s of the r e a c t i o n mixture showed two products i n the r a t i o of 5:90. Com-pound 4_9 was shown to be a p h t h a l o n i t r i l e d e r i v a t i v e (see E x p e r i -mental S e c t i o n ) , and the major product was shown (vide i n f r a ) to have the diketone s t r u c t u r e 50_ (eq.(35)). 4 , 5 - D i m e t h y l p h t h a l o n i t r i l e 49_ i s a known compound wi t h melt-i n g p o i n t 179-180°C (n-hexane-acetone) ( l i t . 3 4 mpil78-179°C). The s t r u c t u r e o f the major product 50_ was deduced from i t s s p e c t r a l d a ta. The i n f r a r e d spectrum o f 5_0 shows a cyano band a t 2232 cm and a c a r b o n y l band a t 1739 cm . While s a t u r a t e d n i t r i l e s t r e t --1 3 ching f r e q u e n c i e s are u s u a l l y found to occur a t around 2250 cm , the c o n j u g a t i o n w i t h a double bond may e x p l a i n the r e d - s h i f t of the cyano band t o 2232 cm . Moreover, the str o n g peak a t 1739 cm i n d i c a t e s ketone f u n c t i o n a l i t y i n a five-membered r i n g . The n.m.r. spectrum r e v e a l s two t e r t i a r y methyl groups as sharp s i n g l e t s a t <5 0.95 and 1.17. Another s i n g l e t i s observed a t 6 3.40 (Figure 9) which i s assig n e d to the C(7) methine s i n c e i n s p e c t i o n o f a model shows t h a t the d i h e d r a l angle between the C(7) and C(3) methine i s almost 90°, hence on the b a s i s o f the Karplus r e l a t i o n s h i p , 3 ^ the v i c i n a l c o u p l i n g constant should be near zero. A l s o , the C(3) methine appears as a doublet a t 6 3.59 (J=5 Hz), which i s due to - 4 1 -C10"H2 3.59 3.40 2.80 2.55 2.27 6 F i g u r e 9 A 2 7 0 - M H z P M R s p e c t r u m o f 8 , 9 - d i c y a n o - l , 6 - d i m e t h y l --3 7 t r i c y c l o [ 4 . 4 . 0 . 0 ' ] d e c - 8 - e n e - 2 , 5 - d i o n e (50_) . c o u p l i n g w i t h t h e C ( 4 ) e x o - h y d r o g e n a n d n o t t o t h e e n d o - h y d r o g e n s i n c e t h e d i h e d r a l a n g l e w i t h t h e l a t t e r i s c l o s e t o 9 0 ° . A c c o r d -i n g l y , t h e d o u b l e t o f d o u b l e t s i g n a l s a t 6 2 . 8 5 - 2 . 7 6 w i t h c o u p l i n g c o n s t a n t s 5 H z a n d 1 8 H z a r e d u e t o t h e C ( 4 ) e x o - p r o t o n . T h e e n d o -p r o t o n s i g n a l , w h i c h i s o b s e r v e d a t 6 2 . 3 , i s s p l i t i n t o a d o u b l e t b y t h e e x o - p r o t o n w i t h a g e m i n a l c o u p l i n g c o n s t a n t o f 1 8 H z . S i m i l a r s p l i t t i n g p a t t e r n s b e t w e e n t h e C ( 3 ) m e t h i n e a n d t h e C ( 4 ) 3 7 m e t h y l e n e s h a v e b e e n o b s e r v e d w i t h c o m p o u n d s 5JL a n d 5 2 . - 42 -51 52 The remaining C(10) methylenes show up as an AB q u a r t e t (J= 20 Hz) a t 6 2.80-2.55. I t should be noted t h a t although 50_ and 19_ ( c f . eqs. (35) and (33)) have i d e n t i c a l r i n g s k e l e t o n s , the d i f f e r e n c e i n t h e i r sub-s t i t u e n t p a t t e r n s shows t h a t they are formed by d i f f e r e n t mechani-sms. Again i f the r i n g opening of a l k o x i d e 26' (Scheme V I I I , R^= CH^, R2=CN, R3 =H) i s the f i r s t step, bond b i s p r e f e r e n