UBC Theses and Dissertations

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UBC Theses and Dissertations

Studies directed towards a synthesis of resistomycin Kingston, John Francis 1974

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c /  STUDIES DIRECTED TOWARDS A SYNTHESIS OF RESISTOMYCIN  by  JOHN FRANCIS KINGSTON B . S c . ( H o n s . ) , C a r l e t o n U n i v e r s i t y , 1969  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY  i n the Department of  Chemistry  We a c c e p t t h i s t h e s i s a s c o n f o r m i n g t o t h e required standard  THE UNIVERSITY OF B R I T I S H COLUMBIA J a n u a r y , 1974  In p r e s e n t i n g an a d v a n c e d  this  thesis  d e g r e e at  t h e L i b r a r y s h a l l make I further for  scholarly  by h i s of  agree  this  written  it  freely  British  available  for  that permission for extensive  purposes  may be g r a n t e d  for  It  financial gain  of  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada  Columbia  Date  / W  the  requirements  Columbia, reference  copying of  I agree and this  shall  that  not  for that  study. thesis  by t h e Head o f my D e p a r t m e n t  is understood  permission.  Department  fulfilment of  the U n i v e r s i t y of  representatives. thesis  in p a r t i a l  or  copying or p u b l i c a t i o n  be a l l o w e d w i t h o u t my  iii ABSTRACT  A possible route to the synthesis of resistomycin i s o u t l i n e d and t h e f i r s t s t e p s i n t h i s a r e r e p o r t e d and d i s c u s s e d . A c e t y l a t i o n o f t h e known compound  2-(3,5-dimethoxyphenyl)-  2-methylpropionitri1e afforded 2-(4-acetyl-3,5-dimethoxyphenyl)2 - m e t h y l p r o p i o n i t r i l e (22_). C o n d e n s a t i o n o f 22^ w i t h t h e d i a n i o n o f m e t h y l a c e t o a c e t a t e , f o l l o w e d by d e h y d r a t i o n a f f o r d e d an E,Z m i x t u r e o f methyl  5-(4-1 -cyano-1 -methylethyl-2,6-dimethoxyphenyl)-3-oxo1  1  h e x - 4 - e n o a t e s ( 2 5 ) . S e v e r a l a t t e m p t s t o c y c l i s e 25_ and a c l o s e l y r e l a t e d model compound v i a t h e i r monoanions o r t h e i r e n o l e t h e r s o r a c e t a t e s were u n s u c c e s s f u l . In a model s t u d y r e l a t e d t o t h e p r o p o s e d . s y n t h e s i s c f r e s i s t o m y c i n t h e d i a n i o n o f a c e t i c a c i d was c o n d e n s e d w i t h 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e (94_). D e h y d r a t i o n o f t h e p r o d u c t y i e l d e d a m i x t u r e o f 3 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t - 2 and 3 - e n o i c a c i d s (96_ and 1 1 3 ) . A t t e m p t s t o a c y l a t e t h e m e t h y l e s t e r s and a c i d c h l o r i d e s o f 96 and 113 w i t h t h e e n o l a t e a n i o n o f 94_ were u n s u c c e s s f u l . S e v e r a l methods o f g e n e r a t i n g t h e d i a n i o n s o f g - d i k e t o n e s and c o n d e n s i n g them w i t h h i n d e r e d k e t o n e s s u c h as 94_, 22^ and 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (3_9) were i n v e s t i g a t e d . The s y n t h e s i s o f l - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t a n e 1 , 3 - d i o n e (121) was a c c o m p l i s h e d by c o n d e n s a t i o n o f 94_ w i t h methyl acetate. One a l t e r n a t i v e t o t h e d i a n i o n a p p r o a c h t o t h e f u n c t i o n a l i s a t i o n o f t h e y c a r b o n o f 8 - d i k e t o n e s was e x a m i n e d . T h i s i n v o l v e d t h e s y n t h e s i s o f 3 - m e t h y l - 5 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) i s o x a z o l e (183)  iv  f r o m 121. A t t e m p t s t o f u n c t i o n a l i s e t h e C-3 m e t h y l group o f 183 and i t s methyl f l u o r o s u l p h o n a t e s a l t were n o t s u c c e s s f u l . C o n d e n s a t i o n o f t h e d i a n i o n o f 4(3 w i t h 94 a f f o r d e d 5-hydroxy-l-phenyl-5-(2,4,6-trimethoxyphenyl)hexane-l,3-dione  (158).  T h i s compound was d e h y d r a t e d and i n a n o v e l r e a c t i o n was c y c l i s e d , i n the presence o f hydrogen c h l o r i d e , v i a l o s s o f methanol, t o 5,7-dimethoxy-2-hydroxy-4-methyl-l-naphthyl  phenyl ketone (156).  The d i a n i o n o f 121 was r e a c t e d w i t h k e t o n e s 3_9 and 22^ and t h e p r o d u c t s were d e h y d r a t e d w i t h boron t r i f l u o r i d e e t h e r a t e . In t h e s e c a s e s s t a n n i c c h l o r i d e was r e q u i r e d t o e f f e c t c y c l i s a t i o n to 2-hydroxy-5-methoxy-4-methyl-l-naphthyl  2,4,6-trimethoxyphenyl  k e t o n e (217) and 2 - ( 7 - h y d r o x y - 5 - m e t h y l - 4 - m e t h o x y - 8 - 2 , 4 ' , 6 ' - t r i ,  methoxybenzoyl-2-naphthyl)-2-methylprOpionitrile (27). Plans t o c o n v e r t 27 t o r e s i s t o m y c i n by a d d i t i o n a l c y c l i s a t i o n s a r e d i s c u s s e d .  V  TABLE OF CONTENTS  Abstract  i i i  Table o f Contents  v  L i s t o f Tables  vii  L i s t o f Schemes  viii  Acknowledgements  ix  Introduction  1  General Synthetic Plan  11  R e s u l t s and D i s c u s s i o n P a r t A:  Synthesis o f 2-(4-acetyl-3,5-dimethoxyphenyl)-  16  2-methylpropionitrile (22) P a r t J3:  The B-ketoester route  P a r t C_: T h e B - d i k e t o n e  22  route  46  S e c t i o n I : The a c e t i c a c i d d i a n i o n approach  48  S e c t i o n I I : Model s t u d i e s on t h e d i a n i o n s o f  58  B-diketones Section I I I : Synthesis o f 2,4,6-trimethoxy-  78  benzoylacetone S e c t i o n I V : Some i s o x a z o l e c h e m i s t r y S e c t i o n V: Experimental  S y n t h e s i s o f n a p h t h y l k e t o n e 27_  91 102 121  Bibliography S p e c t r a l Append  vii  L i s t of Tables Table I  Chemical S h i f t s of the B Protons o f S u b s t i t u t e d  34  Styrenes II  Approximate Percentages of Enol Present i n Para Substituted Benzoylacetones i n Deuterochloroform  85  vi ii L i s t o f Schemes  Scheme 1 2  Proposed S y n t h e s i s of R e s i s t o m y c i n  14  Synthesis of 2-(4-Acetyl-3,5-dimethoxyphenyl)-  17  2-methylpropionitrile 3  (22)  Synthesis of 2-(3,5-Dimethoxyphenyl)-2-methy1propionitrile  18  (21)  4  Reactions of the D i p o t a s s i o S a l t s of e-Diketones  24  5  C a n o n i c a l Forms o f t h e D i a n i o n o f  25  Benzoyl acetone 6  Reactions of the Dianion of Ethyl Acetoacetate  26  7  S y t h e s i s o f e - K e t o e s t e r 68  37  8  Proposed A c e t i c A c i d Dianion Route  49  9  S y n t h e s i s of 3-Diketone  59  10  Tautomeric forms of 2,4,6-Trimethoxybenzoylacetone  84  11  Reactions of 3-Methyl-5-lithiomethylisoxazole  92  12  Proposed  I s o x a z o l e Route  93  13  Mechanism o f t h e A l d o l C o n d e n s a t i o n  105  29  Acknowledgements  I w i s h t o e x p r e s s my g r a t i t u d e t o Dr. S t u a r t N. Dr. R. B a l a j i Rao, and Frank W.B.  Huckin,  Skinner f o r t h e i r f r i e n d s h i p  and l a u g h t e r d u r i n g t h e c o u r s e o f t h i s r e s e a r c h and f o r t h e i r many helpful discussions. I am i n d e b t e d t o P r o f . L . J . M u e n s t e r f o r h i s g e n e r o s i t y i n a l l o w i n g me t o use h i s e q u i p m e n t on numerous o c c a s i o n s . M o s t o f a l l I am g r a t e f u l t o Dr. L a r r y W e i l e r . h i s g u i d a n c e , e n c o u r a g e m e n t , and f r i e n d s h i p I w o u l d n o t have t h i s work.  Without completed  I l e a v e S i s y p h u s a t t h e f o o t o f t h e m o u n t a i n . One a l w a y s f i n d s one's burden a g a i n . But S i s y p h u s t e a c h e s t h e h i g h e r f i d e l i t y t h a t n e g a t e s t h e gods and r a i s e s t h e r o c k s . He t o o c o n c l u d e s t h a t a l l i s w e l l . T h i s u n i v e r s e h e n c e f o r t h w i t h o u t a m a s t e r seems t o him n e i t h e r s t e r i l e nor f u t i l e . Each atom o f t h a t s t o n e , e a c h m i n e r a l f l a k e o f t h a t n i g h t - f i l l e d m o u n t a i n , i n i t s e l f forms a w o r l d . The s t r u g g l e i t s e l f t o w a r d s t h e h e i g h t s i s enough t o f i l l a man's h e a r t . One must i m a g i n e S i s y p h u s happy. A l b e r t Camus, "The M y t h o f S i s y p h u s "  INTRODUCTION The a n t i b i o t i c r e s i s t o m y c i n (1_) was f i r s t i s o l a t e d from t h e bacterium  S t r e p t o m y c e s r e s i s t o m y c i f i c u s by Brockmann and S c h m i d t - K a s t n e r .  It was o b t a i n e d a s a p r e c i p i t a t e f r o m an e t h e r e a l e x t r a c t o f t h e d r i e d b a c t e r i a l mycelia. R e c r y s t a l 1 i z a t i o n from acetone o r dioxane y i e l d e d y e l l o w needles which melted with decomposition compound was s o l u b l e i n c o n c e n t r a t e d  a t 315 d e g r e e s . T h e  sulphuric acid e x h i b i t i n g a strong  l i g h t - g r e e n f l u o r e s c e n c e . I t was r e s i s t a n t (hence i t s name) t o decomposition  i n h o t normal p o t a s s i u m h y d r o x i d e  or hot concentrated  sulphuric acid.  A s e r i e s o f p a p e r s by Brockmann e t a l _ ,  t _ u  established the  s t r u c t u r e o f r e s i s t o m y c i n . The mass s p e c t r a and e l e m e n t a l t h e a n t i b i o t i c and i t s d e r i v a t i v e s showed i t s m o l e c u l a r C  22^16^6*  f :  °  r m a t l o n  °f  a  tetrabenzoate  analyses o f f o r m u l a t o be  and a t e t r a a c e t a t e f r o m  r e s i s t o m y c i n i n d i c a t e d t h a t f o u r o f t h e o x y g e n atoms p r e s e n t i n i t s f o r m u l a b e l o n g t o phenol o r e n o l h y d r o x y l  groups. Examination of the  2  i n f r a r e d (IR) s p e c r t r a o f t h e n a t u r a l p r o d u c t and s e v e r a l o f i t s mono, t r i , and t e t r a m e t h y l e t h e r s e s t a b l i s h e d t h e p r e s e n c e o f two c a r b o n y l g r o u p s . The n u c l e a r m a g n e t i c r e s o n a n c e (NMR)  chelated  spectrum of the  a n t i b i o t i c i n d e u t e r o s u l p h u r i c a c i d d e m o n s t r a t e d t h a t i t had  three  non, o r w e a k l y c o u p l e d a r o m a t i c o r o l e f i n i c p r o t o n s t h a t were q u i t e s t a b l e to deuterium  e x c h a n g e . A l s o shown i n t h e s p e c t r u m were one  a r o m a t i c m e t h y l g r o u p and two e q u i v a l e n t a l i p h a t i c m e t h y l g r o u p s w h i c h , a c c o r d i n g t o t h e y i e l d o f a c e t i c a c i d (1.5 m o l e s ) from a Kuhn-Roth o x i d a t i o n , were g e m i n a l . T h i s was s u b s t a n t i a t e d by t h e i s o l a t i o n o f d i m e t h y l m a l o n a t e ( 2 j from t h e p e r m a n g a n a t e d e c o m p o s i t i o n  of resistomycin.  R e d u c t i o n o f t h e a n t i b i o t i c and i t s d e r i v a t i v e s by z i n c d u s t a t h i g h t e m p e r a t u r e y i e l d e d p r o d u c t s whose u l t r a v i o l e t and v i s i b l e ( U V - V i s ) s p e c t r a and mass s p e c t r a r e v e a l e d t h a t t h e y were m e t h y l d e r i v a t i v e s o f t h e p e n t a c y c l i c a r o m a t i c s 3_ and 4_. T h i s l e d t o t h e f o r m u l a t i o n o f p a r t i a l s t r u c t u r e 5_ f o r r e s i s t o m y c i n .  2  C0 H 2  3  / a C H  aliphatic " 3 C H  aromatic  2: 4-  •OH 3H  aromatic or o l e f i n i c  Hydrogenation o f resistomycin with platinum c a t a l y s t i n g l a c i a l a c e t i c a c i d a f f o r d e d a compound whose f o r m u l a , £ 2 2 ^ 1 8 ^ 5 ' a n d s p e c t r a l d a t a i n d i c a t e d i t t o be a mono deoxy d e r i v a t i v e o f 5^ i n w h i c h t h e newly formed m e t h y l e n e g r o u p was n e x t t o t h e g e m i n a l  methyls.  F u r t h e r e x a m i n a t i o n o f " d e o x y r e s i s t o m y c i n " and i t s d e r i v a t i v e s d i s c l o s e d t h a t i t p o s s e s s e d a c a r b o n y l g r o u p t h a t was c h e l a t e d t o two h y d r o x y l g r o u p s . T h i s was p o s s i b l e o n l y a s shown i n s t r u c t u r e  In a d d i t i o n ,  c o m p a r i s o n o f t h e U V - V i s s p e c t r a w i t h t h o s e o f known compounds e s t a b l i s h e d t h e p r e s e n c e o f t h e c h r o m o p h o r e shown i n t h e t e t r a c y c l i c a r o m a t i c _7. None o f t h e t h r e e a r o m a t i c p r o t o n s i n r e s i s t o m y c i n o r d e o x y r e s i s t o m y c i n a r e c o u p l e d t o one a n o t h e r i n t h e i r NMR s p e c t r a . The h y d r o x y l g r o u p n o t a s s i g n e d i n s t r u c t u r e 6_ must be i n a p o s i t i o n p e r i t o t h e s e c o n d c a r b o n y l group w h i c h was r e d u c e d i n g o i n g from r e s i s t o m y c i n t o d e o x y r e s i s t o m y c i n i n o r d e r t o hydrogen bond w i t h i t . T h e s e c o n d i t i o n s a r e met o n l y i f t h e f o u r t h h y d r o x y l group i s on C-3,  5  t h e g e m i n a l m e t h y l s on C-1, and t h e a r o m a t i c m e t h y l on C-8 o r C-9. The C-9 p o s i t i o n f o r t h e a r o m a t i c m e t h y l was p r e f e r r e d by Brockmann on b i o g e n e t i c grounds and s t r u c t u r e s 8_ and 1_ were a s s i g n e d t o d e o x y r e s i s t o m y c i n and r e s i s t o m y c i n r e s p e c t i v e l y . 7  Rosenbrook  disputed the assignment  of the aromatic  m e t h y l group c l a i m i n g i t s h o u l d be p u t a t C-8. He f o u n d t h a t t h e a r o m a t i c p r o t o n a t C-8 o r C-9 was much more r e s i s t a n t t o d e u t e r i u m e x c h a n g e than t h e o t h e r a r o m a t i c p r o t o n s . In a d d i t i o n , he was  unable  t o c h l o r i n a t e o r b r o m i n a t e t h i s p o s i t i o n . He a s c r i b e d t h i s r e s i s t a n c e to e l e c t r o p h i l i c s u b s t i t u t i o n to the f a c t that the proton i n question must be i n a " p o s i t i o n meta r e l a t i v e t o t h e C-7 and C-10  phenolic  h y d r o x y l g r o u p s " . ^ Hence he p r o p o s e d s t r u c t u r e £ f o r r e s i s t o m y c i n .  QH  O  9  Brockmann and R e s c h k e p r o v e d t h i s h y p o t h e s i s i n c o r r e c t . ' F o r m a t i o n o f t h e t e t r a m e t h y l e t h e r o f r e s i s t o m y c i n f o l l o w e d by r e d u c t i o n i n a c e t i c a c i d o v e r p l a t i n u m g a v e compound 10_. O z o n o l y s i s o f 10  f o l l o w e d by o x i d a t i v e c l e a v a g e w i t h hydrogen p e r o x i d e - f o r m i c a c i d y i e l d e d s e v e r a l p r o d u c t s one o f w h i c h was shown t o be 2- m e t h y l g l u t a r i c a c i d (11_). T h i s compound c o u l d be p r o d u c e d o n l y i f t h e m e t h y l i s on t h e C-9 p o s i t i o n . I f i t were i n t h e C-8 p o s i t i o n 3- m e t h y l g l u t a r i c a c i d would have been p r o d u c e d . Brockmann and  Reschke  were a l s o a b l e t o s e q u e n t i a l l y s u b s t i t u t e a l l t h r e e a r o m a t i c p r o t o n s w i t h bromine ( i n t h e o r d e r 4, 11, 8 ) .  Some doubt e x i s t s as t o t h e c o r r e c t t a u t o m e r i c form o f r e s i s t o m y c i n . I n d e e d , t h e s t r u c t u r e f i r s t p r o p o s e d by Brockmann was L3. T a u t o m e r l ^ a l s o f i t s a l l o f t h e d a t a d e s c r i b e d . The i d e n t i f i c a t o f t h r e e c h e l a t e d h y d r o x y l g r o u p s i n t h e NMR  spectrum of r e s i s t o m y c i n  and two i n t h a t o f d e o x y r e s i s t o m y c i n as w e l l as r e f l e c t i o n on t h e r e a c t i v i t i e s o f t h e v a r i o u s h y d r o x y l g r o u p s has l e d Brockmann e_t aj_. t o r u l e o u t 13_. On t h e b a s i s o f i t s o b v i o u s s t a b i l i t y compared t o 1£, s t r u c t u r e 1_ i s now a c c e p t e d as t h e p r e d o m i n a n t t a u t o m e r i c form.*'  7  Br  8  S t r u c t u r e e l u c i d a t i o n o f t h e a n t i b i o t i c X-340, i s o l a t e d 8 9 from a n o t h e r s o u r c e , ' was p r o c e e d i n g c o n c u r r e n t l y w i t h t h e work d e s c r i b e d above f o r r e s i s t o m y c i n . The two compounds were e v e n t u a l l y p r o v e n t o be i d e n t i c a l . ^ X - r a y c r y s t a l l o g r a p h i c e x a m i n a t i o n dibromoresistomycin  of  t e t r a m e t h y l e t h e r showed i t t o have t h e s k e l e t a l  s t r u c t u r e 14_ t h e r e b y c o n f i r m i n g t h e s t r u c t u r e p u t f o r w a r d  by  Brockmann e t a l _ . f o r r e s i s t o m y c i n . Another a n t i b i o t i c , h e l i o m y c i n , i s o l a t e d from S t r e p t o m y c e s f l a v o c h r o m e n g e s has been s h o w n , o n t h e b a s i s o f i t s s p e c t r a l p r o p e r t i e s , m e l t i n g p o i n t , and a n t i m i c r o b i a l a c t i o n , t o be 12 i d e n t i c a l t o r e s i s t o m y c i n . H . Umezawa l i s t s yet another a n t i b i o t i c , 13 croceomycin,  as b e i n g i d e n t i c a l t o r e s i s t o m y c i n . T h i s seems u n l i k e l y  s i n c e c r o c e o m y c i n i s r e p o r t e d t o have o p t i c a l a c t i v i t y . R e s i s t o m y c i n i s most a c t i v e a g a i n s t g r a m - p o s i t i v e  bacteria 1  n o t a b l y B a c i l l u s s u b t i l i s and M i c r o c o c c u s  pyrogenes var aureus.  8  '  high c o n c e n t r a t i o n s i n h i b i t growth of Mycobacterium t u b e r c u l o s i s . * Heliomycin  i s r e p o r t e d t o be a c t i v e a g a i n s t S t a p h y l o c o c c i , i n f l u e n z a  v i r u s , t o b a c c o m o s a i c v i r u s , and s m a l l pox  vaccine.  R e s i s t o m y c i n was t h e f i r s t i s o l a t e d p e n t a c y c l i c p o l y p h e n o l i c m i c r o b i a l m e t a b o l i t e o f i t s .type. I t s o x y g e n a t i o n  pattern  suggests  t h a t i t s b i o s y n t h e s i s f o l l o w s t h e p o l y k e t i d e pathway. I t b e a r s  an  o b v i o u s l y c l o s e r e l a t i o n s h i p t o t h e n a t u r a l p h e n a l e n o n e s such a s a t r o v e n e t i n ( 1 5 ) ^ ' ^ and t h e i r d i m e r s such as d u c l a u x i n compounds a r e known t o be p o l y k e t i d e d e r i v e d . and B a i l e y e t a l _ . ^ p r o p o s e d  1 7  (16)These  Brockmann e t _ a l _ .  6  t h e t e n a c e t a t e p o l y k e t i d e r o u t e s shown  i n 17a and 17b. C y c l i s a t i o n and d e h y d r a t i o n a l o n g e i t h e r o f t h e s e  9 O  OH  10  paths leads t o an oxygenation  pattern i d e n t i c a l to that of resistomycin  and p l a c e s t h e a r o m a t i c m e t h y l g r o u p i n t h e C-9 p o s i t i o n . R e c e n t l y , r e s i s t o f l a v i n , an a n t i b i o t i c c l o s e l y r e l a t e d 18  to r e s i s t o m y c i n has been i s o l a t e d  and s t r u c t u r e J18 has been  proposed  19  for i t .  T h e p o s i t i o n o f t h e e x t r a h y d r o x y l g r o u p was f a i r l y f i r m l y  e s t a b l i s h e d by e x t e n s i v e NMR s t u d i e s o f t h e compound a n d i t s d e r i v a t i v e s as w e l l a s some d i r e c t c h e m i c a l e v i d e n c e . T h i s a s s i g n m e n t , i f c o r r e c t , i s somewhat p u z z l i n g . No p o l y k e t i d e b i o g e n e t i c pathway c o u l d l e a v e a h y d r o x y l g r o u p i n t h i s p o s i t i o n and i t seems an u n u s u a l an a d d i t i o n t o o c c u r a f t e r c y c l i s a t i o n .  p l a c e f o r such  11  GENERAL_SYNTHETIC PLAN The n o v e l and u n u s u a l s t r u c t u r e o f r e s i s t o m y c i n made i t an a t t r a c t i v e t a r g e t f o r a t o t a l s y n t h e s i s . I t b e a r s a c l o s e r e l a t i o s h i p t o t h e p h e n a l e n o n e s 15_ and Jj5_ and i n i t s B, C, and D r i n g s r e s e m b l e s o t h e r a n t i b i o t i c s such as t e t r a c y c l i n e (19) 21  daunomycinone  (20)."  20  and t h e a n t i t u m o u r a g e n t  T h i s i n v i t e d t h e hope t h a t t h e m e t h o d o l o g y  d e v e l o p e d i n a s y n t h e s i s o f r e s i s t o m y c i n m i g h t be o f w i d e s p r e a d s y n t h e t i c u t i l i t y i n t h e p o l y k e t i d e f i e l d . D i s c o v e r y o f an e f f i c i e n t s y n t h e s i s f o r an a n t i b i o t i c c a n , t h r o u g h s m a l l m o d i f i c a t i o n s , r e s u l t i n t h e s y n t h e s e s o f s e v e r a l s t r u c t u r a l a n a l o g u e s w h i c h may have m e d i c i n a l p r o p e r t i e s s u p e r i o r t o t h o s e o f t h e p a r e n t compound.  12  The a v a i l a b i l i t y o f a l a r g e v a r i e t y o f s u b s t i t u t e d b e n z e n e compounds and t h e l a r g e body o f k n o w l e d g e t h a t e x i s t s a b o u t t h e i r r e a c t i o n s made them o b v i o u s c h o i c e s as s t a r t i n g m a t e r i a l s t o become r i n g s B and E i n r e s i s t o m y c i n . A s e a r c h o f t h e l i t e r a t u r e f o r a s u i t a b l e s t a r t i n g m a t e r i a l f o r r i n g E r e v e a l e d t h a t n i t r i l e 21 been p r e p a r e d as an i n t e r m e d i a t e  i n the syntheses of  had  tetrahydrocannabinol  22  homologs by Adams e t a l _ .  T h i s seemed t o be an i d e a l s t a r t i n g m a t e r i a l  s i n c e i t c o u l d be e l a b o r a t e d i n numerous ways u n d e r a g r e a t 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 w i t h o u t a f f e c t i n g the n i t r i l e s i d e c h a i n . I t was a n t i c i p a t e d t h a t t h i s s i d e c h a i n c o u l d be used i n one o f t h e l a s t s t e p s i n t h e s y n t h e s i s t o f o r m r i n g A by an i n t r a m o l e c u l a r  Hoesch  r e a c t i o n o r a r e l a t e d e l e c t r o p h i l i c s u b s t i t u t i o n on r i n g B w h i c h w o u l d be h i g h l y s u s c e p t i b l e t o e l e c t r o p h i l i c a t t a c k s i n c e i t w o u l d , o f n e c e s s i t y , c o n t a i n two o x y g e n a t e d p o s i t i o n s t o become t h e h y d r o x y l groups in r e s i s t o m y c i n .  21  22  The f i r s t s t e p i n t h e e l a b o r a t i o n o f 21_ r e q u i r e d s u b s t i t u t i o n i n t h e p o s i t i o n p a r a t o t h e n i t r i l e s i d e c h a i n . I t was b e l i e v e d t h a t t h i s would be t h e f a v o u r e d p o s i t i o n f o r e l e c t r o p h i l i c s u b s t i t u t i o n  13 b e c a u s e o f s t e r i c h i n d r a n c e t o o r t h o a t t a c k due t o t h e b u l k i n e s s o f t h e side chain (comparable t o a t e r t i a r y - b u t y l group). The o f t h e m e t h y l g r o u p a t t h e C-9 p o s i t i o n o f t h e r e s i s t o m y c i n  presence  skeleton  made F r i e d e l - C r a f t s a c y l a t i o n an o b v i o u s c h o i c e f o r t h i s s u b s t i t u t i o n . I t was a n t i c i p a t e d t h a t t h e a c e t o p h e n o n e 22. f o r m e d by t h i s a c y l a t i o n c o u l d be s u b j e c t e d t o an a l d o l o r r e l a t e d c o n d e n s a t i o n  whereby t h e  g r o u p s n e c e s s a r y f o r t h e e l a b o r a t i o n o f r i n g D c o u l d be a d d e d . Subsequent dehydration o f t h e a l d o l adduct would then leave a methyl g r o u p i n t h e d e s i r e d C-9 p o s i t i o n . P a r t A o f t h e RESULTS AND  DISCUSSION  d e s c r i b e s t h e s y n t h e s i s o f t h i s k e y i n t e r m e d i a t e a c e t o p h e n o n e 22_. The f i r s t r o u t e p r o p o s e d  f o r the synthesis of resistomycin  f r o m a c e t o p h e n o n e 72_ i s shown i n Scheme 1. B e c a u s e o f t h e e-polyoxygenation  p a t t e r n n e c e s s a r y i n r i n g s D, C, a n d B i t was f e l t t h a t  a B - k e t o e s t e r s h o u l d be added t o t h e a c e t o p h e n o n e t o g i v e an i n t e r m e d i a t e w h i c h m i g h t be u s e d t o form r i n g D v i a c y c l i s a t i o n a n d a l s o a l l o w f o r t h e a t t a c h m e n t o f t h e r i n g B atoms and t h e p r e s e n c e o f t h e o x y g e n a t e d p o s i t i o n a t C-6. I t was a n t i c i p a t e d t h a t a d d i t i o n o f t h e d i a n i o n o f m e t h y l a c e t o a c e t a t e ( 2 3 ) t o a c e t o p h e n o n e 22^ and s u b s e q u e n t would y i e l d t h e u n s a t u r a t e d  dehydration  B - k e t o e s t e r 2J5. I t was hoped t h a t t h i s  compound o r i t s e n o l e t h e r o r a c e t a t e c o u l d be c y c l i s e d v i a l o s s o f m e t h a n o l t o y i e l d t h e m e t h y l n a p h t h o a t e 26_. T h i s was seen a s a k e y i n t e r m e d i a t e w h i c h c o u l d be u s e d t o a c y l a t e 1 , 3 , 5 - t r i m e t h o x y b e n z e n e to y i e l d the naphthyl  k e t o n e 27. An i n t r a m o l e c u l a r H o e s c h r e a c t i o n a n d  l o s s o f methanol would then g i v e r e s i s t o m y c i n t r i m e t h y l e t h e r (23) w h i c h was t o be d e m e t h y l a t e d  t o r e s i s t o m y c i n {I).  T h i s proposed  synthesis  o f r e s i s t o m y c i n was a t t r a c t i v e f o r s e v e r a l r e a s o n s . I t was b e l i e v e d t h a t i n v e s t i g a t i o n o f t h e B - k e t o e s t e r r e a c t i o n s would be o f g e n e r a l  14  Scheme 1. P r o p o s e d S y n t h e s i s o f R e s i s t o m y c i n .  15  value i n the syntheses o f other p o l y p h e n o l i c n a t u r a l products. The symmetry o f t h e i n t e r m e d i a t e s i n v o l v e d l e d t o t h e b e l i e f t h a t t h e s y n t h e s i s would be an e f f i c i e n t one. T h a t i s , c y c l i s a t i o n o f 25 c o u l d o c c u r v i a l o s s o f m e t h a n o l a t e i t h e r o f two e q u i v a l e n t p o s i t i o n s t o g i v e t h e same p r o d u c t w i t h one o f t h e m e t h o x y g r o u p s r e t a i n e d and i n t h e c o r r e c t p o s i t i o n . The same was t r u e f o r t h e H o e s c h r e a c t i o n and l o s s o f m e t h a n o l from 27_. F i n a l l y , t h i s s y n t h e s i s c o u l d , i f s u c c e s s f u l , be m o d i f i e d i n many ways by v a r y i n g t h e s u b s t i t u t i o n p a t t e r n o f t h e s t a r t i n g materials to give several s t r u c t u r a l analogues of resistomycin. P a r t B o f t h e RESULTS AND DISCUSSION, d e s c r i b e s t h e s y n t h e s i s o f t h e unsaturated  B - k e t o e s t e r 25_ and s e v e r a l u n s u c c e s s f u l a t t e m p t s  to cyclise  i t t o t h e m e t h y l n a p h t h o a t e 26_. The f a i l u r e o f t h e above a p p r o a c h t h r o u g h t h e 8 - k e t o e s t e r led to the d e s i r e to obtain the naphthyl  k e t o n e 27 by a n o t h e r  route.  P a r t C o f t h e RESULTS AND DISCUSSION d e s c r i b e s t h e s y n t h e s i s o f t h e unsaturated  B-diketone  29 and i t s c y c l i s a t i o n t o 27_.  16  RESULTSJjUjDJHSCjJSgj ON  P a r t A: S y n t h e s i s o f  2-(4-acetyl-3,5-dimethoxyphenyl)-2-methylpro-  p i o n i t r i l e (22).  The r o u t e used i n t h e s y n t h e s i s o f 22_ i s o u t l i n e d i n Scheme 2. S y n t h e s i s o f t h e i n t e r m e d i a t e  2-(3,5-dimethoxyphenyl)-2-  m e t h y l p r o p i o n i t r i l e ( 2 1 j was a c c o m p l i s h e d by a m o d i f i c a t i o n o f t h e p r o c e d u r e r e p o r t e d by Adams e t al_. w h i c h i s shown i n Scheme 3. The s t a r t i n g m a t e r i a l i n b o t h c a s e s was t h e r e a d i l y a v a i l a b l e 3,5-dimethoxybenzoic  a c i d ( 3 0 ) . In t h e r o u t e by Adams,  r e d u c t i o n of the a c i d to 3,5-dimethoxybenzyl  a l c o h o l (31) was a c c o m p l i s h e d  through the i n t e r m e d i a t e 3,5-dimethoxybenzaldehyde  (32) s i n c e t h i s  compound was d e s i r e d a s an i n t e r m e d i a t e i n o t h e r s y n t h e s e s . I n o u r c a s e t h e a c i d was r e d u c e d d i r e c t l y t o t h e a l c o h o l by t h e a c t i o n o f e x c e s s l i t h i u m aluminum h y d r i d e i n t e t r a h y d r o f u r a n ( T H F ) . The t r a n s f o r m a t i o n was a c c o m p l i s h e d i n 99% y i e l d . The a l c o h o l was c o n v e r t e d t o 3 , 5 - d i m e t h o x y b e n z y l  c y a n i d e (34)  f o l l o w i n g e x a c t l y t h e p r o c e d u r e o u t l i n e d by Adams. I t was r e a c t e d w i t h t h i o n y l c h l o r i d e i n ether i n the presence of p y r i d i n e to g i v e 3,5-dimethoxybenzyl  c h l o r i d e (33) i n 90% y i e l d . T h i s c o u l d be u s e d  w i t h o u t p u r i f i c a t i o n t o r e a c t w i t h sodium c y a n i d e i n a q u e o u s e t h a n o l to produce 3,5-dimethoxybenzyl  c y a n i d e (34) ( 7 5 % ) .  Adams e_t al_. a l k y l a t e d n i t r i l e 3 £ w i t h m e t h y l i o d i d e u s i n g sodium amide as base t o g i v e t h e d e s i r e d d i m e t h y l a t e d compound i n a y i e l d o f 75%. Our p r o c e d u r e s u b s t i t u t e d t h e use o f t h e more c o n v e n i e n t sodium h y d r i d e f o r sodium amide. A d d i t i o n o f  £1  17  Scheme 2. S y n t h e s i s o f 2 - ( 4 - A c e t y l - 3 , 5 - d i m e t h o x y p h e n y l ) - 2 - m e t h y l p r o p i o n i t r i l e (22).  18  Scheme 3. S y n t h e s i s o f 2 - ( 3 , 5 - D i m e t h o x y p h e n y l ) - 2 - m e t h y l p r o p i o n i t r i l e ( 2 1 ) .  3 , 5 - d i m e t h o x y b e n z y l c y a n i d e t o a s u s p e n s i o n o f e x c e s s sodium  hydride  i n 1 , 2 - d i m e t h o x y e t h a n e (DME), f o l l o w e d by a d d i t i o n o f e x c e s s methyl i o d i d e and r e f l u x i n g l e d t o t h e f o r m a t i o n  o f 21 i n 80%  yield. F r i e d e l - C r a f t s a c y l a t i o n t o t h e d e s i r e d a c e t o p h e n o n e 22 was i n i t i a l l y c a r r i e d out w i t h a c e t i c a n h y d r i d e and aluminum c h l o r i d e u s i n g c a r b o n d i s u l p h i d e as s o l v e n t . T h i s p r o c e d u r e r e s u l t e d i n low y i e l d s o f p r o d u c t i n t h e r a n g e 25%-35%. A c y l a t i o n s u s i n g a c e t i c 23 a n h y d r i d e and aluminum c h l o r i d e a r e t h o u g h t  to proceed v i a p r i o r  r e a c t i o n o f t h e s e two components t o y i e l d a c e t y l c h l o r i d e ( 3 5 ) . A s e c o n d e q u i v a l e n t o f aluminum c h l o r i d e i s r e q u i r e d to form a L e w i s a c i d - a c i d c h l o r i d e complex (36) w h i c h i s the a c t u a l a c y l a t i n g a g e n t . N e i t h e r aluminum c h l o r i d e nor i t s complex w i t h a c e t y l c h l o r i d e i s 24 soluble i n a non-polar solvent l i k e carbon disulphide. the reaction i s completely  As a c o n s e q u e n c e  h e t e r o g e n e o u s . I t was b e l i e v e d t h a t t h i s was  t h e r e a s o n f o r the d i s a p p o i n t i n g y i e l d s o f p r o d u c t i n our a c y l a t i o n s i n c e t h e aluminum c h l o r i d e a n d / o r i t s complex w i t h a c e t y l c h l o r i d e had t e n d e d to coagulate  i n t o l a r g e lumps i n t h e c a r b o n d i s u l p h i d e t h u s d r a s t i c a l l y .  r e d u c i n g t h e e f f i c i e n c y o f any h e t e r o g e n e o u s  process.  o  AICI  o  35  Cl  AICI Cl  3  20  C h l o r i n a t e d hydrocarbons such as e t h y l e n e c h l o r i d e o r 24 m e t h y l e n e c h l o r i d e a r e known a c y l a t i n g complex.  t o be e x c e l l e n t s o l v e n t s f o r t h e  When m e t h y l e n e c h l o r i d e was s u b s t i t u t e d a s s o l v e n t  i n t h e a c y l a t i o n o f 2\_ t h e r e a c t i o n p r o c e e d e d s m o o t h l y t o t h e a c e t o phenone 22 i n 7 9 % y i e l d . The IR s p e c t r u m o f t h e p r o d u c t showed t h e c a r b o n y l a b s o r p t i o n e x p e c t e d f o r an a r y l k e t o n e (1700 c m ) a s w e l l a s n i t r i l e (2250 c m ) , - 1  - 1  a r o m a t i c (1580, 1610 c m " ) , and a r y l e t h e r (1250 c m ) b a n d s . 1  UV s p e c t r u m (x max =262mu) m  26  - 1  2 5  The  and m i c r o a n a l y s i s o f t h e compound were  c o n s i s t e n t w i t h t h e p r o p o s e d s t r u c t u r e . I t s mass s p e c t r u m showed t h e c o r r e c t p a r e n t a t m/e 247 and a l a r g e peak a t m/e 232 due t o l o s s o f methyl r a d i c a l from t h e p a r e n t i o n . A l l o f t h e above d a t a a r e c o n s i s t e n t w i t h e i t h e r t h e .desired acetophenone  22_ i n w h i c h t h e a c e t y l and a l k y l ( n i t r i l e ) s i d e  c h a i n s a r e p a r a t o one a n o t h e r o r i t s i s o m e r 37 w h i c h would have been p r o d u c e d had a c e t y l a t i o n - t a k e n p l a c e i n t h e h i n d e r e d p o s i t i o n o r t h o t o t h e a l k y l g r o u p . T h e NMR s p e c t r u m o f t h e p r o d u c t p r o v i d e d e v i d e n c e 27  t h a t i t was t h e s y m m e t r i c a l a c e t o p h e n o n e .  I t consisted of as i x  p r o t o n s i n g l e t a t 61.78 b e l o n g i n g t o t h e gem-dimethyl  g r o u p on  t h e a l k y l s i d e c h a i n , a t h r e e p r o t o n s i n g l e t a t 62.50 c o n s i s t e n t w i t h an a r y l m e t h y l k e t o n e , a s i x p r o t o n s i n g l e t a t 63.89 f o r t h e methoxy g r o u p s , and a two p r o t o n s i n g l e t a t 66.71 f o r t h e a r o m a t i c protons. The c l o s e s t a v a i l a b l e analogy t o t h e u n d e s i r e d product i s 2,4-diniethoxyacetophenone  ( 3 8 ) w h i c h shows  d i f f e r e n t chemical  shifts  f o r t h e methoxy g r o u p s p a r a (63.72) and o r t h o (63.79) t o t h e a c e t y l group a s w e l l a s d i f f e r e n t s h i f t s (66.28, 6.35) f o r t h e a r o m a t i c  21  p r o t o n s meta t o t h e a c e t y l g r o u p . The s p e c t r u m o f 2 , 6 - d i m e t h o x y a c e t o phenone (39) shows a s i n g l e t f o r t h e two methoxy g r o u p s a t 63.80.  22  Part B: The 6-ketoester route.  The obvious applicability of 3-polycarbonyl compounds to the synthesis of acetogenins containing 8-polyoxygenated functionalities has been mentioned in a previous section. In particular, i t was evident that condensation  of acetophenone 22 with the y carbon of  methyl acetoacetate would yield a 6-hydroxy-B-ketoester 24_ possessing the correct oxygenation pattern for the synthesis of the C and D rings in resistomycin.  23. F u n c t i o n a l i s a t i o n o f t h e y c a r b o n o f 8 - d i c a r b o n y l compounds 29 was f i r s t a c c o m p l i s h e d by H a u s e r and H a r r i s i n 1958.  Treatment  o f t h e two 3 - d i k e t o n e s , b e n z o y l a c e t o n e ( 1 - p h e n y l b u t a n e - l , 3 - d i o n e ) ( 4 0 ) and a c e t y l a c e t o n e ( p e n t a n e - 2 , 4 - d i o n e )  ( 4 1 ) , w i t h p o t a s s i u m amide i n  l i q u i d ammonia r e s u l t e d i n f o r m a t i o n o f t h e i r d i p o t a s s i o s a l t s 42 and 4 3 . T h e s e s a l t s showed a h i g h d e g r e e o f r e g i o s p e c i f i c i t y i n t h e i r r e a c t i o n s , p r e f e r r i n g t o r e a c t a t t h e y p o s i t i o n i n s e v e r a l c a r b o n - c a r b o n bond f o r m i n g c o n d e n s a t i o n s i n c l u d i n g a l k y l a t i o n , a c y l a t i o n , and c a r b o n a t i o n . T h e s e r e a c t i o n s a r e summarized i n Scheme 4. B e n z y l a t i o n p r o c e e d e d r a p i d l y w i t h one e q u i v a l e n t o f b e n z y l c h l o r i d e t o y i e l d t h e monop o t a s s i o s a l t w h i c h was h y d r o l y s e d w i t h ammonium c h l o r i d e t o g i v e o n l y t h e y a l k y l a t e d compounds 44_ a n d 4 5 . P h e n y l a t i o n o f 43 was a c c o m p l i s h e d w i t h bromobenzene p r o d u c i n g 46_. A c y l a t i o n o f b o t h d i a n i o n s w i t h m e t h y l b e n z o a t e p r o c e e d e d s m o o t h l y t o y i e l d t r i k e t o n e s 47 a n d 4)8. The d i k e t o a c i d 49 was f o r m e d f r o m 42_ by r e a c t i o n w i t h c a r b o n d i o x i d e . An a l d o l c o n d e n s a t i o n o f 4 2 ^ w i t h b e n z a l d e h y d e y i e l d e d the 6-hydroxy-e-diketone  (presumably)  5 £ w h i c h was d e h y d r a t e d w i t h p a r a t o l u e n e -  s u l p h o n i c a c i d and c h a r a c t e r i z e d a s t h e u n s a t u r a t e d d i k e t o n e 51_. Four p o s s i b l e c a n o n i c a l forms e x i s t f o r t h e d i a n i o n (52) 30 o f b e n z o y l a c e t o n e . T h e s e a r e i l l u s t r a t e d i n Scheme 5. NMR s t u d i e s have i n d i c a t e d t h a t most o f t h e c h a r g e i n t h e d i a n i o n r e s i d e s on t h e o x y g e n atoms i n d i c a t i n g t h a t 52d i s p r o b a b l y t h e m a j o r c o n t r i b u t o r . However, i n o r d e r t o i l l u s t r a t e t h e r e a c t i v i t y o f t h e y c a r b o n d i a n i o n s i n t h i s t h e s i s w i l l u s u a l l y . b e drawn i n t h e d i c a r b a n i o n form 52a.  24 Scheme 4. R e a c t i o n s o f t h e D i p o t a s s i o S a l t s o f B - D i k e t o n e s .  