t i a l l y c l e a v e d f o r reasons o f carbanion s t a b i l i z a t i o n through c o n j u g a t i o n w i t h the cyano group. The p r e f e r e n c e of bond a cleavage i n the case of the hexamethyl enone-alcohol 3_ (R2=CH3) and the dimethyl enone-alcohol 2_4_ (R2=H) may be p a r t i a l l y accounted f o r by the f a c t t h a t f o r enone-alcohols bond a i s longer, hence weaker, than bond b. For example, the X-ray c r y s t a l s t r u c t u r e of hexamethyl compound 3_ shows t h a t the l e n g t h s of bonds a and b are 1.563 and 1.547 A* 3 8 r e s p e c t i v e l y . A s i m i l a r t r e n d i s noted f o r dicyano-dimethyl enone-alcohol 4_8 although the d i f f e r e n c e i s s m a l l e r (a:b = 1.568: 1.561 8 ) . 3 9 A f t e r the cleavage of bond b, there are s e v e r a l m e c h a n i s t i c pathways t h a t the r e s u l t i n g a l l y l anion 53' can undergo to y i e l d - 43 -49' 55' 50' I Scheme X 50 diketone 5_0_. One p o s s i b i l i t y i s a t h e r m a l l y allowed ' 1,4-sigma-t r o p i c a c y l s h i f t to g i v e a l l y l anion 54' which then can r i n g c l o s e v i a an i n t e r n a l M i c h a e l a d d i t i o n i n the same f a s h i o n as the co n v e r s i o n of 43' to diketone 2_ or 19_ ( c f . Scheme VIII) to give e n o l a t e o f diketone _50_, 50' (Scheme X) . S u p r a f a c i a l - s u p r a f a c i a l 1,4-anionic s h i f t s which proceed by way of t r a n s i t i o n s t a t e c o r -ii responding to 5_6 (eq.(36)) would c o n t a i n 6 T r - e l e c t r o n s i n a Huckel a r r a y of f i v e o r b i t a l s , and hence the t h e r m a l l y induced process i s f a v o r a b l e (see I n t r o d u c t i o n S e c t i o n ) . Although [1,4] a n i o n i c s h i f t s 40 are r a r e , the rearrangement of 2 - a l k o x y p y r i d i n e N-oxides 5_7 to 41 N-alkoxy-2-pyridones 5_8 may serve as an example (eq.(37)). The R group (R=CHDCgH^) migrates with r e t e n t i o n o f c o n f i g u r a t i o n which i s c o n s i s t e n t w i t h a concerted s u p r a f a c i a l - s u p r a f a c i a l [1,4] s i g -matropic s h i f t . - 44 -56 R (36) [1,4] (37) 58 A second p o s s i b i l i t y i n v o l v e s r i n g opening of 53' to the 6 7 ketene e n o l a t e 55' which then undergoes a symmetry allowed ' s u p r a f a c i a l - s u p r a f a c i a l [4 + 2] c y c l o a d d i t i o n to g i v e , once again, the e n o l a t e of diketone _50. I n t e r m o l e c u l a r [4 + 2] c y c l o a d d i t i o n s of a l l y l anions with unsaturated systems to g i v e c y c l o p e n t y l anions (eq.(38)), although not as common as t h e i r c o r r e s p o n d i n g n e u t r a l c o u n t e r p a r t s ( i . e . , the famous D i e l s - A l d e r r e a c t i o n ) are n e v e r t h e l e s s w e l l - e s t a b l i s h e d p r o v i d e d t h a t the c y c l o p e n t y l anion thus formed i s s t a b i l i z e d by c o n j u g a t i o n , f o r example, wi t h an 42 e l e c t r o n - w i t h d r a w i n g X group (eq.(38)). The c y c l o a d d i t x o n of carbanion 59' to d i e t h y l f u m a r a t e (60) to g i v e c y c l o a d d u c t 6_1 i s 4 3 one example.(eq.