51 R = C H 6  5  25 Scheme 5. C a n o n i c a l Forms o f t h e D i a n i o n o f  Benzoylacetone.  The u s e o f a l k a l i m e t a l a m i d e s i n t h e g e n e r a t i o n o f t h e d i a n i o n s o f B - d i c a r b o n y l compounds as a means o f f u n c t i o n a l i s i n g 31 t h e y p o s i t i o n has s i n c e been e x t e n d e d t o i n c l u d e B - k e t o a l d e h y d e s , 32 33 B-ketoesters, and B - k e t o l a c t o n e s . However r e a c t i o n s i n v o l v i n g t h e d i a n i o n s o f B - k e t o e s t e r s have u s u a l l y p r o c e e d e d  in disappointing  y i e l d s . A l k y l a t i o n o f t h e d i p o t a s s i o , d i s o d i o , and d i l i t h i o s a l t s o f e t h y l a c e t o a c e t a t e i n l i q u i d ammonia have been e x t e n s i v e l y 32 3^ investigated.  ' ' Y i e l d s o f t h e y a l k y l a t e d p r o d u c t s 54 were  g e n e r a l l y below 50% and i n no c a s e e x c e e d e d  65%. T h i s and o t h e r r e a c t i o n s  o f t h e d i a n i o n (53) o f e t h y l a c e t o a c e t a t e a r e i l l u s t r a t e d i n Scheme 6.  27 Reaction with carbon d i o x i d e i n ether gave a c e t o n e d i c a r b o x y l i c or  a c i d m o n o e t h y l e s t e r (55_) i n 55% y i e l d .  The C l a i s e n  condensation  o f t h e d i a n i o n w i t h m e t h y l b e n z o a t e g a v e t h e B,<5-diketoester 56_ 32  which y i e l d e d , a f t e r a c i d treatment, An a l d o l c o n d e n s a t i o n k e t o e s t e r 58 i n 50%  p y r o n e 57_ i n o n l y 11% y i e l d .  o f 53 w i t h b e n z o p h e n o n e p r o d u c e d t h e h y d r o x y yield.  3 5  The low y i e l d s i n t h e a b o v e r e a c t i o n s were f e l t t o be by t h e low t e m p e r a t u r e r e q u i r e d f o r t h e l i q u i d ammonia c o n d i t i o n s  caused and  the p o s s i b l e a m i d o l y s i s of the e s t e r f u n c t i o n s i n s t a r t i n g m a t e r i a l s and p r o d u c t s . D i e t h y l e t h e r and DME  have a l s o been u s e d as  solvents 32 35  i n the r e a c t i o n s of the d i p o t a s s i o s a l t s of ethyl acetoacetate  5  but t h e s e r e q u i r e l a b o r i o u s i s o l a t i o n o f t h e s a l t s f r o m l i q u i d ammonia, and p r o b a b l y r e s u l t i n c o n s i d e r a b l e l o s s o f y i e l d . F o r t h e s e  reasons,  a new method o f g e n e r a t i n g t h e d i a n i o n s o f 8 - k e t o e s t e r s v/as s o u g h t i n our l a b o r a t o r y . " I t was b e l i e v e d t h a t a homogeneous r e a c t i o n  mixture  i n w h i c h t h e d i a n i o n r e m a i n e d d i s s o l v e d would g i v e y i e l d s s u p e r i o r t o a h e t e r o g e n e o u s s y s t e m i n w h i c h t h e s a l t was p r e s e n t as a p r e c i p i t a t e . Tetrahydrofuran  has been r e p o r t e d  t o have b e t t e r s o l v e n t p r o p e r t i e s  f o r a n i o n s t h a n o t h e r e t h e r s and was t h e r e f o r e c h o s e n as s o l v e n t . Formation  o f t h e d i a n i o n r e q u i r e d a s t r o n g , non n u c l e o p h i l i c b a s e .  W h i l e n - b u t y l l i t h i u m was known t o be a s t r o n g enough b a s e t o a b s t r a c t t h e two p r o t o n s i t was shown  '  t h a t a d d i t i o n o f two  equivalents  o f n - b u t y l l i t i u m t o a s o l u t i o n o f e t h y l a c e t o a c e t a t e i n THF r e s u l t e d i n a t t a c k on the c a r b o n y l f u n c t i o n r a t h e r t h a n f o r m a t i o n o f t h e d i a n i o n . One method o f p r o t e c t i n g a c a r b o n y l f u n c t i o n f r o m  28 nucleophilie attack during a reaction i s prior formation o f i t s e n o l a t e a n i o n . As a n example g - k e t o a l d e h y d e s undergoing  c a n be p r e v e n t e d  from  c o n d e n s a t i o n w i t h ammonia by p r e f o r m i n g t h e i r sodium s a l t s .  I t was a n t i c i p a t e d t h a t r e a c t i o n o f t h e 8 - k e t o e s t e r w i t h one e q u i v a l e n t o f a weak n o n - n u c l e o p h i l i c b a s e t o form t h e m o n o a n i o n f o l l o w e d by r e a c t i o n w i t h n - b u t y l 1 i t h i u m would have a good c h a n c e o f p r o d u c i n g t h e d e s i r e d d i a n i o n . T h i s p o s t u l a t e was g i v e n some c r e d e n c e by t h e r e p o r t e d production o f t h e d i a n i o n (61) o f phenylpropanone (59) v i a i t s monoanion ( 6 0 ) . o  o  61  As e x p e c t e d , i t was f o u n d t h a t t r e a t m e n t o f m e t h y l  aceto-  a c e t a t e (23_) w i t h one e q u i v a l e n t o f s o d i u m h y d r i d e i n THF f o l l o w e d by a d d i t i o n o f one e q u i v a l e n t o f n - b u t y l l i t h i u m r e s u l t e d i n t h e f o r m a t i o n o f t h e d i a n i o n ( 6 3 ) from t h e m o n o a n i o n ( 6 2 ) .  p  O  O  N *  I l  THF  23  0  O  1  I ~  62  0 1 1  n-B U U  "  63  '  29-  R e a c t i o n s o f t h e d i a n i o n o f methyl a c e t o a c e t a t e  produced  u s i n g sodium h y d r i d e and n - b u t y l 1 i t h i u m have s i n c e been e x t e n s i v e l y i n v e s t i g a t e d and d o c u m e n t e d . " 4 0  4 3  A l k y l a t i o n proceeds a t the y p o s i t i o n  i n good y i e l d , u s u a l l y i n e x c e s s o f 7 5 % .  4 0  Aldol reactions with  and a l d e h y d e s g i v e h i g h y i e l d s o f 6 - h y d r o x y - 8 - k e t o e s t e r s  ketones  e x c e p t where  proton t r a n s f e r from the carbonyl s u b s t r a t e t o the d i a n i o n i s a competing  r e a c t i o n . ' The d i a n i o n has a l s o been u s e d , i n C l a i s e n 42 43 condensations ' and i t s r e a c t i o n s w i t h n i t r i l e s have been m v e s 42 tigated. 4 1  4 2  R e a c t i o n o f t h e d i a n i o n o f methyl a c e t o a c e t a t e , formed as d e s c r i b e d a b o v e , w i t h a c e t o p h e n o n e  22^ gave back o n l y s t a r t i n g m a t e r i a l  o r a v e r y low y i e l d o f t h e d e s i r e d 6 - h y d r o x y - 8 - k e t o e s t e r  24 when t h e  two r e a g e n t s were used i n e q u i v a l e n t amounts. However, when t h e d i a n i o n was used i n t e n f o l d e x c e s s c o n d e n s a t i o n p r o d u c t 24_ c o u l d be i s o l a t e d in s a t i s f a c t o r y y i e l d (88%).  T h e p r o d u c t was homogeneous t o t h i n l a y e r c h r o m a t o g r a p h y and i t s s p e c t r a l d a t a were i n a c c o r d w i t h t h e s t r u c t u r e (24)  proposed  f o r t h e compound. The IR s p e c t r u m showed a h y d r o x y l a b s o r p t i o n  (tic)  30"  (3700-3500 c m " ) , bands f o r s a t u r a t e d e s t e r (1745 c m ) 1  -1  (1710 c m " ) , a s w e l l as a r o m a t i c (1610, 1575 cm" ) 1  1  and  ketone  and n i t r i l e (2250 cm  bands. The a b s e n c e o f an a r y l k e t o n e band a t 1700 c m  -1  p r o o f t h a t an a l d o l c o n d e n s a t i o n had o c c u r r e d . The NMR  was f u r t h e r spectrum of  methyl a c e t o a c e t a t e c o n s i s t s o f t h r e e s i n g l e t s a t 63.74 (3H, OCH^), 63.48 (2H, CHg), and 62.27 (3H, C C H ) . The NMR 3  s p e c t r u m o f 24 showed  no a b s o r p t i o n i n t h e 62.27 r e g i o n but d i d have a two p r o t o n s i n g l e t a t 63.47. T h i s was t a k e n a s p r o o f t h a t t h e c o n d e n s a t i o n had o c c u r r e d a t t h e y c a r b o n o f t h e m e t h y l a c e t o a c e t a t e . The r e a c t i o n had  produced  an a s s y m e t r i c c e n t r e i n t h e m o l e c u l e a t t h e h y d r o x y l c a r b o n . The  NMR  a b s o r p t i o n f o r the methylene protons a to t h i s p o s i t i o n r e f l e c t e d t h i s f a c t showing an AB p a t t e r n c o n s i s t i n g o f two d o u b l e t s (J=16  cps)  a t 62.95 and 63.52. The mass s p e c t r u m o f 24 showed no p a r e n t peak (P) a t m/e 363 but d i d show a s t r o n g peak a t m/e 345 (P-18) d e m o n s t r a t i n g the f a c i l i t y with which the h y d r o x y k e t o e s t e r undergoes The compound was a l s o u n s t a b l e t o d i s t i l l a t i o n  dehydration.  and, c o n s e q u e n t l y ,  a sample o f s u f f i c i e n t p u r i t y f o r e l e m e n t a l a n a l y s i s c o u l d n o t be o b t a i n e d . T h i s i s not p a r t i c u l a r l y u n u s u a l f o r a l d o l p r o d u c t s , p a r t i c u l a r l y t h o s e t h a t a r e t e t r a s u b s t i t u t e d o r have a r o m a t i c substituents. L i t e r a t u r e precedent e x i s t s ^ f o r t h e i r decomposition by r e t r o - a l d o l on h e a t i n g o r by l o s s o f w a t e r i f t r a c e amounts o f acid are present. F u l l c h a r a c t e r i z a t i o n o f 2A_ was a c c o m p l i s h e d t h r o u g h i t s t r i m e t h y l s i l y l e t h e r d e r i v a t i v e 64_ , w h i c h was p r e p a r e d by s t a n d a r d p r o c e dA u r e s . 46  As e x p e c t e d , t h e IR s p e c t r u m o f 64_ showed no  hydroxy!  a b s o r p t i o n , but was i n o t h e r r e s p e c t s s i m i l a r t o t h a t o f t h e h y d r o x y k e t o e s t e r . I t s NMR  s p e c t r u m had a n i n e p r o t o n s i n g l e t a t 6-0.04,  d e m o n s t r a t i n g t h e p r e s e n c e o f t h e t r i m e t h y l s i l y l g r o u p , and l a c k e d t h e b r o a d s i n g l e t a t 65.85 a t t r i b u t e d t o t h e h y d r o x y ! p r o t o n i n t h e a l c o h o l 24_. The mass s p e c t r u m o f t h e compound showed t h e e x p e c t e d p a r e n t peak a t m/e  435. D u r i n g t h e c o u r s e o f i d e n t i f i c a t i o n o f t h e h y d r o x y k e t o e s t e r 24  i t had been o b s e r v e d t h a t samples l e f t f o r a l o n g p e r i o d o f t i m e i n t h e NMR s o l v e n t , d e u t e r o c h l o r o f o r m , r e a c t e d s l o w l y t o become non-homogeneous t o t i c . I t was b e l i e v e d t h a t t h i s m i g h t be due t o d e h y d r a t i o n o f the. a l c o h o l t o t h e y > 6 - u n s a t u r a t e d  B - k e t o e s t e r 25 and  was  p r o b a b l y c a u s e d by s m a l l amounts o f d e u t e r i u m c h l o r i d e p r e s e n t i n t h e d e u t e r o c h l o r o f o r m . (Normal l a b o r a t o r y c h l o r o f o r m c o n t a i n s a s m a l l q u a n t i t y o f e t h a n o l t o p r e v e n t i t s d e c o m p o s i t i o n t o hydrogen c h l o r i d e and phosgene.  E t h a n o l i s not added t o t h e NMR  solvent.) This observation  l e d t o t h e smooth and e f f i c i e n t (98%) c o n v e r s i o n o f t h e h y d r o x y k e t o e s t e r t o an E,Z m i x t u r e o f t h e y»^-unsaturated  B - k e t o e s t e r 25 by d i s s o l u t i o n  32.  o f t h e s t a r t i n g m a t e r i a l i n c h l o r o f o r m s a t u r a t e d w i t h hydrogen c h l o r i d e gas.  25E  Dehydrations using hydrogen c h l o r i d e i n e t h e r or parat o l u e n e s u l p h o n i c a c i d i n b e n z e n e were f o u n d t o be l e s s e f f i c i e n t , due to the formation o f other p r o d u c t s , but i n each case the primary p r o d u c t was t h e same E,Z m i x t u r e . The IR s p e c t r u m o f t h i s m i x t u r e o f i s o m e r s had no h y d r o x y l a b s o r p t i o n and d e m o n s t r a t e d (1680 cm" ) 1  t h e p r e s e n c e o f an a,6 u n s a t u r a t e d c a r b o n y l  and r e t e n t i o n o f t h e s a t u r a t e d e s t e r (1740 cm" ) 1  and •  33n i t r i l e (2250 cm" ) f u n c t i o n a l i t i e s . 1  The f o r m a t i o n o f t h e d o u b l e bond was f u r t h e r p r o v e n by t h e NMR s p e c t r u m o f t h e m i x t u r e w h i c h showed two q u a r t e t s w i t h a t o t a l i n t e g r a t i o n v a l u e o f one p r o t o n a t 66.16 and 66.32, a r e g i o n t y p i c a l o f v i n y l p r o t o n s . T h e s e were c o u p l e d (J=2 c p s ) t o two d o u b l e t s w i t h a t o t a l i n t e g r a t i o n v a l u e o f t h r e e p r o t o n s a t 62.09 and 62.32 w h i c h were a s s i g n e d t o t h e v i n y l methyl g r o u p s i n t h e two compounds. w i t h t h e NMR s p e c t r a o f o t h e r s t y r e n e s y s t e m s  4 7  Comparison  allowed individual  a s s i g n m e n t o f t h e s e peaks t o t h e E and Z i s o m e r s . From T a b l e I i t i s e v i d e n t that a v i n y l proton c i s t o an aromatic r i n g appears, as might be e x p e c t e d , d o w n f i e l d from a p r o t o n w h i c h i s t r a n s t o t h e r i n g . On t h i s b a s i s t h e s i g n a l s a t 66.32 and 62.09 were a s s i g n e d t o t h e E i s o m e r o f 25_ and t h o s e a t 66.16 a n d 62.32 t o i t s Z i s o m e r . From t h e i n t e g r a t i o n o f t h e NMR s p e c t r u m t h e E:Z r a t i o was c a l c u l a t e d t o be 2:1. P a r t i a l s e p a r a t i o n o f t h e m i x t u r e by t i c l e d t o t h e a s s i g n m e n t o f t h e o t h e r peaks i n t h e s p e c t r u m . I n t h e E i s o m e r t h e s i n g l e t s f o r t h e a m e t h y l e n e and methoxy p r o t o n s o f t h e 3 - k e t o e s t e r g r o u p a p p e a r e d a t 63.24 a n d 63.65 r e s p e c t i v e l y . I n t h e Z i s o m e r , where t h i s g r o u p i s ci_s t o t h e a r o m a t i c r i n g t h e s e s i g n a l s were s h i f t e d d o w n f i e l d t o 63.53 a n d 63.75 respectively. E x t e n s i o n o f t h e w a v e l e n g t h o f maximum i n t h e UV s p e c t r u m  absorbance  from 275mu f o r t h e h y d r o x y k e t o e s t e r t o 285my f o r t h e  p r o d u c t m i x t u r e was t a k e n a s f u r t h e r p r o o f t h a t t h e d e s i r e d d e h y d r a t i o n had o c c u r r e d . High r e s o l u t i o n mass s p e c t r o s c o p y e s t a b l i s h e d t h e m o l e c u l a r f o r m u l a o f t h e p r o d u c t t o be C j g H ^ O g N , s t r u c t u r e 25.  a s  r e q u i r e d by  34  '  Table I Chemical S h i f t s o f the g Protons of S u b s t i t u t e d Styrenes  F i r s t attempts at c y c l i s a t i o n of the unsaturated ketoe s t e r 2_5 t o t h e m e t h y l n a p h t h o a t e 26 were based on t h e work o f 48 H a s s a l l et_-al_.  I n s t u d i e s on t h e s y n t h e s i s o f a n t h r a q u i n o n e s t h e y  s u c c e e d e d i n c o n v e r t i n g t h e benzophenone 6_5 t o a n t h r a c e n e 67_ by h e a t i n g i t s c a r b a n i o n 66_ i n d i m e t h y l s u l p h o x i d e .  25  26  35  T r e a t m e n t o f t h e k e t o e s t e r 25_ w i t h sodium h y d r i d e i n dimethyl s u l p h o x i d e o r hexamethylphosphoramide  a t room t e m p e r a t u r e  f o r t w e n t y - f o u r hours y i e l d e d o n l y s t a r t i n g m a t e r i a l (by t i c a n a l y s i s ) . H e a t i n g t h e m i x t u r e s t o 110 d e g r e e s l e d , i n b o t h c a s e s , t o complex m i x t u r e s o f compounds ( a t l e a s t f o u r by t i c ) , t h e p r i m a r y component o f w h i c h was s t a r t i n g m a t e r i a l . The f o l l o w i n g c o n d i t i o n s l e d t o s i m i l a r r e s u l t s : p o t a s s i u m t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a t 140 d e g r e e s , sodium m e t h o x i d e i n h e x a m e t h y l p h o s p h o r a m i d e  a t 140 d e g r e e s ,  l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e 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 and in refluxing xylene.  36  At t h i s p o i n t , i n view of the d i f f i c u l t i e s  encountered  i n t h e c y c l i s a t i o n s t e p and t h e d e s i r e t o use enough s t a r t i n g m a t e r i a l i n each r e a c t i o n t o g e t a b e t t e r i d e a (by NMR and IR as opposed t o t i c ) o f t h e p r o d u c t s f o r m e d , t h e d e c i s i o n was t a k e n t o s w i t c h t o a model system r a t h e r than expend l a r g e q u a n t i t i e s o f t h e k e t o e s t e r 25 w h i c h was a v a i l a l a b l e o n l y t h r o u g h t h e seven s t e p s y n t h e s i s d e s c r i b e d a b o v e . I t was b e l i e v e d t h a t t h e k e t o e s t e r 68 was a model s u f f i c i e n t l y c l o s e t o 2_5 t o e n g e n d e r c o n f i d e n c e t h a t r e s u l t s o b t a i n e d f o r e i t h e r w o u l d be a p p l i c a b l e t o b o t h .  The model compound 68_ c o u l d be s y n t h e s i s e d i n t h r e e h i g h y i e l d i n g s t e p s , t h r o u g h i n t e r m e d i a t e s 3_9 and 7TJ, from t h e  commercially  a v a i l a b l e 2 , 6 - d i h y d r o x y a c e t o p h e n o n e (69) a c c o r d i n g t o Scheme 7. M e t h y l a t i o n o f 69 t o 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (39) was f i r s t 49 f o l l o w i n g p r o c e d u r e s o u t l i n e d by C a r t w r i g h t e_t a l _ .  accomplished  using aqueous  sodium h y d r o x i d e and d i m e t h y l s u l p h a t e . L a t e r , i t was f o u n d t h a t more  3 7  Scheme 7 . S y n t h e s i s o f B - K e t o e s t e r 68.  68E  38-  r e p r o d u c i b l e r e s u l t s c o u l d be o b t a i n e d by t r e a t i n g t h e d i h y d r o x y compound w i t h sodium h y d r o x i d e and d i m e t h y l s u l p h a t e i n d i o x a n e c o n t a i n i n g a s m a l l q u a n t i t y o f w a t e r . T h i s p r o c e d u r e a f f o r d e d t h e p r o d u c t i n 95% y i e l d . T h e d i a n i o n o f m e t h y l a c e t o a c e t a t e r e a c t e d w i t h 3_9 a s e x p e c t e d t o p r o d u c e t h e h y d r o x y k e t o e s t e r 70_ i n 79% y i e l d . A s i n t h e p r e v i o u s c a s e , t e n e q u i v a l e n t s o f t h e d i a n i o n were n e c e s s a r y t o o b t a i n s a t i s f a c t o r y r e s u l t s i n t h i s condensation with the hindered acetophenone. S p e c t r a l d a t a o b t a i n e d f o r t h e d i a n i o n a d d u c t were i n a c c o r d w i t h t h o s e a n t i c i p a t e d f o r s t r u c t u r e 70 and were c o n s i s t e n t w i t h t h o s e o b s e r v e d f o r t h e p r e v i o u s l y s y n t h e s i s e d d i a n i o n a d d u c t 24. Once a g a i n , t h i s a l d o l p r o d u c t v/as u n s t a b l e t o d i s t i l l a t i o n and v/as c h a r a c t e r i z e d as i t s t r i m e t h y l s i l y l e t h e r d e r i v a t i v e 71_.  D e h y d r a t i o n o f t h e h y d r o x y k e t o e s t e r 70 t o t h e u n s a t u r a t e d compound 68_ c o u l d a g a i n be e f f e c t e d u s i n g h y d r o g e n c h l o r i d e i n c h l o r o f o r m and t h e same E:Z=2:1 m i x t u r e o f i s o m e r s a s had been o b t a i n e d t h e o t h e r s e r i e s was f o u n d h e r e . S p e c t r a l d a t a were a g a i n c o n s i s t e n t w i t h  39  t h o s e d e s c r i b e d f o r t h e m i x t u r e i n t h e o t h e r s e r i e s and t h e m o l e c u l a r f o r m u l a o f 68 (C^H^gO,-) was c o n f i r m e d by m i c r o a n a l y s i s . In p r e p a r a t i o n s o f t h i s compound s u b s e q u e n t  t o t h e one d e s c r i b e d t h e i n t e r m e d i a t e  h y d r o x y k e t o e s t e r 70 was not i s o l a t e d o r p u r i f i e d . The c r u d e  product  from the d i a n i o n r e a c t i o n , c o n t a i n i n g a ( t h e o r e t i c a l ) nine f o l d e x c e s s o f m e t h y l a c e t o a c e t a t e , was t r e a t e d d i r e c t l y w i t h t h e d e h y d r a t i o n c o n d i t i o n s . A l a r g e p a r t o f t h e m e t h y l a c e t o a c e t a t e c o u l d t h e n be d i s t i l l e d from t h e m i x t u r e and t h e d e h y d r a t e d p r o d u c t c o u l d be f u r t h e r p u r i f i e d by p r e p a r a t i v e t i c . T h i s a v o i d e d a l e n g t h y s e p a r a t i o n p r o c e d u r e f o r t h e h y d r o x y k e t o e s t e r , i n v o l v i n g l a b o r i o u s column  chromatography,  w h i c h had been n e c e s s a r y b e c a u s e o f t h e s i m i l a r i t y i n t h e c h r o m a t o g r a p h i c p r o p e r t i e s o f t h e m e t h y l a c e t o a c e t a t e and  hydroxyketoester.  A l t e r n a t i v e l y , t h e c r u d e p r o d u c t f r o m t h e d i a n i o n a d d i t i o n c o u l d be s u b j e c t e d d i r e c t l y t o d i s t i l l a t i o n t o remove m e t h y l  acetoacetate  f o l l o w e d by d e h y d r a t i o n t o t h e u n s a t u r a t e d k e t o e s t e r . T h i s m e t h o d , however, l e d t o some d e h y d r a t i o n d u r i n g t h e d i s t i l l a t i o n p r o c e s s and t h e p r o d u c t m i x t u r e o b t a i n e d a p p e a r e d t o c o n t a i n some o f t h e l e s s c o n j u g a t e d i s o m e r 7 2 as w e l l a s t h e two i s o m e r s a l r e a d y d e s r i b e d . . E v i d e n c e f o r t h e p r e s e n c e o f 72 i n t h e m i x t u r e came from i t s NMR s p e c t r u m w h i c h had s i g n a l s a t 65.55 and 65.83 a t t r i b u t e d t o t h e v i n y l p r o t o n s and one a t 63.38 a s s i g n e d t o t h e m e t h y l e n e carbon of the B-ketoester  group.  p r o t o n s on t h e y  40  o  o 72  A t t e m p t s t o c y c l i s e t h e a n i o n 7_3 o f k e t o e s t e r 68_ met w i t h no s u c c e s s . C o n d i t i o n s s i m i l a r t o t h o s e w h i c h had g i v e n m i x t u r e s o f p r o d u c t s i n t h e p r e v i o u s l y d e s c r i b e d s e r i e s were used on amounts o f t h e E,Z m i x t u r e l a r g e enough t o a l l o w some s p e c t r o s c o p i c e x a m i n a t i o n o f t h e p r o d u c t s . In no c a s e d i d any o f t h e m i x t u r e o f compounds o b t a i n e d show any p r o m i s e o f c o n t a i n i n g t h e d e s i r e d m e t h y l n a p h t h o a t e 74.  41  The n e x t a p p r o a c h t a k e n t o w a r d s a c h i e v i n g a c y c l i s a t i o n of the B-ketoester of stilbene  (75)  was based on t h e w e l l known o x i d a t i v e p h o t o c y c l i s a t i o n and i t s d e r i v a t i v e s t o p h e n a n t h r e n e s ( 7 6 ) .  5 0 , 5 1  Both c i s  and t r a n s s t i l b e n e s a r e known t o undergo t h i s r e a c t i o n , t h e t r a n s v i a prior photoisomerization  t o t h e c i s . I t was hoped t h a t t h e e n o l e t h e r 7_7  or a c e t a t e 78; o f t h e B - k e t o e s t e r m i g h t u n d e r g o a s i m i l a r r e a c t i o n t o y i e l d t h e c y c l i s e d s t r u c t u r e 79_. T h i s hope was g i v e n f u r t h e r c r e d e n c e by t h e r e p o r t e d c y c l i s a t i o n o f c i s and t r a n s 2 - s t y r y l f u r a n ( 8 0 ) t o t h e naphthylfuran  8J_,  a l b e i t i n low y i e l d  (^10%).  5 2  77R=Me 78  R=Ac  * F o u r p o s s i b l e i s o m e r s e x i s t f o r compounds 77_ and 7 8 d e p e n d i n g on t h e o r i e n t a t i o n o f t h e g r o u p s a b o u t t h e two d o u b l e bonds. O n l y one is i l l u s t r a t e d here.  42'  I n i t i a l a t t e m p t s t o s y n t h e s i z e t h e enol e t h e r 77 were made u s i n g sodium h y d r i d e and d i m e t h y l s u l p h a t e i n h e x a m e t h y l p h o s p h o r a m i d e , 53 54 which i s known  '  t o be a s o l v e n t f a v o u r i n g 0 - a l k y l a t i o n . The c r u d e  p r o d u c t m i x t u r e d i d show some p r o m i s e o f c o n t a i n i n g t h e d e s i r e d methyl e n o l e t h e r . I t s IR s p e c t r u m showed c o n s i d e r a b l e weakening o f t h e s a t u r a t e d e s t e r and u n s a t u r a t e d k e t o n e bands and a new band a p p e a r e d a t 1720  cm , -1  a s s i g n a b l e t o an u n s a t u r a t e d e s t e r . However,the c r u d e m i x t u r e c o n t a i n e d a t l e a s t seven compounds (by t i c ) and r e s i s t e d a l l a t t e m p t s a t p u r i f i c a t i o n by c h r o m a t o g r a p h y ,  which seemed t o g i v e back p r i m a r i l y c r u d e s t a r t i n g  m a t e r i a l , o r by d i s t i l l a t i o n , which l e d t o e x t e n s i v e d e c o m p o s i t i o n . On one o c c a s i o n , a s m a l l sample o f what a p p e a r e d  (from i t s IR s p e c t r u m ) t o be  t h e enol e t h e r was o b t a i n e d by p r e p a r a t i v e t i c and s u b j e c t e d t o p h o t o l y s i s . The p r o d u c t m i x t u r e formed showed no p r o m i s e o f b e i n g t h e c y c l i s e d system hoped f o r . In t h i s e x p e r i m e n t and ones t o be d e s c i b e d l a t e r t h e UV s p e c t r u m o f t h e p r o d u c t m i x t u r e was used as an a s s a y to look f o r the presence of the naphthalene  chromophore.  S e v e r a l o t h e r methods o f p r e p a r i n g e n o l e t h e r s were i n v e s t i g a t e d w i t h a v i e w t o f i n d i n g one t h a t p r o d u c e d a c l e a n e r p r o d u c t t h a n t h e c o n d i t i o n s d e s c r i b e d a b o v e . Sodium h y d r i d e and methyl c h l o r i d e  43 o r methyl  i o d i d e i n h e x a m e t h y l p h o s p h o r a m i d e g a v e back c r u d e s t a r t i n g  m a t e r i a l a s d i d sodium h y d r i d e and t r i m e t h y l s i l y l c h l o r i d e i n e t h e r . J o h n s o n and P o s v i c  5 5  made e n o l e t h e r s o f B - k e t o a l d e h y d e s  u s i n g sodium  c a r b o n a t e and i s o p r o p y l i o d i d e . When 68 was t r e a t e d w i t h sodium h y d r i d e and i s o p r o p y l i o d i d e i n h e x a m e t h y l p h o s p h o r a m i d e a compound t h a t a p p e a r e d , from i t s IR s p e c t r u m , t o be t h e e n o l e t h e r was i s o l a t e d , but i n v e r y l o w y i e l d  (<20%).  T h e e n o l e t h e r s o f a c e t y l a c e t o n e have  been p r e p a r e d by r e a c t i o n w i t h d i a z o m e t h a n e .  5 5  Treatment  o f 68 w i t h  excess diazomethane returned p r i m a r i l y s t a r t i n g m a t e r i a l . A l l o f t h e attempts t o form enol e t h e r s d e s c r i b e d thus f a r i n v o l v e d p r i o r formation o f t h e e n o l a t e with base (except t h e d i a z o methane c a s e ) . T h e i r f a i l u r e t o p r o d u c e a c l e a n , i s o l a b l e p r o d u c t i n good yield l e d to a desire to t r y acid c a t a l y s i s conditions. Sulphuric acid c a n be used t o c a t a l y s e t h e r e a c t i o n between e t h y l a c e t o a c e t a t e ( 8 2 ) and t r i e t h y l o r t h o f o r m a t e  ( 8 3 ) i n w h i c h e n o l e t h e r 84 i s f o r m e d ,  5 7  T h e s e r e a c t i o n c o n d i t i o n s r e t u r n e d o n l y c r u d e s t a r t i n g m a t e r i a l when a p p l i e d t o B - k e t o e s t e r 68.  Some a t t e m p t s were t h e n made t o s y n t h e s i z e t h e e n o l a c e t a t e 78_ u s i n g sodium h y d r i d e and a c e t y l c h l o r i d e i n h e x a m e t h y l p h o s p h o r a m i d e  ,44  and i n d i g l y m e ( d i e t h y l e n e g l y c o l d i m e t y l e t h e r ) . R e s u l t s h e r e were s i m i l a r t o t h o s e d e s c r i b e d f o r t h e e n o l e t h e r p r e p a r a t i o n s u s i n g sodium h y d r i d e . W h i l e t h e c r u d e p r o d u c t m i x t u r e showed some e v i d e n c e (IR c a r b o n y l r e g i o n ) o f b e i n g t h e e n o l a c e t a t e , d i f f i c u l t i e s were a g a i n  encountered  i n o b t a i n i n g p u r e , c h a r a c t e r i z e a b l e p r o d u c t . In t h e hope t h a t t h e c y c l i s e d p r o d u c t m i g h t m i g h t be more e a s i l y p u r i f i e d , t h e c r u d e o b t a i n e d from an a c e t y l a t i o n e x p e r i m e n t  mixture  was s u b j e c t e d t o p h o t o l y s i s . No  e v i d e n c e was f o r t h c o m i n g t h a t i n d i c a t e d t h e p r e s e n c e o f any o f t h e hoped f o r n a p h t h a l e n e  system.  At t h i s p o i n t , t h i s approach to the s y n t h e s i s of r e s i s t o m y c i n was abandoned on t h e g r o u n d s t h a t i t w o u l d , a t b e s t , be a r a t h e r i n e f f i c i e n t r o u t e . In r e t r o s p e c t , t h e f a i l u r e o f t h e e n o l e t h e r o r a c e t a t e ( i f i n d e e d t h e s e p r o d u c t s were o b t a i n e d ) t o p h o t o c y c l i s e was not t o o s u r p r i s i n g i n l i g h t o f r e c e n t l y p u b l i s h e d work by Kanakoa 58 and I t o h  who s u c c e e d e d  phenanthridone  i n c y c l i s i n g o-methoxybenzanilide  (85) t o  ( 8 7 ) . T h e y p r o p o s e d t h a t p a r t i c i p a t i o n o f t h e amide  g r o u p as i l l u s t r a t e d i n i n t e r m e d i a t e 86 may be n e c e s s a r y f o r c y c l i s a t i o n to occur. Photolysis of o-methoxystilbene  (8J3) i s known t o y i e l d  p r i m a r i l y 1 - m e t h o x y p h e n a n t h r e n e ( 8 9 ) . O n l y s m a l l q u a n t i t i e s of 50 phenanthrene i t s e l f are formed.  46 P a r t C: T h e e - d i k e t o n e  route.  The f a i l u r e o f t h e B - k e t o e s t e r a p p r o a c h  to the synthesis  o f r e s i s t o m y c i n was f e l t t o be d u e , a t l e a s t i n p a r t , t o t h e l a c k o f enol ( 2 5 a , 68a) p r e s e n t i n t h e i n t e r m e d i a t e s (;25, 68_) t o be c y c l i s e d . S t u d i e s on t h e NMR s p e c t r a o f B - d i c a r b o n y l  compounds have shown t h a t  the percentage o f enol present i n B-ketoesters i s low, both f o r t h e pure compounds 59 and f o r t h e i r s o l u t i o n s . 60 I n d e e d , methyl a c e t o a c e t a t e c o n t a i n s no d e t e c t a b l e (NMR) e n o l form i n i t s pure s t a t e and t h e B-ketoesters,2J5  and 68_, examined i n t h i s work c o n t a i n e d no n o t i c e a b l e  e n o l form i n d e u t e r o c h l o r o f o r m  68  R=H  o r c a r b o n t e t r a c h l o r i d e . On t h e o t h e r  68a  5 hand, B - d i k e t o n e s a r e known t o e x i s t p r i m a r i l y i n t h e i r e n o l f o r m s . As an example b e n z o y l a c e t o n e (40) has been shown t o e x i s t 98% i n i t s 62 e n o l form i n c a r b o n t e t r a c h l o r i d e s o l u t i o n . T h i s knowledge l e d t o  47'  t h e d e s i r e t o s y n t h e s i z e t h e g - d i k e t o n e 29. w h i c h , i t v/as a s s u m e d , would e x i s t p r i m a r i l y i n i t s e n o l f o r m , a s i l l u s t r a t e d . I t was a n t i c i p a t e d t h a t t h i s compound c o u l d be c y c l i s e d t o y i e l d t h e n a p h t h y l k e t o n e 27_ w h i c h m i g h t t h e n be u s e d i n t h e s y n t h e s i s o f r e s i s t o m y c i n f o l l o w i n g t h e l a s t s t e p s i n Scheme 1.  48  S e c t i o n I: The a c e t i c a c i d d i a n i o n  approach.  S e v e r a l r o u t e s d i r e c t e d t o w a r d s a s y n t h e s i s o f B-diketone 29 were i n v e s t i g a t e d . One o f t h e s e i s shown i n Scheme 8.  I t was  a n t i c i p a t e d t h a t t h e d i a n i o n o f a c e t i c a c i d c o u l d be used i n an a l d o l c o n d e n s a t i o n w i t h a c e t o p h e n o n e 2_2 t o g i v e t h e a l d o l a d d u c t 90 w h i c h would l o s e water t o p r o d u c e t h e a , B - u n s a t u r a t e d a c i d -91_. T h i s was t o be c o n v e r t e d t o i t s e s t e r 92_ or a c i d c h l o r i d e 93 and r e a c t e d i n a C l a i s e n condensation with the enolate anion of 2,4,6-trimethoxyacetophenone to y i e l d the d e s i r e d g-diketone I n i t i a l experiments  (94)  29, i n t h i s s e r i e s were done u s i n g p r i m a r i l y  2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e (94) as a model f o r t h e " r e a l " o r " r e s i s t o m y c i n " a c e t o p h e n o n e 22_. T h i s was f e l t t o be a r e a s o n a b l e model w h i c h m i g h t be c a r r i e d t h r o u g h i n t e r m e d i a t e s 95, 96_, and 97_ ( o r 98) t o p r o d u c e t h e B-diketone 99^which c o u l d then be used t o i n v e s t i g a t e c y c l i s a t i o n c o n d i t i o n s . Some model e x p e r i m e n t s 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (39)  were a l s o done u s i n g  as s u b s t r a t e .  The s y n t h e t i c v a l u e o f t h e d i a n i o n s o f c a r b o x y l i c a c i d s 63 was f i r s t f u l l y r e c o g n i z e d by C r e g e r  who f o r m e d t h e d i a n i o n 102 o f  i s o b u t y r i c a c i d (101) 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 . The d i a n i o n c o u l d be a l k y l a t e d w i t h a number o f r e a g e n t s i n h i g h y i e l d p r o v i d i n g an e f f i c i e n t s y n t h e s i s o f a l k y l d i m e t h y l a c e t i c a c i d s  (103).  49 Scheme 8.  Proposed A c e t i c A c i d Dianion  Route.  50  C r e g e r l a t e r e x t e n d e d t h i s work t o i n c l u d e t h e a l k y l a t i o n of monoalkylacetic  a c i d s , t h i s time forming the d i a n i o n with  one  e q u i v a l e n t o f sodium h y d r i d e f o l l o w e d by one e q u i v a l e n t o f l i t h i u m 64 diisopropylamide. Evidence e x i s t s which suggests that the major c o n t r i b u t o r o f t h e r e s o n a n c e s t r u c t u r e s o f t h e d i a n i o n 104 may be t h e one i n w h i c h t h e c h a r g e i s d e l o c a l i z e d on t h e oxygen atoms (104a) r a t h e r t h a n c a r b a n i o n i c form (104b). P f e f f e r and S i l b e r t of the dianion of trans-2-hexenoic  6 5  found t h a t t h e  the  formation  a c i d (105) f o l l o w e d by q u e n c h i n g  with mineral a c i d r e s u l t e d i n i s o m e r i z a t i o n of the s t a r t i n g material t o a m i x t u r e o f c i s and t r a n s - 3 - h e x e n o i c  a c i d s (106, 107). When t h e  3 - h e x e n o i c a c i d s were t r e a t e d u n d e r t h e same c o n d i t i o n s t h e y were returned unchanged. T h i s r e s u l t suggested m i g h t e x i s t as s t r u c t u r e  108.  t o the authors that the d i a n i o n  51 Other evidence  i n support of resonance s t r u c t u r e  104a  comes f r o m t h e r e p o r t ^ t h a t t h e d i a n i o n s r e a c t w i t h t r i m e t h y l s i l y l c h l o r i d e to p r o d u c e k e t e n b i s - t r i m e t h y l s i l y l a c e t a l s  R  R'  p-  104a  N  109.  R  CISiMeg  0—  R  V  OSiMe  109  0SiMe  3  3  In an e f f o r t to overcome t h e l i m i t e d s o l u b i l i t y o f some o f t h e d i a n i o n s i n t e t r a h y d r o f u r a n , t h e s o l v e n t i n i t i a l l y u s e d by C r e g e r , t h e use o f t h e h i g h l y p o l a r h e x a m e t h y l p h o s p h o r a m i d e as a c o - s o l v e n t has been i n v e s t i g a t e d by P f e f f e r e t a l _ . ^ ' ^ T h e y f o u n d t h a t h e x a m e t h y l p h o s p h o r a m i d e was u s e f u l i n d i s s o l v i n g t h e  dianions,  p a r t i c u l a r l y o f s t r a i g h t c h a i n a c i d s , and r e s u l t e d i n i m p r o v e d y i e l d s o f t h e a l k y l a t i o n p r o d u c t s o f t h e s e compounds, but t h a t i t r e d u c e d t h e y i e l d s of the a l k y l a t i o n products of a-branched c a r b o x y l i c a c i d s . T h i s e f f e c t was a t t r i b u t e d t o t h e i n d u c e m e n t , by t h e h e x a m e t h y l p h o s p h o r a m i d e , o f t h e e l i m i n a t i o n r e a c t i o n .between a l k y l h a l i d e and t h e b a s e s amide and  (unreacted  dianion). The r e a c t i o n s o f t h e d i a n i o n s o f c a r b o x y l i c a c i d s have  r e c e n t l y been e x t e n d e d t o i n c l u d e a l d o l c o n d e n s a t i o n s and a l d e h y d e s t o p r o d u c e B - h y d r o x y a c i d s . ^ ' ^  with ketones  9  In our l a b o r a t o r y t h e f o l l o w i n g p r o c e d u r e was u s e d t o g e n e r a t e t h e d i a n i o n o f a c e t i c a c i d . The a c i d was f i r s t r e a c t e d  with  a s e c o n d a r y amine (110) t o p r o d u c e t h e s a l t 111. R e a c t i o n o f t h e s a l t  52 in a tetrahydrofuran-hexamethylphosphoramide  m i x t u r e w i t h 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 p r o d u c e d t h e d i a n i o n ( 1 1 2 ) . I n t h e work d e s c r i b e d h e r e , d i c y c l o h e x y l a m i n e was u s e d t o f o r m t h e s a l t , p r i m a r i l y  because  o f i t s low c o s t and a v a i l a b i l i t y .  CH C0 H 3  2  -f~  R  2  N  H  >CH C02R 3  110  111  2  N H  2  .  /°"  n-BuLi  THF  HMPA  /  >  CYte=\  112  \ O-  When t h e d i a n i o n was r e a c t e d w i t h an e q u i v a l e n t amount of 2,4,6-trimethoxyacetophenone  (94_) o n l y r e t u r n e d s t a r t i n g m a t e r i a l  c o u l d be d e t e c t e d o n workup. I n t h i s , a s i n t h e m e t h y l a c e t o a c e t a t e d i a n i o n c a s e , a t e n f o l d e x c e s s o f t h e d i a n i o n was n e c e s s a r y t o a c h i e v e s a t i s f a c t o r y r e s u l t s i n t h e r e a c t i o n . When t e n e q u i v a l e n t s were used t h e r e a c t i o n y i e l d e d , n o t t h e e x p e c t e d 8 - h y d r o x y a c i d 95_, b u t a m i x t u r e o f i t s d e h y d r a t e d i s o m e r s . * T h e b r o a d h y d r o x y l band (3500-2500 c m ) i n t h e IR s p e c t r u m o f t h i s m i x t u r e i n d i c a t e d t h e - 1  p r e s e n c e o f a c a r b o x y l i c a c i d w h i l e t h e a r o m a t i c bands (1575, 1620 c m " ) 1  * In other experiments i n v o l v i n g t h e d i a n i o n o f a c e t i c a c i d and 2 , 6 - d i m e t h o x y a c e t o p h e n o n e t h e 8 - h y d r o x y a c i d 100 was i s o l a t e d . I t s NMR s p e c t r u m showed t h e s i n g l e t e x p e c t e d f o r t h e m e t h y l g r o u p o n t h e 8 c a r b o n a t 61.66 and t h e AB q u a r t e t (J=15 c p s , 62.85, 63.45) e x p e c t e d f o r t h e d i a s t e r e o t o p i c a-methylene protons.  53 p r o v i d e d p r o o f t h a t t h e c o n d e n s a t i o n had o c c u r r e d . A b r o a d c a r b o n y l band (1730-1710 c m ) p o i n t e d t o t h e f a c t t h a t b o t h t h e c o n j u g a t e d -1  and n o n - c o n j u g a t e d d o u b l e bond i s o m e r s were p r e s e n t i n t h e m i x t u r e . T h i s f a c t was c o n f i r m e d by t h e NMR s p e c t r u m w h i c h had s i g n a l s a s s i g n a b l e t o a l l t h r e e p o s s i b l e isomers,96JE, 96Z, and 113. T h e m i x t u r e c o u l d be s e p a r a t e d by p r e p a r a t i v e t i c i n t o t h e n o n - c o n j u g a t e d component 113 and t h e m i x t u r e o f c o n j u g a t e d components 96E,Z. The s p e c t r u m o f t h e E,Z m i x t u r e had d o u b l e t s ( J = l c p s ) f o r t h e m e t h y l g r o u p a t 62.37 and 62.10 and q u a r t e t s f o r t h e v i n y l p r o t o n s a t 65.81 and 66.02 f o r t h e Z and E compounds r e s p e c t i v e l y ( a s s i g n e d on t h e same b a s i s a s t h e E,Z m i x t u r e o f 8 - k e t o e s t e r 25_ (page 3 3 ) . T h e n o n - c o n j u g a t e d component showed two d o u b l e t s (J=2 c p s ) w i t h an i n t e g r a l v a l u e o f one p r o t o n each i n t h e v i n y l r e g i o n (65.21, 5.56) and a s i n g l e t w i t h an i n t e g r a l v a l u e o f two p r o t o n s a t 63.40 w h i c h was a s s i g n e d t o t h e m e t h y l e n e p r o t o n s a t o the c a r b o x y l i c a c i d . I n t e g r a t i o n o f the spectrum o f t h e crude mixture i n d i c a t e d t h a t t h e compounds were p r e s e n t i n t h e r a t i o 96E:96_Z:113=2:6:5.  113  54  The c r u d e m i x t u r e d e s c r i b e d above was used d i r e c t l y i n t h e subsequent  s t e p s w i t h t h e hope t h a t i f t h e r o u t e proved s u c c e s s f u l  the non-conjugated  component c o u l d be i s o m e r i z e d t o t h e d e s i r e d  isomer l a t e r i n the s y n t h e s i s . E s t e r i f i c a t i o n o f t h e m i x t u r e was a c c o m p l i s h e d diazomethane.  using  T h e p r o d u c t showed t h e e x p e c t e d l o s s o f h y d r o x y l a b s o r p t i o n  i n i t s IR spectrum and a s h i f t o f t h e c a r b o n y l a b s o r p t i o n t o 1720-1740 cm"  1  The NMR spectrum showed two s i n g l e t s , w i t h a t o t a l ' i n t e g r a l o f t h r e e p r o t o n s , i n t h e methoxy r e g i o n , which were n o t p r e s e n t i n t h e a c i d s t a r t i n g m a t e r i a l . In o t h e r r e s p e c t s t h e s p e c t r a were s i m i l a r . P a r t i a l s e p a r a t i o n o f t h e m i x t u r e by p r e p a r a t i v e t i c l e d t o a s s i g n m e n t o f t h e s e peaks' a t 63.70 and 63.62 t o t h e c o n j u g a t e d and n o n - c o n j u g a t e d esters respectively. Some a t t e m p t s were made t o s y n t h e s i z e t h i s e s t e r more d i r e c t l y u s i n g p r o c e d u r e s d e v e l o p e d by R a t h k e ,  7 0  who used t h e base  l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e t o g e n e r a t e e s t e r e n o l a t e s a t -78 d e g r e e s . T h e s e e n o l a t e s c o u l d be a l k y l a t e d by a d d i n g them t o a s o l u t i o n o f a l k y l h a l i d e i n dimethyl sulphoxide. Cregge e t a l _ .  7 1  elaborated this  p r o c e d u r e b y g e n e r a t i n g t h e e n o l a t e a t -78 d e g r e e s i n THF and a d d i n g t h e a l k y l a t i n g a g e n t t o t h i s s o l u t i o n . Good y i e l d s o f t h e a l k y l a t e d d e r i v a t i v e s were o b t a i n e d i n most c a s e s . T h i s method o f e n o l a t e g e n e r a t i o n m i n i m i z e d t h e problem o f s e l f c o n d e n s a t i o n p r e v i o u s l y 72 73 experienced i n the use o f e s t e r e n o l a t e s . Cregge e _ t a l _ .  7 1  '  d i d , however, have some d i f f i c u l t y w i t h  s e l f c o n d e n s a t i o n o f t h e v e r y a c t i v e e s t e r , methyl a c e t a t e . F o r t h i s reason our i n i t i a l experiments u t i l i z e d e t h y l a c e t a t e . Reaction o f l i t h i o e t h y l a c e t a t e , produced a s d e s c r i b e d a b o v e , w i t h 2,6-dimethoxy-  55  a c e t o p h e n o n e (39) c o u l d be a c h i e v e d o n l y when a t e n f o l d e x c e s s of t h e e n o l a t e v/as used and t h e m i x t u r e v/as a l l o w e d t o warm t o 0 d e g r e e s . The r e a c t i o n y i e l d e d a p r o d u c t b e l i e v e d t o be t h e h y d r o x y e s t e r 114. T h i s was d e h y d r a t e d i n c h l o r o f o r m s a t u r a t e d w i t h hydrogen c h l o r i d e t o g i v e , i n 59% y i e l d ( c r u d e , f r o m k e t o n e ) , a m i x t u r e b e l i e v e d , from i t s NMR s p e c t r u m , t o c o n t a i n t h e E a n d Z i s o m e r s o f t h e a , 6 - u n s a t u r a t e d e s t e r 115.  116R  = Me  115R=Et  A t t e m p t s t o form t h e m e t h y l e s t e r 116 i n an a n a l a g o u s way u s i n g m e t h y l a c e t a t e p r o v e d f r u i t l e s s . T h e e s t e r e n o l a t e c o u l d be f o r m e d a t -78 d e g r e e s a n d i n o n e e x p e r i m e n t was r e a c t e d w i t h b e n z a l d e h y d e ( 1 1 7 ) , a t -78 d e g r e e s , t o p r o d u c e t h e e x p e c t e d h y d r o x y e s t e r 118 i n 82% ( c r u d e ) y i e l d . However, t h e n e c e s s i t y o f warming  56  t h e r e a c t i o n m i x t u r e t o 0 d e g r e e s t o a c h i e v e r e a c t i o n w i t h t h e more hindered 2,6-dimethoxyacetophenone  apparently increased the r a t e of  s e l f c o n d e n s a t i o n and t h e d e s i r e d h y d r o x y e s t e r 116 was not p r o d u c e d . Because t h e more a c t i v e m e t h y l e s t e r was d e s i r e d f o r t h e n e x t s t e p i n Scheme 8, t h i s method o f p r e p a r a t i o n was  abandoned.  *CHO 117  The a c i d c h l o r i d e s o f t h e m i x t u r e o f u n s a t u r a t e d a c i d s d e s c r i b e d above  were  standard p r o c e d u r e s .  prepared using oxalyl c h l o r i d e according to 7 4  They were i d e n t i f i e d by t h e IR s p e c t r u m o f t h e  m i x t u r e ( l o s s o f h y d r o x y l band, c a r b o n y l s a t 1800, 1770 cm" )  and u s e d  1  d i r e c t l y i n t h e n e x t s t e p w i t h no p u r i f i c a t i o n . Formation of the enolate anion of 2,4,6-trimethoxyacetophenone (94) i n i t i a l l y p r e s e n t e d g r e a t d i f f i c u l t i e s , t o be d e s c r i b e d i n more d e t a i l l a t e r . I t was f i r s t s u c c e s s f u l l y p r e p a r e d u s i n g t r i t y l p o t a s s i u m ( t r i p h e n y l m e t h y l p o t a s s i u m ) (120) and t h i s b a s e was u s e d i n t h e e x p e r i m e n t s d e s c r i b e d h e r e . T r i t y l p o t a s s i u m was 75 f o l l o w i n g t h e p r o c e d u r e o u t l i n e d by House and Kramar  formed  by r e a c t i n g  p o t a s s i u m w i t h t r i p h e n y l m e t h a n e (119) i n DME. T h i s r e s u l t s i n a r e d s o l u t i o n o f t h e base w h i c h can be used t o t i t r a t e s o l u t i o n s o f k e t o n e s or o t h e r (C a c Ht i)vCH e m e t h y l e n e compounds. — DME 6  5  " 9  3  >  (C H )C-K 6  5  120  +  57  T i t r a t i o n o f a s o l u t i o n o f 2,4,6-trimethoxyacetophenone i n THF w i t h t r i t y l p o t a s s i u m r e s u l t e d i n t h e f o r m a t i o n  of a white  p r e c i p i t a t e presumed t o be t h e p o t a s s i u m e n o l a t e o f t h e k e t o n e . A d d i t i o n of hexamethylphosphoramide t o t h e m i x t u r e , e i t h e r before o r a f t e r formation  of the s a l t , f a i l e d to increase i t s s o l u b i l i t y . Addition  o f e i t h e r t h e e s t e r o r a c i d c h l o r i d e m i x t u r e s d e s c r i b e d above t o t h e s a l t i n THF f a i l e d t o p r o d u c e a n y o f t h e d e s i r e d B - d i k e t o n e 39_, e v e n when a l l o w e d  t o r e a c t f o r l o n g p e r i o d s o f t i m e (up t o s i x t y h o u r s )  or when r e f l u x e d f o r t h r e e h o u r s . I n t h e a c i d c h l o r i d e c a s e t h e c a r b o x y l i c a c i d s and a c e t o p h e n o n e and a m i x t u r e o f s e v e r a l  other,  m i n o r , u n i d e n t i f i e d , p r o d u c t s were r e t u r n e d a f t e r workup. E x t e n d e d r e a c t i o n t i m e s l e d t o some h y d r o l y s i s o f t h e e s t e r b u t t h e a c e t o p h e n o n e was r e t u r n e d  i n t a c t from t h i s r e a c t i o n . The f a i l u r e o f t h e a b o v e r e a c t i o n s t o p r o d u c e t h e B - d i k e t o n e  was a t t r i b u t e d t o t h e i n s o l u b i l i t y o f t h e k e t o n e e n o l a t e a n d t h e hindered  p o s i t i o n a t w h i c h t h e r e a c t i o n had t o o c c u r . A C l a i s e n  c o n d e n s a t i o n o f t h i s e n o l a t e , t o be d e s c r i b e d  l a t e r , was  achieved  w i t h m e t h y l a c e t a t e , b u t o n l y when t h i s v e r y a c t i v e e s t e r was u s e d i n large  excess.  58  S e c t i o n I I : Model s t u d i e s on t h e d i a n i o n s o f e - d i k e t o n e s . A n o t h e r r o u t e t o t h e B - d i k e t o n e 2 9 ^ t h a t was  examined  and e v e n t u a l l y l e d t o i t s s y n t h e s i s i n v o l v e d t h e d i a n i o n o f t h e B-diketone l-(2,4,6-trimethoxyphenyl)-l,3-butanedione methoxybenzoylacetone)  (2,4,6-tri-  (121) and i s i l l u s t r a t e d in.Scheme 9. I t was  a n t i c i p a t e d that the r e a c t i o n of the d i a n i o n of the trimethoxybenzoylacetone with the acetophenone  22_  would y i e l d t h e  6-hydroxy-B-diketone  122 which c o u l d t h e n be d e h y d r a t e d , i n a manner a n a l a g o u s t o t h e d i a n i o n a d d u c t s a l r e a d y d e s c r i b e d , t o y i e l d t h e u s u a l E,Z m i x t u r e o f i s o m e r s o f t h e y » 6 - u n s a t u r a t e d B - d i k e t o n e 2£. T h i s r o u t e was a t t r a c t i v e b e c a u s e i t was s l i g h t l y more c o n v e r g e n t t h a n any o f t h e o t h e r r o u t e s d e s c i b e d so f a r . The a l d o l c o n d e n s a t i o n s o f t h e d i a n i o n s o f  8-diketones  w i t h k e t o n e s and a l d e h y d e s were a l l u d e d t o b r i e f l y i n an e a r l i e r 29 s e c t i o n . H a u s e r e l a b o r a t e d h i s i n i t i a l work on t h i s s u b j e c t in a nc  l a t e r paper  i n w h i c h t h e d i a n i o n s o f b e n z o y l a c e t o n e (40) and  a c e t y l a c e t o n e (41) were c o n d e n s e d w i t h a v a r i e t y o f a l d e h y d e s  and  k e t o n e s . The d i p o t a s s i o s a l t s o f t h e B - d i k e t o n e s , g e n e r a t e d i n l i q u i d ammonia, were f o u n d t o undergo a d d i t i o n r e a c t i o n s , i n good y i e l d , w i t h k e t o n e s h a v i n g no a h y d r o g e n s 6-hydroxy-B-diketones.  to produce the corresponding  However,dipotassiobenzoylacetone  condense w i t h acetophenone  f a i l e d to  under s i m i l a r c o n d i t i o n s r e t u r n i n g b o t h  k e t o n e and B - d i k e t o n e i n t a c t . I t was p o s t u l a t e d t h a t p r o t o n e x c h a n g e had o c c u r r e d between t h e a c e t o p h e n o n e  and t h e d i a n i o n t h e r e b y p r e v e n t i n g 72 further reaction. Since l i t h i o ethyl acetate and l i t h i o t - b u t y l 77 78 acetate but n o t s o d i o e t h y l a c e t a t e were known t o c o n d e n s e w i t h  60  a c e t o p h e n o n e , t h e r e a c t i o n c o n d i t i o n s were c h a n g e d t o g e n e r a t e t h e d i l i t h i o s a l t (125) o f b e n z o y l a c e t o n e by u s i n g l i t h i u m amide i n l i q u i d ammonia. T h i s p r o c e d u r e l e d t o t h e d e s i r e d r e a c t i o n and Hauser e t al_. were a b l e t o i s o l a t e 1 , 5 - d i p h e n y l - 5 - h y d r o x y h e x a n e - l , 3 - d i o n e  (126)  7 Fi  i n 40% y i e l d .  Hauser a l s o i n v e s t i g a t e d t h e d e h y d r a t i o n o f t h i s  compound u s i n g h y d r o c h l o r i c a c i d i n r e f l u x i n g m e t h a n o l . T h e s e c o n d i t i o n s l e d t o t h e f o r m a t i o n o f two compounds, t h e e x p e c t e d u n s a t u r a t e d 6 - d i k e t o n e 127_ i n 13% y i e l d and t h e d i h y d r o p y r o n e 128 i n 66% y i e l d . Hauser p o s t u l a t e d t h a t 128 m i g h t a r i s e f r o m d e h y d r a t i o n o f t h e h e m i a c e t a l s t r u c t u r e 129 p r e s e n t i n e q u i l i b r i u m w i t h t h e k e t o o r e n o l f o r m o f t h e hydroxy-3-diketone i n acid s o l u t i o n .  127  61  Once a g a i n , i t was hoped t h a t a p r o c e d u r e developed  c o u l d be  f o r o u r work w h i c h d i d n o t i n v o l v e t h e u s e o f l i q u i d ammonia  as s o l v e n t . B e s i d e s b e i n g a t r o u b l e s o m e s o l v e n t t o work i n , i t was f e l t , i n the l i g h t of the p r e v i o u s l y described experiments,  that the  low t e m p e r a t u r e r e q u i r e d f o r r e a c t i o n s i n l i q u i d ammonia m i g h t p u t a l i m i t i n g r e s t r i c t i o n on t h e r e a c t i o n o f a d i a n i o n w i t h t h e h i n d e r e d k e t o n e t o be used i n t h e s y n t h e s i s o f r e s i s t o m y c i n . H a u s e r has a l s o i n v e s t i g a t e d t h e f u n c t i o n a l i s a t i o n o f t h e Y c a r b o n o f s - d i k e t o n e s u s i n g t h e b a s e sodium h y d r i d e i n r e f l u x i n g 79 DME a s s o l v e n t .  Experiments involving the a r o y l a t i o n of  w i t h m e t h y l b e n z o a t e and o t h e r a r o m a t i c e s t e r s showed t h a t o f t h e t y p e 130 c o u l d be p r e p a r e d  i n t h i s way u s i n g e x c e s s  benzoylacetone 1,3,5-triketones sodium  h y d r i d e . However, t h e r e a c t i o n was shown n o t t o i n v o l v e t h e d i a n i o n of t h e 3-diketone  s i n c e , o n l y one m o l e o f h y d r o g e n was e v o l v e d a f t e r  a d d i t i o n o f t h e d i k e t o n e t o t h e sodium h y d r i d e . Two more m o l e s were evolved a f t e r a d d i t i o n o f t h e e s t e r , presumably t o form the d i a n i o n of the t r i k e t o n e product  130.  62 Hauser also reported the use of the above conditions in the aldol type condensation of benzoylacetone with benzophenone (123).  79  In this case the unsaturated 8-diketone 131 was isolated (52%) rather than the hydroxy-8-diketone. Similar results were reported for condensations with benzaldehyde and anisaldehyde. While these conditions are of obvious synthetic u t i l i t y in cases where the carbonyl compound contains no a protons, i t is equally obvious that their application to a case such as ours would result in the enolization of the acetophenone and would be expected to return starting materials unreacted. It was believed that in our case generation of the dianion was necessary to achieve reaction at the terminal position.  63  The s e t o f r e a c t i o n c o n d i t i o n s i n i t i a l l y c h o s e n f o r our work were i d e n t i c a l t o t h o s e employed f o r t h e d i a n i o n r e a c t i o n s o f the B-ketoesters  described e a r l i e r , that i s , sequential  generation  o f t h e mono and d i a n i o n s u s i n g s o d i u m h y d r i d e and n - b u t y l l i t h i u m i n THF.  I n i t i a l e x p e r i m e n t s were p e r f o r m e d u s i n g  benzoylacetone  and a c e t o p h e n o n e as m o d e l s i n o r d e r t o a l l o w d i r e c t c o m p a r i s o n t o Hauser's procedure.  A d d i t i o n of benzoylacetone  to a suspension  of  sodium h y d r i d e i n THF r e s u l t e d i n f o r m a t i o n o f a w h i t e p r e c i p i t a t e presumed t o be t h e m o n o s o d i o s a l t . T h i s c o u l d be d i s s o l v e d by hexamethylphosphoramide to the mixture.  adding  I t c o u l d a l s o be d i s s o l v e d  s i m p l y by a d d i n g t h e s o l u t i o n o f n - b u t y l l i t h i u m r e q u i r e d f o r  formation  of the d i a n i o n . T h i s r e s u l t i s i n agreement with s e v e r a l r e p o r t s t h a t l i t h i o s a l t s a r e g e n e r a l l y more s o l u b l e t h a n t h e s o d i o or p o t a s s i o s a l t s . '77,80 7 1  ^  j^p^p  w  a  s  corresponding a  n  o w e c  | to react  w i t h a c e t o p h e n o n e a t 0 d e g r e e s a p r o d u c t was o b t a i n e d whose IR s p e c t r u m i n d i c a t e d i t t o be i d e n t i c a l w i t h t h e 6 - h y d r o x y - g - d i k e t o n e 126 o b t a i n e d by H a u s e r .  I t s NMR s p e c t r u m ( n o t r e p o r t e d by H a u s e r ) a l s o  a g r e e d w i t h s t r u c t u r e 126, s h o w i n g a s i n g l e t a t 61.53 f o r t h e m e t h y l p r o t o n s , two d o u b l e t s (J=15 c p s ) a t 62.78 and  62.92 a s s i g n e d  to  the  d i a s t e r e o t p i c m e t h y l e n e p r o t o n s . I n t e g r a t i o n o f t h e s i n g l e t a t 65.95 assigned to the v i n y l proton of the enol.tautomer t h e compound e x i s t e d a t l e a s t 95% encouraging  indicated that  i n i t s enol form. P a r t i c u l a r l y  was t h e f a c t t h a t t h e p r o d u c t had been i s o l a t e d i n 66%  y i e l d , a c o n s i d e r a b l e improvement o v e r t h e H a u s e r Dehydration  procedure.  o f 126 u s i n g our u s u a l c o n d i t i o n o f  s a t u r a t e d with hydrogen c h l o r i d e a f f o r d e d the dihydropyrone  chloroform 128 i n  64  99% y i e l d . The m e l t i n g p o i n t and IR s p e c t r u m o f t h i s compound  demonstrated  i t s i d e n t i t y w i t h H a u s e r ' s p r o d u c t . I t s NMR s p e c t r u m had s i n g l e t s i n t e g r a t i n g f o r t h r e e p r o t o n s and one p r o t o n r e s p e c t i v e l y a t 61.75 and 65.88 a s s i g n e d t o t h e methyl group and v i n y l p r o t o n , and a p a i r o f d o u b l e t s (J=17 c p s ) a t 62.80 and 62.99 a s s i g n e d t o t h e m e t h y l e n e protons.  Hauser s u c c e e d e d i n e q u i l i b r a t i n g d i h y d r o p y r o n e s s i m i l a r t o 128 w i t h t h e open c h a i n y , 6 - u n s a t u r a t e d g - d i k e t o n e s u s i n g e t h a n o l i c p o t a s s i u m h y d r o x i d e . I n o r d e r t o g e t some r e a s s u r a n c e t h a t f o r m a t i o n o f a s i m i l a r d i h y d r o p y r o n e would n o t r e s u l t i n a dead end when t h e work was e x t e n d e d t o t h e r e s i s t o m y c i n s e r i e s , 128 was s u b j e c t e d t o t h e s e c o n d i t i o n s a n d , i n d e e d , t h e e x p e c t e d u n s a t u r a t e d d i k e t o n e 127 was f o r m e d . I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h i s p r o d u c t i n d i c a t e d t h a t i t c o n s i s t e d o f a 1:1 m i x t u r e o f t h e E and Z i s o m e r s . A mechanism s u g g e s t e d by Hauser f o r t h i s r e a c t i o n i n v o l v e s 8 - e l i m i n a t i o n f r o m t h e d i h y d r o p y r o n e t o g i v e t h e a n i o n 132 which would y i e l d 127 on acidification.  65  O  MeO  O  133  66'. A t t e m p t s were made t o f o r m t h e e n o l e t h e r 133. o f 127_ d i r e c t l y from t h e d i h y d r o p y r o n e by a d d i n g d i m e t h y l s u l p h a t e i n s t e a d o f a c i d t o t h e e t h a n o l i c p o t a s s i u m h y d r o x i d e s o l u t i o n . o f 128 but t h e s e proved f r u i t l e s s g i v i n g o n l y r e t u r n e d s t a r t i n g m a t e r i a l on workup. In a n o t h e r e x p e r i m e n t t h e d i h y d r o p y r o n e was r e a c t e d w i t h sodium h y d r i d e and i s o p r o p y l i o d i d e i n hexamethylphosphoramide  to  g i v e a m i x t u r e o f f o u r compounds ( t i c ) t h e major one o f w h i c h  was  returned starting material. The n e x t r e a c t i o n a t t e m p t e d i n t h i s s e r i e s was one between t h e d i a n i o n o f b e n z o y l a c e t o n e and 2,6-dimethoxyacetophenone  (39).  H e r e , t e n e q u i v a l e n t s o f t h e d i a n i o n were a l l o w e d t o r e a c t w i t h t h e . acetophenone  a t 0 d e g r e e s f o r an e x t e n d e d p e r i o d o f t i m e ( 1 % h o u r s ) .  The c r u d e p r o d u c t m i x t u r e was s u b j e c t e d d i r e c t l y t o t r e a t m e n t w i t h hydrogen c h l o r i d e i n c h l o r o f o r m . C h r o m a t o g r a p h y o f t h e m i x t u r e so p r o d u c e d l e d t o t h e i s o l a t i o n o f s e v e r a l u n i d e n t i f i e d compounds and, s u r p r i s i n g l y , d i h y d r o p y r o n e 128, t h a t i s , t h e same compound t h a t had been i s o l a t e d i n t h e r e a c t i o n between b e n z o y l a c e t o n e and  acetophenone.  T h i s c o u l d have a r i s e n o n l y t h r o u g h c l e a v a g e o f t h e b e n z o y l a c e t o n e t o g i v e a c e t o p h e n o n e f o l l o w e d by r e a c t i o n w i t h t h e d i a n i o n t o g i v e t h e h y d r o x y - B - d i k e t o n e 126_ which was d e h y d r a t e d t o 128-. C l e a v a g e o f e-diketones  by base i s a w e l l known phenomenon'  b u t i s u s u a l l y a s s o c i a t e d w i t h b a s e s s u c h as sodium h y d r o x i d e o r sodium e t h o x i d e a t h i g h t e m p e r a t u r e and was n o t e x p e c t e d i n our c a s e . However, e v i d e n c e t h a t s u c h c l e a v a g e s o f B - d i c a r b o n y l compounds a r e p o s s i b l e w i t h n - b u t y l l i t h i u m comes f r o m a r e c e n t r e p o r t by B r i e g e r 38 and S p e n c e r . They found t h a t excess n - b u t y l l i t h i u m r e a c t s with  67  B-ketoesters  such as e t h y l a - n - b u t y l a c e t o a c e t a t e  (134) t o y i e l d a  m i x t u r e o f ketones 136-140. The p r i n c i p a l p r o d u c t formed i n t h e r e a c t i o n was 5-decanone (136) (24%) and i t was p o s t u l a t e d t h a t t h i s a r o s e by p r e f e r e n t i a l a t t a c k by t h e base on t h e e s t e r c a r b o n y l g r o u p t o p r o d u c e t h e B - d i k e t o n e 135 w h i c h was c l e a v e d t o g i v e t h e f i n a l p r o d u c t s . T h i s t h e o r y was s u p p o r t e d by t h e i s o l a t i o n o f 2-hexanone (137) ( 1 8 % ) , 5-nonanone (138) ( 8 % ) , and 2 - h e p t a n o n e (139) ( 6 % ) .  136  138  137  139  68  Cleavage  of the benzoylacetone  as d e s c r i b e d l e d t o a  s e a r c h f o r a b a s e , somewhat l e s s n u c l e o p h i l i c t h a n n - b u t y l l i t h i u m , with which the d i a n i o n s of B-diketones  c o u l d be p r e p a r e d .  methyl carbanion, a v a i l a b l e with potassium,  Triphenyl-  s o d i u m , o r l i t h i u m as  c o u n t e r i o n , was j u d g e d t o be h i n d e r e d enough not t o i t s e l f a t t a c k t h e c a r b o n y l f u n c t i o n s and y e t s t r o n g enough t o a b s t r a c t b o t h t h e p r o t o n s n e c e s s a r y f o r t h e f o r m a t i o n o f t h e d i a n i o n . The use o f t h i s s t r o n g base as a p r o t o n a b s t r a c t o r i n t h e p r e s e n c e o f a c t i v e c a r b o n y l f u n c t i o n s i s i l l u s t r a t e d by i t s e x t e n s i v e use by House ejt al_. i n t h e 82 83 p r e p a r a t i o n o f l i t h i u m and p o t a s s i u m e n o l a t e s from k e t o n e s and enol a c e t a t e s ^  4  and by H a u s e r ' s ^ use o f t r i t y l s o d i u m i n t h e p r e p a r a t i o n 7  and a l k y l a t i o n o f e s t e r e n o l a t e s . The f e a s i b i l i t y o f u s i n g t h i s b a s e f o r d i a n i o n r e a c t i o n s was examined by a t t e m p t i n g an a l k y l a t i o n o f benzoylacetone  with a l l y ! bromide (140). T h i s a l k y l a t i n g agent i s 40  known t o g i v e good y i e l d s i n r e a c t i o n s w i t h d i a n i o n s i n e x p l o r a t o r y experiments  and i s u s e f u l  because of the ease with which the  product  can be r e c o g n i z e d and d i s t i n g u i s h e d from s t a r t i n g m a t e r i a l by e x a m i n i n g t h e v i n y l p r o t o n r e g i o n i n t h e NMR  spectrum of the crude  mixture. T i t r a t i o n of a s o l u t i o n of benzoylacetone s o l u t i o n o f t r i t y l p o t a s s i u m i n DME,  product  i n THF w i t h a  f o l l o w e d by a d d i t i o n o f a l l y l  b r o m i d e r e s u l t e d i n a p r o d u c t m i x t u r e w h i c h d i d a p p e a r , from i t s NMR  s p e c t r u m , t o c o n t a i n some o f t h e d e s i r e d a l k y l a t e d p r o d u c t  The t i t r a t i o n w i t h t r i t y l p o t a s s i u m was a t t e n d e d w i t h  141.  considerable  d i f f i c u l t y b e c a u s e t h e s o l u t i o n had t u r n e d a d a r k y e l l o w c o l o u r b e f o r e a d d i t i o n o f t h e f u l l two e q u i v a l e n t s o f base making i t v e r y d i f f i c u l t to determine  t h e end p o i n t . T h i s p r o b a b l y l e d t o t h e use  o f an i n s u f f i c i e n t amount o f b a s e t o f u l l y p r o d u c e t h e d i a n i o n and  69  could account for the presence of unreacted benzoylacetone in the product mixture. This d i f f i c u l t y might have been avoided had trityllithium been used as base since i t can be generated from triphenylmethane and standard n-butyllithium solution. Also, lithium would probably have been a better counterion for the desired aldol reactions according 7 F> to Mauser's work described earlier.  However, use of the t r i t y l anion  as a base for dianion generation was not further pursued at this point because of the d i f f i c u l t i e s attending purification of the product mixture which, of necessity, contained two molar equivalents of triphenylmethane. It was f e l t that the amide bases would be easier to u t i l i z e because they could be removed from the other products simply by washing with aqueous acid.  (C H ) C" 6  5  3  K  +  140  141  The lithium amides of several secondary amines have recently gained popularity as strong non-nucleophilic bases. These o r  include lithium diethylamide (142), (143),  4 4  '  6 3  '  6 4  '  8 7  '  8 8  '  oc  o p  '  lithium diisopropylamide  lithium dicyclohexylamide (144),  88  lithium  70 RR R9 isopropylcyclohexylamide (145), piperidide ( 1 4 6 J ,  88,90  '  '  lithium  2,2,6,6-tetramethyl-  and lithium bis-(trimethylsilyl)amide  (147).  91  70  IM  Li  N  -  Li  +  142 143 144  Me Si 3  N  IM"  Li  Li  \l  +  Li  +  Me Si/ 3  145  147  146  L i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e was r u l e d o u t f o r our 42 work b e c a u s e o f o t h e r r e s u l t s o b t a i n e d i n o u r l a b o r a t o r y  which  i n d i c a t e d t h a t i t was not a s t r o n g enough base t o form t h e d i a n i o n of m e t h y l a c e t o a c e t a t e . A p p a r e n t l y , d e r e a l i z a t i o n o f t h e l o n e p a i r o f e l e c t r o n s on t h e n i t r o g e n atom t o t h e s i l i c o n atoms o c c u r s v i a 92 93  d-rr-p-rr b o n d i n g  r e n d e r i n g t h i s base weaker t h a n a d i a l k y l a m i d e .  A r e c e n t paper  '  88  examining a range of d i a l k y l a m i d e s ,  i n c l u d i n g 142-146, w i t h r e s p e c t t o t h e i r p r o t o n a b s t r a c t i n g a b i l i t y versus t h e i r n u c l e o p h i l i c i t y e x t o l l s the advantages  o f such h i g h l y  h i n d e r e d "H^arpoon" b a s e s as l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i d e (146), O n l y one o f t h e d i a l k y l a m i d e b a s e s i s known t o have been  71  used i n t h e p r e p a r a t i o n o f m u l t i p l e a n i o n s . L i t h i u m  diisopropylamide  has been employed as m e n t i o n e d e a r l i e r i n t h e p r o d u c t i o n o f d i a n i o n s from c a r b o x y l i c a c i d s .  4 4  '  6 3  '  6 4 , 6 5  '  6 7 , 6 9  Harris  9 4  has r e c e n t l y employed  t h i s base t o form t h e t r i a n i o n 149 o f 2 , 4 , 6 - h e p t a n e t r i o n e w h i c h was then a c y l a t e d w i t h m e t h y l  (148)  benzoate to give the t e t r a k e t o n e  150. R e p e t i t i o n o f t h i s p r o c e d u r e l e d t o f o r m a t i o n o f t h e 152, p r e s u m a b l y t h r o u g h t h e t e t r a a n i o n 151.  pentaketone  72  H a r r i s has a l s o made t h e d i a n i o n o f b e n z o y l a c e t o n e w i t h l i t h i u m d i i s o p r o p y l a m i d e and r e a c t e d i t i n a C l a i s e n t y p e c o n d e n s a t i o n w i t h t h e monoanion 153 o f e t h y l b e n z o y l a c e t a t e t o p r o d u c e t h e t e t r a 95 k e t o n e 154. The d i a n i o n o f a c e t y l a c e t o n e i s a l s o known t o have been 96 generated u s i n g t h i s base.  Our f i r s t e x p e r i m e n t s i n t h e u s e 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 p r e d a t e d t h e above r e p o r t s and i n v o l v e d t h e u n n e c e s s a r y s t e p o f r e f l u x i n g t h e THF s o l u t i o n o f b e n z o y l a c e t o n e and two e q u i v a l e n t s o f base t o g e n e r a t e t h e d i a n i o n . The f a c t t h a t no p r o d u c t s d e r i v e d from c l e a v a g e o f t h e b e n z o y l a c e t o n e were o b s e r v e d u n d e r t h e s e c o n d i t i o n s  73 i s a t e s t a m e n t t o t h e n o n - n u c l e o p h i l i c i t y o f t h i s b a s e . The model compound 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e (94_) was r e a c t e d w i t h t e n molar e q u i v a l e n t s of the d i a n i o n of benzoylacetone produced i n t h i s way. The c r u d e p r o d u c t m i x t u r e was t r e a t e d w i t h hydrogen c h l o r i d e i n chloroform f o r a lengthy  p e r i o d o f t i m e ( f i v e h o u r s ) and t h e r e s u l t a n t  m i x t u r e was s e p a r a t e d i n t o i t s s e v e r a l components. The e x p e c t e d Y,6- u n s a t u r a t e d B - d i k e t o n e 155 was p r o d u c e d as t h e u s u a l E,Z m i x t u r e o f i s o m e r s i n 25% y i e l d ( b a s e d on t r i m e t h o x y a c e t o p h e n o n e ) . However, t o o u r s u r p r i s e (and d e l i g h t ) , t h e m a j o r p r o d u c t from t h e r e a c t i o n was t h e n a p h t h y l k e t o n e 156 e x p e c t e d from t h e c y c l i s a t i o n o f t h e u n s a t u r a t e d compound. I t was o b t a i n e d i n 53% y i e l d .  155E  155Z  156  7.4.  The IR spectrum o f n a p h t h y l ketone 156 showed a s h a r p c a r b o n y l a b s o r p t i o n a t 1640 c m  -1  t y p i c a l o f c a r b o n y l groups  hydrogen  bonded t o a p h e n o l i c h y d r o x y l group and c e r t a i n l y not i n k e e p i n g w i t h t h e broad band e x p e c t e d f o r a g - d i k e t o n e . The NMR s p e c t r u m o f t h e compound p r o v i d e d f u r t h e r e v i d e n c e t h a t t h e c y c l i s a t i o n had o c c u r r e d . The a r o m a t i c methyl group appeared as a broad s i n g l e t a t 62.49. T h i s was c o n s i s t e n t w i t h t h e NMR s p e c t r a d e s c r i b e d by B r o c k m a n n  6  f o r r e s i s t o m y c i n and i t s d e r i v a t i v e s i n which t h e a r o m a t i c methyl g r o u p s had c h e m i c a l s h i f t s i n t h e r a n g e 52.85-62.96 and were weakly c o u p l e d ( J = l c p s ) t o t h e C-8 a r o m a t i c p r o t o n . I n t e g r a t i o n o f two n e a r l y c o i n c i d e n t s i n g l e t s a t 63.85 gave a t o t a l v a l u e o f s i x p r o t o n s showing t h a t one o f t h e methoxy g r o u p s had been l o s t i n t h e c y c l i s a t i o n . A group o f t h r e e p r o t o n s i n t h e range 66.10-66.40 were a s s i g n e d t o t h e p r o t o n s on t h e n a p h t h a l e n e r i n g and t h o s e i n t h e r a n g e 6 7.30-6 6.40 t o t h e p r o t o n s on t h e p h e n y l r i n g . The U V - V i s s p e c t r u m o f t h i s y e l l o w c r y s t a l l i n e compound was a l s o c o n s i s t e n t w i t h t h e n a p h t h y l ketone s t r u c t u r e 156 h a v i n g a b s o r p t i o n maxima a t 240, 260, 285,  415,  and 435mu. The mass s p e c t r u m showed a p a r e n t peak a t m/e 322 c o n f i r m i n g t h e l o s s o f w a t e r and methanol  from t h e a l d o l a d d u c t . The m o l e c u l a r  f o r m u l a o f 156 was e s t a b l i s h e d by m i c r o a n a l y s i s . P r o d u c t i o n o f t h e k e t o n e 156 r e p r e s e n t e d a s i g n i f i c a n t breakthrough i n t h a t i t demonstrated the f e a s i b i l i t y of both the d i a n i o n a l d o l r e a c t i o n and t h e s u b s e q u e n t c y c l i s a t i o n s t e p w h i c h were n e c e s s a r y f o r o u r p r o p o s e d r o u t e t o r e s i s t o m y c i n . I n a l a t e r s e r i e s o f e x p e r i m e n t s t h e a b o v e work was r e p e a t e d i n o r d e r t o i s o l a t e and c h a r a c t e r i z e t h e i n t e r m e d i a t e s between t h e d i a n i o n r e a c t i o n and p r o d u c t  156.  75 A r e c e n t p u b l i c a t i o n by House et_ aj_.  97  pointed to the  f a c t t h a t a l d o l r e a c t i o n s are e q u i l i b r i a processes i n which the e q u i l i b r i u m i s r a p i d l y s e t up i n s o l u t i o n . Long r e a c t i o n t i m e s t h e r e f o r e s e r v e no p u r p o s e . P r i o r t o t h i s p u b l i c a t i o n i t was f e l t t h a t t h e r e l u c t a n c e o f h i n d e r e d k e t o n e s 2_2, 39, and 9 £ t o u n d e r g o a l d o l r e a c t i o n s w i t h one e q u i v a l e n t o f d i a n i o n m i g h t have been due t o k i n e t i c f a c t o r s . 97 However, House e t al_.  s u c c e e d e d i n p r e p a r i n g and r e a c t i n g t h e  e n o l a t e a n i o n o f t h e h i n d e r e d k e t o n e 2 , 4 , 6 - t r i m e t h y l a c e t o p h e n o n e (157) w i t h b e n z a l d e h y d e . R e p o r t e d r e a c t i o n c o n d i t i o n s were -5 d e g r e e s and f i v e minutes. A c c o r d i n g l y , the r e a c t i o n times f o r our d i a n i o n aldol c o n d e n s a t i o n s were s h o r t e n e d t o f r o m f i v e t o t e n m i n u t e s and a t e m p e r a t u r e o f 0 d e g r e e s was u s e d . T h i s p r o b a b l y r e s u l t e d i n an i n c r e a s e i n y i e l d s by m i n i m i z i n g any c o m p e t i n g s i d e r e a c t i o n s .  94 39  R=OMe  R=H  L i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e (145) was u s e d t o g e n e r a t e t h e d i a n i o n o f b e n z o y l a c e t o n e a t room t e m p e r a t u r e . . R e a c t i o n o f t h i s dianion ( f i v e e q u i v a l e n t s ) with 2,4,6-trimethoxyacetophenone, a t 0 degrees, p r o d u c e d , a f t e r p u r i f i c a t i o n by p r e p a r a t i v e t i c , t h e e x p e c t e d h y d r o x y - 6 diketone  158 i n q u a n t i t a t i v e y i e l d . I t s h o u l d be n o t e d h e r e t h a t  t h i s and o t h e r y i e l d s r e p o r t e d i n t h i s work f o r t h i c k o i l s s u c h a s  76  compound 158 a r e somewhat i n a c c u r a t e . G r e a t d i f f i c u l t y a t t e n d s t h e removal o f t h e l a s t t r a c e s o f s o l v e n t s f r o m such compounds s i n c e t h e i r l a b i l i t y does not a l l o w s o l v e n t removal by h e a t i n g under vacuum o r d i s t i l l a t i o n . T y p i c a l y i e l d s o f t h i s o i l f o r t h e r e a c t i o n under d i s c u s s i o n h e r e a c t u a l l y r a n g e d f r o m 101% t o 105% o f t h e o r e t i c a l .  