(39)). In t h i s system the c y c l i c ketone a c t s as the e l e c t r o n - w i t h d r a w i n g X group. S i m i l a r l y , i n the c o n v e r s i o n o f 55' to 50' (Scheme X), the product c y c l o p e n t y l anion i s resonance s t a b i l i z e d by the ketone f u n c t i o n a l i t y . - 46 -A t h i r d m e c h a n i s t i c p o s s i b i l i t y f o r the c o n v e r s i o n of 26' to 50' i n v o l v e s n u c l e o p h i l i c a t t a c k by C(2) on C(6) of 53' f o l l o w e d by cleavage of the C(5)-C(6) bond to gi v e 54' which can c l o s e again v i a an i n t e r n a l M i c h a e l a d d i t i o n to produce 50' (eq.(40)). This process may be looked upon as the non-concerted e q u i v a l e n t of the 1,4-acyl s h i f t process d i s c u s s e d p r e v i o u s l y . To account f o r the formation o f the d i n i t r i l e 49_, i t i s pro-posed t h a t e x p u l s i o n of the b i s - k e t e n e fragment C^I^C^ (6_2) from e i t h e r 53' or 55' a f f o r d s carbanion 49', which a f t e r p r o t o n a t i o n and a r o m a t i z a t i o n d u r i n g workup, y i e l d s compound 49_. No products r e s u l t i n g from r e a c t i o n o f the i n t e r e s t i n g b i s - k e t e n e 6_2 have been i s o l a t e d thus f a r , however.(eq.(41)). D. C o n c l u s i o n As f a r as the mechanism of the base-induced rearrangement of cyclobutanone i s concerned, i t i s concluded t h a t a l k o x i d e o f enone-alcohol 3_ i s not an in t e r m e d i a t e i n the c o n v e r s i o n of c y c l o -butanone 1 to diketone 2_ s i n c e the t r a n s f o r m a t i o n o f 3_[_ to 2J_ r e q u i r e s a r o t a t i o n through an e c l i p s e d bridgehead methyl group arrangement and i s c o n f o r m a t i o n a l l y f o r b i d d e n ( c f . Scheme V I I I ) , and a t the same time, the c o n v e r s i o n of 17' i n t o ( c f . 25'-->-26' (X=Y=Z=CH3), Scheme V), which would r e s u l t i n the l o s s o f e n o l a t e resonance s t a b i l i z a t i o n energy, w i l l not be f a v o r a b l e . In c o n t r a s t , the d i r e c t c o n v e r s i o n of 17' to 2/_ ( e q . ( 6 ) ) , which r e p r e s e n t s v i n y l o g o u s a n i o n i c a c c e l e r a t i o n of a d i s a l l o w e d [1,3] s h i f t , does not i n v o l v e bridgehead methyl-methyl e c l i p s i n g and a t the same - 47 -time maintains equal degrees of resonance s t a b i l i z a t i o n . Thus, i t i s v ery l i k e l y t h a t the mechanism of the b a s e - c a t a l y z e d c o n v e r s i o n of cyclobutanone 1 i n t o diketone 2_ i n v o l v e s rearrangement v i a an i n i t i a l [2,3] s i g m a t r o p i c s h i f t of 1_[_ to 17' f o l l o w e d by a d i s -allowed [1,3] s i g m a t r o p i c rearrangement to g i v e 2/_. Although under the same r e a c t i o n c o n d i t i o n s f o r cyclobutanone rearrangement (KOH, r e f l u x i n g aqueous dioxane) enone-alcohol 3_ d i d not r e a c t (as i s c o n s i s t e n t w i t h the above argument), under f o r c i n g c o n d i t i o n s (KH, r e f l u x i n g dimethoxyethane) i t rearranged to g i v e diketone 2_ and twistane d e r i v a t i v e s . Since the twistane d e r i v a t i v e s are of 23-25 i n t e r e s t to chemists, enone-alcohols of d i f f e r e n t s u b s t i t u e n t p a t t e r n s were s t u d i e d . The experimental r e s u l t s r e v e a l e d t h a t twistane formation i s not a g e n e r a l process, and the d i v e r g e n t r e s u l t s were e x p l i c a b l e on the b a s i s of the s u b s t i t u e n t - c o n t r o l l e d d i r e c t i o n of r i n g opening (Schemes V I I I and X) i n a d d i t i o n to product c o n t r o l through r e s t r i c t i o n of r o t a t i o n of the i n t e r -mediates so produced (Scheme V I I I ) . P a r t i c u l a r l y i n t r i g u i n g were the unusual m e c h a n i s t i c p o s s i b i l i t i e s presented by the formation of diketone 50 (Scheme X). - 48 -EXPERIMENTAL General M e l t i n g p o i n t s , which were determined on a F i s h e r - J o h n s hot-stage m e l t i n g p o i n t apparatus, are a l l u n c o r r e c t e d . I n f r a r e d ( i r ) s p e c t r a were recorded on Perkin-Elmer Model 137 and 257 s p e c t r o -photometers u s i n g potassium bromide d i s c s f o r s o l i d samples and a t h i n f i l m pressed between two sodium c h l o r i d e p l a t e s f o r pure l i q u i d s . The i r s p e c t r a were c a l i b r a t e d w i t h the 16 01 cm ^ band of p o l y s t y r e n e . The assignment of each a b s o r p t i o n i s i n d i c a t e d i n parentheses a f t e r each band. Nuclear magnetic resonance (nmr) s p e c t r a were recorded w i t h e i t h e r a V a r i a n XL-100 or H-270 spe c t -rometers. The s i g n a l p o s i t i o n s are r e p o r t e d u s i n g the 6 s c a l e w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l standard, and 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 n t e g r a t e d peak areas and proton assignments are i n d i c a t e d i n parentheses a f t e r each s i g n a l . U l t r a v i o l e t (uv) s p e c t r a were measured on a Cary 15 spectrophotometer, and mass s p e c t r a (ms) were o b t a i n e d e i t h e r on an A t l a s CH-4B mass s p e c t r o -meter (low r e s o l u t i o n ) or on an AEI MS-902 instrument (high r e s o l -ution) . Both instruments were operated a t an i o n i z i n g p o t e n t i a l of 70 e l e c t r o n v o l t s . Elemental analyses were performed by the departmental m i c r o a n a l y s t , Mr. P. Borda. For gas l i q u i d p a r t i t i o n chromatography (glpc) Hewlett-Packard 5830A and Varian-Aerograph Model 90-P instruments were used. K grade n i t r o g e n and helium were used as the c a r r i e r gases r e s p e c t i v e l y . The f o l l o w i n g columns were used: (6 1 x 1/8") 10% OV210 on Chromosorb W 80/100 mesh - 49 -(column A); (6* x 1/8") 5% 0V17 on Chromosorb W 80/100 mesh ( c o l -umn B); (5' x 1/4") 10% OV210 on Chromosorb W 60/80 mesh (column C). For t h i n l a y e r chromatography ( t i c ) , pre-coated t i c sheets, F-254 from E. Merck, were used, and f o r column chromatography, columns were s l u r r y packed i n the e l u t i n g s o l v e n t with s i l i c a g e l (from E. Merck) < 0.063 mm and e l u t e d under 5-10 p s i n i t r o g e n p r e s s u r e . 