158  The IR s p e c t r u m o f 158 i l l u s t r a t e d t h e p r e s e n c e o f a h y d r o x y l g r o u p (3550-3500, cm" ) 1  r e g i o n (1650-1550 cm" ) 1  and t h e b r o a d band i n t h e c a r b o n y l  was t y p i c a l o f B - d i k e t o n e s . The NMR  spectrum  c o n f i r m e d t h a t t h e d e s i r e d a d d i t i o n had t a k e n p l a c e , showing a f i v e p r o t o n m u l t i p l e t (67.2-7.8) a s s i g n e d t o t h e p r o t o n s on t h e l e s s s u b s t i t u t e d a r o m a t i c r i n g and a n i n e p r o t o n peak a t 63.75 a s s i g n e d t o t h e t h r e e methoxy g r o u p s on t h e o t h e r a r o m a t i c r i n g . T h e s i n g l e t f o r t h e m e t h y l g r o u p on t h e c a r b i n o l c a r b o n a p p e a r e d a t 61.75  and  t h e s i n g l e t a t 66.18 was a s s i g n e d t o t h e a r o m a t i c p r o t o n s on t h e t e t r a s u b s t i t u t e d r i n g . The m e t h y l e n e p r o t o n s n e x t t o t h e  B-diketone  g r o u p a p p e a r e d a s two d o u b l e t s (J=14 c p s ) a t 62.89 and 63.24. T h i s p a t t e r n was s i m i l a r t o t h a t d e s c r i b e d f o r t h e 8 - k e t o e s t e r d i a n i o n a d d u c t s and p r o v i d e d c o n f i r m a t i o n t h a t t h e c o n d e n s a t i o n had o c c u r r e d  77. a t t h e t e r m i n a l c a r b o n o f t h e b e n z o y l a c e t o n e . The v i n y l p r o t o n o f t h e e n o l t a u t o m e r o f 158 a p p e a r e d i n t h e s p e c t r u m as a s i n g l e t a t 66.15. T h i s compound, l i k e t h e o t h e r a l d o l a d d u c t s , p r o v e d t o be e x t r e m e l y l a b i l e and c o u l d n o t be d i s t i l l e d o r o t h e r w i s e p u r i f i e d f o r a n a l y s i s . I t s mass s p e c t r u m showed no p a r e n t peak but d i d show a peak a t m/e 354 (P-18) due t o l o s s o f w a t e r . High r e s o l u t i o n mass s p e c t r o m e t r y c o n f i r m e d t h e f o r m u l a f o r t h i s peak t o be  ^21^22^5*  An a t t e m p t was made t o f o r m t h e t r i m e t h y l s i l y l e t h e r d e r i v a t i v e o f t h i s a l c o h o l i n a manner a n a l o g o u s t o t h a t d e s c r i b e d f o r t h e o t h e r a l d o l a d d u c t s . The same s e t o f r e a c t i o n c o n d i t i o n s as had been used to produce these d e r i v a t i v e s f o r the B-ketoester d i a n i o n adducts r e s u l t e d , i n t h i s c a s e , o n l y i n d e h y d r a t i o n o f t h e s u b s t r a t e . No s u i t a b l e c o n d i t i o n s were f o u n d f o r t h e p r e p a r a t i o n o f t h i s d e r i v a t i v e . T r e a t m e n t o f t h e a l c o h o l 158 w i t h hydrogen c h l o r i d e i n chloroform f o r a s h o r t time r e s u l t e d i n c o n v e r s i o n to p r i m a r i l y t h e u n s a t u r a t e d d i k e t o n e 155, but t i c o f t h e m i x t u r e i n d i c a t e d t h a t i t c o n t a i n e d some o f t h e c y c l i s e d p r o d u c t 156 a s w e l l . The IR s p e c t r u m o f t h e m i x t u r e , a s e x p e c t e d , showed no h y d r o x y l a b s o r p t i o n . I t s NMR s p e c t r u m showed t h e u s u a l d o u b l e t s (J=2 c p s ) f o r t h e v i n y l m e t h y l g r o u p s (62.15, 2 . 4 9 ) . U n f o r t u n a t e l y , one o f t h e s e was c o i n c i d e n t w i t h t h e a r o m a t i c methyl o f t h e c y c l i s e d p r o d u c t , so no a t t e m p t  was  made t o c a l c u l a t e an E,Z r a t i o . A complex group o f s i n g l e t s i n t h e methoxy r e g i o n i n t e g r a t e d c o r r e c t l y t o a v a l u e o f n i n e p r o t o n s . . I n t e g r a t i o n i n t h e r e g i o n 65.90-66.40 i n d i c a t e d t h e p r e s e n c e o f f o u r p r o t o n s w h i c h were a s s i g n e d t o t h e v i n y l p r o t o n , t h e v i n y l p r o t o n o f t h e e n o l , and t h e p r o t o n s on t h e t e t r a s u b s t i t u t e d a r o m a t i c r i n g . The p r o t o n s on t h e m o n o s u b s t i t u t e d a r o m a t i c r i n g a p p e a r e d i n t h e r a n g e 67.30- 8.20.  78 Section I I I : Synthesis of 2,4,6-trimethoxybenzoylacetone  (121).  In t h e e x p e r i m e n t s d e s c r i b e d i n t h e p r e v i o u s s e c t i o n we had d e v e l o p e d c o n d i t i o n s whereby t h e d i a n i o n s o f 8 - d i k e t o n e s c o u l d be p r o d u c e d and c o n d e n s e d , i n good y i e l d i n g r e a c t i o n s , w i t h the hindered type o f acetophenone necessary i n the s y n t h e s i s o f r e s i s t o m y c i n . In a d d i t i o n , t h e r e was e v e r y i n d i c a t i o n t h a t t h e f i r s t c y c l i s a t i o n s t e p c o u l d be a c c o m p l i s h e d e a s i l y . The n e x t p r o b l e m t o be a d d r e s s e d was t h e s y n t h e s i s o f t h e d i k e t o n e ,  2,4,6-trimethoxy-  b e n z o y l a c e t o n e ( 1 2 1 ) , r e q u i r e d i n o u r r o u t e (Scheme 9 ) . T h e s y n t h e s i s o f e - d i k e t o n e s has r e c e i v e d a g r e a t d e a l o f s t u d y and i s t h e s u b j e c t o f an e x t e n s i v e r e v i e w .  T h e two methods  most commonly u s e d i n v o l v e t h e b o r o n t r i f l u o r i d e c a t a l y s e d a c y l a t i o n o f k e t o n e s w i t h a c i d a n h y d r i d e s , and t h e C l a i s e n a c y l a t i o n o f k e t o n e e n o l a t e s w i t h e s t e r s o r a c i d c h l o r i d e s . U s i n g t h e l a t t e r m e t h o d , two r o u t e s were p o s s i b l e t o 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e  from c o m m e r c i a l l y  a v a i l a b l e compounds. T h e s e were a c y l a t i o n o f a c e t o n e w i t h m e t h y l 2,4,6-trimethoxybenzoate  (159) and a c y l a t i o n o f 2 , 4 , 6 - t r i m e t h o x y -  a c e t o p h e n o n e (94) w i t h m e t h y l o r e t h y l a c e t a t e . MeO  OMe Me CO 2  C0 Me  MeO  2  MeC0 R 2  OMe  79 Hauser has examined t h e a c y l a t i o n o f k e t o n e s u s i n g sodium 99 100 amide and sodium h y d r i d e as bases t o form the e n o l a t e s o f the k e t o n e s . Good r e s u l t s were r e p o r t e d u s i n g b o t h t h e s e b a s e s and t h e i r use was recommended o v e r weaker b a s e s such a s sodium e t h o x i d e w h i c h may, i n some c a s e s , not be s t r o n g enough t o c o m p l e t e l y f o r m t h e e n o l a t e o f t h e k e t o n e . Hauser a l s o recommended t h e u s e o f two e q u i v a l e n t s o f base i n t h e r e a c t i o n . The second e q u i v a l e n t i s r e q u i r e d t o form t h e e n o l a t e 163 o f t h e 3 - d i k e t o n e 162 formed d u r i n g t h e r e a c t i o n w h i c h would o t h e r w i s e be e n o l i z e d by p r o t o n t r a n s f e r f r o m t h e e n o l 161 o f t h e s t a r t i n g k e t o n e 160. Sodium h y d r i d e has been u s e d t o f o r m benz o y l a c e t o n e f r o m m e t h y l b e n z o a t e and a c e t o n e i n 66% y i e l d . ^ The same d i k e t o n e was p r o d u c e d f r o m a c e t o n e and e t h y l b e n z o a t e i n 63% y i e l d u s i n g sodium amide as b a s e . ^ 1  o  NaH  II CH CR 3  o  .  9  0  _ || > -CH CR  R'C0 *' 2  2  160  1  ->  161  R  /  U  ^CH^  'A  ^R'  162  NaH O  O  II  R  II X  CH  ^  R  163  Our i n i t i a l e x p e r i m e n t s u s i n g a c e t o n e , m e t h y l 2 , 4 , 6 - t r i methoxybenzoate  and sodium h y d r i d e o r sodium amide i n d r y e t h e r ( t h e  s o l v e n t reccomended  by H a u s e r ) r e t u r n e d o n l y t h e s t a r t i n g e s t e r a f t e r  80  workup. C o n s e q u e n t l y ,  t h e h i g h e r b o i l i n g e t h e r s o l v e n t s , DME  and  d i g l y m e were t r i e d and t h e m i x t u r e was r e f l u x e d f o r s e v e r a l h o u r s . The DME  (bp 83 d e g r e e s ) a g a i n r e t u r n e d 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 .  U s i n g d i g l y m e as s o l v e n t (bp 160 d e g r e e s ) c o n s i d e r a b l e  decomposition  o f t h e e s t e r , w h i c h seemed t o i n v o l v e e s t e r h y d r o l y s i s and c l e a v a g e , o c c u r r e d and none o f t h e d e s i r e d B - d i k e t o n e  ether  121  c o u l d be d e t e c t e d . S h o r t e r r e f l u x t i m e s r e s u l t e d o n l y i n l e s s decomp o s i t i o n o f t h e e s t e r . C o m p a r a b l e r e s u l t s were o b t a i n e d even when l a r g e e x c e s s e s o f a c e t o n e and sodium h y d r i d e were u s e d . A p p a r e n t l y t h e e s t e r was j u s t t o o h i n d e r e d t o u n d e r g o a r e a c t i o n a t t h e c a r b o n y l w i t h a n u c l e o p h i l e as b u l k y as t h e e n o l a t e o f  carbon  acetone.  T h e r e f o r e , our a t t e n t i o n was t u r n e d t o t h e a c y l a t i o n o f 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e (94) i n w h i c h t h e r e a c t i o n s i t e 1  one atom removed from t h e c a r b o n y l c a r b o n . Kimura and H o s i  was  no  succeeded  i n a c y l a t i n g t h i s ketone w i t h  e t h y l b e n z o a t e u s i n g m e t a l l i c sodium  as b a s e t o g i v e t h e B - d i k e t o n e  164_ i n 33% y i e l d .  94  164  The above r e a c t i o n c o n d i t i o n s were n o t c h o s e n f o r our work, p a r t l y b e c a u s e o f t h e low y i e l d r e p o r t e d , and p a r t l y b e c a u s e i t was b e l i e v e d t h a t a more c o n v e n i e n t b a s e c o u l d be f o u n d w i t h w h i c h  81  t o form t h e e n o l a t e o f 94. H a u s e r ' s recommendation a b o u t t h e u s e o f two e q u i v a l e n t s o f base r e s u l t e d i n i n c r e a s e d y i e l d s i n many c a s e s but t h i s method s u f f e r e d one d i s a d v a n t a g e .  T h e e x c e s s base p r e s e n t  d u r i n g t h e a d d i t i o n o f t h e e s t e r was c a p a b l e , n o t o n l y o f e n o l i z i n g the product diketone, but a l s o o f r e a c t i n g with t h e ester i t s e l f i f t h e e s t e r had any e n o l i z a b l e h y d r o g e n s . T h i s was f e l t t o be a c o n s i d e r a t i o n of p a r t i c u l a r importance i n our case because o f t h e slow r a t e o f r e a c t i o n a n t i c i p a t e d f o r t h e C l a i s e n condensation and b e c a u s e o f t h e a c t i v i t y o f t h e e s t e r t o be u s e d (methyl o r e t h y l acetate). When 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e (94} was added t o one equivalent of lithium dicyclohexylamide  i n THF a s m a l l q u a n t i t y o f a  w h i t e p r e c i p i t a t e , assumed t o be t h e e n o l a t e s a l t , v/as formed g r a d u a l l y over a p e r i o d o f an h o u r . A d d i t i o n o f e t h y l a c e t a t e f a i l e d t o d i s s o l v e t h i s p r e c i p i t a t e a n d , upon workup, t h e s t a r t i n g a c e t o p h e n o n e was recovered  i n t a c t . I d e n t i c a l r e s u l t s were o b t a i n e d u s i n g l i t h i u m  diisopropylamide  as base. In order t o check whether t h e enolate  anion  o f t h e k e t o n e h a d , i n f a c t , been f o r m e d t h e r e a c t i o n was  repeated,  but t h i s t i m e d e u t e r i u m o x i d e was added r a t h e r t h a n e t h y l  acetate.  I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h e r e t u r n e d k e t o n e i n d i c a t e d t h a t i t had been o n l y p a r t i a l l y d e u t e r a t e d  (^50%) a t t h e m e t h y l group  t h a t t h e r e f o r e t h e e n o l a t e had n o t been c o m p l e t e l y  formed.  Somewhat i n c r e d u l o u s l y we p o s t u l a t e d t h a t t h e amide b a s e s m i g h t n o t have been s t r o n g enough t o c o m p l e t e l y  form t h e e n o l a t e  o f a c e t o p h e n o n e 94_. I n t h e hope t h a t t h i s k e t o n e m i g h t be h i n d e r e d enough t o be e n o l i z e d by n - b u t y l l i t h i u m r a t h e r t h a n undergo a G r i g n a r d  82  t y p e r e a c t i o n t h i s base was t r i e d a t 0 d e g r e e s . Quenching w i t h d e u t e r i u m o x i d e y i e l d e d a p r o d u c t whose IR s p e c t r u m i n d i c a t e d i t t o be a G r i g n a r d a d d u c t ( h y d r o x y l band a t 3590 c m , -1  no c a r b o n y l b a n d ) .  The n e x t base t r i e d was t h e h i g h l y h i n d e r e d c a r b a n i o n i c base t r i t y l p o t a s s i u m . I t i s debatable  whether t h i s base i s s t r o n g e r  o r weaker t h a n t h e amide b a s e s but i t d i d have t h e a d v a n t a g e t h a t i t c o u l d be t i t r a t e d t o an end p o i n t w h i c h p r e s u m a b l y would i n d i c a t e complete formation of the enolate. T i t r a t i o n of a s o l u t i o n of 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e i n DME w i t h a s o l u t i o n o f t r i t y l p o t a s s i u m i n DME r e s u l t e d i n r a p i d f o r m a t i o n o f a f l o c c u l e n t p r e c i p i t a t e s i m i l a r t o t h e one o b t a i n e d w i t h t h e amide bases but i n l a r g e r q u a n t i t y . A d i s t i n c t end p o i n t was r e a c h e d but o n l y a f t e r a d d i t i o n o f what a p p e a r e d t o be an amount i n c o n s i d e r a b l e e x c e s s o f one e q u i v a l e n t o f t r i t y l p o t a s s i u m . Quenching w i t h d e u t e r i u m o x i d e and e x a m i n a t i o n o f t h e NMR o f t h e p r o d u c t m i x t u r e i n d i c a t e d t h e l o s s o f one p r o t o n from the acetophenone  methyl  group.  With t h e r e a s s u r a n c e t h a t t h e e n o l a t e a n i o n was c o m p l e t e l y formed a C l a i s e n c o n d e n s a t i o n was a t t e m p t e d  being  using  t r i t y l p o t a s s i u m t o g e n e r a t e t h e e n o l a t e o f 94_. S i n c e e t h y l a c e t a t e had f a i l e d t o d i s s o l v e t h e p r e c i p i t a t e i n p r e v i o u s e x p e r i m e n t s ,  methyl  a c e t a t e was c h o s e n f o r t h e a c y l a t i o n and i t was used i n l a r g e e x c e s s (10-15 e q u i v a l e n t s ) . R e f l u x i n g t h i s r e a c t i o n m i x t u r e f o r f o u r h o u r s r e s u l t e d i n c o m p l e t e d i s s o l u t i o n o f t h e p r e c i p i t a t e and t h e d e s i r e d 2,4,6-trimethoxybenzoylacetone from  (121) c o u l d be i s o l a t e d . i n 33% y i e l d  t h e p r o d u c t m i x t u r e . When t h e r e a c t i o n m i x t u r e was a l l o w e d t o  s t a n d a t room t e m p e r a t u r e f o r s e v e r a l h o u r s , t h e p r e c i p i t a t e c o m p l e t e l y d i s s o l v e d , and t h e d i k e t o n e was i s o l a t e d i n s l i g h t l y h i g h e r y i e l d ( 3 7 % ) .  83 The o v e r a l l y i e l d c o u l d , o f c o u r s e , be improved by r e c y c l i n g t h e acetophenone  r e c o v e r e d from t h e p r o d u c t m i x t u r e . A f t e r two  r e c y c l i n g s o f t h e v e r y c r u d e ( n o t s e p a r a t e d from t h e  such  triphenylmethane)  s t a r t i n g m a t e r i a l t h e y i e l d was r a i s e d t o 55%. S p e c t r a l d a t a g a t h e r e d f o r t h e p r o d u c t were i n a c c o r d with the s t r u c t u r e proposed  ( 1 2 1 ) . The IR s p e c t r u m showed t h e b r o a d  c a r b o n y l band (1650-1560 c m ) -1  expected f o r a chelated  and n o t t h e s h a r p band a t 1695 c m the acetophenone  -1  8-diketone  a s s o c i a t e d with the carbonyl of  s t a r t i n g m a t e r i a l . The mass s p e c t r u m o f t h e compound  showed t h e c o r r e c t m o l e c u l a r i o n (m/e 252) c o n f i r m i n g t h e a d d i t i o n o f an a c e t y l group t o t h e a c e t o p h e n o n e  and m i c r o a n a l y s i s e s t a b l i s h e d  t h e m o l e c u l a r f o r m u l a as C ^ H j g O ^ . 103 S h a p i r o et_ al_.  c o n d u c t e d NMR  s t u d i e s on s e v e r a l p a r a  s u b s t i t u t e d benzoylacetones i n order to o b t a i n i n f o r m a t i o n about the k e t o - e n o l e q u i l i b r i a o f s u c h compounds. F i v e p o s s i b l e t a u t o m e r i c e x i s t f o r unsymmetrical  forms  s-diketones. These are i l l u s t r a t e d , f o r  2,4,6-trimethoxybenzoylacetone  i n Scheme 10. The NMR  spectra i n the  above study i n d i c a t e d t h a t , i n the enol forms, the hydroxyl  group  e x h i b i t e d s t r o n g hydrogen b o n d i n g , d e m o n s t r a t i n g t h a t 121d and e were m i n o r c o n t r i b u t o r s . The c h o i c e between 121b and c_ was more d i f f i c u l t t o make, but a n a l y s i s o f t h e s u b s t i t u e n t e f f e c t s s u g g e s t e d t h a t t h e r e was a p p r e c i a b l e o v e r l a p between t h e u s y s t e m o f t h e p h e n y l g r o u p and t h e r e m a i n d e r o f t h e e n o l s y s t e m . S i n c e 121b i s f u l l y c o n j u g a t e d w h i l e 121c i s c r o s s c o n j u g a t e d , 121b m i g h t be e x p e c t e d t o p r e d o m i n a t e . The p e r c e n t a g e o f e n o l p r e s e n t i n s o l u t i o n was c o n c e n t r a t i o n dependent  slightly  but a l w a y s h i g h . F o r e x a m p l e , t h e p e r c e n t a g e  of enol present f o r 4-methoxybenzoylacetone  i n deuterochloroform  84  Scheme 10. T a u t o m e r i c Forms o f 2 , 4 , 6 - T r i m e t h o x y b e n z o y l a c e t o n e .  121d  121e  85 v a r i e d from 8 8 % t o 90% d e p e n d i n g on c o n c e n t r a t i o n . E l e c t r o n w i t h d r a w i n g g r o u p s were f o u n d t o s t a b i l i z e t h e e n o l f o r m . The a p p r o x i m a t e  percentages  o f e n o l p r e s e n t i n d e u t e r o c h l o r o f o r m f o r t h e l i s t o f compounds studied are given in Table I I .  Table II A p p r o x i m a t e P e r c e n t a g e s o f Enol P r e s e n t i n Para S u b s t i t u t e d 103 Benzoylacetones i n Deuterochloroform  The NMR s p e c t r u m o f 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e  agreed  w e l l w i t h t h e s e r e s u l t s . In d e u t e r o c h l o r o f o r m t h e compound a p p e a r e d t o be a b o u t 6 6 % e n o l i z e d . T h i s f i g u r e i s based on i n t e g r a t i o n o f t h e m e t h y l s i n g l e t s a t 62.11 and 62.26 a s s i g n e d t o t h e e n o l and k e t o  86 f o r m s r e s p e c t i v e l y . I t was s u p p o r t e d by i n t e g r a t i o n o f t h e v i n y l proton at  65.74.  In c a r b o n t e t r a c h l o r i d e s o l u t i o n t h e  percentage  o f e n o l p r e s e n t r o s e t o a p p r o x i m a t e l y 80%. T h i s i s i n a g r e e m e n t w i t h r e s u l t s o b t a i n e d by R o g e r s and B u r d e t t  6 0  who d e m o n s t r a t e d  that the  percentage of enol present i n a c e t y l a c e t o n e i n c r e a s e s with d e c r e a s i n g p o l a r i t y of i t s solvent. The i n a b i l i t y o f t h e d i a l k y l a m i d e bases t o c o m p l e t e l y form the a n i o n o f 2,4,6-trimethoxyacetophenone  was p u z z l i n g , as  was  t h e a p p a r e n t e x c e s s o f t r i t y l p o t a s s i u m needed t o form i t . A l s o , t h e i n s o l u b i l i t y o f t h e a n i o n ( p a r t i c u l a r l y t h e l i t h i u m e n o l a t e ) i n THF was u n u s u a l . Even a d d i t i o n o f h e x a m e t h y l p h o s p h o r a m i d e had f a i l e d t o d i s s o l v e e i t h e r t h e l i t h i u m o r p o t a s s i u m e n o l a t e . N a r a s i m h a n and M a l i have r e c e n t l y r e p o r t e d t h e l i t h i a t i o n o f a r o m a t i c r i n g s w i t h methoxy s u b s t i t u e n t s . In a n o v e l s y n t h e s i s o f f u r o q u i n o l i n e a l k a l o i d s , 2,4-dimethoxyquinoline  was l i t h i a t e d t o g i v e 165. T r e a t m e n t  of this  o r g a n o m e t a l ! i c compound w i t h N-methy! f o r m a n i l i d e gave t h e  3-formyl  d e r i v a t i v e 166, The a u t h o r s a l s o r e p o r t e d t h e l i t h i a t i o n o f 2-methoxy naDhthalene  t o g i v e i n t e r m e d i a t e 167. U n f o r t u n a t e l y , no  experimental  d e t a i l s were g i v e n i n t h i s r e p o r t and t h e b a s e u s e d t o f o r m l i t h i a t e d i n t e r m e d i a t e s 165 and 167 was not d i s c l o s e d .  167  the  87  To i n v e s t i g a t e t h e s l i m c h a n c e t h a t p r o t o n removal  from  t h e a r o m a t i c n u c l e u s was o c c u r r i n g i n o u r c a s e a s h o r t s t u d y o f t h e base s t r e n g t h s r e q u i r e d t o remove p r o t o n s from t r i m e t h o x y l a t e d a r o m a t i c r i n g s was u n d e r t a k e n . The f i r s t compound examined was 1 , 3 , 5 - t r i m e t h o x y b e n z e n e ( 1 6 8 ) . I t was a l l o w e d t o r e a c t w i t h e q u i v a l e n t amounts of sodium h y d r i d e , l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e , and n - b u t y l l i t h i u m i n THF. In t h e n - b u t y l l i t h i u m c a s e a w h i t e p r e c i p i t a t e was The r e a c t i o n m i x t u r e s were quenched examined  by NMR  formed.  w i t h d e u t e r i u m o x i d e and t h e p r o d u c t s  s p e c t r o s c o p y . N e i t h e r sodium h y d r i d e nor l i t h i u m  i s o p r o p y l c y c l o h e x y l a m i d e r e s u l t e d i n any l o s s o f i n t e n s i t y i n t h e a r o m a t i c p r o t o n s i g n a l compared t o t h e m e t h o x y p r o t o n s i g n a l . In t h e n - b u t y l l i t h i u m c a s e however, t h e a r o m a t i c s i g n a l i n t e g r a t e d a l m o s t e x a c t l y to an i n t e n s i t y o f two p r o t o n s i n d i c a t i n g t h a t > d e u t e r a t i o n had t a k e n p l a c e t o form 169, and t h a t t h e s a l t formed had p r o b a b l y been t h e l i t h i a t e d d e r i v a t i v e 170.  168  170  The n e x t compound s t u d i e d was  169  2,4,6-trimethoxyacetophenone  (94_). I t was m i x e d , i n s e p a r a t e e x p e r i m e n t s , w i t h one and two e q u i v a l e n t s o f sodium h y d r i d e i n THF and t h e r e a c t i o n m i x t u r e s were quenched  with  88 d e u t e r i u m o x i d e as d e s c r i b e d above. I n t e g r a t i o n o f t h e NMR  spectra  o f t h e p r o d u c t s o b t a i n e d from t h e s e r e a c t i o n s i n d i c a t e d unchanged s t a r t i n g m a t e r i a l i n b o t h c a s e s . The m e t h y l , methoxy, and a r o m a t i c p r o t o n s i g n a l s remained s h a r p s i n g l e t s i n t h e r a t i o 3:9:2. No p r e c i p i t a t e had formed i n e i t h e r c a s e . A p p a r e n t l y , s o d i u m  h y d r i d e was n o t a s u i t a b l e  base f o r t h e p r e p a r a t i o n o f t h e e n o l a t e o f 94_. The a c e t o p h e n o n e  was  t h e n r e a c t e d w i t h one and two e q u i v a l e n t s o f l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e i n THF and quenched w i t h d e u t e r i u m o x i d e as u s u a l . In t h e one e q u i v a l e n t c a s e , i n t e g r a t i o n o f t h e NMR  s p e c t r u m gave a v a l u e  o f 2.5 p r o t o n s f o r t h e ketone m e t h y l peak i n d i c a t i n g an e n o l a t e f o r m a t i o n o f a p p r o x i m a t e l y 50%. T h i s r e s u l t a g r e e d w i t h t h a t r e p o r t e d e a r l i e r f o r l i t h i u m d i c y c l o h e x y l a m i d e . I n t e g r a t i o n o f t h e NMR  spectrum  f o r t h e two e q u i v a l e n t c a s e showed t h a t e n o l i z a t i o n had been e s s e n t i a l l y c o m p l e t e . In n e i t h e r c a s e was any l o s s o f a r o m a t i c p r o t o n i n t e n s i t y o b s e r v e d . The p o s s i b i l i t y e x i s t e d t h a t t h e commercial  2,4,6-trimethoxy-  a c e t o p h e n o n e m i g h t be a h y d r a t e c o n t a i n i n g one h a l f a m o l e o f w a t e r ( o r some o t h e r h y d r o x y ! i c s o l v e n t ) . A c c o r d i n g l y , a sample was  sublimed  and r e a c t e d w i t h one e q u i v a l e n t o f l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e and d e u t e r i u m o x i d e , a s above. I n t e g r a t i o n o f t h e NMR s p e c t r u m a g a i n i n d i c a t e d o n l y a 50% i n c o r p o r a t i o n o f d e u t e r i u m . T h i s e l i m i n a t e d the p o s s i b i l i t y of 2,4,6-trimethoxyacetophenone  b e i n g a h y d r a t e . In o r d e r  t o p r o v e t h a t t h e p r e c i p i t a t e o b t a i n e d i n t h e s e e x p e r i m e n t s was  indeed  t h e l i t h i u m e n o l a t e o f t h e k e t o n e , t h e e x p e r i m e n t w i t h two e q u i v a l e n t s o f base was r e p e a t e d and t h e p r e c i p i t a t e and s u p e r n a t a n t s o l u t i o n were s e p a r a t e d and quenched  s e p a r a t e l y w i t h d e u t e r i u m o x i d e , The b u l k o f  t h e d e u t e r a t e d p r o d u c t a p p e a r e d i n t h e p r e c i p i t a t e component ( 8 5 % ) . No v a l i d r e a s o n was e v e r d i s c o v e r e d f o r t h e need f o r e x c e s s base i n  89  t h i s r e a c t i o n . I t remains a matter o f s p e c u l a t i o n . To g a i n some r e a s s u r a n c e t h a t a s i m i l a r s i t u a t i o n d i d n o t e x i s t f o r 2,4,6-trimethoxybenzoylacetone  w h i c h would c o m p l i c a t e t h e  p r o d u c t i o n o f t h e d i a n i o n o f t h i s compound i t was t r e a t e d i n an f a s h i o n w i t h two e q u i v a l e n t s o f 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  analagous  isopropylcyclohexylamide  o x i d e . I n t e g r a t i o n o f t h e NMR s p e c t r u m  t h e f u l l l o s s o f one p r o t o n f r o m t h e t e r m i n a l m e t h y l g r o u p  indicated demonstrating  t h a t t h e d i a n i o n had been f o r m e d a s e x p e c t e d . The r e a l i z a t i o n t h a t t h e e n o l a t e o f  2,4,6-trimethoxy-  a c e t o p h e n o n e c o u l d be c o m p l e t e l y f o r m e d by u s i n g two e q u i v a l e n t s o f t h e l i t h i u m d i a l k y l a m i d e b a s e s l e d t o a s l i g h t l y more e f f i c i e n t synthesis o f 2,4,6-trimethoxybenzoylacetone F o r m a t i o n o f t h e e n o l a t e was a c c o m p l i s h e d  than t h a t d e s c r i b e d above. u s i n g two e q u i v a l e n t s o f  l i t h i u m d i c y c l o h e x y l a m i d e and r e a c t i o n a t room t e m p e r a t u r e f i f t e e n e q u i v a l e n t s o f methyl a c e t a t e produced  with  t h e B-diketone i n 41%  y i e l d . T h i s s y n t h e s i s had. t h e added a d v a n t a g e t h a t r e c y c l i n g t h e r e c o v e r e d a c e t o p h e n o n e was more e a s i l y a c c o m p l i s h e d r e c o v e r e d n e a r l y p u r e a n d , o f c o u r s e , f r e e from t h e used i n t h e p r e v i o u s  s i n c e i t was triphenylmethane  procedure.  I t was b e l i e v e d t h a t t h e maximum y i e l d a t t a i n a b l e u n d e r t h e c o n d i t i o n s d e s c r i b e d above was 5 0 % b e c a u s e o f p r o t o n t r a n s f e r from t h e diketone product t o t h e e n o l a t e o f t h e s t a r t i n g ketone. was c o n s i d e r e d t o be a much more r a p i d p r o c e s s t h a n t h e v e r y  slow  C l a i s e n r e a c t i o n by w h i c h t h e d i k e t o n e was f o r m e d . T h e r e f o r e , f o r each m o l e c u l e o f p r o d u c t f o r m e d , one a d d i t i o n a l m o l e c u l e o f t h e e n o l a t e was q u e n c h e d . I t was f e l t t h a t t h e y i e l d o f t h e d i k e t o n e m i g h t be r a i s e d , i f , a f t e r a d d i t i o n o f h a l f an e q u i v a l e n t o f t h e  This  90  e s t e r , the e n o l a t e was r e g e n e r a t e d  by a d d i t i o n o f a n o t h e r h a l f an  e q u i v a l e n t o f b a s e , b e f o r e a d d i n g more e s t e r . T h i s would r a i s e t h e maximum t h e o r e t i c a l y i e l d o f t h e r e a c t i o n t o 75% and one  quarter  o f an e q u i v a l e n t o f e s t e r would t h e n a g a i n c o m p l e t e l y quench t h e e n o l a t e . I t was p o s s i b l e t h a t a l t e r n a t e a d d i t i o n s o f base and e s t e r , i n amounts d e c r e a s i n g by h a l v e s , would e v e n t u a l l y r a i s e t h e t h e o r e t i c a l y i e l d t o n e a r l y 100%. An a t t e m p t was made t o t e s t t h i s f o r the s y n t h e s i s of 2,4,6-trimethoxybenzoylacetone.  Two  procedure equivalents  o f base were used t o g e n e r a t e t h e e n o l a t e . T h i s was f e l t t o be an e x c e s s s i n c e one e q u i v a l e n t had been s u f f i c i e n t t o p r o d u c e 50% o f i t . T h e r e f o r e , i t was deemed n e c e s s a r y t o s e p a r a t e t h e e n o l a t e s a l t from the supernatant  s o l u t i o n c o n t a i n i n g t h e e x c e s s b a s e . T h i s was  accomplished  and more s o l v e n t and m e t h y l a c e t a t e were added ( h a l f an e q u i v a l e n t ) . U n f o r t u n a t e l y the time taken f o r d i s s o l u t i o n of the enolate under these c o n d i t i o n s (not complete a f t e r twenty-four  hours) rendered t h i s  method i m p r a c t i c a l and i t was n o t f u r t h e r  pursued.  91 S e c t i o n IV: Some i s o x a z o l e c h e m i s t r y . One a l t e r n a t i v e t o t h e d i a n i o n method o f f u n c t i o n a l i s i n g t h e t e r m i n a l methyl g r o u p o f B - d i k e t o n e s s u c h a s 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e v/as a l s o e x a m i n e d . T h i s a p p r o a c h was based p r i m a r i l y 105 on t h e work o f M i c e t i c h  who s u c c e e d e d  in lithiating  i s o x a z o l e (171) and 3 - p h e n y l - 5 - m e t h y l i s o x a z o l e  3,5-dimethyl-  (172) a t t h e C-5  methyl g r o u p b y r e a c t i o n w i t h n - b u t y l l i t h i u m . T h e s e l i t h i a t e d d e r i v a t i v e s 173 and 174 r e a c t e d w i t h c a r b o n d i o x i d e t o g i v e  3-methylisoxazole-5-  a c e t i c a c i d (175) and 3 - p h e n y l i s o x a z o l e - 5 - a c e t i c a c i d ( 1 7 6 ) . S e v e r a l o t h e r r e a c t i o n s were a c h i e v e d w i t h  3-methyl-5-1ithiomethylisoxazole  (173) and some o f t h e s e a r e i l l u s t r a t e d i n Scheme 11. A l k y l a t i o n was a c c o m p l i s h e d u s i n g b e n z y l c h l o r i d e to. g i v e 177 i n 6 2 % y i e l d .  Coupling  w i t h i o d i n e y i e l d e d t h e d i m e r 178_ ( 4 8 % ) . A c y l a t i o n w i t h e s t e r 17_9 p r o d u c e d t h e k e t o n e 180 ( 7 5 % ) and a n a l d o l t y p e c o n d e n s a t i o n w i t h benzophenone (123) g a v e t h e a l c o h o l 181^ i n 5 1 % y i e l d . R  R  R n-BuLi  C0  CH 171R=Me 172R=C H 6  CH Li 2  1 7 3 R=Me 5  2  174 R = C H 6  1 7 5 R = Me 5  176 R = C H 6  S i n c e i s o x a z o l e s a r e r e a d i l y p r e p a r e d from e - d i c a r b o n y l compounds u s i n g h y d r o x y l a m i n e ' 1 0 6  1 0 7  t h e r o u t e shown i n Scheme 12  5  92 Scheme 11.  Reactions of  3-Methyl-5-1ithiomethylisoxazole.  MeC»  v  OMe  MeO  94 was p r o p o s e d . R e a c t i o n o f 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e (121) h y d r o x y l a m i n e c o u l d y i e l d two p o s s i b l e i s o m e r i c i s o x a z o l e s ,  with  182  and 183. In p r a c t i c e , o n l y one o f t h e s e was p r o d u c e d and i t was a s s i g n e d s t r u c t u r e 183 w i t h t h e m e t h y l g r o u p a t C-3  (see l a t e r ) . I t  was hoped t h a t l i t h i a t i o n o f t h i s compound would y i e l d 184 w h i c h would u n d e r g o an a l d o l r e a c t i o n w i t h a k e t o n e ( e v e n t u a l l y t o be a c e t o p h e n o n e 22 n e c e s s a r y  i n the s y n t h e s i s of r e s i s t o m y c i n )  p r o d u c e t h e a l c o h o l 185. R e d u c t i o n  to  o f i s o x a z o l e s t o enamino k e t o n e s  s u c h as 186 i s a w e l l documented p h e n o m e n o n ^ as i s t h e h y d r o l y s i s 1  o f t h e s e d e r i v a t i v e s t o B - d i k e t o n e s 187. A r e c e n t example o f s u c h 108 a p r o c e d u r e was p r o v i d e d by Buchi and V e d e r a s t h e use o f i s o x a z o l e s i n t h e t r a n s f o r m a t i o n to B - d i k e t o n e s .  who  investigated  of a .^-unsaturated  They r e p o r t e d the p r o d u c t i o n of diketones  ketones  such as  190 f r o m i s o x a z o l e . 188. I t was e n v i s i o n e d t h a t i f a p r o c e d u r e such as t h a t o u t l i n e d i n Scheme 12 c o u l d be f o u n d f o r f u n c t i o n a l i s i n g t h e t e r m i n a l m e t h y l g r o u p 'of B - d i k e t o n e 121 i t would p r o v i d e a v i a b l e and g e n e r a l l y a p p l i c a b l e a l t e r n a t i v e t o t h e d i a n i o n method o f of B-polycarbonyl  compounds.  190  synthesis  95 Reaction o f unsubstituted benzoylacetone with  hydroxylamine  h y d r o c h l o r i d e i n r e f l u x i n g ethanol produced e x c l u s i v e l y 3-methyl5 - p h e n y l i s o x a z o l e ( 1 9 1 ) . None o f t h e o t h e r i s o m e r ,  5-methyl-3-phenyl-  i s o x a z o l e ( 1 7 2 ) , was d e t e c t e d . S t r u c t u r e 191 was a s s i g n e d by c o m p a r i n g 109 the melting point o f the product t o the l i t e r a t u r e values for t h e two i s o m e r s and by c o n t r a s t i n g i t s NMR s p e c t r u m w i t h t h a t d e s c r i b e d 105 by M i c e t i c h  f o r isomer 172. I s o x a z o l e f o r m a t i o n f r o m  and h y d r o x y l a m i n e  3-diketones  i s k n o w n ^ t o o c c u r v i a p r i o r f o r m a t i o n o f t h e oxime 1  d e r i v a t i v e o f one o f t h e k e t o g r o u p s . T h i s i s i l l u s t r a t e d f o r b e n z o y l a c e t o n e by t h e f o r m a t i o n o f 192. C y c l i s a t i o n o f 192 t o 193 and l o s s o f w a t e r y i e l d s t h e i s o x a z o l e 191. T h e d i r e c t i o n o f e n o l i z a t i o n o f t h e s t a r t i n g d i k e t o n e c a n be a g o v e r n i n g f a c t o r i n d e t e r m i n i n g w h i c h isomer i s f o r m e d , ^ ' ^ 1  That i s , the hydroxylamine  reacts at  t h e c a r b o n y l c a r b o n r a t h e r t h a n t h e h y d r o x y l c a r b o n o f t h e e n o l i z e d 107 f o r m . W h i l e t h e r e a r e a g r e a t many e x c e p t i o n s t o t h i s g e n e r a l r u l e , ' i t i s a p p a r e n t t h a t t h e i-soxazole 191 o b t a i n e d i n o u r c a s e was t h e et xa pu etcotmeedr one ce benzoylacetone showns i n103  (40) e x i s t s p r i m a r i l y as t h e  96  When 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e  (121) was r e a c t e d  w i t h 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 u n d e r t h e same c o n d i t i o n s as d e s c r i b e d above a s i n g l e p r o d u c t was a g a i n f o r m e d . T h i s has been a s s i g n e d s t r u c t u r e 183  by a n a l o g y t o t h e b e n z o y l a c e t o n e c a s e . I t was b e l i e v e d  t h a t t h e same p r e p a r a t i v e p r o c e d u r e would p r o d u c e s i m i l a r r e s u l t s f o r b o t h r e a c t i o n s . A l s o , f o r m a t i o n o f t h e i s o m e r i c i s o x a z o l e 182 would r e q u i r e r e a c t i o n o f t h e h y d r o x y l a m i n e a t t h e h i g h l y h i n d e r e d c a r b o n a t o t h e t r i m e t h o x y p h e n y l r i n g . I t s h o u l d be emphasized t h a t t h i s a s s i g n m e n t i s p u r e l y s p e c u l a t i v e and i n v o l v e d no d e f i n i t i v e c h e m i c a l o r s p e c t r o s c o p i c p r o o f . The NMR s p e c t r u m o f 183 showed t h e peaks e x p e c t e d f o r t h e v i n y l p r o t o n ( 6 6 . 2 5 ) , a r o m a t i c p r o t o n s ( 6 6 . 2 0 ) , and methoxy p r o t o n s (63.80, 3 . 8 5 ) . The peak a s s i g n e d t o t h e m e t h y l group p r o t o n s (62.33) was n e a r l y c o i n c i d e n t w i t h t h a t f o r i s o x a z o l e 191 ( 6 2 . 3 2 ) , p r o v i d i n g f u r t h e r e v i d e n c e t h a t t h e i s o m e r a s s i g n e d v/as c o r r e c t . The mass s p e c t r u m o f t h e compound showed t h e e x p e c t e d m o l e c u l a r i o n a t m/e 249-and m i c r o a n a l y s i s e s t a b l i s h e d i t s f o r m u l a as C H 0 N . 1 3  1 5  4  97 A t t e m p t s t o form t h e l i t h i o d e r i v a t i v e 184 o f 3 - m e t h y l - 5 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) i s o x a z o l e (183) a c c o r d i n g t o t h e 105 p r o c e d u r e o u t l i n e d by M i c e t i c h ,  and t h e n a l k y l a t e t h i s a n i o n w i t h a l  bromide were f r u i t l e s s . The i s o x a z o l e was t r e a t e d w i t h n - b u t y l l i t h i u m a t -78 d e g r e e s and a l l y ! b r o m i d e was added t o t h e m i x t u r e . O n l y s t a r t i n g m a t e r i a l , q u i t e pure and i n h i g h y i e l d , was o b t a i n e d on workup. I d e n t i c a l r e s u l t s were o b t a i n e d u s i n g l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i d e a s base a t room t e m p e r a t u r e . In o t h e r e x p e r i m e n t s 37 performed i n our l a b o r a t o r y  s i m i l a r n e g a t i v e r e s u l t s were o b t a i n e d  i n t h e a t t e m p t e d a l k y l a t i o n o f 3 - m e t h y l - 5 - p h e n y l i s o x a z o l e ( 1 9 1 ) . In t h i s c a s e t h e r e a s o n f o r t h e f a i l u r e o f t h e r e a c t i o n was d i s c o v e r e d by q u e n c h i n g t h e i s o x a z o l e , n - b u t y l l i t h i u m m i x t u r e w i t h d e u t e r i u m o x i d e . E x a m i n a t i o n o f t h e NMR s p e c t r u m o f t h e p r o d u c t showed t h a t d e u t e r a t i o n had t a k e n p l a c e s o l e l y a t t h e C-4 p o s i t i o n o f t h e i s o x a z o l r i n g t o p r o d u c e 194. No s u b s t i t u t i o n by d e u t e r i u m was o b s e r v e d a t t h e C-3 m e t h y l  group.  