1,4-Dioxane and 1,2-dimethoxyethane (DME) were d r i e d by r e f l u x i n g over sodium metal f o r a minimum of three hours p r i o r to use. - 50 -Base-Catalyzed Rearrangement of 1,3,4,6,8,9-Hexamethyl-5-hydroxy-5 9 t r i c y c l o [4. 4 . 0. 0 ' ]deca-3, 7-dien-2-one (3_) (1) Potassium t e r t - B u t o x i d e and 1,4-Dioxane An ov e n - d r i e d 50 ml two necked f l a s k was equipped w i t h a mag-n e t i c s t i r r i n g bar and a condenser which was attached to a source of dry n i t r o g e n . When the i n e r t atmosphere had been e s t a b l i s h e d , to the f l a s k 0.30 g (1.2 mmol) of enone-alcohol 3_ and 0.22 g ( 2.0 mmol) of potassium t e r t - b u t o x i d e (from A l d r i c h ) were added. The second neck of the f l a s k was stoppered w i t h a rubber septum. To the s o l i d mixture 30 ml of f r e s h l y d i s t i l l e d (from sodium met-al) 1,4-dioxane was added from a s y r i n g e . A f t e r s t i r r i n g f o r 15 minutes, the r e s u l t i n g white heterogeneous mixture was r e f l u x e d f o r 52 hours. Water (20 ml) was then added c a r e f u l l y to the dark brown s o l u t i o n and the r e s u l t i n g s o l u t i o n was n e u t r a l i z e d w i t h 1M h y d r o c h l o r i c a c i d . The r e a c t i o n mixture was then e x t r a c t e d with s i x 10 ml p o r t i o n s of chl o r o f o r m . A f t e r washing with 2 x 20 ml of water and 20 ml of s a t u r a t e d sodium c h l o r i d e s o l u t i o n , the c h l o r -oform l a y e r was d r i e d over magnesium s u l f a t e . The s o l v e n t was removed by ev a p o r a t i o n under reduced pressure to g i v e 0.27 g ( 90%) o f o i l y p roducts. On g l p c (column A, 180°C, 29 ml/min) the formation of three major products 2_, 2_9, and 2_8 was observed i n a r a t i o 2_:29:2_8 = 47:20:28. (Retention times: 2, 5.2 min; 2_9, 6.8 min; 28_, 8.3 min.) On t i c (8% e t h y l a c e t a t e - t o l u e n e ) two spots were observed under uv-lamp, which corresponded to compound 2_9_ (R , 0.38) and compounds 2 and 28 (R , 0.33). S i l i c a g e l (27 g) - 51 -column chromatography (4% e t h y l a c e t a t e - t o l u e n e ) a f f o r d e d ( a f t e r two r e c r y s t a l l i z a t i o n from n-hexane) 14 mg of pure 2_9 (5%) and 75 mg of a 1:3 mixture of .28 and 2. F u r t h e r s e p a r a t i o n of 2_8 from 2_ was achieved by adding n-hexane to the mixture and c e n t r i -f u g a t i o n . A f t e r r e c r y s t a l l i z a t i o n twice from n-hexane, 22 mg (7%) of pure 2_8_ was ob t a i n e d . The diketone 2_ was p u r i f i e d f u r t h e r by p r e p a r a t i v e gas l i q u i d chromatography (column C, 180°C, 150 ml/ min), and 40 mg (13%) was ob t a i n e d . 3 7 Compound 2_, 1, 3, 4 , 6 , 8 , 9 - h e x a m e t h y l t r i c y c l o [4 . 4 . 0 . 0 ' ]dec-8-ene-2,5-dione, a c o l o r l e s s o i l , was c h a r a c t e r i z e d by comparison 12 of i t s i r and nmr s p e c t r a w i t h those o f an a u t h e n t i c sample. 3 8 Compound 28, 1,3,4,6,8,9-hexamethyltricyclo[4.4.0.0 ' ]dec-9-ene-2,5-dione, c o l o r l e s s c r y s t a l s of m e l t i n g p o i n t (mp) 138.0-138.5°C (n-hexane), was c h a r a c t e r i z e d by: i r (KBr) 1710 (C=0) and 1720 c m - 1 (C=0); 270-MHz nmr (CDClg) 6 5.24 (d, J=2Hz, IH, C(10)H ), 2.61 (q, J=7Hz, IH, C(4)H), 1.85 (d, J=2Hz, 3H, C(9) methyl), 1.81 (d, J=13Hz, IH, one of C(7) methylenes), 1.36 (d, J=13Hz,' 1lH, one o f C(7) methylenes), 1.20 (s, 3H, CH 3), 1.08 (s, 3H, CH 3), 0.96 (s, 3H, CH 3), 0.94 (s, 3H, CH 3), and 0.92 (d, J=7Hz, 3H, MP>DW C(4) methyl); uv 287 nm (e 370); ms parent (70 eV) m/e 246. in 3. x A n a l . C a l c d f o r C±eE2202: C ' 7 8 - 0 1 ; H ' 9 - 0 0 - Found: C, 77.80; H, 8.98. Compound 29_, 1, 3, 4 , 6 , 8-pentamethyl-exo-9-methylene-tricyclo-[4 . 4 . 0 . 0"^ '^ ] decane-2, 5-dione, mp 94.5-95.0°C (n-hexane), showed i r (KBr) 900 (C=CH 2), 1710 (C=0), and 1720 c m - 1 (C=0); 270-MHz - 52 -nmr (CDCl 3) 6 4.87 (d, J=3Hz, IH, one of the exo-methylenes), 4.78 (broad s, IH, one of the exo-methylenes), 2.78 (dt, J=15Hz and 3Hz, IH, one o f C(10) methylenes), 2.71 (q, J=7Hz, IH, C(4)H), 2.04 (d, J=15Hz, IH, one of C(10) methylenes), 1.86 (d, J=14Hz, IH, one of C(7) methylenes), 1.77 (d, J=14Hz, IH, one of C(7) methylenes), 1.10 (s, 3H, CH 3), 1.03 (s, 3H, CH 3), 0.92 (d, J=7Hz, 3H, C(4) methyl), 0.88 (s, 3H, CH 3), and 0.87 (s, 3H, CH 3); uv e 285 nm (e 8 0); ms parent (70 eV) m/e 246. max \ i i r I I A n a l . C a l c d f o r C,_H_„0_: C, 78.01; H, 9.00. Found: l b 22 2. C, 77.70; H, 9.20. (2) Potassium Hydride and 1,2-Dimethoxyethane Potassium h y d r i d e (from A l f a ) , as a 22.4% m i n e r a l o i l d i s p e r -s i o n (1.29 g, 7.2 mmol) was weighed i n t o an oven- d r i e d 15 ml two necked f l a s k . I t was washed w i t h 2 x 5 ml of DME to get r i d o f the m i n e r a l o i l . F r e s h l y d i s t i l l e d DME (5 ml) was then added to the f l a s k a f t e r an i n e r t atmosphere was e s t a b l i s h e d w i t h n i t r o g e n . To the o i l - f r e e potassium h y d r i d e suspension i n DME, 0.80 g (3.3 mmol) of enone-alcohol 3_, which was d i s s o l v e d i n 6 ml of dry DME, was added from a s y r i n g e w i t h v i g o r o u s s t i r r i n g . A f t e r the r e s u l t -i n g mixture was r e f l u x e d f o r 4 hours, the r e a c t i o n f l a s k was c o o l -ed to 0°C w i t h an i c e bath. Then to the brown c o l o r e d r e a c t i o n mixture about 10 ml of water was added, dropwise f o r the f i r s t 2 ml. I t was then n e u t r a l i z e d w i t h IM h y d r o c h l o r i c a c i d and f i n a l l y e x t r a c t e d w i t h 5 x 10 ml of ch l o r o f o r m . The combined o r g a n i c l a y e r was then washed with 2 x 25 ml of water, 25 ml of b r i n e and d r i e d - 53 -over magnesium s u l f a t e . The s o l v e n t was removed by e v a p o r a t i o n under reduced p r e s s u r e to g i v e 0.71 g (89%) of crude products. Glpc a n a l y s i s showed t h a t the r a t i o o f the products was 2:29:28 = 10:1:77, with 12% of unreacted s t a r t i n g m a t e r i a l remaining. Using a procedure s i m i l a r to t h a t used p r e v i o u s l y , 8 mg (1%) of 29, 460 mg (58%) o f 2_8, and 40 mg (5%) o f 2 were i s o l a t e d , and 40 mg (5%) o f s t a r t i n g m a t e r i a l 3_ was reco v e r e d . Base-Catalyzed Rearrangement of Twistane 28 Treatment o f 60 mg (0.24 mmol) of 2_8_ wit h 23 mg (0.57 mmol) of o i l - f r e e potassium h y d r i d e i n 5 ml of r e f l u x i n g DME f o r 9 hours gave