N—O 184  OMe  98 A p p a r e n t l y , f o r i s o x a z o l e s t h e C-4 r i n g p r o t o n i s more a c i d i c t h a n C-3 m e t h y l g r o u p p r o t o n s . I t must, however, be l e s s a c i d i c t h a n p r o t o n s on a C-5 m e t h y l g r o u p a c c o r d i n g t o M i c e t i c h ' 105 results.  On t h i s p r e m i s e , i t a p p e a r e d u n f o r t u n a t e t h a t f o r m a t i o n  o f t h e i s o x a z o l e had l e d t o t h e 3-methyl i s o m e r r a t h e r t h a n t h e 5-methyl i s o m e r . A l k y l a t i o n m i g h t have p r o c e e d e d had t h e i s o m e r i c i s o x a z o l e been o b t a i n e d . An a t t e m p t t o f o r m t h e d i a n i o n 195 o f i s o x a z o l e 191 a l s o f a i l e d . The compound 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 n - b u t y l 1 i t h i u m and t h e m i x t u r e was quenched w i t h d e u t e r i u m o x i d e . Here a g a i n , d e u t e r a t i o n was o b s e r v e d o n l y a t t h e C-4 p o s i t i o n and not a t t h e C-3 37  methyl  group.  N—O 195  Formation of nitrogen quaternary s a l t s of i s o x a z o l e s i s known t o i n c r e a s e t h e a c t i v i t y o f t h e C-3 and C-5 m e t h y l  groups.  T h i s i s i l l u s t r a t e d by t h e r e a c t i o n s r e p o r t e d by Lampe and S m o l i n s k a o f 3 , 5 - d i m e t h y l i s o x a z o l e m e t h i o d i d e (196) and 3 - m e t h y l - 5 - p h e n y l i s o x a z o l e e t h i o d i d e ( 1 9 7 ) . F o r t h e l a t t e r compound, c o n d e n s a t i o n w i t h p - N , N - d i m e t h y l a m i n o b e n z a l d e h y d e (198) o c c u r s r e a d i l y i n t h e p r e s e n c e o f p i p e r i d i n e and r e f l u x i n g e t h a n o l t o y i e l d t h e s t y r y l i s o x a z o l e derivative 199.  W i t h t h e 3 , 5 - d i m e t h y l compound r e a c t i o n w i t h 112 v a n i l l i n (200) o c c u r s a t b o t h m e t h y l g r o u p s t o y i e l d 201. 1 1 1  99  201  100  F o r m a t i o n o f an a l k y l q u a t e r n a r y s a l t o f 3-methyl-5-(2,4,6-trimethoxyphenyl)isoxazole  (183) was  accomplished  u s i n g m e t h y l f l u o r o s u l p h o n a t e , "magic m e t h y l " , which i s known t o be an e x t r e m e l y a c t i v e a l k y l a t i n g a g e n t , r e a c t i n g e x o t h e r m i c a l l y 113  w i t h amines and r e a d i l y a l k y l a t i n g a m i d e s and n i t r i l e s .  Addition  o f e x c e s s "magic m e t h y l " t o a s o l u t i o n o f t h e i s o x a z o l e 183 i n m lethylene c h l o r i d e produced, a f t e r approximately ten minutes, a f i n e w h i t e c r y s t a l l i n e p r e c i p i t a t e which was i d e n t i f i e d as t h e f l u o r o s u l p h o n a t e s a l t 202. A l l t h e peaks i n t h e NMR  s p e c t r u m o f t h i s compound  showed a s i g n i f i c a n t d o w n f i e l d s h i f t when compared t o s t a r t i n g m a t e r i a l . The C-3 m e t h y l s i n g l e t a p p e a r e d a t 62.60, t h e methoxy p r o t o n s as two p o o r l y r e s o l v e d s i n g l e t s a t 63.98. A t h r e e p r o t o n s i n g l e t a t  64.16  was a s s i g n e d t o t h e N-methyl g r o u p p r o t o n s . The a r o m a t i c p r o t o n s and t h e v i n y l p r o t o n a p p e a r e d as s i n g l e t s a t 66.38 and 67.19 r e s p e c t i v e l y . The i n s o l u b i l i t y o f t h e compound i n a l l b u t t h e most p o l a r o f o r g a n i c s o l v e n t s made r e c r y s t a l l i - z a t i o n i m p o s s i b l e . The s a l t c o u l d be p u r i f i e d o n l y by p r e c i p i t a t i n g i t f r o m a c e t o n i t r i l e w i t h e t h y l e t h e r . C o n s e q u e n t l y , a sample o f h i g h p u r i t y was n o t o b t a i n e d . However, m i c r o a n a l y s i s d i d r e v e a l p e r c e n t a g e s o f c a r b o n , h y d r o g e n , and n i t r o g e n t h a t were c l o s e enough t o t h e t h e o r e t i c a l v a l u e s t o i n d i c a t e t h a t t h e m o l e c u l a r f o r m u l a was i n d e e d C ^ H j g O y F N S . MeCv  ^  N—O  .OMe  "  M e 0  OMe 183  Me FSO3-  202  101  The f i r s t use o f t h e s a l t 202 was an a t t e m p t t o a p p l y 11111?  t h e p r o c e d u r e s o f Lampe and S m o l i n s k a ,  '  described earlier,  t o our s y s t e m . The s a l t , p i p e r i d i n e , and a c e t o p h e n o n e were mixed i n e t h a n o l and r e f l u x e d . On workup, o n l y r e t u r n e d s t a r t i n g m a t e r i a l c o u l d be i s o l a t e d . A t t e m p t s were made t o a c y l a t e t h e s a l t w i t h b e n z o y l c h l o r i d e . The two compounds were mixed w i t h t r i e t h y l a m i n e i n d i o x a n e and i n a c e t o n i t r i l e and a l l o w e d t o r e a c t f o r l o n g p e r i o d s . In b o t h e x p e r i m e n t s o n l y s t a r t i n g m a t e r i a l was i s o l a t e d a f t e r v/orkup. A n o t h e r s i m i l a r e x p e r i m e n t i n v o l v i n g r e f l u x i n g d i o x a n e had i d e n t i c a l results. A t t h i s p o i n t , t h i s r o u t e was abandoned i n f a v o u r o f t h e d i a n i o n r o u t e w h i c h , by t h i s t i m e , had p r o d u c e d p o s i t i v e r e s u l t s . I t s h o u l d , however, be p o i n t e d o u t t h a t f o r m a t i o n o f t h e m e t h y l f l u o r o s u l p h o n a t e s a l t p r o b a b l y d i d i n c r e a s e t h e a c i d i t y o f t h e C-3 m e t h y l 37 p r o t o n s . In o t h e r e x p e r i m e n t s  i t was f o u n d t h a t a d d i t i o n o f d e u t e r o  sodium h y d r o x i d e t o an NMR sample o f t h e s i m i l a r s a l t 203 i n d e u t e r i u m o x i d e and d e u t e r o a c e t o n i t r l i e r e s u l t e d i n c o m p l e t e and f a c i l e e x c h a n g e o f t h e m e t h y l g r o u p p r o t o n s by d e u t e r i u m . However, a l l a t t e m p t s t o a l k y l a t e o r a c y l a t e t h e presumed i n t e r m e d i a t e were u n s u c c e s s f u l .  FSO"  203  FS0  3  204  102 S e c t i o n V: S y n t h e s i s o f n a p h t h y l k e t o n e 27.  The d e u t e r a t i o n s t u d i e s d e s c r i b e d i n a p r e v i o u s s e c t i o n demonstrated  the formation of the dianion of  2,4,6-trimethoxybenzoyl-  a c e t o n e (121) u s i n g l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e a s base. The f i r s t e x p e r i m e n t s u n d e r t a k e n w i t h t h i s d i a n i o n were a g a i n e x p l o r a t o r y , and i n v o l v e d an a l k y l a t i o n w i t h a l l y ! b r o m i d e and an a l d o l c o n d e n s a t i o n with  acetophenone. R e a c t i o n o f t h e d i a n i o n w i t h one e q u i v a l e n t o f a l l y !  b r o m i d e g a v e a p r o d u c t m i x t u r e c o n t a i n i n g some s t a r t i n g m a t e r i a l , ( t i c ) but p r e d o m i n a n t l y one p r o d u c t . The NMR s p e c t r u m o f t h e c r u d e m a t e r i a l i n d i c a t e d t h a t t h e d e s i r e d a l k y l a t i o n had o c c u r r e d t o p r o d u c e 205. A m u l t i p l e t i n t h e r a n g e 62.20 t o 62.75 was a s s i g n e d t o t h e p r o t o n s o f t h e two m e t h y l e n e g r o u p s . T h e v i n y l p r o t o n o f t h e e n o l and t h e a r o m a t i c p r o t o n s a p p e a r e d a s s i n g l e t s a t 65.73 and 66.13 r e s p e c t i v e l y . A m u l t i p l e t i n t h e r e g i o n 64.7-5.2 was a s s i g n e d t o t h e t e r m i n a l v i n y l group p r o t o n s . I n t e g r a t i o n w i t h r e s p e c t t o t h e peaks a s s i g n e d t o t h e t e r m i n a l methyl g r o u p o f t h e s t a r t i n g m a t e r i a l i n d i c a t e d t h e r e a c t i o n t o be 90% c o m p l e t e .  103'. The r e a c t i o n w i t h a c e t o p h e n o n e a l s o p r o c e e d e d  smoothly  t o g i v e o n l y one p r o d u c t (and some s t a r t i n g m a t e r i a l ) . A f t e r t h e p r o d u c t had been p u r i f i e d by p r e p a r a t i v e t i c i t s NMR s p e c t r u m showed i t t o be p r i m a r i l y t h e d e s i r e d s - h y d r o x y - B - d i k e t o n e 206 a l t h o u g h some d e h y d r a t i o n a p p e a r e d t o have t a k e n p l a c e . T h i s i n i t i a l a l d o l a d d u c t was t r e a t e d i m m e d i a t e l y w i t h hydrogen c h l o r i d e i n c h l o r o f o r m and t h e d i h y d r o p y r o n e 207 was p r o d u c e d . T h e IR s p e c t r u m o f t h i s compound had t h e s h a r p c a r b o n y l band e x p e c t e d a t 1655 c m . I t s NMR -1  s p e c t r u m was c o m p a r a b l e t o t h a t o b t a i n e d f o r t h e s i m i l a r d i h y d r o p y r o n e 128 formed f r o m b e n z o y l a c e t o n e and a c e t o p h e n o n e which was d e s c r i b e d e a r l i e r . Formation o f such dihydropyrones from t h e d i a n i o n a l d o l a d d u c t s o c c u r r e d o n l y when u n s u b s t i t u t e d a c e t o p h e n o n e was used a s s u b s t r a t e . A p p a r e n t l y , s t e r i c h i n d r a n c e p r e v e n t e d t h e i r f o r m a t i o n from the aldol adducts of t h e di-ortho-methoxy s u b s t i t u t e d acetophenones, 22, 39, and 94^ In t h e s e c a s e s t h e open c h a i n u n s a t u r a t e d d i k e t o n e s were o b t a i n e d e x c l u s i v e l y . o  OMe  HCl  >  MeO  CHCI  o.  OMe 207  206  O  128  104 It s h o u l d be p o i n t e d o u t t h a t d i a n i o n r e a c t i o n s i n v o l v i n g 2,4,6-trimethoxybenzoylacetone  were a c h i e v e d w i t h a l l y l b r o m i d e u s i n g  s e v e r a l bases o t h e r t h a n l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e . T h e s e included lithium dicyclohexylamide, lithium 2,2,6,6-tetramethylpiperidide, and t r i t y l l i t h i u m . A l l t h e a l k y l a t i o n s p r o c e e d e d a l t h o u g h no c o m p r e h e n s i v e  in reasonable y i e l d ,  s t u d y v/as u n d e r t a k e n t o d e t e r m i n e  their  r e l a t i v e e f f i c i e n c i e s . L i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e had  advantages  o v e r a l l t h e o t h e r b a s e s . The d i f f i c u l t y , e n c o u n t e r e d on workup, i n v o l v i n g t h e s e p a r a t i o n o f t r i p h e n y l m e t h a n e from t h e p r o d u c t has a l r e a d y been m e n t i o n e d  mixture  f o r the triphenylmethide bases. Lithium  d i c y c l o h e x y l a m i n e was i n c o n v e n i e n t t o use b e c a u s e o f t h e a p p a r e n t l i m i t e d s o l u b i l i t y of the hydrochloride of dicyclohexylamine i n w a t e r . T h i s made workup o f t h e r e a c t i o n somewhat cumbersome, s i n c e i t i n v o l v e d f o r m a t i o n o f a f l o c c u l e n t p r e c i p i t a t e w h i c h c o u l d be removed o n l y by r e p e a t e d w a s h i n g s w i t h h y d r o c h l o r i c a c i d . T h i s was a d i s a d v a n t a g e i n t h e a l d o l r e a c t i o n s s i n c e i t c o u l d l e a d t o some dehydration of the products. Lithium 2,2,6,6-tetramethylpiperidide was as c o n v e n i e n t t o use as l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e but  was  r e j e c t e d p r i m a r i l y because of i t s r e l a t i v e l y high c o s t . The n e x t a l d o l c o n d e n s a t i o n o f t h e d i a n i o n o f 2,4,6-trimethoxybenzoylacetone  t h a t v/as i n v e s t i g a t e d i n v o l v e d t h e  model k e t o n e 2 , 6 - d i m e t h o x y a c e t o p h e n o n e . R e a c t i o n o f e q u i v a l e n t amounts of t h e d i a n i o n and t h e k e t o n e g a v e t h e d e s i r e d p r o d u c t 208, but i n low y i e l d ( 2 0 % ) . In a r e c e n t paper House e t a l _ .  9 7  have i n v e s t i g a t e d  t h e use o f metal c o m p l e x e s t o c o n t r o l a l d o l c o n d e n s a t i o n s .  Simple  a l d o l c o n d e n s a t i o n s i n v o l v i n g t h e e n o l a t e o f a k e t o n e and  another  c a r b o n y l c o n t a i n i n g compound a r e t h o u g h t t o p r o c e e d v i a t h e mechanism  106 shown i n Scheme 13. A r e a c t i o n f o l l o w i n g such a mechanism would r e s u l t i n a poor y i e l d o f p r o d u c t 212 i f t h e i n t e r m e d i a t e 211 i s l e s s s t a b l e t h a n t h e m i x t u r e o f s t a r t i n g e n o l a t e 209 and c a r b o n y l compound 210 s i n c e , i n t h i s c a s e , t h e e q u i l i b r i u m would l i e t o t h e l e f t and q u e n c h i n g w i t h a c i d would m e r e l y r e g e n e r a t e t h e s t a r t i n g m a t e r i a l s . House i n t r o d u c e d t h e i d e a o f i n c r e a s i n g t h e s t a b i l i t y o f t h e i n t e r m e d i a t e 211 t h r o u g h t h e use o f m e t a l complexes a s i l l u s t r a t e d by 213. F o r m a t i o n o f s u c h a complex c o u l d e x p l a i n t h e g r e a t e r s u c c e s s o f a l d o l t y p e c o n d e n s a t i o n s when l i t h i u m i s used as c o u n t e r 7?  i o n a s compared  t o sodium o r p o t a s s i u m . '  7R  76  '  L i t h i u m would be  b e t t e r s u i t e d t o form t h e complex t h a n t h e o t h e r two m e t a l s  because  o f i t s s m a l l i o n i c r a d i u s . In an e f f o r t t o enhance t h e s t a b i l i t y o f t h e m e t a l c h e l a t e 213, House e_t al_. examined common m e t a l c a t i o n s w i t h a s m a l l i o n i c r a d i u s s i m i l a r t o l i t h i u m but w i t h a g r e a t e r i o n i c c h a r g e . T h e s e i n c l u d e d Zn 2+ , Mg 2+ , and A l 3+ . L a r g e i n c r e a s e s i n t h e y i e l d s o f t h e a l d o l a d d u c t s were a c h i e v e d by t h e a d d i t i o n o f one mole o f a n h y d r o u s magnesium bromide o r a n h y d r o u s z i n c c h l o r i d e p e r mole o f e n o l a t e i n t h e r e a c t i o n m i x t u r e . An example p a r t i c u l a r l y i n s t r u c t i v e i n our c a s e was t h e r e a c t i o n o f t h e e n o l a t e 214 o f t h e h i n d e r e d 2 , 4 , 6 - t r i m e t h y l a c e t o p h e n o n e w i t h b e n z a l d e h y d e . In THF a t -5 d e g r e e s w i t h no a d d i t i v e s t h e h y d r o x y compound 215 was i s o l a t e d i n o n l y 16% y i e l d , a l t h o u g h some o f t h e enone formed by d e h y d r a t i o n o f 215 was a l s o o b s e r v e d . Under t h e same c o n d i t i o n s , but w i t h t h e a d d i t i o n o f an e q u i v a l e n t o f magnesium b r o m i d e , t h e h y d r o x y compound 215 c o u l d be i s o l a t e d i n 93% y i e l d .  9 7  107  While the s i t u a t i o n i n v o l v i n g t h e aldol  condensations  o f d i a n i o n s i s o b v i o u s l y more complex than t h e s i m p l e c a s e s  described  a b o v e , i t was f e l t t h a t t h e same p r i n c i p l e s m i g h t a p p l y . However, t h r e e p o s s i b l e c o - o r d i n a t i o n s i t e s e x i s t e d f o r t h e c a t i o n , two on t h e g - d i k e t o n e and one on t h e a c e t o p h e n o n e . I t was b e l i e v e d t h a t a d d i t i o n o f o n l y one mole o f s a l t p e r mole o f d i a n i o n m i g h t r e s u l t o n l y i n c o - o r d i n a t i o n o f t h e two n e g a t i v e c h a r g e s on t h e d i a n i o n ,  thereby  s t a b i l i z i n g t h e s t a r t i n g m a t e r i a l s and a c t u a l l y r e d u c i n g t h e y i e l d o f p r o d u c t . F o r t h i s r e a s o n , two m o l e s o f s a l t were added p e r m o l e o f d i a n i o n . G e n e r a t i o n o f t h e d i a n i o n was a c c o m p l i s h e d  as usual and  t h e 2 , 6 - d i m e t h o x y a c e t o p h e n o n e a n d s a l t were added t o g e t h e r . When a n h y d r o u s z i n c c h l o r i d e was used no i n c r e a s e i n y i e l d o v e r t h e c a s e w i t h no a d d i t i v e s was o b s e r v e d  (as evidenced  by t i c o n l y ) . T h e a d d i t i o n  o f a n h y d r o u s magnesium b r o m i d e d i d r e s u l t i n a s u b s t a n t i a l i n c r e a s e i n t h e y i e l d o f t h e a l d o l a d d u c t 208, w h i c h t h i s t i m e was i s o l a t e d in 39% y i e l d . The above y i e l d v/as s t i l l f e l t t o be u n s a t i s f a c t o r y and t h e method o f u s i n g a l a r g e e x c e s s o f t h e d i a n i o n was a g a i n i n v e s t i g a t e d and f o u n d t o g i v e much b e t t e r r e s u l t s . When t h e d i a n i o n was used i n f i v e f o l d e x c e s s t h e a l d o l a d d u c t c o u l d be i s o l a t e d a s  108 a crude o i l i n q u a n t i t a t i v e y i e l d (from the acetophenone)  and 80%  of the t h e o r e t i c a l excess of 2,4,6-trimethoxybenzoylacetone  could  be r e c o v e r e d . The p r o d u c t had s p e c t r a l p r o p e r t i e s i n k e e p i n g w i t h s t r u c t u r e 208. I t s IR s p e c t r u m had t h e bands e x p e c t e d f o r an a l c o h o l (3700-3200 cm" ) 1  and a B - d i k e t o n e (1650-1560 c m ) . I t s NMR  spectrum  - 1  p r o v i d e d p r o o f t h a t t h e c o n d e n s a t i o n had t a k e n p l a c e by showing f o r t h e a r o m a t i c p r o t o n s on b o t h t h e d i m e t h o x y  peaks  (3H, 66.50-7.40)  and t r i m e t h o x y (2H, 66.07) a r o m a t i c r i n g s . The v i n y l p r o t o n o f t h e e n o l a p p e a r e d a t 65.70 and i n t e g r a t i o n o f t h e methoxy r e g i o n i n d i c a t e d t h e p r e s e n c e o f f i f t e e n p r o t o n s . The methyl group a p p e a r e d as two s i n g l e t s , p r e s u m a b l y f o r t h e e n o l i z e d and n o n - e n o l i z e d t a u t o m e r s , a t 61.60 61.72. The d i a s t e r e o t o p i c p r o t o n s on t h e m e t h y l e n e g r o u p  and  appeared,  as u s u a l , as an AB q u a r t e t (J=14 c p s , 62.87, 63.07) a l t h o u g h t h i s p a t t e r n was c o m p l i c a t e d by t h e p r e s e n c e o f t h e two  tautomers.  L i k e t h e o t h e r a l d o l a d d u c t s , t h i s compound p r o v e d t o o l a b i l e f o r p u r i f i c a t i o n . J t s mass s p e c t r u m , a l s o l i k e t h e a l d o l  adducts  a l r e a d y d e s c r i b e d , showed no p a r e n t . H i g h r e s o l u t i o n m e a s u r e m e n t s on t h e peak a t m/e 414 (P-18) e s t a b l i s h e d i t s f o r m u l a t o be  C  23 26°7' H  as e x p e c t e d . T r e a t m e n t o f t h e d i a n i o n a d d u c t 208 w i t h hydrogen c h l o r i d e i n c h l o r o f o r m r e s u l t e d i n a complex m i x t u r e c o n t a i n i n g a t l e a s t f o u r p r o d u c t s ( t i c ) . In t h e hope t h a t t h e s e m i g h t a l l be d r i v e n t o one p r o d u c t , t h e c y c l i s e d n a p h t h y l k e t o n e 217, t h e same sample v/as t r e a t e d f o r t w e n t y hours under t h e s e c o n d i t i o n s . S e p a r a t i o n o f t h e p r o d u c t m i x t u r e r e s u l t e d i n t h e i s o l a t i o n , i n p o o r y i e l d (^38%), o f t h e v e r y c r u d e d e h y d r a t e d compound 216 i n an E:Z r a t i o o f 9:7. None o f t h e c y c l i s e d p r o d u c t v/as d e t e c t e d .  A s e a r c h f o r m i l d e r c o n d i t i o n s by w h i c h t h e a l c o h o l 208 m i g h t be d e h y d r a t e d and h o p e f u l l y c y c l i s e d i n one s t e p was  launched.  R e a c t i o n o f t h e h y d r o x y compound w i t h p a r a - t o l u e n e s u l p h o n i c a c i d i n benzene r e s u l t e d i n d e h y d r a t i o n but once a g a i n s e v e r a l products were formed and t h e y i e l d o f t h e d e h y d r a t e d  i s o m e r s was n o t s a t i s f a c t o r y .  P o l y p h o s p h o r i c a c i d i s known t o be an e f f e c t i v e c a t a l y s t f o r a v a r i e t y o f a r o m a t i c c y c l i s a t i o n s . F o r e x a m p l e , Newman and S e s h a d r i used t h i s r e a g e n t i n a c y c l i s a t i o n o f a l d e h y d e 218 t o t h e 219. R e a c t i o n o f t h e h y d r o x y - 8 - d i k e t o n e  1 1 4  benzanthracene  208 i n p o l y p h o s p h o r i c a c i d  p r o d u c e d a complex m i x t u r e c o n t a i n i n g a t l e a s t f i v e compounds by t i c . T r e a t m e n t o f 208 w i t h hydrogen c h l o r i d e i n e t h e r s o l u t i o n l e d t o e x t e n s i v e d e c o m p o s i t i o n w h i c h seemed t o i n v o l v e some c l e a v a g e o f t h e  110  m e t h y l e t h e r f u n c t i o n s . T h i s a s s u m p t i o n was based on i n t e g r a t i o n o f t h e methoxy r e g i o n i n t h e NMR s p e c t r u m o f t h e c r u d e m i x t u r e . Boron t r i f l u o r i d e e t h e r a t e has been used i n d e h y d r a t i o n r e a c t i o n s •J I  c  such as t h e c o n v e r s i o n o f t h e 1 1 - 8 - h y d r o x y s t e r o i d 220 t o 221.  220  221  T h i s r e a g e n t gave t h e b e s t r e s u l t s o f a l l t h o s e t r i e d f o r t h e dehyd r a t i o n o f 208, p r o d u c i n g a c r u d e m i x t u r e o f t h e d e h y d r a t e d i s o m e r s 216E, Z_ i n a r a t i o o f 2:1. T h i s r a t i o was a s s i g n e d on t h e b a s i s o f t h e NMR  s p e c t r u m o f t h e m i x t u r e w h i c h showed d o u b l e t s f o r t h e v i n y l  m e t h y l group a t 62.11 and 62.59 a s s i g n e d t o t h e E and Z i s o m e r s r e s p e c t i v e l y . A complex g r o u p o f l i n e s i n t h e v i n y l and a r o m a t i c r e g i o n s c o u l d not be a s s i g n e d i n d i v i d u a l l y but were a s c r i b e d t o t h e v a r i o u s v i n y l and a r o m a t i c p r o t o n s i n t h i s m i x t u r e o f i s o m e r s and  Ill  t a u t o m e r s . The IR s p e c t r u m and mass s p e c t r u m were a l s o i n agreement w i t h t h e p r o p o s e d s t r u c t u r e o f B - d i k e t o n e 216 One a t t e m p t was made t o c y c l i s e 216 by t r e a t i n g i t w i t h b o r o n t r i f l u o r i d e e t h e r a t e f o r a l o n g t i m e (16 h o u r s ) but t h i s r e s u l t e d o n l y i n some d e c o m p o s i t i o n . None o f t h e c y c l i s e d p r o d u c t v/as o b s e r v e d . Consequently, a search f o r other acid catalysts f o r the c y c l i s a t i o n was u n d e r t a k e n . The a c t i o n o f h y d r o g e n c h l o r i d e i n c h l o r o f o r m and i n benzene was examined. In b o t h c a s e s s t a r t i n g m a t e r i a l was r e t u r n e d intact. R e a c t i o n o f 216 w i t h aluminum c h l o r i d e i n m e t h y l e n e c h l o r i d e p r o d u c e d a m i x t u r e o f compounds w h i c h c o n t a i n e d n e i t h e r s t a r t i n g m a t e r i a l (by t i c ) n o r t h e d e s i r e d n a p h t h y l k e t o n e 217. E v i d e n c e t h a t t h e c y c l i s a t i o n had n o t o c c u r r e d came f r o m t h e NMR s p e c t r u m o f t h e c r u d e p r o d u c t w h i c h s t i l l showed two d o u b l e t s f o r t h e v i n y l m e t h y l g r o u p p r o t o n s . Some c l e a v a g e o f t h e e t h e r g r o u p s p r o b a b l y o c c u r r e d under t h e s e c o n d i t i o n s . Aluminum c h l o r i d e i s known t o be an e f f e c t i v e c a t a l y s t f o r s u c h t r a n s f o r m a t i o n s , as i l l u s t r a t e d by t h e d e m e t h y l a t i o n o f 222 t o 2 2 3 .  1 1 6  Br  Br  222  223  F i n a l l y , s t a n n i c c h l o r i d e was f o u n d t o be an e f f e c t i v e c a t a l y s t f o r the d e s i r e d c y c l i s a t i o n . T h i s Lewis a c i d c a t a l y s t i s  112  m i l d e r than aluminum c h l o r i d e and i s not known t o c l e a v e e t h e r s . I t has been used t o e f f e c t t h e c o n d e n s a t i o n with para-xylene  (224).  117  of ethyl ketomalonate  (225)  S t o r k and G r e g s o n ^ used s t a n n i c c h l o r i d e 1 1  i n benzene c o n t a i n i n g a s m a l l q u a n t i t y o f w a t e r t o c y c l i s e t h e c y c l o p r o p y l k e t o n e 2Z7  t o two i s o m e r i c p r o d u c t s 228  and 229-  The f u n c t i o n  o f t h e w a t e r i n t h i s r e a c t i o n was not e x p l a i n e d but a s i m i l a r f o r wet s o l v e n t has been o b s e r v e d c a t a l y s e d by b o r o n t r i f l u o r i d e .  119  requirement  i n c y c l i s a t i o n s i n methylene c h l o r i d e  113  A sample o f t h e u n s a t u r a t e d B - d i k e t o n e 216 v/as r e a c t e d w i t h s t a n n i c c h l o r i d e i n wet benzene f o l l o w i n g S t o r k ' s p r o c e d u r e . T h i s r e s u l t e d i n t h e f o r m a t i o n o f a y e l l o w c r y s t a l l i n e compound o b t a i n e d i n 52% y i e l d a f t e r p u r i f i c a t i o n . T h i s p r o d u c t was i d e n t i f i e d as t h e n a p h t h y l ketone 217. The NMR  spectrum provided evidence t h a t the  c y c l i s a t i o n had o c c u r r e d s i n c e i t showed one broad s i n g l e t f o r t h e a r o m a t i c methyl group a t 62.55, c o m p a r a b l e  to that observed f o r the  o t h e r n a p h t h y l ketone 156 d e s c r i b e d p r e v i o u s l y . The d o u b l e t s c h a r a c t e r i s t i c o f t h e v i n y l methyl g r o u p s i n t h e u n c y c l i s e d m a t e r i a l were not p r e s e n t i n t h e s p e c t r u m . The IR s p e c t r u m o f t h e p r o d u c t showed a s h a r p c h e l a t e d c a r b o n y l a b s o r p t i o n a t 1640 cm" . 1  I t s mass s p e c t r u m  had a p a r e n t peak a t m/e 382 d e m o n s t r a t i n g t h a t methanol  had  been  l o s t from 216 d u r i n g t h e c y c l i s a t i o n . The UV-Vis s p e c t r u m o f t h e compound a l s o c o n f i r m e d t h e n a p h t h a l e n e s t r u c t u r e and was c l o s e l y  comparable  t o t h a t o b s e r v e d f o r n a p h t h y l k e t o n e 156. The m o l e c u l a r f o r m u l a o f 217, ^22^22^6'  was  con  ^'' ^ °y m i c r o a n a l y s i s . rme  MeO.  MeO\  ^OMe  OMe  217  156  114 The e x t e n s i o n o f t h e a b o v e work t o t h e r e s i s t o m y c i n r o u t e c o u l d now be a p p r o a c h e d w i t h c o n f i d e n c e . The d i a n i o n o f 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e was r e a c t e d ( i n f i v e f o l d e x c e s s ) w i t h t h e a c e t o p h e n o n e 22_ r e q u i r e d i n t h e r e s i s t o m y c i n s y n t h e s i s . T h i s procedure l e d to the q u a n t i t a t i v e p r o d u c t i o n of the d i a n i o n adduct  122.  The e x c e s s 2 , 4 , 6 - t r i m e t h o x y b e n z o y l a c e t o n e was r e c o v e r e d e f f i c i e n t l y ( 7 8 % ) . The IR s p e c t r u m o f 122 was i n a l l r e s p e c t s c o m p a r a b l e t o t h a t d e s c r i b e d f o r t h e o t h e r d i a n i o n a d d u c t s and had an a d d i t i o n a l band a t 2255 f o r t h e n i t r i l e . I t s NMR  cm"  1  s p e c t r u m showed s i n g l e t s f o r t h e v i n y l p r o t o n  o f t h e e n o l ( 6 5 . 7 2 ) , t h e a r o m a t i c p r o t o n s on t h e t r i m e t h o x y s u b s t i t u t e d r i n g ( 6 6 . 1 5 ) , and t h e a r o m a t i c p r o t o n s on t h e o t h e r r i n g ( 6 6 . 7 1 ) . The g e m - d i m e t h y l g r o u p a p p e a r e d a s a s i n g l e t a t 61.70. In a l l o t h e r r e s p e c t s t h e s p e c t r u m was s i m i l a r t o t h a t o b s e r v e d f o r d i a n i o n a d d u c t 208.  122  115 D e h y d r a t i o n o f 122 was a c c o m p l i s h e d e a s i l y 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 a s i n t h e p r e v i o u s c a s e . However, t h e p r o d u c t a p p e a r e d t o be p r i m a r i l y t h e n o n - c o n j u g a t e d i s o m e r 230 and c o n t a i n e d o n l y m i n o r amounts o f t h e d e s i r e d 29E and 1_. E v i d e n c e f o r t h i s came f r o m t h e NMR s p e c t r u m o f t h e m i x t u r e w h i c h showed d o u b l e t s a t 55.23 and 65.52 i n t h e v i n y l r e g i o n s i m i l a r t o t h o s e d e s c r i b e d f o r t h e u n s a t u r a t e d a c i d 113. O n l y s m a l l peaks were o b s e r v e d f o r t h e d o u b l e t s a s s i g n e d t o t h e v i n y l m e t h y l g r o u p s i n 29E and Z_. T h e IR s p e c t r u m o f t h e p r o d u c t was c o n s i s t e n t w i t h i t s b e i n g a m i x t u r e o f t h e t h r e e d e h y d r a t e d i s o m e r s shown.  116 •  No a t t e m p t was made t o p u r i f y o r c h a r a c t e r i z e a n y o f t h e u n s a t u r a t e d i s o m e r s i n t h e m i x t u r e d e s c r i b e d above. I t was b e l i e v e d t h a t i t would be e a s i e r t o c a r r y t h e c r u d e p r o d u c t t h r o u g h t h e c y c l i s a t i o n s t e p and t h e n i s o l a t e and c h a r a c t e r i z e t h e c y c l i s e d p r o d u c t w h i c h was e x p e c t e d t o have c h r o m a t o g r a p h i c and s o l u b i l i t y p r o p e r t i e s q u i t e d i f f e r e n t from any u n c y c l i s e d i m p u r i t i e s . A c c o r d i n g l y , t h e c r u d e m i x t u r e o f 29E, 29Z, and 230 was t r e a t e d w i t h s t a n n i c c h l o r i d e i n wet benzene. T h i s p r o d u c e d a d i s c o u r a g i n g m i x t u r e o f compounds w h i c h d i d n o t c o n t a i n a d e t e c t a b l e amount o f t h e c y c l i s e d m a t e r i a l 27. T h e NMR s p e c t r u m o f t h e p r o d u c t m i x t u r e had no peak r e s e m b l i n g t h e s i n g l e t o b t a i n e d f o r t h e a r o m a t i c m e t h y l g r o u p i n t h e p r e v i o u s two n a p h t h y l k e t o n e s . S i m i l a r r e s u l t s were o b t a i n e d u s i n g s t a n n i c c h l o r i d e i n m e t h y l e n e  chloride.  Once a g a i n , o t h e r c a t a l y s t s were t r i e d i n an e f f o r t t o f i n d e f f e c t i v e c o n d i t i o n s f o r t h e c y c l i s a t i o n . T h e s e i n c l u d e d aluminum c h l o r i d e i n benzene, p o l y p h o s p h o r i c a c i d , and c o n c e n t r a t e d s u l p h u r i c a c i d . None o f t h e s e p r o d u c e d a d e t e c t a b l e amount o f t h e n a p h t h y l k e t o n e 27. F i n a l l y , a l m o s t i n d e s p e r a t i o n , t h e o r i g i n a l c a t a l y s t f o u n d f o r t h e s e c y c l i s a t i o n s , hydrogen c h l o r i d e , was t r i e d , t h i s t i m e i n benzene.  .  While t h i s d i d not produce any c y c l i s e d product, i t d i d i s o m e r i z e t h e n o n - c o n j u g a t e d i s o m e r 230 t o a m i x t u r e w h i c h c o n t a i n e d p r e d o m i n a n t l y 29E and Z_. When t h i s m i x t u r e was t r e a t e d w i t h s t a n n i c c h l o r i d e i n wet benzene t h e c y c l i s e d n a p h t h y l k e t o n e 27_ was p r o d u c e d . T h i s compound p r o v e d r a t h e r u n s t a b l e and d i f f i c u l t t o p u r i f y . C h r o m a t o g r a p h y  on  s i l i c a g e l , a l u m i n a , and c e l l u l o s e a l l l e d t o s i g n i f i c a n t d e c o m p o s i t i o n . A r e l a t i v e l y p u r e sample was o b t a i n e d by r e c r y s t a l l i z a t i o n o f t h e c r u d e product mixture g i v i n g t h e naphthyl ketone i n 46% y i e l d . S u b l i m a t i o n  117  o f t h e s e c r y s t a l s gave a sample whose m i c r o a n a l y s i s was c o n s i s t e n t w i t h t h e m o l e c u l a r f o r m u l a C ^ g ^ y O g N . S p e c t r a l d a t a were a l s o i n a c c o r d w i t h s t r u c t u r e 27. I t s IR s p e c t r u m showed t h e s t r o n g l y c h e l a t e d c a r b o n y l band e x p e c t e d a t 1640 c m  -1  and was s i m i l a r i n t h i s and a l l  o t h e r r e s p e c t s t o t h e two n a p h t h y l k e t o n e s a l r e a d y d e s c r i b e d . The U V - V i s and mass s p e c t r a were a l s o c o n s i s t e n t w i t h t h e s t r u c t u r e a s s i g n e d . A sample o f 27_ l a r g e enough and p u r e enough t o g i v e a good NMR  s p e c t r u m has n o t y e t . b e e n o b t a i n e d . However, t h e s p e c t r u m o f t h e  u n s u b l i m e d m a t e r i a l p r o v i d e d a d d i t i o n a l s u p p o r t f o r s t r u c t u r e 27_. The broad a r o m a t i c methyl s i n g l e t a p p e a r e d a t 62.51, a s e x p e c t e d . I n t e g r a t i o n o f t h e methoxy p r o t o n peaks w i t h r e s p e c t t o t h e gem-dimethyl p r o v i d e d e v i d e n c e t h a t one methoxy group had been  group  lost.  The mechanism , o f t h e c y c l i s a t i o n s o f t h e u n s a t u r a t e d 3-diketones t o the naphthyl ketones deserves.some 120 p u b l i c a t i o n s by O l a h et. al_.  have d e m o n s t r a t e d  comment. R e c e n t the protonation of  p o l y a l k o x y aromatic r i n g s i n s t r o n g a c i d s o l u t i o n . For example, t r i m e t h o x y t o l u e n e (231) i n a s u l p h u r y ! f l u o r i d e c h l o r i d e , f l u o r o s u l p h o n i c a c i d m i x t u r e formed t h e two c a t i o n s 232 and 233 w i t h 232 b e i n g t h e  118 p r e d o m i n a n t t a u t d m e r . T h i s phenomenon s u g g e s t e d t h a t t h e mechanism o f c y c l i s a t i o n i n our c a s e m i g h t w e l l i n v o l v e t h e p r o t o n a t e d s p e c i e s 234_ w h i c h c o u l d c y c l i s e t o 235 a s shown. L o s s o f m e t h a n o l f r o m t h i s s p e c i e s would p r o d u c e t h e f i n a l p r o d u c t 27_ ( o r 2 J 7 , 156). Such a  ISO  . R =  OMe  Ar = C H 6  5  119 mechanism c o u l d e x p l a i n t h e ease w i t h which t h e n a p h t h y l k e t o n e 156 was formed compared t o t h e o t h e r two. I t was p r o d u c e d i n t h e p r e s e n c e of hydrogen c h l o r i d e o n l y . No s t a n n i c c h l o r i d e was n e c e s s a r y i n t h i s c a s e . The p r e s e n c e o f t h e t h i r d methoxy group (R=0Me) on t h e r i n g r e q u i r i n g p r o t o n a t i o n would make t h e p r o t o n a t i o n somewhat e a s i e r . A l s o , no c o m p l i c a t i o n s i n v o l v i n g p r o t o n a t i o n o f t h e o t h e r a r o m a t i c r i n g would a r i s e i n t h i s c a s e ( A r = p h e n y l ) whereas s u c h p r o t o n a t i o n c o u l d o c c u r i n t h e o t h e r two c a s e s ( A r = t r i m e t h o x y p h e n y l ) . I f t h i s mechanism i s t h e c o r r e c t o n e , t h e f u n c t i o n o f t h e w a t e r i n t h e r e a c t i o n was t o p r o d u c e hydrogen c h l o r i d e from t h e s t a n n i c c h l o r i d e . T h e f u n c t i o n of t h e s t a n n i c c h l o r i d e i t s e l f remains u n c l e a r although i t appears to be n e c e s s a r y f o r t h e p r o d u c t i o n o f n a p h t h y l k e t o n e s 27 and 217 s i n c e hydrogen c h l o r i d e a l o n e d i d n o t f o r m t h e s e c y c l i s e d compounds. I t m i g h t a s s i s t i n t h e c y c l i s a t i o n s by f o r m i n g a c h e l a t e i n w h i c h the r i n g s a r e held i n a convenient conformation f o r c y c l i s a t i o n to occur. I t i s hoped t h a t t h e l a b i l i t y o f t h e n a p h t h y l k e t o n e 27_ and t h e m e d i o c r e y i e l d i n which i t was o b t a i n e d i s due t o i t s f u r t h e r c y c l i s a t i o n t o t h e t e t r a c y c l i c compound 236. T h i s p o s s i b i l i t y i s p r e s e n t l y under i n v e s t i g a t i o n a s i s t h e p o s s i b i l i t y o f c o n v e r t i n g t h e m i x t u r e o f d e h y d r a t e d i s o m e r s 29 d i r e c t l y . t o 236 w i t h o u t i s o l a t i o n o f the intermediate naphthyl  ketone.  120  121 EXPERIMENTAL  General. Spectral Data. I n f r a r e d (IR) s p e c t r a were t a k e n i n c h l o r o f o r m s o l u t i o n ( u n l e s s o t h e r w i s e n o t e d ) . T h e y were r e c o r d e d on a P e r k i n - E l m e r model 700 s p e c t r o p h o t o m e t e r and were c a l i b r a t e d w i t h t h e 1601  cm  -1  band o f p o l y s t y r e n e . The a s s i g n m e n t o f e a c h band i s l i s t e d i n p a r e n theses a f t e r i t . N u c l e a r m a g n e t i c r e s o n a n c e (NMR)  s p e c t r a were t a k e n i n  d e u t e r o c h l o r o f o r m ( u n l e s s o t h e r w i s e n o t e d ) and were r e c o r d e d on a V a r i a n model T-60 s p e c t r o p h o t o m e t e r . T e t r a m e t h y l s i l a n e was used a s an i n t e r n a l s t a n d a r d e x c e p t where i n d i c a t e d . C h e m i c a l s h i f t s a r e r e p o r t e d u s i n g t h e 6 s c a l e . The f o l l o w i n g a b b r e v i a t i o n s a r e used regarding the m u l t i p l i c i t y of peaks: s = s i n g l e t , d=doublet, t = t r i p l e t , q = q u a r t e t , m = m u l t i p l e t . C o u p l i n g c o n s t a n t s a r e d e n o t e d by J and a r e q u o t e d i n c y c l e s p e r second ( c p s ) . 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 a r e a s and p r o t o n a s s i g n m e n t s a r e l i s t e d i n p a r e n t h e s e s a f t e r each s i g n a l . U l t r a v i o l e t - v i s i b l e ( U V - V i s ) s p e c t r a were r e c o r d e d on e i t h e r a Unicam model SP 800 o r a P e r k i n - E l m e r model 202 s p e c t r o p h o t o m e t e r . U n l e s s o t h e r w i s e n o t e d t h e s p e c t r a were t a k e n i n m e t h a n o l . The m o l a r e x t i n c t i o n c o e f f i c i e n t s o f t h e m a i n bands a r e l i s t e d i n parentheses a f t e r the absorptions. The mass s p e c t r a were o b t a i n e d u s i n g an A t l a s CH-4b mass s p e c t r o m e t e r . H i g h r e s o l u t i o n m e a s u r e m e n t s were made on an AEI  MS-9  mass s p e c t r o m e t e r . Each mass (m/e) has i t s r e l a t i v e i n t e n s i t y l i s t e d  122 i n p a r e n t h e s e s a f t e r i t . B o t h i n s t r u m e n t s were o p e r a t e d a t an i o n i s i n g p o t e n t i a l o f 70 v o l t s . Physical Data. M e l t i n g p o i n t s (mp) were d e t e r m i n e d on a K o f l e r hot s t a g e m i c r o s c o p e and a r e u n c o r r e c t e d . E l e m e n t a l m i c r o a n a l y s e s were p e r f o r m e d by Mr. P e t e r B o r d a , U n i v e r s i t y of B r i t i s h Columbia. Chromatography. S i l i c a g e l was o b t a i n e d from E. Merck. The g r a d e f i n e r t h a n 200 mesh was used f o r column c h r o m a t o g r a p h y . T h i n l a y e r  chroma-  t o g r a p h y was done u s i n g t h e g r a d e PF-254+366. A l u m i n a f o r t h i n l a y e r c h r o m a t o g r a p h y was o b t a i n e d f r o m Macherey, Nagel and Co. and was t h e g r a d e  G/irv^^.  P r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y was done on 20 X 20 cm p l a t e s w i t h an a d s o r b e n t t h i c k n e s s o f 0.9  mm.  Solvents A n h y d r o u s e t h e r r e f e r s t o M a l l i n k r o d t AR e t h y l e t h e r anhydrous. The t e r m " d r y " i n t h i s t h e s i s r e f e r s t o s o l v e n t s d r i e d i n t h e f o l l o w i n g w a y s T T e t r a h y d r o f u r a n ( T H F ) , e t h y l e t h e r , 1,2-dimethoxye t h a n e (DME), d i g l y m e ( d i e t h y l e n e g l y c o l d i m e t h y l e t h e r ) , and d i o x a n e were d r i e d by r e f l u x i n g o v e r l i t h i u m aluminum h y d r i d e f o r a minimum o f 2 hours p r i o r t o u s e . In most c a s e s t h e s e s o l v e n t s were d i s t i l l e d d i r e c t l y from l i t h i u m aluminum h y d r i d e i n t o t h e r e a c t i o n f l a s k s . t o l u e n e , and x y l e n e were d r i e d o v e r sodium.  Benzene,  Hexamethylphosphoramide  was d r i e d by d i s t i l l a t i o n f r o m sodium. A c e t o n i t r i l e was d i s t i l l e d f r o m c a l c i u m h y d r i d e . P y r i d i n e was d r i e d o v e r p o t a s s i u m h y d r o x i d e .  Reagents. Sodium h y d r i d e , o b t a i n e d from V e n t r o n , was used as a 57% d i s p e r s i o n m i n e r a l o i l . In most c a s e s t h e m i n e r a l o i l was removed p r i o r t o use by washing w i t h p e t r o l e u m  ether.  A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane, a l s o o b t a i n e d from V e n t r o n , w a s 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 t - b u t y l a l c o h o l using 1,10-phenanthroline  as i n d i c a t o r , a c c o r d i n g t o p r o c e d u r e s 121  o u t l i n e d by Watson and Eastham. Amines, i n c l u d i n g d i e t h y l a m i d e , d i i s o p r o p y l a m i n e , d i c y c l o hexylamine, isopropylcyclohexylamine, 2,2,6,6-tetramethylpiperidine, and t r i e t h y l a m i n e were p u r i f i e d by d i s t i l l a t i o n f r o m p o t a s s i u m They were s t o r e d o v e r p o t a s s i u m  hydroxide.  hydroxide.  M e t h y l a c e t a t e and e t h y l a c e t a t e were p u r i f i e d by  washing  w i t h aqueous sodium hydrogen c a r b o n a t e , d r y i n g o v e r magnesium s u l p h a t e , and d i s t i l l i n g f r o m p h o s p h o r o u s p e n t o x i d e .  124 3,5-Dimethoxybenzyl  a l c o h o l (31)  OMe 31  A 1000 ml t h r e e - n e c k e d f l a s k was f i t t e d w i t h a d r o p p i n g f u n n e l , a c o n d e n s e r w i t h a c a l c i u m s u l p h a t e d r y i n g t u b e , and a m a g n e t i c s t i r r e r . I t was c h a r g e d w i t h a s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e (4.80 g , 126 mmole) i n THF (200 m l ) . A s o l u t i o n o f 3 , 5 - d i m e t h o x y b e n z o i c a c i d ( 3 0 ) ( 1 0 . 0 g , 55.0 mmole) i n d r y THF (200 m l ) was added d r o p w i s e a t a r a t e t h a t m a i n t a i n e d g e n t l e r e f l u x . A f t e r t h e a d d i t i o n was c o m p l e t e (1 h o u r ) t h e m i x t u r e was a l l o w e d t o s t i r f o r an a d d i t i o n a l h hour. T h i s was f o l l o w e d by t h e d r o p w i s e a d d i t i o n o f e t h e r (250 m l ) s a t u r a t e d w i t h w a t e r a n d t h e d r o p w i s e a d d i t i o n o f 6N s u l p h u r i c a c i d (180 m l ) . T h e aqueous a n d o r g a n i c p h a s e s were s e p a r a t e d a n d t h e aqueous phase was e x t r a c t e d w i t h e t h e r (2 X 100 m l ) . The combined o r g a n i c phases were washed w i t h water (3 X 50 m l ) , d r i e d o v e r  sodium  s u l p h a t e , and e v a p o r a t e d under r e d u c e d p r e s s u r e t o y i e l d 31_ (9.17 g , 99%); IR 3400 ( 0 - H ) , 1600 c m  - 1  (C=C a r o m a t i c ) ;  NMR 62.16 ( s , 1, h y d r o x y l p r o t o n , e x c h a n g e a b l e  i n D^O),  3.70 ( s , 6, methoxy group p r o t o n s ) , 4.47 ( s , 2, m e t h y l e n e p r o t o n s ) , 6.25 (m, 3, a r o m a t i c p r o t o n s ) .  125 3 , 5 - D i m e t h o x y b e n z y l c h l o r i d e (33)  A 1000 ml t h r e e - n e c k e d f l a s k was f i t t e d w i t h a d r o p p i n g f u n n e l , a c o n d e n s e r , a n d a m a g n e t i c s t i r r e r . I t was c h a r g e d w i t h a . s o l u t i o n o f 3 , 5 - d i m e t h o x y b e n z y l a l c o h o l (31) (28.4 g. 169 mmole) and p y r i d i n e (3 m l ) i n a n h y d r o u s e t h e r (300 m l ) . A s o l u t i o n o f t h i o n y l c h l o r i d e (50.0 g , 324 mmole) i n a n h y d r o u s e t h e r (250 m l ) was added d r o p w i s e o v e r a p e r i o d o f 1 h o u r . T h e s o l u t i o n was t h e n a l l o w e d t o s t i r an a d d i t i o n a l 1 hour b e f o r e w a t e r (60 m l ) was a d d e d , c a r e f u l l y , t h r o u g h t h e d r o p p i n g f u n n e l . T h e aqueous and o r g a n i c p h a s e s were s e p a r a t e d and t h e o r g a n i c phase was washed w i t h w a t e r (2 X 100 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e s o l v e n t s were removed under r e d u c e d p r e s s u r e t o y i e l d 33_ (28.6 g , 90%) a s a y e l l o w i s h o i l w h i c h 22  c r y s t a l l i z e d on s t a n d i n g ; mp 42-44 d e g r e e s ; l i t .  mp 46 d e g r e e s ;  IR no 0-H band; NMR  (S3.70 ( s , 6, methoxy g r o u p p r o t o n s ) , 4.40 ( s , 2,  m e t h y l e n e p r o t o n s ) , 6.25 (m, 3, a r o m a t i c p r o t o n s ) .  126 3,5- Dimethoxybenzyl cyanide (34)  OMe  34  A mixture of 3,5-dimethoxybenzyl chloride (33_) (33.0 g, 187 mmole), sodium cyanide (60.0 g, 1.23 mole), ethanol (600 ml) and water (150 ml) was refluxed for four hours. The solution was poured onto 1000 g of ice. The precipitate formed was collected on a f i l t e r .and dissolved i n ..ether. This . s o l u t i o n ,was dried -over .magnesium sulphate and the solvents were removed under reduced pressure to yield 34 (23.7 g, 75%); mp 50-51 degrees; l i t .  2 2  mp 53 degrees;  IR 2260 cm" (C=N); 1  NMR 63.55 (s, 2, methylene protons), 3.71 (s, 6, methoxy group protons), 6.25 (m, 3, aromatic protons).  127 2 - ( 3 , 5 - D i m e t h o x y p h e n y l ) - 2 - m e t h y l p r o p i o n i t r i 1 e (21)  A 500 ml t h r e e - n e c k e d f l a s k was f i t t e d w i t h a d r o p p i n g f u n n e l , a c o n d e n s e r , and g a s i n l e t and o u t l e t t u b e s . I t was c h a r g e d w i t h sodium h y d r i d e a s a 5 7 % d i s p e r s i o n i n m i n e r a l o i l ( 1 2 . 0 g, 289 mmole) and t h e m i n e r a l o i l was removed by washing w i t h p e t r o l e u m e t h e r (2 X 20 m l ) . D r y DME (150 m l ) was added and t h e f l a s k was f l u s h e d with n i t r o g e n . A s o l u t i o n o f 3,5-dimethoxybenzyl  cyanide (34)  (12.0 g , 67.8 mmole) i n d r y DME (100 m l ) was added d r o p w i s e o v e r a p e r i o d o f \ hour. The m i x t u r e was a l l o w e d t o s t i r f o r 15 m i n u t e s and t h e n m e t h y l i o d i d e ( 4 1 . 0 g , 288 mmole) was added d r o p w i s e o v e r a p e r i o d o f 20 m i n u t e s . T h e m i x t u r e was r e f l u x e d f o r 24 hours and t h e n c o o l e d t o room t e m p e r a t u r e . Water (100 m l ) and e t h e r (150 m l ) were added .and t h e phases s e p a r a t e d . T h e aqueous phase was e x t r a c t e d w i t h e t h e r (2 X 150 m l ) and t h e combined  o r g a n i c s were washed w i t h water  (2 X 150 m l ) , d r i e d o v e r magnesium s u l p h a t e , and t h e s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e . T h e c r u d e o i l o b t a i n e d was d i s t i l l e d i n vacou to' a f f o r d 21^ (11.1 g 8 0 % ) ; bp 97 d e g r e e s (2 mm); lit.  2 2  bp 147-150 d e g r e e s (760 mm);  128 NMR 61.67 ( s , 6, gem-dimethyl  g r o u p p r o t o n s ) , 3.75 ( s , 6,  methoxy group p r o t o n s ) , 6.45 (m, 3, a r o m a t i c p r o t o n s ) .  2 - ( 4 - A c e t y l - 3 , 5 - d i m e t h o x y p h e n y l ) - 2 - m e t h y l p r o p i o n i t r i l e (22)  (a) U s i n g c a r b o n d i s u l p h i d e a s s o l v e n t . * A s o l u t i o n o f 21_ ( 0 . 5 0 g , 2.4 mmole) i n c a r b o n d i s u l p h i d e (10 m l ) was added t o a c e t i c a n h y d r i d e (0.51 g , 5.0 mmole) d i s s o l v e d i n c a r b o n d i s u l p h i d e (15 m l ) i n a 50 ml t h r e e - n e c k e d f l a s k e q u i p p e d w i t h a m e c h a n i c a l s t i r r e r and n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s . Aluminum c h l o r i d e ( 2 . 0 g , 15.0 mmole) was a d d e d , a p o r t i o n a t a t i m e , w i t h s t i r r i n g , o v e r a p e r i o d o f one h o u r . A f t e r t h e f i n a l a d d i t i o n o f aluminum c h l o r i d e t h e m i x t u r e was s t i r r e d f o r two h o u r s a t room t e m p e r a t u r e . Water (10 m l ) was added d r o p w i s e t o t h e s e m i s o l i d p r o d u c t . T h e m i x t u r e was t h e n e x t r a c t e d w i t h benzene (3 X 10 m l ) . The e x t r a c t s were combined, washed w i t h w a t e r (2 X 5 m l ) , and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were removed under r e d u c e d  * E x p e r i m e n t p e r f o r m e d by Mr. B. M. J o y c e  129  p r e s s u r e and t h e d a r k y e l l o w s e m i - s o l i d m a t e r i a l o b t a i n e d was r e c r y s t a l l i z e d t h r e e t i m e s from 1 i g r o i n - c a r b o n t e t r a c h l o r i d e t o yield  22 (190  mg,  32%);  (b) U s i n g m e t h y l e n e  mp  118-120  d e g r e e s ; s p e c t r a l d a t a as below.  c h l o r i d e as s o l v e n t .  A s o l u t i o n o f 21. (511 mg, 2.50 mmole) and a c e t i c a n h y d r i d e (600 mg, 5.88 mmole) i n m e t h y l e n e c h l o r i d e (50 m l ) was a d d e d t o a 50 ml t h r e e - n e c k e d f l a s k f i t t e d w i t h n i t r o g e n i n l e t a n d o u t l e t s y r i n g e n e e d l e s and a m a g n e t i c  s t i r r e r . T h e f l a s k was f l u s h e d w i t h n i t r o g e n  and c o o l e d t o -10 d e g r e e s i n an i c e - s a l t b a t h . Aluminum c h l o r i d e (2.0 g , 15.0 mmole) was a d d e d , a p o r t i o n a t a t i m e , w i t h s t i r r i n g , o v e r a p e r i o d o f h hour. T h e m i x t u r e was a l l o w e d t o s t i r a t 0 d e g r e e s f o r an a d d i t i o n a l lk h o u r s a f t e r t h e a d d i t i o n o f t h e aluminum c h l o r i d e was c o m p l e t e . VJater (15 m l ) was added w i t h v i g o r o u s s h a k i n g . T h e phases were s e p a r a t e d a n d t h e a q u e o u s p h a s e was e x t r a c t e d w i t h methylene  c h l o r i d e (2 X 15 m l ) . T h e combined o r g a n i c s were washed  w i t h w a t e r (2 X 15 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e s o l v e n t s were removed under r e d u c e d p r e s s u r e t o y i e l d c r u d e brown c r y s t a l s which were r e c r y s t a l l i z e d t w i c e from 1 i g r o i n - c a r b o n t e t r a c h l o r i d e to a f f o r d  22 (491  mg,  79%)  a s f i n e t a n c o l o u r e d c r y s t a l s ; mp  120-121  d e g r e e s ; s p e c t r a page 220; IR  1250  cm"  1  2250 ( C H N ) , 1700 (C=0), 1610,1580  (C=C  aromatic),  (Ar-0CH ); 3  NMR 51.78 ( s , 6, g e m - d i m e t h y l group p r o t o n s ) , 2.50 ( s , 3, a c e t y l m e t h y l group p r o t o n s ) , 3.89 ( s , 6, methoxy group p r o t o n s ) , 6.71 ( s , 2, a r o m a t i c p r o t o n s ) ; UV 262 mu  (3240)  130  Mass s p e c t r u m m/e 2 4 7 ( 2 3 ) , 2 3 3 ( 1 5 ) , 2 3 2 ( 1 0 0 ) ,  216(11),  175(5), 165(5), 121(3), 119(5), 116(5), 115(5), 91(8), 83(6), 57(3), 56(3), 55(5); A n a l y s i s c a l c ' d f o r C H 0 N : C 68.00  H 6.93  N 5.66  f o u n d : C 67.73  H 7.05  N 5.38.  1 4  Methyl  1 7  3  5-(4-1 -cyano-1 -methylethyl-2,6-dimethoxyphenyl)-5-hydroxy1  1  3-oxohexanoate ( 2 4 ) *  (a) W i t h l o w t e m p e r a t u r e , s h o r t t i m e , p r e p a r a t i v e t i c workup. Sodium h y d r i d e a s a 5 7 % d i s p e r s i o n on m i n e r a l o i l (175 mg, 4.17 mmole) was w e i g h e d i n t o a 50 ml f l a s k e q u i p p e d w i t h a m a g n e t i c s t i r r e r . The m i n e r a l o i l was removed by w a s h i n g w i t h d r y THF (5 m l ) a n d a f u r t h e r 10 ml o f d r y THF v/as added a s s o l v e n t . The f l a s k was s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , f l u s h e d w i t h n i t r o g e n , and c o o l e d t o 0 d e g r e e s i n an i c e b a t h . M e t h y l a c e t o a c e t a t e (464 mg, 4.00 mmole) * F i r s t p r e p a r e d by Mr. B. M. J o y c e .  131 was added d r o p w i s e t o t h e s t i r r e d m i x t u r e a t a r a t e w h i c h m a i n t a i n e d a v i g o r o u s b u t n o t e x c e s s i v e e v o l u t i o n o f h y d r o g e n . The r e a c t i o n was a l l o w e d t o s t i r f o r 10 m i n u t e s a f t e r t h e a d d i t i o n was c o m p l e t e . N e x t , a s o l u t i o n o f n - b u t y l l i t h i u m (165 m l , 2.50M, 4.12 mmole) was added dropwise to the r e a c t i o n mixture over a period of 1 minute. A f t e r a f u r t h e r 10 m i n u t e s o f s t i r r i n g , a s o l u t i o n o f k e t o n e 22_ (100 mg, 0.405 mmole) i n d r y THF (10 ml) was added t o t h e r e a c t i o n m i x t u r e , s t i l l a t 0 d e g r e e s . The r e a c t i o n was a l l o w e d t o s t i r a t t h i s t e m p e r a t u r e f o r a f u r t h e r 10 m i n u t e s and t h e n N h y d r o c h l o r i c a c i d (10 m l ) was added i n one p o r t i o n . The m i x t u r e was p o u r e d i n t o e t h e r (100 ml) and t h e phases were s e p a r a t e d . The o r g a n i c p h a s e was washed w i t h w a t e r (5 X 15 m l ) and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were removed under r e d u c e d p r e s s u r e and t h e o i l o b t a i n e d was s e p a r a t e d i n t o i t s components by p r e p a r a t i v e t i c on s i l i c a g e l (5 p l a t e s ) u s i n g a m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (2:1 v / v ) as d e v e l o p i n g s o l v e n t . The band l y i n g i n t h e r e g i o n  0.1-0.2 was  removed and e x t r a c t e d w i t h c h l o r o f o r m . The s o l v e n t v/as removed u n d e r r e d u c e d p r e s s u r e t o y i e l d 24_ (129 mg, 8 8 % ) ; s p e c t r a page 221; IR 3500 ( 0 - H ) , 2250 (C=N), 1745 ( e s t e r C=0), ( k e t o n e C=0), 1610, 1575 cm"  1  1710  (C=C a r o m a t i c ) ;  NMR 61.60 ( s , 3, c a r b i n o l c a r b o n m e t h y l g r o u p p r o t o n s ) , 1.70 (gem-dimethyl g r o u p p r o t o n s ) , 2.95 ( d , J=16 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.52 ( d , J=16 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.47 ( s , 2, m e t h y l e n e p r o t o n s on c a r b o n a t o e s t e r ) , 3.68 ( s , 3, e s t e r methoxy g r o u p p r o t o n s ) , 3.90 ( s , 6, e t h e r methoxy g r o u p p r o t o n s ) , 6.72 ( s , 2, a r o m a t i c protons);  132 UV 276 mu ( 1 6 7 0 ) , 283 ( s h o u l d e r ) ; Mass s p e c t r u m ( a ) l o w r e s o l u t i o n m/e 3 4 5 ( 2 ) , 3 3 2 ( 8 ) , 314(13), 249(21), 248(100), 233(11), 232(65), 230(27), 217(12), 162(25), 129(21), 101(10), 85(12), 59(14), 57(15), 55(10); (b) h i g h r e s o l u t i o n c a l c ' d f o r C H 0 N i g  2 3  5  (P-18)  345.153 amu, f o u n d 345.162 m/e.  (b) A t room t e m p e r a t u r e , l o n g t i m e , i s o l a t i o n by column  chromatography.  I s o l a t i o n o f t h e p r o d u c t by p r e p a r a t i v e t i c was i m p r a c t i c a l f o r l a r g e s c a l e p r e p a r a t i o n s . I n one l a r g e s c a l e e x p e r i m e n t t h e f o l l o w i n g p r o c e d u r e was employed. T h e u s e o f room t e m p e r a t u r e a n d l o n g r e a c t i o n t i m e s d e s c r i b e d h e r e a r e n o t recommended. T h e d i a n i o n was g e n e r a t e d , a t 0 d e g r e e s , a s d e s c r i b e d a b o v e , f r o m sodium h y d r i d e (1.27 g , 30.3 mmole), m e t h y l a c e t o a c e t a t e ( 3 . 5 0 g , 30.1 mmole), a n d n - b u t y l l i t h i u m s o l u t i o n ( 1 3 . 4 m l , 2.25M, 30.1 mmole) i n a 100 ml f l a s k c o n t a i n i n g 55 ml of. d r y THF. T h e s o l u t i o n was a l l o w e d t o warm t o room t e m p e r a t u r e a n d 22_ (0.500 g , 2.02 mmole) i n d r y THF ( 1 0 m l ) was added o v e r a p e r i o d o f 10 m i n u t e s . T h e r e a c t i o n was a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r 45 m i n u t e s . D r y e t h e r ( 3 0 m l ) was added and t h e n c o n c e n t r a t e d h y d r o c h l o r i c a c i d was added d r o p w i s e u n t i l t h e aqueous l a y e r v/as a c i d i c . T h e aqueous p h a s e was t h e n e x t r a c t e d w i t h e t h e r (2 X 25 m l ) and t h e combined o r g a n i c s were washed w i t h s a t u r a t e d aqueous sodium c a r b o n a t e s o l u t i o n ( 5 X 20 m l ) and w a t e r (2 X 20 m l ) , and d r i e d o v e r magnesium s u l p h a t e . T h e s o l v e n t s were removed u n d e r r e d u c e d p r e s s u r e t o y i e l d a y e l l o w o i l w h i c h was p u r i f i e d by column c h r o m a t o g r a p h y on s i l i c a g e l ( 6 0 g ) . A l l t h e compounds r u n n i n g b e f o r e  133 the product  ( b y t i c ) were e l u t e d w i t h e t h y l a c e t a t e - b e n z e n e ( 1 : 9 v / v ) .  The p r o p o r t i o n o f e t h y l a c e t a t e was t h e n r a i s e d (1:4 v / v ) and 24 (0.568 g , 77%) was e l u t e d ; s p e c t r a l p r o p e r t i e s a s a b o v e .  ( c ) A t t e m p t u s i n g one e q u i v a l e n t o f d i a n i o n . The r e a c t i o n p r o c e d u r e f o l l o w e d method ( b ) a b o v e and involved the use of the following q u a n t i t i e s of reagents: h y d r i d e d i s p e r s i o n (10 mg, 0.24 mmole), THF (2 m l ) , m e t h y l  sodium acetoacetate  (25 mg, 0.21 mmole), n - b u t y l l i t h i u m s o l u t i o n (0.092 m l , 2.25M, 0.21 mmole), 22 (40 mg, 0.17 mmole) i n THF (1 m l ) . I s o l a t i o n o f t h e s e m i - s o l i d p r o d u c t m i x t u r e showed i t t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l 22 by t i c . R e c r y s t a l l i z a t i o n a f f o r d e d 22^ (30 mg, 7 5 % ) .  134 Methyl  5-(4-1'-cyano-l'-methylethyl-2,6-dimethoxyphenyl)-3-oxo-5-tri-  m e t h y l s i l o x y h e x a n o a t e (64)  Methyl 5-(4-1 -cyano-l'-methyl 1  -5-hydroxy-3-oxohexanoate  ethyl-2,6-dimethoxyphenyl)-  ( 2 4 ) (95 mg, 0.26 mmole), t r i m e t h y l s i l y l  c h l o r i d e (30 mg, 0-.28 mmole), and h e x a m e t h y l d i s i l a z a n e (24 mg, 0.15 mmole) were d i s s o l v e d i n d r y p y r i d i n e ( 5 m l ) and t h e s o l u t i o n was s t i r r e d a t room t e m p e r a t u r e f o r h hour. T h e f i n e , w h i t e p r e c i p i t a t e formed was f i l t e r e d o f f and washed w i t h a n h y d r o u s e t h e r ( 5 m l ) . The washing was combined  w i t h t h e f i l t r a t e and t h e s o l v e n t s were  removed under r e d u c e d p r e s s u r e . T h e o i l o b t a i n e d was p u r i f i e d by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) u s i n g an e t h e r - c a r b o n t e t r a c h l o r i d e m i x t u r e ( 1 : 2 v / v ) a s d e v e l o p i n g s o l v e n t . T h e band a t R^ 0.3-0.4 was removed and e x t r a c t e d w i t h c h l o r o f o r m . T h e s o l v e n t was removed under r e d u c e d p r e s s u r e t o y i e l d 64 (52 mg, 4 6 % ) ; s p e c t r a page 222; 2250  IR  1610, 1575 cm"  1  (CHN),  1745 ( e s t e r C = 0 ) , 1710 ( k e t o n e C = 0 ) ,  (C=C aromatic);  NMR 6-0.04 ( s , 9, s i l y l m e t h y l g r o u p p r o t o n s ) ,  135 1.66 ( s , 6, gem-dimethyl g r o u p p r o t o n s ) , 1.80 ( s , 3, p r o t o n s on methyl group a t o s i l y l e t h e r c a r b o n ) , 2.95 ( d , 1, p r o t o n on m e t h y l e n e group a t o s i l y l e t h e r c a r b o n ) , 3.30 ( d , 1, p r o t o n on m e t h y l e n e group a t o s i l y l e t h e r c a r b o n ) , 3.55 ( s , 2, m e t h y l e n e p r o t o n s on c a r b o n a to. e s t e r ) , 3.66 ( s , 3, e s t e r methoxy group p r o t o n s ) , 3.76 ( s , 6, e t h e r methoxy group p r o t o n s ) , 6.60 ( s , 2, a r o m a t i c p r o t o n s ) ; UV 283 my ( 1 6 4 0 ) ; Mass s p e c t r u m ( a ) low r e s o l u t i o n m/e 4 3 6 ( 3 ) , 4 2 1 ( 3 ) , 406(3), 345(17), 321(10), 315(21), 314(100), 272(17), 248(28), 232(14), 230(10), 162(11), 101(10), 75(14), 59(11); (b) h i g h r e s o l u t i o n c a l c ' d f o r C ^ H - ^ O g N S i , 435.207 amu, f o u n d 435.200 m/e.  Methyl  5-(4-1 -cyano-1 -methylethyl-2,6-dimethoxyphenyl)-3-oxo1  1  h e x - 4 - e n o a t e (25)  25E  25Z  (a) U s i n g hydrogen c h l o r i d e i n c h l o r o f o r m . C h l o r o f o r m (25 m l ) was s a t u r a t e d w i t h hydrogen c h l o r i d e  136 ' by b u b b l i n g t h e a n h y d r o u s gas d i r e c t l y t h r o u g h t h e s o l v e n t f o r 20 m i n u t e s . M e t h y l  5-(4-1*-cyano-l'-methylethyl-2,6-dimethoxyphenyl)-  - 5 - h y d r o x y - 3 - o x o h e x a n o a t e (24_) (135 mg, 0.372 mmole) was added and t h e s o l u t i o n was a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r 2 h o u r s . I t was t h e n washed w i t h s a t u r a t e d aqueous sodium hydrogen  carbonate  s o l u t i o n (3 X 10 ml) and w a t e r (3 X 10 m l ) , and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e t o a f f o r d 25 (125 mg, 98%) as an E,Z m i x t u r e ; s p e c t r a page 223; IR 2250 (C=N), 1740 ( e s t e r C=0), 1680 ( k e t o n e C=0), 1610, 1575 cm'  1  NMR  (C=C); 61.75 ( s , 6, g e m - d i m e t h y l g r o u p p r o t o n s ) , 2.09,  2.32  ( 2 d , J=2 c p s , 3 t o t a l , v i n y l m e t h y l g r o u p s i n E and Z i s o m e r s r e s p e c t i v e l y ) , 3.24, 3.53 ( 2 s , 2 t o t a l , m e t h y l e n e p r o t o n s on c a r b o n a t o e s t e r i n E and Z i s o m e r s r e s p e c t i v e l y ) , 3.65, 3.75 ( 2 s , 3 t o t a l , e s t e r methoxy g r o u p p r o t o n s f o r E and Z i s o m e r s r e s p e c t i v e l y ) , 3.87 ( s , 6, e t h e r m e t h o x y g r o u p p r o t o n s ) , 6.16, 6.32  ( 2 q , J=2 c p s , 1 t o t a l ,  v i n y l p r o t o n s i n Z and E i s o m e r s r e s p e c t i v e l y ) , 6.70 ( s , 2, a r o m a t i c protons); UV 285 mu  (6400);  Mass s p e c t r u m (a) low r e s o l u t i o n m/e 3 4 5 ( 2 ) , 3 1 5 ( 1 1 ) , 314(70), 272(13), 257(21), 256(100), 214(13), 176(11),  162(12),  161(10), 101(12), 59(12), 51(36); (b) h i g h r e s o l u t i o n c a l c ' d f o r C-^nHpjOgN, 345.158 amu, f o u n d 345.158 m/e.  137 . (b) P a r t i a l s e p a r a t i o n o f i s o m e r s by p r e p a r a t i v e t i c . The m i x t u r e d e s c r i b e d i n p a r t (a) was s e p a r a t e d  by  p r e p a r a t i v e t i c on s i l i c a g e l (2 p l a t e s ) . The p l a t e s were d e v e l o p e d t w i c e u s i n g a m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (2:1 as s o l v e n t . The band l y i n g a t  v/v)  0.3-0.4 was removed and e x t r a c t e d  w i t h c h l o r o f o r m . The s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e t o y i e l d 25E_ (40 mg, 31% from 2 4 ) ; s p e c t r u m page 224; NMR 3.24  <S2.09 ( d , J=2 c p s , 3, v i n y l methyl g r o u p p r o t o n s ) ,  ( s , 2, m e t h y l e n e p r o t o n s on c a r b o n a t o e s t e r ) , 3.65  e s t e r methoxy g r o u p p r o t o n s ) , 6.32 The band l y i n g a t R  f  ( q , J=2 c p s , v i n y l  ( s , 3,  proton).  0.4-0.5 was removed and 25Z (46 mg, 36% from  c o n t a i n i n g some 25E was i s o l a t e d as d e s c r i b e d a b o v e ; s p e c t r u m NMR 3.53  24),  page 224;  62.32 ( d , J=2 c p s , 3, v i n y l methyl g r o u p p r o t o n s ) ,  ( s , 2, m e t h y l e n e p r o t o n s on c a r b o n a t o e s t e r ) , 3.75  e s t e r methoxy g r o u p p r o t o n s ) , 6.16  ( q , J=2 c p s , 1, v i n y l  ( s , 3, proton).  (c) Using hydrogen c h l o r i d e i n e t h e r . A sample o f 24_ was t r e a t e d as i n (a) u s i n g e t h e r as s o l v e n t r a t h e r t h a n c h l o r o f o r m . The t i c ( c a r b o n t e t r a c h l o r i d e : e t h e r = 2 : l ) showed t h r e e s p o t s , t h e m a j o r one o f w h i c h c o r r e s p o n d e d as i n ( a ) . The NMR  t o 25E,Z  o f t h e m i x t u r e was s i m i l a r t o t h a t d e s c r i b e d i n (a)  but had e x t r a s i g n a l s i n t h e r e g i o n 61.0-2.0 and s e v e r a l o f t h e s i g n a l s i n t h e r a n g e 63.0-4.0 were weakened.  (d) U s i n g p a r a - t o ! u e n e s u l p h o n i c  a c i d i n benzene.  A sample o f 2_4 was s t i r r e d i n d r y b e n z e n e c o n t a i n i n g a c a t a l y t i c amount o f p a r a - t o i u e n e s u l p h o n i c a c i d f o r 1 hour. The  NMR  138 • spectrum o f t h e p r o d u c t m i x t u r e was s i m i l a r t o t h a t d e s c r i b e d i n (a) b u t had e x t r a s i g n a l s i n t h e r e g i o n 65.0-7.0.  Attempts t o C y c l i s e Methyl phenyl )-3-oxohex-4-enoate  5-(4-1'-cyano-l'-methylethyl-2,6-dimethoxy(25_) by T r e a t m e n t w i t h Base  (a) Sodium h y d r i d e i n d i m e t h y l s u l p h o x i d e a t room  temperature.  Sodium h y d r i d e a s a 5 7 % d i s p e r s i o n i n m i n e r a l o i l ( a p p r o x i m a t e l y 5 mg, 0.12 mmole) was added t o d i m e t h y l s u l p h o x i d e (2 m l ) i n a 5 ml f l a s k . T h e f l a s k was s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f 25_ (5 mg, 0.014 mmole) i n d i m e t h y l s u l p h o x i d e (1 m l ) was added and t h e m i x t u r e v/as a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r 24 h o u r s . I t was poured i n t o N/10 h y d r o c h l o r i c a c i d ( 2 0 m l ) a n d e x t r a c t e d w i t h e t h e r (2 X 10 m l ) . The e x t r a c t s were v/ashed w i t h water (2 X 5 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e s o l v e n t s were removed under r e d u c e d p r e s s u r e . T h e t i c ( c a r b o n t e t r a c h l o r i d e , e t h e r 2:1) o f t h e p r o d u c t o b t a i n e d showed i t t o be u n c h a n g e d s t a r t i n g material.  (b) U s i n g sodium h y d r i d e i n h e x a m e t h y l p h o s p h o r a m i d e The p r o c e d u r e employed  a t room  temperature.  was i d e n t i c a l t o t h a t d e s c r i b e d  in (a) except that hexamethylphosphoramide  was used a s s o l v e n t . Once  again, the t i c o f the product i n d i c a t e d returned s t a r t i n g m a t e r i a l .  139 • ( c ) U s i n g sodium h y d r i d e and d i m e t h y l s u l p h o x i d e o r h e x a m e t h y l phosphoramide  a t 110 d e g r e e s . The p r o c e d u r e used was a s d e s c r i b e d i n ( a ) b u t t h e  m i x t u r e s were h e a t e d t o 110 d e g r e e s f o r lh hour i n s t e a d o f b e i n g a l l o w e d t o s t a n d a t room t e m p e r a t u r e f o r 24 h o u r s . T h e t i c o f t h e c r u d e p r o d u c t m i x t u r e s i n d i c a t e d them t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l b u t i n each c a s e t h r e e e x t r a s p o t s were e v i d e n t (one common t o b o t h , two uncommon).  (d) U s i n g p o t a s s i u m t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a t 140 d e g r e e s , The r e a c t i o n p r o c e d u r e v/as a n a l o g o u s t o t h a t d e s c r i b e d i n ( a ) b u t employed p o t a s s i u m t - b u t o x i d e (10 mg, 0.090 mmole) and 25 (5 mg, 0.014 mmole). T h e m i x t u r e was h e a t e d t o 140 d e g r e e s f o r 15 m i n u t e s . A f t e r workup, t h e t i c o f t h e p r o d u c t showed a t l e a s t s i x s p o t s , t h e p r i m a r y one b e i n g s t a r t i n g m a t e r i a l ,  (e) U s i n g sodium m e t h o x i d e i n h e x a m e t h y l p h o s p h o r a m i d e  a t 140 d e g r e e s .  The p r o c e d u r e was a n a l o g o u s t o t h a t d e s c r i b e d i n ( a ) but employed sodium m e t h o x i d e  (20 mg, 0.36 mmole), 25_ (6 mg, 0.017  mmole), and h e x a m e t h y l p h o s p h o r a m i d e  a s s o l v e n t . T h e m i x t u r e was  h e a t e d t o 140 d e g r e e s f o r 15 m i n u t e s .  The t i c o f t h e product  showed f o u r s p o t s .  ( f ) U s i n g l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e i n r e f l u x i n g THF. A s o l u t i o n o f l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e (0.50 m l , 0.52M, 0.26 mmole) was added t o a s o l u t i o n o f 25_ (5 mg, 0.014 mmole) i n d r y THF under n i t r o g e n . T h e s o l u t i o n was r e f l u x e d i n a n i t r o g e n  140  atmosphere  •  f o r t h r e e hours b e f o r e b e i n g poured i n t o N/10 h y d r o c h l o r i c  a c i d (20 m l ) . The m i x t u r e o b t a i n e d was e x t r a c t e d w i t h e t h e r (2 X 15 m l ) and t h e e x t r a c t s were washed w i t h w a t e r (2 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were removed under r e d u c e d p r e s s u r e and t i c o f t h e o i l o b t a i n e d i n d i c a t e d i t t o be unchanged s t a r t i n g material.  (g) U s i n g l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e i n r e f l u x i n g x y l e n e . In t h i s c a s e t h e c o n d i t i o n s and amounts were i d e n t i c a l t o t h o s e d e s c r i b e d i n ( f ) b u t x y l e n e was used a s s o l v e n t and t h e . r e a c t i o n v/as r e f l u x e d f o r 16 h o u r s . The t i c o f t h e p r o d u c t m i x t u r e showed i t t o c o n t a i n p r i m a r i l y two compounds, one o f w h i c h was starting material.  141 2,6-Dimethoxyacetophenone  (39)  O  OMe  39  Sodium h y d r o x i d e acetophenone (best  (69)  (2.00 q ,  (4.00 g ,  1 3 . 2 mmole)  r e s u l t s were o b t a i n e d stir  time  d a r k g r e e n and t h e n  9 5 . 4 mmole)  a t room t e m p e r a t u r e  f o r 1 hour.  light yellow.  extracted aqueous  with  The m i x t u r e  ether  Dimethyl  solution  p r e s s u r e and t h e c r u d e  During  f o r lh  hours  l i t .  4 6  IR  mp 6 5 - 6 6 1700  (s,  6, m e t h o x y g r o u p  (s,  (12.00  g,  which  onto  being  i c e (500 g) and  w e r e w a s h e d w i t h 20% (6 X 5 0 m l ) ,  The s o l v e n t s were removed obtained  under  was r e c r y s t a l l i z e d 9 5 % ) ; mp 66-67  degrees;  (C=0),  NMR 6 2 . 4 5  this  during  before  f r o m c a r b o n t e t r a c h l o r i d e - ! i g r o i n t o y i e l d 3_9 ( 2 . 2 4 g , degrees;  mixture  sulphate  (2 X 20 m l ) and w a t e r  product  (150 m l )  T h e r e a c t i o n m i x t u r e was  v/as p o u r e d  and d r i e d o v e r m a g n e s i u m s u l p h a t e . reduced  f o r % hour.  ( 3 X 75 m l ) . T h e e x t r a c t s  sodium hydroxide  and t h e  a period of h hour,  a l l o w e d t o s t a n d a t room t e m p e r a t u r e refluxed  2,6-dihydroxy-  were added t o d i o x a n e  black.  was a d d e d d r o p w i s e o v e r  time the s o l u t i o n turned  and  using undried dioxane)  was a l l o w e d t o it.turned  100 mmole)  1595 c m " 1 ( O C 3 , a c e t y l methyl  protons),  6.4-7.4  aromatic), group  no h y d r o x y l  protons),  (m, 3 , a r o m a t i c  3.80  protons).  band;  142 • M e t h y l 5 - ( 2 , 6 - d i m e t h o x y p h e n y l ) - 5 - h y d r o x y - 3 - o x o h e x a n o a t e (70)  T h i s compound was p r e p a r e d and i s o l a t e d by t h e same p r o c e d u r e as was employed f o r m e t h y l 5 - ( 4 - 1 ' - c y a n o - 1 ' - m e t h y l e t h y l - 2 , 6 - d i m e t h o x y p h e n y l ) - 5 - h y d r o x y - 3 - o x o h e x a n o a t e (24_) (method ( b ) ) . The r e a g e n t s used were: sodium h y d r i d e as a 57% d i s p e r s i o n i n m i n e r a l o i l (1.050 g , 26.2 mmole), m e t h y l a c e t o a c e t a t e (2.924 g , 25.2  mmole),  n - b u t y l l i t h i u m s o l u t i o n (11.30 m l , 2.25M, 25.4 mmole), and 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (3_9) (492 mg, 2.52 mmole). A f t e r column c h r o m a t o g r a p h y on s i l i c a g e l (60 g) 7_0 (616 mg, 79%) was i s o l a t e d as an o i l ; s p e c t r a page 225; IR 3500 ( 0 - H ) , 1745 ( e s t e r C=0), 1710 ( k e t o n e C=0), 1595 cm"  1  (C=C a r o m a t i c ) ; NMR 61.53 ( s , 3, c a r b i n o l c a r b o n m e t h y l g r o u p p r o t o n s ) ,  2.75 ( d , J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.30 ( d , J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.25 ( d , J=16 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o e s t e r ) , 3.35 ( d , J=16 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o e s t e r ) , 3.60 ( s , 3, e s t e r methoxy g r o u p p r o t o n s ) , 3.80 ( s , 6, e t h e r methoxy  143 • g r o u p p r o t o n s ) , 5.63 ( s b r o a d , 1, h y d r o x y l p r o t o n ) , 6.40-7.40 (m, 3, a r o m a t i c p r o t o n s ) ; Mass s p e c t r u m ( a ) low r e s o l u t i o n m/e 2 7 8 ( 1 2 ) , 2 4 8 ( 1 8 ) , 247(80), 246(15), 220(42), 215(13), 205(40), 190(63), 189(100), 180(22), 177(12), 175(11), 174(34), 165(58), 163(30), 162(32), 161(22), 150(12), 149(11), 148(12), 147(38), 146(12), 142(14), 138(10), 135(18), 133(11), 131(15), 121(21), 117(10), 116(56), 115(15), 107(15), 105(15), 103(14), 101(28), 91(33), 88(11), 85(35), 84(23), 77(24), 74(29), 69(34), 65(15), 63(11), 59(37), 58(15), 57(35), 56(12), 51(14); (b) high r e s o l u t i o n c a l c ' d f o r C H 0 1 5  1 8  5  278.115 amu, f o u n d 278.115 m/e.  An a t t e m p t was made t o s y n t h e s i z e 70 u s i n g o n l y one equivalent o f the d i a n i o n o f methyl acetoacetate using a procedure a n a l o g o u s t o t h a t d e s c r i b e d a b o v e . The t i c o f t h e c r u d e p r o d u c t m i x t u r e i n d i c a t e d i t t o be p r i m a r i l y r e t u r n e d 2 , 6 - d i m e t h o x y a c e t o phenone and m e t h y l a c e t o a c e t a t e .  (P-18),  144 Methyl 5-(2,6-dimethoxyphenyl)-3-oxo-5-trimethylsiloxyhexanoate  (71)  T h i s compound was p r e p a r e d i n a manner a n a l o g o u s t o t h a t d e s c r i b e d f o r methyl  5-(4-1'-cyano-l -methylethyl-2,6-dimethoxy1  p h e n y l ) - 3 - o x o - 5 - t r i m e t h y l s i l o x y h e x a n o a t e ( 6 4 ) . The r e a g e n t s used i n t h i s c a s e were: h e x a m e t h y l d i s i l a z a n e (107 mg, 0.665 mmole), t r i m e t h y l s i l y l c h l o r i d e (38 mg, 0.356 mmole), and m e t h y l thoxyphenyl)-5-hydroxy-3-oxohexanoate  (70)  (92 mg, 0.314  5-(2,6-dimemmole)  i n d r y p y r i d i n e (6 m l ) . The p r o d u c t was p u r i f i e d by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) u s i n g a m i x t u r e o f e t h y l a c e t a t e and c h l o r o f o r m (1:9 v / v ) a s d e v e l o p i n g s o l v e n t . The band l y i n g a t 0.5-0.6 was removed and e x t r a c t e d w i t h c h l o r o f o r m . The s o l v e n t was removed under r e d u c e d p r e s s u r e t o y i e l d 71_ (55 mg, 48%.). An a n a l y t i c a l sample was p r e p a r e d by K u g e l r o h r d i s t i l l a t i o n a t 100 d e g r e e s (0,05 mm);  s p e c t r a page 226;  IR 1745 ( e s t e r C=0), 1710 ( k e t o n e C=0), 1595 cm"  1  (C=C  aromatic); NMR  6-0.05 ( s , 9, s i l y l m e t h y l g r o u p p r o t o n s ) , 1.76  ( s , 3, p r o t o n s on m e t h y l g r o u p  a  t o s i l y l e t h e r c a r b o n ) , 2.85 ( d ,  J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p  a  to s i l y l ether carbon),  145 3.20 ( d , J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o s i l y l e t h e r c a r b o n ) , 3.35 ( s , 2, p r o t o n s on m e t h y l e n e g r o u p a t o e s t e r ) ,  3.58  ( s , 3, e s t e r methoxy g r o u p p r o t o n s ) , 3.73 ( s , 6, e t h e r methoxy g r o u p p r o t o n s ) , 6.35-7.35 (m, 3, a r o m a t i c p r o t o n s ) ; UV 278 mp ( 1 3 8 0 ) ; Analysis calc'd for i8 28°6 " c  H  S l  :  found:  C  5 8 , 6 7  C 58.99  Methyl 5-(2,6-dimethoxyphenyl)-3-oxohex-4-eneoate  68Z  (a) From p u r i f i e d m e t h y l  H  7 , 6 5  H 7.60.  (68)  68E 5-(2,6-dimethoxyphenyl)-5-hydroxy-3-oxo-  hexanoate (70). A sample o f 7_0 (100 mg, 0.338 mmole) v/as t r e a t e d w i t h hydrogen c h l o r i d e i n c h l o r o f o r m f o l l o w i n g the procedure o u t l i n e d f o r the p r e p a r a t i o n of methyl  5-(4-1*-cyano-1'-methylethyl-2,6-dime-  thoxyphenyl )-3-oxohex-4-enoate  (25) (method ( a ) ) . The p r o d u c t 68  (91 mg, 97%) v/as i s o l a t e d as a c r u d e o i l , a p o r t i o n o f w h i c h was K u g e l r o h r d i s t i l l e d (115 d e g r e e s , 0.1 mm) t o o b t a i n a sample f o r  146 m i c r o a n a l y s i s ; s p e c t r a page 227; IR 1740 ( e s t e r C=0), 1680 ( k e t o n e C=0), 1610, 1585 cm"  1  (C=C);  NMR 62.10, 2.36 ( 2 d , J=2 c p s , 3 t o t a l , v i n y l m e t h y l g r o u p p r o t o n s i n E and Z i s o m e r s r e s p e c t i v e l y ) , 3.15-4.00 ( s e v e r a l s, 11 t o t a l , methoxy g r o u p p r o t o n s and p r o t o n s on m e t h y l e n e g r o u p a t o e s t e r ) , 6.19, 3.30 ( 2 q , J=2 c p s , 1 t o t a l , v i n y l p r o t o n s i n Z and E i s o m e r s r e s p e c t i v e l y ) , 6.50-7.50 (m, 3, a r o m a t i c p r o t o n s ) ; UV 280 mu ( 5 4 8 0 ) ; Mass s p e c t r u m m/e 2 7 8 ( 3 1 ) , 2 4 9 ( 1 1 ) , 2 4 8 ( 4 5 ) , 2 4 7 ( 1 0 0 ) , 246(34), 232(10), 220(30), 216(20), 215(80), 206(15), 205(80), 200(11), 197(11), 194(10), 193(13), 192(10), 191(14), 190(54), 189(93), 188(20), 187(17), 178(11), 177(18), 175(22), 174(35), 165(17), 163(32), 162(48), 161(42), 160(12), 159(13), 151(10), 150(12), 149(23), 148(21), 147(54), 146(17), 145(13), 142(19), 138(17), 137(10), 135(22), 134(11), 133(10), 131(22), 129(15), 127(14), 123(14), 121(34), 119(15), 117(13), 115(28), 1 1 0 ( 1 9 ) , 1 0 9 ( 1 5 ) , 108(11)., 1 0 7 ( 1 4 ) , 1 0 5 ( 2 0 ) , 1 0 4 ( 1 0 ) , 1 0 3 ( 2 2 ) , 1 0 1 ( 2 5 ) , 95(12), 91(29), 89(14), 85(10), 81(12), 79(13), 78(15), 77(30), 76(12), 75(19), 69(18), 65(22), 63(13), 59(21), 57(15), 55(12), 53(12), 51(21); Analysis calc'd for C H 0 :  C 64.74  H  found:  C 64.77  H 6.67.  1 5  1 8  5  6.52  (b) D i r e c t l y f r o m 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (39) The d i a n i o n r e a c t i o n was p e r f o r m e d as d e s c i b e d f o r the p r e p a r a t i o n o f methyl  5-(4-l'-cyano-l'-methy1ethyl-2,6-dimethoxy-  phenyl)-5-hydroxy-3-oxohexanoate  (24) (method ( b ) ) . The f o l l o w i n g  r e a g e n t s were u s e d : sodium h y d r i d e as a 57% d i s p e r s i o n i n m i n e r a l o i l (1.23 g, 29.3 mmole), m e t h y l a c e t o a c e t a t e (3.36 g , 29.0 mmole),  147 n - b u t y l l i t h i u m s o l u t i o n ( 1 3 . 2 m l , 2.2M, 2,6-dimethoxyacetophenone  29.0 mmole), and  (3_9) (0.520 g, 2.89 mmole). The c r u d e o i l  o b t a i n e d a f t e r workup was not s e p a r a t e d by c h r o m a t o g r a p h y  but was  i n s t e a d s u b j e c t e d d i r e c t l y t o t r e a t m e n t w i t h hydrogen c h l o r i d e i n c h l o r o f o r m a s d e s c r i b e d a b o v e . The o i l o b t a i n e d a f t e r workup was h e a t e d i n a K u g e l r o h r a p p a r a t u s (95 d e g r e e s , 2.0 mm) u n t i l t h e b u l k o f t h e e x c e s s m e t h y l a c e t o a c e t a t e had been removed by d i s t i l l a t i o n . The o i l which r e m a i n e d u n d i s t i l l e d was p u r i f i e d by p r e p a r a t i v e t i c on s i l i c a g e l (4 p l a t e s ) u s i n g a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (2:1 v / v ) as d e v e l o p i n g s o l v e n t . The band l y i n g i n t h e r e g i o n 0.4-0.6 was removed and e x t r a c t e d w i t h c h l o r o f o r m . The s o l v e n t was removed under r e d u c e d p r e s s u r e t o a f f o r d 68 (502 mg, 62% f r o m 3 9 ) ; s p e c t r a s i m i l a r t o above. In a n o t h e r e x p e r i m e n t t h e o r d e r o f t h e d i s t i l l a t i o n and hydrogen c h l o r i d e t r e a t m e n t d e s c i b e d above were r e v e r s e d . The NMR s p e c t r u m o f t h e c r u d e p r o d u c t f r o m t h e h y d r o g e n c h l o r i d e t r e a t m e n t was s i m i l a r t o t h a t d e s c r i b e d above b u t had e x t r a s i g n a l s a t 6 3 . 3 8 ( s ) and 5.55, 5.83 ( 2 d , J = l c p s ) .  148 Attempts t o C y c l i s e Methyl 5-(2,6-dimethoxyphenyl)-3-oxohex-4-enoate (68) W i t h Base.  (a) U s i n g sodium h y d r i d e i n h e x a m e t h y l p h o s p h o r a m i d e . A s o l u t i o n o f 68_ (20 mg, 0.072 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (1 m l ) v/as added t o a s u s p e n s i o n o f sodium h y d r i d e ( a s a 57% d i s p e r s i o n on m i n e r a l o i l ) (20 mg, 0.475 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (5 m l ) i n a 10 ml f l a s k u n d e r a n i t r o g e n a t m o s p h e r e . The m i x t u r e was h e a t e d t o 115 d e g r e e s f o r 45 m i n u t e s and t h e n added t o N/10 h y d r o c h l o r i c a c i d (20 m l ) . T h i s m i x t u r e v/as e x t r a c t e d w i t h e t h e r (2 X 20 m l ) a n d t h e e x t r a c t s were washed w i t h w a t e r ( 5 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e s o l v e n t s were e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e . T h e t i c o f t h e c r u d e p r o d u c t m i x t u r e showed t h r e e s p o t s , t h e m a i n one c o r r e s p o n d i n g t o s t a r t i n g m a t e r i a l . S p e c t r o s c o p i c e x a m i n a t i o n o f t h e m i x t u r e g a v e no e v i d e n c e o f c y c l i s a t i o n ; IR 1740, 1680 cm"  1  ( s a t u r a t e d e s t e r and u n s a t u r a t e d k e t o n e )  bands s t i l l s t r o n g , no h y d r o x y ! band; NMR no c h a n g e i n d o u b l e t s a s s i g n e d t o v i n y l m e t h y l g r o u p s in starting material.  (b) U s i n g l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e i n x y l e n e . A s o l u t i o n o f l i t h i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e (1.3 m l , • 0.50M, 0.65 mmole) i n THF was added t o a s o l u t i o n o f 68_ (22 mg, 0.079 mmole) i n x y l e n e (25 m l ) u n d e r n i t r o g e n . T h e s o l u t i o n was r e f l u x e d u n d e r n i t r o g e n f o r f o u r h o u r s and t h e n p o u r e d i n t o N/10 h y d r o c h l o r i c a c i d (20 m l ) . T h e p h a s e s were s e p a r a t e d and t h e o r g a n i c  149 phase was washed w i t h w a t e r (5 m l ) and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t was removed under r e d u c e d p r e s s u r e . S p e c t r o s c o p i c e x a m i n a t i o n o f t h e p r o d u c t m i x t u r e i n d i c a t e d c o n s i d e r a b l e decompos i t i o n o f t h e s t a r t i n g m a t e r i a l ( l o s s o f methoxy p r o t o n s i g n a l s i n NMR s p e c t r u m ) b u t g a v e no e v i d e n c e o f c y c l i s a t i o n .  A t t e m p t s t o Form and P h o t o c y c l i s e t h e E n o l E t h e r o f Methyl 5-(2,6-dimethoxyphenyl)-3-oxohex-4-enoate  (68)  (a) U s i n g sodium h y d r i d e and d i m e t h y l s u l p h a t e . Sodium h y d r i d e a s a 57% d i s p e r s i o n on m i n e r a l o i l (50 mg, 1.19 mmole) was added t o h e x a m e t h y l p h o s p h o r a m i d e  (50 m l )  i n a 100 ml f l a s k e q u i p p e d w i t h a m a g n e t i c s t i r r e r and n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s . T h e f l a s k was f l u s h e d w i t h n i t r o g e n and 68 (240 mg, 0.864 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e  (5 m l )  was added. The m i x t u r e was a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r  lh hours b e f o r e d i m e t h y l s u l p h a t e ( 2 0 0 mg, 1.59 mmole) was a d d e d . The r e a c t i o n was a l l o w e d t o s t i r an a d d i t i o n a l 1% h o u r s and was t h e n poured i n t o s a t u r a t e d aqueous sodium hydrogen c a r b o n a t e s o l u t i o n (100 m l ) . T h i s m i x t u r e was e x t r a c t e d w i t h e t h e r (2 X50 m l ) and t h e e x t r a c t s were washed w i t h w a t e r (5 X 20 m l ) and d r i e d o v e r magnesium, s u l p h a t e . T h e IR s p e c t r u m o f t h e c r u d e p r o d u c t showed a b r o a d c a r b o n y l band (1740-1680 c m ) . I t s t i c showed - 1  seven s p o t s . T h e  m i x t u r e was s e p a r a t e d i n t o i t s c o m p o n e n t s by p r e p a r a t i v e t i c (4 p l a t e s ) u s i n g a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (2:1 v / v ) a s d e v e l o p i n g s o l v e n t . T h e f i v e m a j o r bands were removed and e x t r a c t e d w i t h c h l o r o f o r m .  150 The s o l v e n t was removed f r o m each under r e d u c e d p r e s s u r e . T h e m a j o r component was r e t u r n e d s t a r t i n g m a t e r i a l 68_ (130 mg, 5 4 % ) . O n l y one band, l y i n g a t R^ 0.60-0.65 , showed p r o m i s e o f b e i n g an e n o l e t h e r (IR s p e c t r u m 1720 c m , p o s s i b l e u n s a t u r a t e d e s t e r ) (60 mg, 22%) - 1  The p h o t o l y s i s o f t h i s f r a c t i o n i s d e s c r i b e d i n ( b ) below. In a n o t h e r e x p e r i m e n t s i m i l a r t o t h e one d e s c r i b e d a b o v e t h e c r u d e p r o d u c t m i x t u r e was d i s t i l l e d i n a K u g e l r o h r a p p a r a t u s (95 d e g r e e s , 2.0 mm). T h e NMR s p e c t r u m o f t h e c r u d e m a t e r i a l o b t a i n e d i n d i c a t e d t h a t c o n s i d e r a b l e d e c o m p o s i t i o n had o c c u r r e d and g a v e no e v i d e n c e t h a t t h e m i x t u r e c o n t a i n e d a n y e n o l e t h e r .  (b) P h o t o l y s i s o f p o s s i b l e e n o l e t h e r . A sample o f t h e f r a c t i o n d e s c r i b e d i n ( a ) was d i s s o l v e d i n a n h y d r o u s e t h e r and p h o t o l y s e d ( m e r c u r y H a n o v i a lamp, 450 w a t t s ) through a Vycor f i l t e r f o r f o u r hours. S p e c t r o s c o p i c examination o f t h e p r o d u c t (UV Xmax 2 5 3 ) i n d i c a t e d t h a t c y c l i s a t i o n had n o t o c c u r r e d , M = V  ( c ) U s i n g sodium h y d r i d e and m e t h y l  chloride.  A s o l u t i o n o f 68 ( 1 2 0 mg, 0.432 mmole) i n d r y THF ( 1 0 m l ) was added t o a m a g n e t i c a l l y ' s t i r r e d s u s p e n s i o n o f sodium h y d r i d e (as a 57% d i s p e r s i o n i n m i n e r a l o i l ) (40 mg, 0.954 mmole) i n hexamethylphosphoramide  (6 m l ) i n a n i t r o g e n a t m o s p h e r e . T h e m i x t u r e  v/as a l l o w e d t o s t i r f o r two hours b e f o r e m e t h y l c h l o r i d e v/as b u b b l e d s l o w l y t h r o u g h t h e l i q u i d phase f o r 3 h o u r s . T h e m i x t u r e was t h e n poured i n t o s a t u r a t e d aqueous sodium h y d r o g e n c a r b o n a t e s o l u t i o n (20 m and e x t r a c t e d w i t h e t h e r (2 X 20 m l ) . T h e e x t r a c t s were washed w i t h w a t e r (2 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . Removal o f t h e  151 s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a n o i l whose IR s p e c t r u m and t i c i n d i c a t e d i t t o be p r i m a r i l y s t a r t i n g m a t e r i a l .  (d) U s i n g sodium h y d r i d e and i s o p r o p y l i o d i d e . A s o l u t i o n o f 68 (120 mg, 0.432 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (2 m l ) v/as added t o a m a g n e t i c a l l y s t i r r e d  suspension  of sodium h y d r i d e ( a s a 57% d i s p e r s i o n i n m i n e r a l o i l ) (35 mg, 0.834mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (2 m l ) under a n i t r o g e n a t m o s p h e r e . T h e m i x t u r e was a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r 1% hours b e f o r e i s o p r o p y l i o d i d e (83 mg, 0.490 mmole) v/as added. The r e a c t i o n was s t i r r e d f o r 1 hour and t h e n p o u r e d i n t o s a t u r a t e d a q u e o u s sodium  hydrogen  c a r b o n a t e s o l u t i o n (20 m l ) . T h i s was e x t r a c t e d w i t h e t h e r (2 X 20 m l ) and t h e e x t r a c t s were washed w i t h water (2 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . The o i l o b t a i n e d when t h e s o l v e n t v/as e v a p o r a t e d under r e d u c e d p r e s s u r e v/as s e p a r a t e d i n t o i t s components by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) u s i n g a n e t h e r - c h l o r o f o r m m i x t u r e ( 1 : 2 v / v ) as d e v e l o p i n g s o l v e n t . T h e band a t R  f  0.9 was removed and e x t r a c t e d  w i t h c h l o r o f o r m . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d  pressure  a f f o r d e d 18 mg o f an o i l whose IR s p e c t r u m showed a b r o a d c a r b o n y l a b s o r p t i o n a t 1710-1720 cm" -. 1  (e) U s i n g sodium h y d r i d e and t r i m e t h y l s i l y l c h l o r i d e . The p r o c e d u r e used v/as t h a t d e s c r i b e d i n ( d ) b u t anhydrous  e t h e r was s u b s t i t u t e d a s s o l v e n t . T h e f o l l o w i n g r e a g e n t s  were u s e d : sodium h y d r i d e d i s p e r s i o n (6 mg, 0.143 mmole), 68_ (37 mg, 0.133 mmole), and t r i m e t h y l s i l y l c h l o r i d e (17 mg, 0.156 mmole). T h e IR spectrum and t i c o f t h e o i l o b t a i n e d a f t e r workup i n d i c a t e d p r i m a r i l y  152  returned s t a r t i n g material.  ( f ) U s i n g sodium h y d r i d e and m e t h y l i o d i d e . The p r o c e d u r e employed was t h a t d e s c r i b e d i n ( d ) . The f o l l o w i n g r e a g e n t s were u s e d : sodium h y d r i d e d i s p e r s i o n (2.5 mg, 0.050 mmole), 68 (15 mg, 0.054 mmole), and methyl  i o d i d e (9 mg,  0.064 mmole). T h e IR s p e c t r u m and t i c o f t h e o i l o b t a i n e d a f t e r workup i n d i c a t e d i t t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l ,  (g) U s i n g  diazomethane. A sample o f 68^ i n a n h y d r o u s  e t h e r was t r e a t e d w i t h  a l a r g e excess of a s o l u t i o n o f diazomethane  i n e t h e r . The s o l u t i o n  was s t i r r e d f o r 1% hours b e f o r e t h e s o l v e n t was removed under  reduced  p r e s s u r e . The IR s p e c t r u m and t i c o f t h e p r o d u c t i n d i c a t e d i t t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l .  (h) U s i n g t r i e t h y l o r t h o f o r m a t e and s u l p h u r i c a c i d , A m i x t u r e o f 68 (48 mg, 0.173 mmole), t r i e t h y l o r t h o f o r m a t e (5 m l ) and c o n c e n t r a t e d s u l p h u r i c a c i d (5 u l ) was s t i r r e d a t room t e m p e r a t u r e f o r 60 h o u r s a f t e r w h i c h t i m e i t was p o u r e d i n t o water (20 m l ) and e x t r a c t e d w i t h e t h e r (2 X 10 m l ) . The e t h e r e x t r a c t s were washed w i t h water (2 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d an o i l whose IR s p e c t r u m and t i c i n d i c a t e d i t t o be p r i m a r i l y r e t u r n e d starting material.  153 A t t e m p t s t o Form and P h o t o c y c l i s e t h e E n o l A c e t a t e o f Methyl 5-(2,6-dimethoxyphenyl)-3-oxohex-4-enoate (68).  (a) U s i n g sodium h y d r i d e and a c e t y l c h l o r i d e i n h e x a m e t h y l p h o s p h o r a m i d e . A s o l u t i o n o f 68_ (75 mg, 0.270 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (3 ml) was added t o a m a g n e t i c a l l y s t i r r e d s u s p e n s i o n o f sodium h y d r i d e (as a 57% d i s p e r s i o n i n m i n e r a l o i l ) (12 mg, 0.286 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (2 m l ) u n d e r a n i t r o g e n a t m o s p h e r e . The m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 1% h o u r s b e f o r e a c e t y l c h l o r i d e (23 mg, 0.281 mmole) was a d d e d . A f t e r s t i r r i n g f o r a n o t h e r 1% h o u r s t h e m i x t u r e was p o u r e d i n t o s a t u r a t e d aqueous sodium h y d r o g e n c a r b o n a t e s o l u t i o n (20 m l ) and e x t r a c t e d w i t h e t h e r (2 X 20 m l ) . The e x t r a c t s were washed w i t h w a t e r ( 3 X 10 m l ) and d r i e d o v e r a n h y d r o u s sodium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e y i e l d e d an o i l whose IR s p e c t r u m i n d i c a t e d t h e p o s s i b l e p r e s e n c e o f v i n y l i c (1770 cm" ) and c t , 8 - u n s a t u r a t e d 1  (1720 cm" ) 1  e s t e r g r o u p s . T h i s m i x t u r e was s e p a r a t e d by p r e p a r a t i v e  t i c on s i l i c a g e l (1 p l a t e ) d e v e l o p e d w i t h c a r b o n t e t r a c h l o r i d e - e t h e r (2:1 v / v ) i n t o two components ( R 0.2 and 0 . 3 ) , e a c h o f w h i c h had f  t h e IR a b s o r p t i o n s m e n t i o n e d a b o v e . B o t h f r a c t i o n s were s u b j e c t e d t o f u r t h e r p u r i f i c a t i o n by p r e p a r a t i v e t i c on a l u m i n a (h p l a t e e a c h ) u s i n g c h l o r o f o r m as d e v e l o p i n g s o l v e n t . A f t e r r e m o v a l and e x t r a c t i o n o f t h e bands l y i n g a t R^ 0.6 t h e two f r a c t i o n s were o b t a i n e d i n y i e l d s o f 8 mg and 6 mg. B o t h had t h e IR a b s o r p t i o n s d e s c r i b e d a b o v e .  154 (b) U s i n g e x c e s s sodium h y d r i d e and a c e t y l c h l o r i d e i n d i g l y m e . The same p r o c e d u r e as d e s c r i b e d i n (a) was used i n t h i s e x p e r i m e n t but d r y d i g l y m e was used as s o l v e n t . The r e a g e n t s used were: sodium h y d r i d e d i s p e r s i o n (200 mg, 4.76 mmole), 68^ (185  mg,  0.649 mmole), and a c e t y l c h l o r i d e (400 mg, 5.10 mmole). The IR s p e c t r u m o f t h e c r u d e p r o d u c t m i x t u r e was s i m i l a r t o t h a t d e s c r i b e d i n ( a ) . I t was s e p a r a t e d i n t o s e v e r a l components by column chromat o g r a p h y on s i l i c a g e l . ( 6 g) ( e l u t e d w i t h c a r b o n t e t r a c h l o r i d e : e t h e r , 17:3 v / v ) . Two f r a c t i o n s , t h e f i r s t and second e l u t e d , h a v i n g IR s p e c t r a s i m i l a r t o t h o s e d e s c i b e d a b o v e , were o b t a i n e d i n low y i e l d (30 mg, 16 mg r e s p e c t i v e l y ) .  (c) P h o t o l y s i s o f c r u d e p r o d u c t f r o m ( b ) . A sample o f t h e c r u d e p r o d u c t o b t a i n e d f r o m an e x p e r i m e n t s i m i l a r t o t h a t d e s c r i b e d i n (b) was d i s s o l v e d i n e t h e r and p h o t o l y s e d ( m e r c u r y H a n o v i a lamp, 25'0 w a t t s ) t h r o u g h a Pyrex f i l t e r f o r 2% h o u r s . The e t h e r was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o y i e l d an o i l whose IR s p e c t r u m and t i c were s i m i l a r t o s t a r t i n g m a t e r i a l . The sample was r e d i s s o l v e d i n e t h e r and p h o t o l y s e d t h r o u g h a V y c o r f i l t e r f o r 3 h o u r s . The t i c o f t h e p r o d u c t o b t a i n e d i n d i c a t e d t h a t i t c o n t a i n e d a m i x t u r e o f s e v e r a l compounds (9 s p o t s ) .  155 Dicyclohexylammonium  acetate  D i c y c l o h e x y l a m i n e (1.510 g , 8.34 mmole) was added dropwise t o a r a p i d l y s t i r r e d s o l u t i o n of g l a c i a l a c e t i c acid (0.500 g , 8.34 mmole) i n a n h y d r o u s  e t h e r (15 m l ) . A w h i t e  precipitate  was formed i m m e d i a t e l y . T h e m i x t u r e was a l l o w e d t o s t i r f o r 15 m i n u t e s b e f o r e t h e e t h e r was e v a p o r a t e d under r e d u c e d p r e s s u r e . The p r o d u c t o b t a i n e d was powdered a n d d r i e d i n vacuo a t room t e m p e r a t u r e t o y i e l d 2.02 g (1003) o f t h e s a l t .  3-(2,4,6-Trimethoxyphenyl)but-2-enoic  a c i d (96) and  3-(2,4,6-trimethoxyphenyl)but-3-enoic  a c i d (113).  (a) F o r m a t i o n o f m i x t u r e . A 500 ml f l a s k c o n t a i n i n g a m a g n e t i c a l l y s t i r r e d of dicyclohexylammonium  solution  a c e t a t e (11.747 g , 48.7 mmole) i n d r y THF  (300 m l ) and d r y h e x a m e t h y l p h o s p h o r a m i d e  (50 m l ) was s t o p p e r e d  w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e  156 n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (41.5 m l , 2.4M, 99.5 mmole) was added d r o p w i s e , o v e r a p e r i o d o f 10 m i n u t e s .  T h e m i x t u r e was s t i r r e d f o r 20 m i n u t e s b e f o r e  a s o l u t i o n o f 2,4,6-trimethoxyacetophenone  (94) (1.079 g, 5.14 mmole)  i n d r y THF (10 m l ) was added. A f t e r 2 hours c o n c e n t r a t e d h y d r o c h l o r i c a c i d was added u n t i l t h e aqueous phase was a c i d i c . T h e m i x t u r e was poured i n t o water (100 m l ) and e t h e r (500 m l ) . The phases were s e p a r a t e d and t h e aqueous phase was e x t r a c t e d w i t h e t h e r (3 X 100 m l ) . The combined o r g a n i c s were washed w i t h N h y d r o c h l o r i c " a c i d (5 X 50 m l ) and w a t e r (50 m l ) . They were t h e n e x t r a c t e d w i t h N sodium h y d r o x i d e (3 X 100 m l ) . The combined base e x t r a c t s were a c i d i f i e d by t h e dropwise a d d i t i o n of concentrated h y d r o c h l o r i c a c i d . The mixture obtained was e x t r a c t e d w i t h e t h e r (3 X 100 m l ) and t h e e x t r a c t s were washed w i t h w a t e r (2 X 50 m l ) . A f t e r d r y i n g o v e r magnesium s u l p h a t e t h e s o l v e n t s were removed under r e d u c e d p r e s s u r e t o y i e l d a m i x t u r e o f 96E, 96Z, and 113 (1.097 g , 8 5 % ) ; mp 136-140 d e g r e e s ; s p e c t r a page 228; IR 3500-2500 ( 0 - H ) , 1730-1710 '(0=0), 1650 (C=C o l e f i n i c ) , 1620,1575cm"  1  (C=C a r o m a t i c ) ;  NMR F o r a s s i g n m e n t s s e e s e p a r a t i o n o f i s o m e r s p a r t (b) ; Analysis calc'd f o r C H 0 : 1 3  l g  5  found:  C 61.90  H6.39.  C 61.96 H 6.30.  An a t t e m p t was made t o s y n t h e s i z e t h e above m i x t u r e of i s o m e r s u s i n g e q u i v a l e n t amounts o f d i c y c l o h e x y l a m m o n i u m and 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e  acetate  i n a manner a n a l o g o u s t o t h a t  d e s c i b e d above. T h e IR s p e c t r u m a n d t i c o f t h e c r u d e p r o d u c t m i x t u r e indicated that i t consisted mainly of returned starting material.  157 (b) P a r t i a l s e p a r a t i o n o f  isomers.  A sample (53 mg) o f t h e p r o d u c t o b t a i n e d i n (a) was s e p a r a t e d i n t o two components by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) u s i n g a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (1:1 v/v) as d e v e l o p i n g s o l v e n t . The band a t R  f  0.60-0.65 was removed and e x t r a c t e d w i t h  c h l o r o f o r m . The s o l v e n t was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o y i e l d 96 (27 mg,  5 1 % ) ; mp 141-143 d e g r e e s ; s p e c t r u m NMR  62.10, 2.37  229;  ( 2 d , J = l c p s , 3 t o t a l , v i n y l methyl  p r o t o n s i n E and Z i s o m e r s r e s p e c t i v e l y ) , 3.75 g r o u p p r o t o n s ) , 3.81  page  ( s , 6, o r t h o - m e t h o x y  ( s , 3, p a r a - m e t h o x y g r o u p p r o t o n s ) , 5.81,  (2q, J = l c p s , 1 t o t a l , v i n y l p r o t o n s i n Z and E i s o m e r s 6.15  ( s , 2, a r o m a t i c  group  6.02  respectively),  protons).  The band l y i n g a t R  f  0.55-0.60 on t h e t i c p l a t e was  removed and 113 (21 mg, 40%) was i s o l a t e d ; mp 146-148 d e g r e e s ; s p e c t r u m page 229; NMR  63.40 ( s , 2, p r o t o n s on m e t h y l e n e g r o u p a t o c a r b o x y l i c  a c i d ) , 3 . 7 5 ( s , 6, o r t h o - m e t h o x y g r o u p p r o t o n s ) , 3.81 methoxy g r o u p p r o t o n s ) , 5.21  ( s , 3, p a r a -  ( d , J=2 c p s , 1, v i n y l p r o t o n ) ,  ( d , J=2 c p s , 1, v i n y l p r o t o n ) , 6.15  ( s , 2, a r o m a t i c  protons).  5.56  158 M e t h y l 3 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t - 2 - e n o a t e (97) and Methyl 3-(2,4,6-trimethoxyphenyl)but-3-enoate  (237)  A sample (50 mg, 0.187 mmole) o f t h e m i x t u r e o f 96JE, 96Z, and 113 o b t a i n e d a s d e s c r i b e d above was d i s s o l v e d i n a n h y d r o u s e t h e r and t r e a t e d w i t h a l a r g e e x c e s s o f a s o l u t i o n o f  diazomethane  i n e t h e r . I t was a l l o w e d t o s t a n d f o r 45 m i n u t e s b e f o r e t h e e t h e r was e v a p o r a t e d under r e d u c e d p r e s s u r e t o y i e l d a c r u d e m i x t u r e o f 97_ and 237 (53 mg, 1 0 0 % ) . P a r t i a l s e p a r a t i o n o f t h e i s o m e r s was a c c o m p l i s h e d by p r e p a r a t i v e t i c on s i l i c a g e l u s i n g a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (2:1 v / v ) as d e v e l o p i n g s o l v e n t . T h i s a l l o w e d a s s i g n m e n t o f t h e NMR  s i g n a l s g i v e n below;  IR 1740-1720 ( 0 0 ) , 1650 (C=C o l e f i n i c ) , 1610, 1590  cm"  1  (C=C a r o m a t i c ) ; NMR  62.05, 2.35 ( 2 d , J = l c p s , v i n y l m e t h y l g r o u p p r o t o n s  f o r E and Z i s o m e r s o f 9 7 ) , 3,35 ( s , p r o t o n s on m e t h y l e n e g r o u p a t o e s t e r i n 2 3 7 ) , 3.62 ( s , e s t e r m e t h o x y g r o u p p r o t o n s i n 2 3 7 ) , 3.70 ( s , e s t e r methoxy g r o u p p r o t o n s i n 97_), 3.79, 3.81  (2s, ether  methoxy group p r o t o n s ) , 5.15, 5 . 4 8 ( 2 d , J=2 c p s , v i n y l p r o t o n s i n 2 3 7 ) , 5.78, 6.02 ( 2 q , J=l c p s , v i n y l p r o t o n s i n E and Z i s o m e r s o f 9 7 ) , 6.18  (s, aromatic protons).  159 Ethyl 3-(2,6-dimethoxypheny1)but-2-enoate  (115)  A 50 ml f l a s k c o n t a i n i n g i s o p r o p y l c y c l o h e x y l a m i n e (720 mg, 5.10 mmole), d r y THF (15 m l ) , and a m a g n e t i c s t i r r e r was s t o p p e r e d w i t h a serum c a p and f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s . The f l a s k was f l u s h e d w i t h n i t r o g e n and a s o l u t i o n of n - b u t y l l i t h i u m i n hexane (2.05 m l , 2.50M, 5.13 mmole) was a d d e d . The s o l u t i o n was a l l o w e d t o s t i r a t room t e m p e r a t u r e f o r 5 m i n u t e s and was t h e n c o o l e d t o -78 d e g r e e s i n a d r y i c e - a c e t o n e b a t h . E t h y l a c e t a t e (440 mg, 5.00 mmole) was added and t h e s o l u t i o n was s t i r r e d a t -78 d e g r e e s f o r 25 m i n u t e s . A s o l u t i o n o f 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (39) (90 mg, 0.500 mmole) i n THF (2 m l ) was added and t h e s o l u t i o n was a l l o w e d t o warm t o 0 d e g r e e s . A f t e r s t i r r i n g f o r 45 m i n u t e s a t t h i s t e m p e r a t u r e N h y d r o c h l o r i c a c i d (10 m l ) was a d d e d . T h e phases were s e p a r a t e d and t h e aqueous phase was e x t r a c t e d w i t h e t h e r (2 X 20 m l ) . The combined o r g a n i c s wefe washed w i t h N h y d r o c h l o r i c a c i d (10 m l ) and water (3 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e o i l o b t a i n e d a f t e r e v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d  pressure  was s e p a r a t e d i n t o i t s components by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) . T h e band a t  0.'4 was removed a n d e x t r a c t e d w i t h c h l o r o f o r m .  A n h y d r o u s hydrogen c h l o r i d e was b u b b l e d t h r o u g h t h e c h l o r o f o r m s o l u t i o n f o r 10 m i n u t e s and i t was a l l o w e d t o s t a n d f o r 1% hours b e f o r e b e i n g washed w i t h s a t u r a t e d aqueous sodium hydrogen c a r b o n a t e s o l u t i o n (3 X 10 m l ) and water (2 X 10 m l ) . A f t e r d r y i n g o v e r magnesium s u l p h a t e t h e s o l v e n t was e v a p o r a t e d t o y i e l d c r u d e 115 (73 mg, 5 9 % ) ; NMR 61.1-1.5 (m, 3, e s t e r m e t h y l g r o u p p r o t o n s i n E a n d  160 Z i s o m e r s ) , 2.05, 2.35 ( 2 d , 3 t o t a l , v i n y l methyl group p r o t o n s i n E a n d Z i s o m e r s ) , 3.75 ( s , 6, methoxy group p r o t o n s ) , 3.8-4.4 (m, 2, e s t e r m e t h y l e n e  group p r o t o n s i n E and Z i s o m e r s ) , 5.75, 6.00  (2q, 1 t o t a l , v i n y l p r o t o n s i n E and Z i s o m e r s ) , 6.4-7.4 (m, 3, aromatic protons).  A t t e m p t s t o form t h e above p r o d u c t f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d b u t m a i n t a i n i n g t h e r e a c t i o n t e m p e r a t u r e a t -78 d e g r e e s t h r o u g h o u t r e s u l t e d o n l y i n t h e r e t u r n o f f a i r l y pure 2 , 6 - d i m e t h o x y acetophenone.  Methyl 3-hydroxy-3-phenylpropionate  (118)  A.10 ml f l a s k c o n t a i n i n g i s o p r o p y l c y c l o h e x y l a m i n e (143 mg, 1.02 mmole), d r y THF (5 m l ) , and a m a g n e t i c  s t i r r e r was s t o p p e r e d  w i t h a serum c a p and f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s . The f l a s k v/as f l u s h e d w i t h n i t r o g e n and a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.440 m l , 2.50M, 1.10 mmole) was a d d e d . The s o l u t i o n was c o o l e d t o -78 d e g r e e s i n a d r y i c e - a c e t o n e b a t h and methyl a c e t a t e (74 mg, 1.00 mmole) was a d d e d . T h e r e a c t i o n was s t i r r e d f o r 20 m i n u t e s a t -78 d e g r e e s b e f o r e b e n z a l d e h y d e  (106 mg,  1.00 mmole) was a d d e d . The s o l u t i o n v/as s t i r r e d f o r 45 m i n u t e s a t -78 d e g r e e s and t h e n N h y d r o c h l o r i c a c i d (4 m l ) was a d d e d . T h e m i x t u r e o b t a i n e d was poured i n t o e t h e r (75 m l ) and t h e o r g a n i c p h a s e was washed w i t h N h y d r o c h l o r i c a c i d (15 m l ) and water (3 X 15 m l ) ,  161  and d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . Removal  of the solvents  under r e d u c e d p r e s s u r e a f f o r d e d 118 (147 mg, 8 2 % ) ; NMR 62.73 ( d , J=7 c p s , 2, m e t h y l e n e p r o t o n s ) , 3.65 ( s , 3, methoxy g r o u p p r o t o n s ) , 5.12 ( t , J=7 c p s , 1, p r o t o n on c a r b i n o l c a r b o n ) , 7.1-8.0 (m, 5, a r o m a t i c p r o t o n s ) .  A t t e m p t s t o Condense M e t h y l a c e t a t e w i t h 2 , 6 - D i m e t h o x y a c e t o p h e n o n e  (39).  Two a t t e m p t s were made t o c o n d e n s e t h e e n o l a t e a n i o n of methyl a c e t a t e with 2,6-dimethoxyacetophenone  using a procedure  analogous t o t h a t d e s c r i b e d f o r t h e s y n t h e s i s o f methyl  3-hydroxy-  - 3 - p h e n y l p r o p i o n a t e ( 1 1 8 ) . In one e x p e r i m e n t t h e t e m o e r a t u r e was m a i n t a i n e d a t -78 d e g r e e s t h r o u g h o u t t h e e n t i r e r e a c t i o n t i m e . In t h e o t h e r , t h e t e m p e r a t u r e was r a i s e d t o 0 d e g r e e s a f t e r t h e a d d i t i o n o f 2,6-dimethoxyacetophenone.  In each c a s e t h e r e a g e n t s u s e d were:  i s o p r o p y l c y c l o h e x y l a m i n e (720 mg, 5.10 mmole), n - b u t y l l i t h i u m i n hexane (2.05 m l , 2.50M, 5.13 mmole), m e t h y l a c e t a t e (370 mg, 5.00 mmole), and 2 , 6 - d i m e t h o x y a c e t o p h e n o n e  (90 mg, 0.500 mmole). The NMR s p e c t r a  and t i c o f t h e c r u d e p r o d u c t m i x t u r e s . o b t a i n e d f r o m t h e s e r e a c t i o n s i n d i c a t e d them t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l .  162 3-(2,4,6-Trimethoxyphenyl)but-2-enoyl  c h l o r i d e (98) and  3-(2,4,6-Trimethoxyphenyl)but-3-enoyl  c h l o r i d e (238)  A sample (48 mg, 0.19 mmole) o f t h e m i x t u r e o f 3 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t - 2 - e n o i c a c i d and 3 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t - 3 - e n o i c a c i d d e s c r i b e d above was d i s s o l v e d i n o x a l y l c h l o r i d e (1 m l ) and t h e s o l u t i o n was s t i r r e d f o r two hours a t room t e m p e r a t u r e . E v a p o r a t i o n o f t h e e x c e s s o x a l y l c h l o r i d e under r e d u c e d p r e s s u r e and i n vacuo a f f o r d e d , a s a c r u d e gum, a m i x t u r e o f 98 and 238 (50 mg, 9 7 % ) ; IR 1800 (C=0 i n 2 3 8 ) , 1770 cm" .(C=0 i n 9 8 ) . 1  Attempted Condensation o f 2,4,6-Trimethoxyacetophenone  (94) w i t h  A c i d c h l o r i d e s 98 and 238..  A 25 ml f l a s k c o n t a i n i n g  2,4,6-trimethoxyacetophenone  (94) (64 mg, 0.34 mmole), d r y THF (10 m l ) , and a m a g n e t i c  stirrer  was s t o p p e r e d w i t h a serum c a p a n d f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s . T h e f l a s k was f l u s h e d w i t h n i t r o g e n and a s o l u t i o n o f t r i t y l p o t a s s i u m i n DME (^0.5M) was added  dropwise  u n t i l a red colour persisted i n the reaction mixture. During the a d d i t i o n o f t r i t y l p o t a s s i u m a w h i t e p r e c i p i t a t e was f o r m e d . A s o l u t i o n , i n d r y THF (5 m l ) o f t h e a c i d c h l o r i d e s 98_, 238, formed a s d e s c r i b e d a b o v e , f r o m t h e m i x t u r e o f u n s a t u r a t e d a c i d s %,  1_13 (76 mg, 0.30 mmole),  was added t o t h e r e a c t i o n m i x t u r e . A f t e r b e i n g s t i r r e d a t room  163 t e m p e r a t u r e f o r 18 hours t h e p r e c i p i t a t e was s t i l l p r e s e n t i n t h e m i x t u r e . The c o n t e n t s o f t h e f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s steel cannula to a r a p i d l y s t i r r e d mixture of N h y d r o c h l o r i c a c i d (10 ml) and e t h e r (50 m l ) . The o r g a n i c phase was washed w i t h w a t e r (3 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a p r o d u c t whose t i c showed f i v e s p o t s . The t h r e e m a j o r s p o t s c o r r e s p o n d e d t o t r i p h e n y l m e t h a n e , t h e m i x t u r e o f a c i d s 96, 113, and  2,4,6-trimethoxyacetophenone.  The IR s p e c t r u m o f t h e m i x t u r e d i d n o t i n d i c a t e t h e p r e s e n c e o f any c h e l a t e d c a r b o n y l compounds. In a n o t h e r e x p e r i m e n t , p r o c e d u r e s and amounts o f r e a g e n t s i d e n t i c a l t o t h o s e d e s c r i b e d above were u s e d , but t h e r e a c t i o n was r e f l u x e d f o r t h r e e hours a f t e r the a d d i t i o n of the a c i d c h l o r i d e s , and t h e n worked up as d e s c r i b e d . The IR s p e c t r u m and t i c o f t h e p r o d u c t m i x t u r e were s i m i l a r t o t h o s e o b t a i n e d above.  Attempted Condensation o f 2,4,6-Trimethoxyacetophenone E s t e r s 97 and  (94) w i t h  237.  A 25 ml f l a s k c o n t a i n i n g a m a g n e t i c a l l y s t i r r e d s o l u t i o n of 2,4,6-trimethoxyacetophenone  (94) (73 mg, 0.35 mmole) i n d r y  THF (15 ml)'was s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f t r i t y l p o t a s s i u m i n DME  (^0.5M) was added d r o p w i s e u n t i l  a red c o l o u r p e r s i s t e d i n the r e a c t i o n mixture. A white p r e c i p i t a t e  164 was formed d u r i n g t h i s a d d i t i o n . A s o l u t i o n o f e s t e r s 97_, 237 (93 mg, 0.35 mmole) i n d r y THF (5 m l ) was added and t h e r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 60 h o u r s . A f t e r t h i s t i m e t h e p r e c i p i t a t e was s t i l l p r e s e n t . The c o n t e n t s o f t h e f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s s t e e l c a n n u l a t o a r a p i d l y s t i r r e d m i x t u r e o f N h y d r o c h l o r i c a c i d (10 m l ) and e t h e r (50 m l ) . T h e o r g a n i c p h a s e was washed w i t h w a t e r (3 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a p r o d u c t whose t i c i n d i c a t e d i t t o be a m i x t u r e o f t h e s t a r t i n g esters, 2,4,6-trimethoxyacetophenone,  t r i p h e n y l m e t h a n e , and t h e  a c i d s 96_, 113. The p r e s e n c e o f t h e a c i d s was c o n f i r m e d by t h e i r e x t r a c t i o n i n t o N sodium h y d r o x i d e . A c i d i f i c a t i o n o f t h e s e e x t r a c t s f o l l o w e d by r e - e x t r a c t i o n i n t o e t h e r , and e v a p o r a t i o n o f t h e s o l v e n t a f f o r d e d 31 mg (35%) o f t h e a c i d s (IR  spectrum i d e n t i c a l t o a u t h e n t i c  sample). In a n o t h e r ex-periment, p r o c e d u r e s a n d amounts o f r e a g e n t s s i m i l a r t o t h o s e d e s c r i b e d a b o v e were u s e d , b u t t h e r e a c t i o n was r e f l u x e d f o r 3 h o u r s a f t e r t h e a d d i t i o n o f t h e e s t e r s , and t h e n worked up a s d e s c r i b e d . The t i c o f t h e c r u d e p r o d u c t m i x t u r e was s i m i l a r t o t h a t descibed above.  