twistane 2_9_ i n s m a l l amount. Acco r d i n g to g l p c analy-s i s , the r a t i o of 2_8:2_9_ was time independent a f t e r 9 hours o f heat i n g and was found to be 90:10. A f t e r r o u t i n e work-up and r e -moval of s o l v e n t under vacuum, 45 mg (75%) of brown o i l y m a t e r i a l was r e c o v e r e d . S i l i c a g e l (5 g) column chromatography (4% e t h y l a c etate-toluene) a f f o r d e d 2 mg (3%) of 2_9 and 22 mg (37%) of s t a r t i n g m a t e r i a l 28. When twistane 2_9 was s u b j e c t e d to the same r e a c t i o n c o n d i t -i o n s , namely r e f l u x i n g DME i n the presence of potassium h y d r i d e , o n l y polymeric m a t e r i a l c o u l d be ob t a i n e d . - 54 -Base-Catalyzed Rearrangement of 8 , 9 - D i m e t h y l - 5 - h y d r o x y t r i c y c l o - [4.4.0.0 5 , 9]deca-3,7-dien-2-one (24) In an oven-dried 100 ml two necked f l a s k was p l a c e d 0.20 g (5.0 mmol) of o i l - f r e e potassium h y d r i d e . A f t e r an i n e r t atmo-sphere had been e s t a b l i s h e d w i t h dry n i t r o g e n , f r e s h l y d i s t i l l e d dimethoxyethane (DME) (40 ml) was added to the f l a s k which was then c o o l e d to 0°C with an i c e bath. Enone-alcohol 2_4 (0.42 g, 2.2 mmol), which was d i s s o l v e d i n 10 ml of DME, was added dropwise from a s y r i n g e to the c o o l e d s l u r r y , and a f t e r a d d i t i o n , the b l u e c o l o r e d r e a c t i o n mixture was s t i r r e d f o r 10 minutes. A f t e r remov-i n g the i c e bath, 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 a t room temperature. I t was then quenched with 30 ml o f water and n e u t r a l i z e d w i t h 1M h y d r o c h l o r i c a c i d . A f t e r e x t r a c t i o n with c h l o r o f o r m (7 x 10 ml), the combined c h l o r o f o r m l a y e r was washed wi t h 2 x 25 ml of water, 25 ml o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n and d r i e d over magnesium s u l f a t e . The s o l v e n t was evap-o r a t e d by means o f a r o t a r y evaporator to g i v e 0.31 g (74%) of o i l y y e l l o w l i q u i d . Glpc a n a l y s i s (column B, 180°C, 30 ml/min) showed t h a t t h i s mixture c o n t a i n e d mainly one product ( r e t e n t i o n time: 19_, 3.5 min) and i t c o n s t i t u t e d about 9 6% of the t o t a l v o l -a t i l e products formed. S i l i c a g e l (25 g) column chromatography (chloroform) a f f o r d e d ( a f t e r one r e c r y s t a l l i z a t i o n from n-hexane) 3 7 147 mg (35%) of compound 19, 8 , 9 - d i m e t h y l t r i c y c l o [ 4 . 4 . 0 . 0 ' ]dec-8-ene-2,5-dione, mp 90.0-90.5°C ( l i t . 1 2 mp 84-85°C (ether-hexane) ). The s t r u c t u r e of t h i s diketone was e s t a b l i s h e d by comparison - 55 -of i t s i n f r a r e d and nmr s p e c t r a w i t h those of an a u t h e n t i c sam-p i e . Base-Catalyzed Rearrangement of 1,6-Dicyano-8,9-dimethyl-5-5 9 h y d r o x y t r i c y c l o [ 4 . 4 . 0 . 0 ' ]deca-3,7-dien-2-one (48) Dry DME (25 ml) was added to a 50 ml t h r e e necked f l a s k which c o n t a i n e d 0.05 g (1.3 mmol) of o i l - f r e e potassium h y d r i d e a f t e r a n i t r o g e n atmosphere had been e s t a b l i s h e d . The f l a s k was f i t t e d w ith a magnetic s t i r r i n g bar and a low temperature t h e r -mometer, and was c o o l e d to about -50°C by means of a d r y - i c e -acetone bath. Enone-alcohol 4_8_ (0.25 g, 1.0 mmol), which was d i s s o l v e d i n 10 ml dry DME, was added dropwise from a s y r i n g e t o the f l a s k , keeping the temperature of the r e a c t i o n mixture below -40°C. The r e s u l t i n g b l u e c o l o r e d s o l u t i o n was s t i r r e d f o r 15 minutes a t -40°C and then by removing the c o l d bath, the r e a c t i o n mixture was warmed up to room temperature and s t i r r e d f o r an a d d i t i o n a l 6 hours. The r e a c t i o n mixture was then quenched with 25 ml of water, n e u t r a l i z e d w i t h 1M h y d r o c h l o r i c a c i d , e x t r a c t e d with c h l o r o f o r m (10 x 10 ml) and a f t e r washing with 2 x 25 ml of water and 25 ml of b r i n e the combined o r g a n i c l a y e r was d r i e d over 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 0.10 g (40%) of brown o i l which s o l i d i f i e d on stand i n g . Glpc (column B, 200°C, 30 ml/min) i n d i c a t e d the mixture c o n s i s t e d of two major products i n a r a t i o 4_9:50_ = 5:90. (Retent-i o n times: 49, 2.2 min; 50, 7.6 min.) On t i c (with c h l o r o f o r m as - 56 -s o l v e n t ) , £9 a n d 50_ h a v e R f v a l u e s o f 0.70 and 0.35 r e s p e c t i v e l y . A f t e r t r i t u r a t i n g w i t h c h l o r o f o r m ( 2 x 2 ml) t h e l i g h t b r o w n s o l i d was r e c r y s t a l l i z e d f r o m p e t r o l e u m e t h e r ( 6 5 - 1 1 0 ) - a c e t o n e . Compound 50_ (59 mg, 24%) was o b t a i n e d a s w h i t e powder l i k e c r y s -t a l s w h i c h h a d a m e l t i n g r a n g e o f 225.0-226.0°C. The c h l o r o f o r m s o l u t i o n w h i c h h a d b e e n u s e d i n w a s h i n g t h e b r o w n s o l i d was c o n -c e n t r a t e d a n d c h r o m a t o g r a p h e d t h r o u g h a s h o r t s i l i c a g e l c o l u m n ( c h l o r o f o r m a s s o l v e n t ) a f f o r d i n g 5 mg (2%) o f compound 4_9, mp 179.0-180.0°C f r o m n - h e x a n e - a c e t o n e ( l i t . 3 4 mp 178-179°C f r o m m e t h a n o l - p e t r o l e u m ) , p l u s 25 mg (10%) o f 50. The s t r u c t u r e o f 50_, 8 , 9 - d i c y a n o - l , 6 - d i m e t h y l t r i c y c l o -3 7 [4.4.0.0 ' ] d e c - 8 - e n e - 2 , 5 - d i o n e , was d e d u c e d f r o m i t s s p e c t r a l d a t a : i r ( K B r ) 1739 (C=0) and 2232 c m - 1 (C=N); 270-MHz nmr ( a c e t o n e - d 6 ) 6 3.59 ( d , J=5Hz, I H , C ( 3 ) H ) , 3.40 ( s , I H , C ( 7 ) H ) , 2.81 ( d d , J=18Hz a n d 5Hz, I H , C ( 4 ) H ) , 2.77 ( d , J=20Hz, I H , one o f C ( 1 0 ) m e t h y l e n e s ) , 2.59 ( d , J=20Hz, I H , one o f C ( 1 0 ) m e t h y l e n e s ) , 2.30 ( d , J=18Hz, I H , c ( 4 ) H e n d c . ) ' 1 - 1 7 ( s' 3 H ' C H 3 ) / and 0.95 ( s , 3H, CH.,) ; uv 234 nm (e 7 9 0 0 ) ; ms p a r e n t (70 eV) -j ITlcLX m/e 240. A n a l . C a l c d f o r C 1 4 H 1 2 N 2 ° 2 : C ' 6 9 - 9 9 ; H ' 5 - 0 3 ? N ' H - 6 6 . F o u n d : C, 69.70; H, 5.19; N, 1 1 . 7 1 . 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