165 1,5-Diphenyl-5-hydroxyhexane-l,3-dione (126)  Sodium h y d r i d e a s a 57% d i s p e r s i o n i n m i n e r a l o i l (215 mg, 5.13 mmole) was weighed i n t o a 50 ml f l a s k e q u i p p e d w i t h a m a g n e t i c s t i r r e r and d r y THF (20 m l ) v/as added. T h e f l a s k was s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , f l u s h e d w i t h n i t r o g e n , and c o o l e d t o 0 d e g r e e s . A s o l u t i o n o f b e n z o y l a c e t o n e (40) ( 8 1 0 mg, 5.00 mmole) i n d r y THF (.5 m l ) was added d r o p w i s e a t a r a t e w h i c h m a i n t a i n e d a v i g o r o u s e v o l u t i o n o f hydrogen. A white p r e c i p i t a t e formed d u r i n g t h i s a d d i t i o n . The p r e c i p i t a t e was d i s s o l v e d by t h e a d d i t i o n o f h e x a m e t h y l p h o s phoramide (5 m l ) and a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane ( 2 . 3 0 m l , 2.20M, 5.05 mmole) was added o v e r a p e r i o d o f 2 m i n u t e s . A f t e r an a d d i t i o n a l 10 m i n u t e s , a c e t o p h e n o n e (600 mg, 5.00 mmole) was added and t h e r e a c t i o n m i x t u r e was s t i r r e d a t 0 d e g r e e s f o r 2 h o u r s . I t was t h e n quenched by t h e d r o p w i s e a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d u n t i l t h e aqueous l a y e r was a c i d i c . T h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r (100 m l ) a n d t h e o r g a n i c phase v/as washed w i t h w a t e r (3 X 20 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s u n d e r r e d u c e d p r e s s u r e a f f o r d e d 126 a s a c r u d e  166 o i l (1.30 g ) . A p o r t i o n (190 mg) o f t h i s p r o d u c t was p u r i f i e d by column c h r o m a t o g r a p h y on s i l i c a g e l (5 g ) . E l u t i o n w i t h a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (19:1 v / v ) y i e l d e d 126 (135 mg, 6 6 % ) ;  IR 3500 ( 0 - H ) , 1600, 1550 cm" NMR  1  (C=0 and C=C);  ( C C 1 ) 61.53 ( s , 3, m e t h y l g r o u p p r o t o n s ) , 2.78 4  ( d , J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n c l c a r b o n ) , 2.92 ( d , J=15 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 5.95 ( s , 0.95, v i n y l p r o t o n o f e n o l ) , 7.0-7.9 (m, 10, a r o m a t i c p r o t o n s ) .  2,3-Dihydro-2,6-diphenyl-2-methy!-4H-pyran-4-one  (128)  O  128  C h l o r o f o r m (25 ml) was s a t u r a t e d w i t h h y d r o g e n . c h l o r i d e by b u b b l i n g t h e a n h y d r o u s gas d i r e c t l y t h r o u g h t h e s o l v e n t f o r 15 m i n u t e s . A s o l u t i o n o f l , 5 - d i p h e n y l - 5 - h y d r o x y h e x a n e - l , 3 - d i o n e  (126)  (90 mg, 0.32 mmole) i n c h l o r o f o r m (2 m l ) v/as added and t h e m i x t u r e v/as s t i r r e d f o r 45 m i n u t e s b e f o r e b e i n g washed w i t h w a t e r (4 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e t o y i e l d 128. (84 mg, 9 9 % ) ; mp 105-108 d e g r e e s ; lit.  7 6  mp 108-110  167 IR 1660 ( O O ) , 1600, 1575 cm" NMR  ( C C 1 ) 61.75  p r o t o n ) , 5.88  (C=C);  ( s , 3, m e t h y l group p r o t o n s ) ,  4  ( d , J=17 c p s , 1, m e t h y l e n e  1  p r o t o n ) , 2.99  ( d , J=17 c p s , 1,  2.80 methylene  ( s , 1, v i n y l p r o t o n ) , 7.1-7.9 (m, 10, a r o m a t i c p r o t o n s ) .  l,5-Diphenyl-hex-4-ene-l,3-dione  (127)  127Z  A s o l u t i o n of  2,3-dihydro-2,6-diphenyl-2-methyl-4H-  - p y r a n - 4 - o n e (128) (15 mg, 0.057 mmole) and p o t a s s i u m  hydroxide  (1 p e l l e t ) i n 95% e t h a n o l (10 ml) was s t i r r e d a t room  temperature  f o r 2 h o u r s . Water (20 ml) was added and t h e s o l u t i o n was  acidified  w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d . The e t h e r e x t r a c t s (2-X 20 ml) o f t h e m i x t u r e were washed w i t h w a t e r (2 X 10 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d a f f o r d e d 127 (13 mg,  87%);  IR 1650-1500 cm" NMR  pressure  62.26, 2.65  1  ( b r o a d , C=0 and  C=C);  ( 2 d , J=2 c p s , 3 t o t a l , v i n y l m e t h y l  group  p r o t o n s i n E and Z i s o m e r s ) , 5.65, 6.18  ( 2 s , ^1 t o t a l , v i n y l  o f e n o l i n E and Z i s o m e r s ) , 6.02,  (2q, J=2 c p s , 1 t o t a l , v i n y l  6.21  protons  168 p r o t o n i n E and Z i s o m e r s ) , 7.0-8.0 (m, 10, a r o m a t i c p r o t o n s ) .  A t t e m p t s to Form t h e Enol E t h e r o f 1 , 5 - D i p h e n y l - h e x - 4 - e n e - l  (a) U s i n g d i m e t h y l  ,3-dione  (127).  sulphate.  A s o l u t i o n of  2,3-dihydro-2,6-diphenyl-2-methyl-4H-  - p y r a n - 4 - o n e (128) (23 mg, 0.087 mmole) and p o t a s s i u m  hydroxide  (2 p e l l e t s ) i n 95% e t h a n o l (10 ml) was s t i r r e d f o r 2 hours b e f o r e w a t e r (10 ml) was a d d e d . N e x t , d i m e t h y l s u l p h a t e was added u n t i l t h e s o l u t i o n was n e u t r a l t o l i t m u s . I t was e x t r a c t e d w i t h e t h e r (2 X 10 ml) and t h e e x t r a c t s were washed w i t h water (2 X 5 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a c r u d e p r o d u c t whose t i c and IR  spectrum  indicated that i t consisted p r i m a r i l y of returned starting m a t e r i a l .  (b) With sodium h y d r i d e and i s o p r o p y l i o d i d e . A s u s p e n s i o n o f sodium h y d r i d e ( a s a 57% d i s p e r s i o n i n m i n e r a l o i l ) (6.0 mg, 0.14 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (3 ml) was put under an a t m o s p h e r e ' o f  n i t r o g e n . A s o l u t i o n o f 128 (26  mg,  0.10 mmole) i n h e x a m e t h y l p h o s p h o r a m i d e (2 ml) was added a t t h e same t i m e as i s o p r o p y l i o d i d e (18 mg, 1.05 mmole). The m i x t u r e was  stirred  f o r 18 hours a t room t e m p e r a t u r e b e f o r e b e i n g p o u r e d i n t o w a t e r (20 m l ) and e x t r a c t e d w i t h e t h e r (2 X 20 m l ) . The e x t r a c t s were washed w i t h water (5 X 10 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a p r o d u c t whose t i c showed f o u r s p o t s , t h e m a j o r one c o r r e s p o n d i n g t o s t a r t i n g m a t e r i a l .  169 A t t e m p t e d C o n d e n s a t i o n o f B e n z o y l a c e t o n e (40) w i t h 2,6-Dimethoxyacetophenone  (39).  The p r o c e d u r e f o l l o w e d i n t h i s r e a c t i o n was t h e same as t h a t d e s c r i b e d f o r t h e p r e p a r a t i o n o f  1,5-diphenyl-5-hydroxy-  h e x a n e - l , 3 - d i o n e ( 1 2 6 ) . The f o l l o w i n g r e a g e n t s were u s e d :  sodium  h y d r i d e a s a 57% d i s p e r s i o n i n m i n e r a l o i l (430 mg, 10.2 mmole), b e n z o y l a c e t o n e (40) (1.62 g, 10.0 mmole), n - b u t y l l i t h i u m i n hexane • (4.3 m l , 2.35M, 10.1 mmole), 2 , 6 - d i m e t h o x y a c e t o p h e n o n e  (39) (180 mg,  1.00 mmole), and t e t r a h y d r o f u r a n (60 ml t o t a l v o l u m e ) . In t h i s c a s e no h e x a m e t h y l p h o s p h o r a m i d e w a s u s e d . T h e p r e c i p i t a t e f o r m e d d u r i n g t h e a d d i t i o n of the benzoylacetone d i s s o l v e d a f t e r the n - b u t y l l i t h i u m was added. The c r u d e p r o d u c t o b t a i n e d f r o m t h e r e a c t i o n was d i s s o l v e d i n c h l o r o f o r m (100 ml) s a t u r a t e d w i t h h y d r o g e n c h l o r i d e g a s . A f t e r b e i n g s t i r r e d f o r 2 h o u r s t h i s s o l u t i o n was e x t r a c t e d w i t h 3N p o t a s s i u m h y d r o x i d e (3 X 20 ml) ( t o remove u n r e a c t e d b e n z o y l a c e t o n e ) , washed w i t h w a t e r (2 X 20 m l ) , and d r i e d o v e r magnesium s u l p h a t e . The m i x t u r e o f compounds o b t a i n e d a f t e r t h e s o l v e n t s were removed under r e d u c e d p r e s s u r e was s e p a r a t e d i n t o f i v e components by column c h r o m a t o g r a p h y on s i l i c a g e l (20 g ) . The f r a c t i o n s v/ere e l u t e d w i t h a m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (17:1 v / v ) . The m a j o r component was shown (IR and NMR s p e c t r a ) t o be 2 , 3 - d i h y d r o - 2 , 6 - d i phenyl-2-methyl-4H-pyran-4-one  (128) (147 mg, 11% f r o m 4 0 ) .  170 Production of the Dianion of Benzoylacetone with T r i t y l p o t a s s i u m and A l k y l a t i o n w i t h A l l y !  Bromide.  A 50 ml f l a s k c o n t a i n i n g b e n z o y l a c e t o n e (81 mg,0.50 mmole) and d r y THF (25 ml) was e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f t r i t y l p o t a s s i u m (^0.5M) i n DME was added d r o p w i s e u n t i l t h e s o l u t i o n was a v e r y dark y e l l o w c o l o u r , making i t i m p o s s i b l e t o a c c u r a t e l y determine t h e end p o i n t o f t h e t i t r a t i o n . A l l y l bromide (61 mg, 0.50 mmole) was added and t h e m i x t u r e was s t i r r e d f o r 1 hour. A f t e r t h i s t i m e , e t h e r (15 ml) was added and t h e r e a c t i o n was quenched  by t h e a d d i t i o n  o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d u n t i l t h e aqueous phase was  acidic.  The o r g a n i c phase was washed w i t h w a t e r (10 ml) and e x t r a c t e d w i t h N sodium h y d r o x i d e (3 X 10 m l ) . The combined  base e x t r a c t s were  a c i d i f i e d by a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d and r e - e x t r a c t e d w i t h e t h e r (2 X 20 m l ) . T h e s e e t h e r e x t r a c t s were washed w i t h w a t e r (2 X 10 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d 98 mg o f a m i x t u r e o f b e n z o y l a c e t o n e and a l k y l a t e d p r o d u c t . T h i s a s s u m p t i o n was on t h e NMR  based  s p e c t r u m o f t h e m i x t u r e which showed m u l t i p l e t s  a t 64.8-5.3 and 2.2-2.5 a t t r i b u t e d t o t h e v i n y l and m e t h y l e n e  protons  i n t h e a l k y l a t e d p r o d u c t ( s u p e r i m p o s e d on a s p e c t r u m o f b e n z o y l a c e t o n e ) .  171 5,7-Dimethoxy-2-hydroxy-4-methyl-l-naphthyl  phenyl ketone (156)  156  A 50 ml f l a s k c o n t a i n i n g d i i s o p r o p y l a m i n e ( 1 . 0 5 g , 10.4 mmole) and THF (20 m l ) was e q u i p p e d w i t h a m a g n e t i c  stirrer,  s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane ( 4 . 6 0 m l , 2.20M, 10.1 mmole) was added and t h e m i x t u r e was s t i r r e d f o r 5 m i n u t e s ' b e f o r e a s o l u t i o n o f b e n z o y l a c e t o n e (0.810 g , 5.00 mmole) i n d r y THF ( 5 m l ) was added. T h e r e a c t i o n was r e f l u x e d under n i t r o g e n f o r 2 h o u r s and t h e n c o o l e d t o room t e m p e r a t u r e . A s o l u t i o n o f 2,4,6-trimethoxyacetophenone  ( 9 4 ) (0.108 g , 0.515 mmole)  i n d r y THF (5 m l ) was added and t h e s o l u t i o n was s t i r r e d a t room temperature f o r 2 hours. A f t e r t h i s time, t h e contents o f the f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s s t e e l c a n n u l a t o a r a p i d l y s t i r r e d m i x t u r e o f N h y d r o c h l o r i c a c i d (50 m l ) and e t h e r (250 m l ) . The o r g a n i c phase was washed w i t h w a t e r (3 X 50 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e m i x t u r e o f compounds o b t a i n e d a f t e r e v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e was d i s s o l v e d i n c h l o r o f o r m (100 m l ) s a t u r a t e d w i t h a n h y d r o u s h y d r o g e n c h l o r i d e g a s . T h i s s o l u t i o n  172 was s t i r r e d f o r 5 h o u r s and t h e n washed w i t h w a t e r (20 ml) and e x t r a c t e d w i t h N sodium h y d r o x i d e . ( 5 X 20 m l ) . The base i n s o l u b l e p o r t i o n was washed w i t h w a t e r (3 X 20 ml) and d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o y i e l d a m i x t u r e o f compounds which was s e p a r a t e d i n t o two components by p r e p a r a t i v e t i c on s i l i c a g e l (2 p l a t e s ) . A m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (2:1 v / v ) was used t o d e v e l o p t h e p l a t e s . The band l y i n g a t R  f  0.6-0.7 was removed and e x t r a c t e d w i t h c h l o r o f o r m .  Evaporation of the c h l o r o f o r m under reduced p r e s s u r e a f f o r d e d l-phenyl-5-(2,4,6-trimethoxyphenyl)hex-4-ene-l,3-dione  (155)  (46 mg, 2 5 % ) ; s p e c t r a l d a t a as d e s c r i b e d under s y n t h e s i s o f t h i s compound below. E x t r a c t i o n o f t h e band l y i n g a t R  f  0.3-0.4 on t h e  p l a t e s a f f o r d e d ' 1 5 6 . (88 mg, 5 3 % ) . A sample o f t h i s y e l l o w c r y s t a l l i n e compound was s u b l i m e d f o r a n a l y s i s ; mp 135-137 d e g r e e s ; s p e c t r a page 230; IR 1640 ( O O ) , 1600, 1575 cm" NMR  1  (OC aromatic);  62.49 ( s , - 3 , m e t h y l g r o u p p r o t o n s ) , 3.85 ( 2 s , 6,  methoxy group p r o t o n s ) , 6.10-6.40 (m, 3, n a p h t h y l r i n g p r o t o n s ) , 7.30-8.40 (m, 5, p h e n y l r i n g p r o t o n s ) ; UV-Vis 240 ( 3 4 3 0 0 ) , 260 ( s h o u l d e r ) , 285 ( s h o u l d e r ) , 415 ( s h o u l d e r ) , 435 m p ' ( 5 1 , 5 0 0 ) ; Mass s p e c t r u m m/e 3 2 2 ( 7 9 ) , 3 0 5 ( 3 9 ) , 2 4 6 ( 1 6 ) ,  245(100),  230(18), 188(10), 147(10), 105(12), 77(29); Analysis calc'd for C 0 18°4 H  :  2  found:  C 74.52  H 5.63  C 74.40  H  5.60.  173 5-Hydroxy-l-phenyl-5-(2,4,6-trimethoxyphenyl)hexane-l,3-dione  (158)  158  A 50 ml f l a s k c o n t a i n i n g i s o p r o p y l c y c l o h e x y l a m i n e (1.150 g , 8.16 mmole) and d r y THF (20 m l ) was e q u i p p e d w i t h a m a g n e t i c  stirrer,  s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane ( 3 . 3 0 m l , 2.50M, 8.25 mmole) was added and t h e r e a c t i o n was s t i r r e d a t room t e m p e r a t u r e f o r 10 m i n u t e s . A f t e r t h i s t i m e , a s o l u t i o n o f b e n z o y l a c e t o n e ( 4 0 ) (648 mg, 4.00 mmole) i n d r y THF (5 m l ) was added and t h e r e a c t i o n v/as s t i r r e d a t room t e m p e r a t u r e f o r % hour b e f o r e b e i n g c o o l e d t o 0 d e g r e e s . A s o l u t i o n o f 2,4,6-trimethoxyacetophenone  (94) (168 mg, 0.800 mmole) i n d r y  THF (2 m l ) v/as added and t h e r e a c t i o n m i x t u r e was s t i r r e d a t 0 d e g r e e s f o r 10 m i n u t e s b e f o r e b e i n g quenched by t h e a d d i t i o n o f N h y d r o c h l o r i c a c i d (15 m l ) . T h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r (75 m l ) and t h e o r g a n i c phase was washed w i t h w a t e r (5 X 10.ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e y i e l d e d a m i x t u r e o f compounds composed p r i m a r i l y o f b e n z o y l a c e t o n e and 158 (by t i c ) . I s o l a t i o n o f t h e p r o d u c t was  174 a c c o m p l i s h e d by p r e p a r a t i v e t i c on s i l i c a g e l (5 p l a t e s ) u s i n g a c a r b o n t e t r a c h l o r i d e - e t h e r m i x t u r e (2:1 v / v ) a s d e v e l o p i n g s o l v e n t . The band l y i n g a t R  f  0.3-0.4 was removed and e x t r a c t e d w i t h c h l o r o f o r m .  E v a p o r a t i o n o f t h e c h l o r o f o r m under r e d u c e d p r e s s u r e a f f o r d e d 158 (303 mg, 100%) as a l i g h t y e l l o w o i l ; s p e c t r a page 231; IR 3550-3500 ( 0 - H ) , 1650-1550 cm"  1  ( C O and C=C);  NMR ( a s s i g n m e n t s i m p l i f i e d by i g n o r i n g t h e k e t o t a u t o m e r p r e s e n t i n m i n o r amount) 61.75 ( s , 3, c a r b i n o l c a r b o n m e t h y l g r o u p p r o t o n s ) , 2.89 ( d , J=14 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.24 ( d , J=14 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.75 ( 2 s , 9, methoxy group p r o t o n s ) , 6.15 ( s , 1, v i n y l p r o t o n o f e n o l ) , 6.18 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 7.2-7.8 (m, 5, p r o t o n s on p h e n y l r i n g ) ; UV 338 my  (10,200);  Mass s p e c t r u m ( a ) low r e s o l u t i o n m/e 3 5 4 ( 5 0 ) , 3 3 8 ( 1 0 ) , 324(17), 323(76), 322(17), 249(12), 221(17), 219(14), 194(14), 193(43), 177(12), 168(26), 147(45), 106(10), 105(100), 91(14), 77(48), 68(52); (b) h i g h r e s o l u t i o n c a l c ' d f o r C 354.147 amu, f o u n d 354.151 m/e.  HO 21 22  (P-18), 5  175 l - P h e n y l - 5 - ( 2 , 4 , 6 - t i m e t h o x y p h e n y l ) h e x - 4 - e n e - l , 3 - d i o n e (155)  C h l o r o f o r m (40 m l ) was s a t u r a t e d w i t h h y d r o g e n c h l o r i d e by b u b b l i n g t h e a n h y d r o u s g a s t h r o u g h t h e s o l v e n t f o r % hour. A solution of  5-hydroxy-l-phenyl-5-(2,4,6-trimethoxyphenyl)hexane-  - 1 , 3 - d i o n e (158) (149.mg, 0.412 mmole) i n c h l o r o f o r m (2 m l ) was added and t h e s o l u t i o n was s t i r r e d f o r lh h o u r s b e f o r e b e i n g washed w i t h ' w a t e r (5 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d 155 (138 mg, 97%) as a c r u d e o r a n g e o i l c o n t a i n i n g some 156 (by t i c ) ; s p e c t r a page 232; IR 1650-1550 cm"  1  (C=0 and C=C)  NMR 62.15, 2.49 ( 2 d , J=2 c p s , 3 t o t a l , v i n y l m e t h y l g r o u p p r o t o n s i n E and Z i s o m e r s ) , 4.75-4.85 ( s e v e r a l s , 9 t o t a l , methoxy group p r o t o n s ) , 5.90-6.40 (m, v i n y l p r o t o n , v i n y l p r o t o n o f e n o l , t r i m e t h o x y p h e n y l r i n g p r o t o n s ) , 7.30-8.20 (m, 5, p h e n y l ring protons).  176  Attempted A c y l a t i o n o f Acetone with Methyl  2,4,6-trimethoxybenzoate.  In each o f t h e c a s e s d e s c r i b e d below t h e f o l l o w i n g p r o c e d u r e was u s e d . Sodium h y d r i d e a s a 57% d i s p e r s i o n i n m i n e r a l o i l (86 mg, 2.05 mmole), or_ sodium a m i d e (80 mg, 2.05 mmole) was added t o a s o l u t i o n o f m e t h y l 2 , 4 , 6 - t r i m e t h o x y b e n z o a t e  (226 mg,  1.00 mmole) i n t h e d e s i g n a t e d s o l v e n t i n a 50 ml f l a s k . The f l a s k v/as f l u s h e d w i t h n i t r o g e n and a c e t o n e (116 mg, 2.00 mmole) ( d r i e d o v e r p o t a s s i u m c a r b o n a t e ) v/as a d d e d , d r o p w i s e , w i t h s t i r r i n g , o v e r a p e r i o d o f 10 m i n u t e s . The m i x t u r e was t h e n r e f l u x e d under n i t r o g e n f o r 2-3 h o u r s . A f t e r t h i s t i m e c o n c e n t r a t e d h y d r o c h l o r i c a c i d v/as added u n t i l t h e aqueous phase v/as a c i d i c . The c o n t e n t s o f t h e f l a s k were t h e n poured i n t o e t h e r (50 m l ) a n d t h e o r g a n i c . p h a s e , was washed, w i t h w a t e r (4 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e y i e l d e d t h e p r o d u c t s d e s c r i b e d i n each c a s e .  (a) U s i n g anhydrous e t h e r as s o l v e n t . The t i c and IR s p e c t r a o f t h e p r o d u c t s o b t a i n e d f r o m b o t h bases i n d i c a t e d them t o be e x c l u s i v e l y r e t u r n e d s t a r t i n g m a t e r i a l .  (b) U s i n g DME a s s o l v e n t . The DME v/as d r i e d f o r t h i s r e a c t i o n by s t a n d i n g o v e r sodium h y d r i d e . T h e t i c and IR s p e c t r a o f t h e p r o d u c t s o b t a i n e d f r o m b o t h b a s e s i n d i c a t e d them t o be p r i m a r i l y r e t u r n e d s t a r t i n g m a t e r i a l .  177 ( c ) U s i n g d i g l y m e as s o l v e n t . The d i g l y i n e was d r i e d f o r t h i s r e a c t i o n by s t a n d i n g o v e r sodium h y d r i d e . In t h i s c a s e t h e t i c o f t h e p r o d u c t o b t a i n e d f r o m the r e a c t i o n s ( i d e n t i c a l f o r both bases) i n d i c a t e d the presence o f one major p r o d u c t and v e r y l i t t l e s t a r t i n g m a t e r i a l . The f o l l o w i n g s p e c t r a l d a t a v/as g a t h e r e d f o r t h i s compound; IR 3300 ( s h a r p ) , 3500-2500 ( b r o a d ) , 1680, 1630, 1590 NMR 6.17  63.85 ( s , 3 ) , 4.03  ( s , 3 ) , 6.00  cm" ; 1  ( d , J=3 c p s , 1 ) ,  ( d , J=3 c p s , 1 ) . A r e f l u x time of f i v e minutes f o r t h i s r e a c t i o n (using  sodium h y d r i d e ) r e s u l t e d i n a m i x t u r e whose t i c showed f o u r s p o t s . Tv/o o f t h e s e c o r r e s p o n d e d t o s t a r t i n g m a t e r i a l and t h e p r o d u c t d e s c r i b e d above. The IR s p e c t r u m o f t h e m i x t u r e gave no i n d i c a t i o n t h a t i t c o n t a i n e d any  8-diketone.  Attempted A c y l a t i o n of 2,4,6-Trimethoxyacetophenone  (94) w i t h  L i t h i u m D i c y c l o h e x y l a m i d e and E t h y l A c e t a t e ;  A f l a s k containing a s o l u t i o n of dicyclohexylamine (95 mg, 0.53 mmole) i n d r y THF (3 m l ) was e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.225 m l , 0.527 mmole) was added. A f t e r 15 m i n u t e s a s o l u t i o n o f 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e  (94) (105  0.500 mmole) i n d r y THF was added. A w h i t e p r e c i p i t a t e formed  mg,  178 g r a d u a l l y i n t h e r e a c t i o n f l a s k o v e r a p e r i o d o f 1 hour. A f t e r t h i s t i m e , e t h y l a c e t a t e (45 mg, 0.51 mmole) was added and t h e m i x t u r e was s t i r r e d f o r 3 h o u r s . T h e p r e c i p i t a t e d i d n o t d i s s o l v e d u r i n g t h i s t i m e . The c o n t e n t s o f t h e f l a s k were poured i n t o a r a p i d l y s t i r r e d m i x t u r e o f N h y d r o c h l o r i c a c i d (5 m l ) and e t h e r (15 m l ) . The aqueous l a y e r was e x t r a c t e d w i t h e t h e r (2 X 5 m l ) and t h e combined o r g a n i c s were washed w i t h N h y d r o c h l o r i c a c i d (2 X 5 m l ) and water (3 X 10 m l ) , and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d 102 mg o f a compound whose t i c i n d i c a t e d i t t o be r e t u r n e d s t a r t i n g m a t e r i a l . A s i m i l a r experiment  i n which d i i s o p r o p y l a m i n e (51 mg,  0.51 mmole) was used i n s t e a d o f d i c y c l o h e x y l a m i n e had i d e n t i c a l results.  Reaction o f 2,4,6-Trimethbxyacetophenone  (94) w i t h n - B u t y l l i t h i u m .  A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f acetophenone  2,4,6-trimethoxy-  ( 9 4 ) (95 mg, 0.54 mmole) i n d r y THF (5 m l ) was e q u i p p e d  w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , f l u s h e d w i t h n i t r o g e n , and c o o l e d t o 0 d e g r e e s . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.200 m l , 2.34M, 0.477 mmole) was added and t h e r e a c t i o n was s t i r r e d f o r 2 hours w h i l e b e i n g a l l o w e d t o warm t o room  temperature.  A f t e r t h i s t i m e t h e c o n t e n t s o f t h e f l a s k were poured i n t o d e u t e r i u m o x i d e (5 m l ) . E t h e r (25 m l ) was added and t h e o r g a n i c p h a s e was  179  washed w i t h N h y d r o c h l o r i c a c i d (5 m l ) and w a t e r (3 X 5 m l ) , and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e y i e l d e d 109 mg, o f a p r o d u c t whose t i c showed one m a i n s p o t . The IR s p e c t r u m o f t h e p r o d u c t i n d i c a t e d c a r b o n y l a d d i t i o n ; IR 3550, 1610, 1590 cm" . 1  l - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t a n e - l , 3 - d i o n e (121)  (a) Using t r i y l p o t a s s i u m as base. A 250 ml f l a s k c o n t a i n i n g a s o l u t i o n o f 2 , 4 , 6 - t r i m e t h o x y acetophenone  (94) (1.976 g , 9.41 mmole) i n d r y THF (175 m l ) was  e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f t r i t y l p o t a s s i u m i n DME (^O.SM) was added d r o p w i s e u n t i l a permanent r e d c o l o u r a p p e a r e d i n t h e r e a c t i o n m i x t u r e . D u r i n g t h i s a d d i t i o n a f l o c c u l e n t w h i t e p r e c i p i t a t e was f o r m e d . M e t h y l a c e t a t e (10.0 m l , 132 mmole) was added and t h e r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s , d u r i n g w h i c h  180 time the p r e c i p i t a t e d i s s o l v e d . Next, the contents of the f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s s t e e l c a n n u l a t o a r a p i d l y s t i r r e d m i x t u r e o f N h y d r o c h l o r i c a c i d (100 ml) and e t h e r (500 m l ) . The aqueous phase was e x t r a c t e d w i t h e t h e r (2 X 50 ml) and t h e  combined  o r g a n i c s were washed w i t h w a t e r (100 ml) and e x t r a c t e d w i t h N sodium h y d r o x i d e (3 X 75 m l ) . The combined base e x t r a c t s were a c i d i f i e d by t h e a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d and r e - e x t r a c t e d w i t h e t h e r (3 X 75 m l ) . The combined e t h e r e x t r a c t s were washed w i t h w a t e r (3 X 50 ml) and d r i e d o v e r magnesium s u l p h a t e . The p r o d u c t o b t a i n e d a f t e r e v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e was r e c r y s t a l l i z e d f r o m e t h a n o l - 1 i g r o i n t o a f f o r d 121 (0.876 g, 3 7 % ) ; mp 102-104; s p e c t r a page 233; IR 1650-1560 cm"  1  (C=C and  CO);  NMR 62.11 ( s , 2, t e r m i n a l m e t h y l g r o u p i n e n o l t a u t o m e r ) , 2.26 ( s , 1, t e r m i n a l m e t h y l g r o u p i n k e t o t a u t o m e r ) , 3.8 (m,.^10, methoxy g r o u p p r o t o n s and m e t h y l e n e p r o t o n s o f k e t o t a u t o m e r ) , 5.74 ( s , 0.66, v i n y l p r o t o n o f e n o l t a u t o m e r ) , 6.15 ( 2 s , 2 t o t a l , a r o m a t i c p r o t o n s i n k e t o and e n o l t a u t o m e r s ) ; UV 295 mp  (15,200);  Mass s p e c t r u m m/e 2 5 2 ( 1 5 ) , 2 2 1 ( 4 0 ) , 1 9 6 ( 1 3 ) ,  195(100),  168(19), 167(15), 165(15), 153(10), 137(10), 70(12), 61(12); Analysis calc'd for C H 0 :  C 61.90  H  6.39  found:  C 61.79  H  6.40,  1 3  1 6  5  The base i n s o l u b l e p o r t i o n o f t h e p r o d u c t m i x t u r e f r o m t h e above r e a c t i o n ( s t i l l i n e t h e r ) was washed w i t h water (3 X 50 ml) and d r i e d o v e r magnesium s u l p h a t e . The m i x t u r e o b t a i n e d a f t e r t h e  181 • s o l v e n t s were removed under r e d u c e d p r e s s u r e was r e c y c l e d t w i c e f o l l o w i n g t h e same p r o c e d u r e a s o u t l i n e d above. T h i s r e s u l t e d i n an o v e r a l l y i e l d o f 55% f r o m t h e o r i g i n a l  2,4,6-trimethoxyaceto-  phenone. An e x p e r i m e n t s i m i l a r t o t h e one d e s c r i b e d above, i n which t h e r e a c t i o n was r e f l u x e d f o r 4 h o u r s a f t e r t h e a d d i t i o n o f t h e methyl a c e t a t e , and t h e n worked up a s d e s c r i b e d r e s u l t e d i n a 33% y i e l d o f 121 ( w i t h no r e c y c l i n g ) .  (b) U s i n g l i t h i u m d i c y c l o h e x y l a m i d e a s b a s e . A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f d i c y c l o h e x y l a m i n e . (370 mg, 2.05 mmole) i n d r y THF (5 m l ) was e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , a n d f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.875 m l , 2.34M, 2.05 mmole) was added and t h e s o l u t i o n was s t i r r e d f o r 10 m i n u t e s b e f o r e acetophenone  2,4,6-trimethoxy-  (94) (210 mg, 1.00 mmole) i n THF (1 m l ) was added.  The m i x t u r e was s t i r r e d f o r 45 m i n u t e s a t room t e m p e r a t u r e d u r i n g which time a f l o c c u l e n t white p r e c i p i t a t e formed. Methyl a c e t a t e (1.00 m l , 13.2 mmole) was added a n d t h e s o l u t i o n was s t i r r e d f o r 16 h o u r s . A f t e r t h i s t i m e , t h e p r e c i p i t a t e had c o m p l e t e l y d i s s o l v e d and t h e c o n t e n t s o f t h e f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s s t e e l c a n n u l a t o a r a p i d l y s t i r r e d m i x t u r e o f N h y d r o c h l o r i c a c i d (10 m l ) and e t h e r (50 m l ) . T h e aqueous phase was e x t r a c t e d w i t h e t h e r ( 2 X 5 and t h e combined  o r g a n i c s were washed w i t h N h y d r o c h l o r i c a c i d  (3 X 10 m l ) and w a t e r (3 X 10 m l ) b e f o r e b e i n g e x t r a c t e d w i t h N sodium h y d r o x i d e (3 X 20 m l ) . The combined  base e x t r a c t s were  132 ' a c i d i f i e d w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d and r e - e x t r a c t e d w i t h e t h e r (3 X 20 m l ) . The e t h e r e x t r a c t s were washed w i t h water (2 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . T h e c r u d e p r o d u c t o b t a i n e d a f t e r e v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e was r e c r y s t a l l i z e d from e t h a n o l - l i g r o i n t o a f f o r d 121 (104 mg, 4 1 % ) ; s p e c t r a l d a t a a s in ( a ) .  Deuteration Studies.  (a) 1 , 3 , 5 - T r i m e t h o x y b e n z e n e  ( 1 6 8 ) w i t h sodium h y d r i d e .  Sodium h y d r i d e a s a 57% d i s p e r s i o n i n m i n e r a l o i l (48 mg, 1.1 mmole) was suspended  i n d r y THF (5 m l ) i n a 10 ml f l a s k  e q u i p p e d w i t h a m a g n e t i c s t i r r e r . T h e f l a s k was s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f 168 (168 mg, 1.00 mmole) i n d r y THF (2 m l ) was added and t h e m i x t u r e was s t i r r e d f o r 2 h o u r s a t room t e m p e r a t u r e . A f t e r t h i s t i m e , d e u t e r i u m o x i d e (1 m l ) was added. T h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r ( 2 0 m l ) and t h e o r g a n i c phase was washed w i t h N h y d r o c h l o r i c a c i d (5 m l ) and water (3 X 5 m l ) , and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s u n d e r r e d u c e d p r e s s u r e a f f o r d e d a p r o d u c t whose NMR s p e c t r u m was i d e n t i c a l t o t h a t o f t h e s t a r t i n g m a t e r i a l .  (b) 1,3,5-Trimethoxybenzene  (168) w i t h l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e .  A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f i s o p r o p y l c y c l o h e x y l a m i d e (149 mg, 1.06 mmole) i n d r y THF (5 m l ) was e q u i p p e d w i t h  183 • a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane. (0.480 m l , 2.20M, 1.06 mmole) was added. A f t e r 5 m i n u t e s a s o l u t i o n o f 168 (168 mg, 1.00 mmole) i n THF was added and t h e r e a c t i o n was s t i r r e d a t room t e m p e r a t u r e f o r 2 h o u r s . A f t e r t h i s t i m e , d e u t e r i u m o x i d e (1 m l ) was added and t h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r (20 m l ) . The o r g a n i c phase was washed w i t h N h y d r o c h l o r i c a c i d (2 X 5 m l ) and w a t e r (3 X 5 m l ) . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a p r o d u c t whose NMR s p e c t r u m v/as i d e n t i c a l t o t h a t o f t h e s t a r t i n g material.  (c) 1,3,5-Trimethoxybenzene  (168) w i t h n - b u t y l l i t h i u m .  A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f 168 (168 mg, 1.00 mmole) i n d r y THF (5 m l ) v/as e q u i p p e d w i t h a m a g n e t i c  stirrer,  s t o p p e r e d w i t h a serum ca-p, f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.500 m l , 2.20M, 1.10 mmole) was added. A w h i t e p r e c i p i t a t e formed d u r i n g t h i s a d d i t i o n . A f t e r 1% h o u r s  deuterium  o x i d e (1 m l ) was added and t h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r (20 m l ) . T h e o r g a n i c phase v/as washed w i t h N h y d r o c h l o r i c a c i d (5 m l ) and w a t e r (3 X 5 m l ) , a n d d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were e v a p o r a t e d under r e d u c e d p r e s s u r e . I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h e p r o d u c t g a v e t h e f o l l o w i n g peak r a t i o s : methoxy p r o t o n s - . a r o m a t i c  protons=9:2.  184 • (d) 2 , 4 , 6 - T r i m e t h o x y a c e t o p h e n o n e (94) w i t h sodium h y d r i d e (one equivalent). The p r o c e d u r e d e s c r i b e d i n ( a ) was employed i n t h i s e x p e r i m e n t . The f o l l o w i n g r e a g e n t s v/ere u s e d : sodium h y d r i d e d i s p e r s i o n (48 mg, 1.1 mmole), 94_ (210 mg, 1.00 mmole). The NMR s p e c t r u m o f t h e p r o d u c t was i d e n t i c a l t o t h a t o f t h e s t a r t i n g m a t e r i a l .  (e) 2 , 4 , 6 - T r i m e t h o x y a c e t o p h e n o n e (940 w i t h sodium h y d r i d e (tv/o equivalents). The p r o c e d u r e d e s c r i b e d i n ( a ) was employed i n t h i s e x p e r i m e n t . The f o l l o w i n g r e a g e n t s were u s e d : sodium h y d r i d e d i s p e r s i o n (93 mg, 2.2 mmole), 94 (210 mg, 1.00 mmole). The NMR s p e c t r u m o f t h e p r o d u c t was i d e n t i c a l t o t h a t o f t h e s t a r t i n g m a t e r i a l .  ( f ) 2 , 4 , 6 - T r i m e t h o x y a c e t o p h e n o n e (94.) w i t h l i t h i u m i s o p r o p y l c y c l o h e x y l a m i d e (one e q u i v a l e n t ) . The p r o c e d u r e d e s c r i b e d i n ( b ) was employed i n t h i s e x p e r i m e n t . The f o l l o w i n g r e a g e n t s were u s e d : i s o p r o p y l c y c l o h e x y l a m i n e (149 mg, 1.06 mmole), n - b u t y l l i t h i u m i n hexane (0.480 m l , 2.20M, 1.06 mmole), and 94 (210 mg, 1.00 mmole). A w h i t e p r e c i p i t a t e a p p e a r e d i n t h e r e a c t i o n f l a s k over a p e r i o d o f 1 hour a f t e r t h e a d d i t i o n o f 94. I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h e p r o d u c t gave t h e f o l l o w i n g peak r a t i o s : a r o m a t i c p r o t o n s : m e t h o x y g r o u p p r o t o n s : m e t h y l g r o u p p r o t o n s = 2 : 9 : 2 . 5 . The s i g n a l f o r t h e m e t h y l p r o t o n s was b r o a d compared to that f o r the s t a r t i n g m a t e r i a l . A s i m i l a r e x p e r i m e n t i n v o l v i n g one e q u i v a l e n t o f l i t h i u m d i c y c l o h e x y l a m i d e gave c o m p a r a b l e r e s u l t s .  185 ' (g) S u b l i m e d 2 , 4 , 6 - t r i m e t h o x y a c e t o p h e n o n e c y c l o h e x y l a m i d e (one  (94) w i t h l i t h i u m  isopropyl-  equivalent).  A s u b l i m e d (90 d e g r e e s , 0.2 mm) i n t h i s c a s e . The p r o c e d u r e d e s c r i b e d  sample o f 94 was  used  i n (b) and t h e r e a g e n t s  described  i n ( f ) were employed. The r e s u l t s were i d e n t i c a l t o t h o s e o b t a i n e d in ( f ) .  (h) 2 , 4 , 6 - T r i m e t h o x y a c e t o p h e n o n e (two  with lithium isopropylcyclohexylamide  equivalents). The p r o c e d u r e d e s c r i b e d  i n (b) v/as employed. The r e a g e n t s  used were: i s o p r o p y l c y c l o h e x y l a m i n e (298 mg, 2.12 mmole),  n-butyllithium  i n hexane (0.950 m l , 2.20M, 2.09 mmole), and 94^ (210 mg, 1.00 mmole). A w h i t e p r e c i p i t a t e formed o v e r a p e r i o d o f 1 hour a f t e r t h e a d d i t i o n o f 94_. I n t e g r a t i o n o f t h e NMR peak r a t i o s :  aromatic protons:methoxy  protons=2:9:2. the starting  spectrum of the product gave the group protons:methyl  following  group  The m e t h y l g r o u p s i g n a l was broad compared t o t h a t o f material.  T h i s e x p e r i m e n t was r e p e a t e d i n a t e s t t u b e and a f t e r t h e p r e c i p i t a t e had f o r m e d t h e t u b e was c e n t r i f u g e d separation  to get a clear  between t h e p r e c i p i t a t e and t h e s u p e r n a t a n t  solution.  The s u p e r n a t a n t was t r a n s f e r r e d , u n d e r n i t r o g e n , v i a a s t a i n l e s s s t e e l c a n n u l a , t o a n o t h e r f l a s k . The two components were w i t h d e u t e r i u m o x i d e and worked up s e p a r a t e l y . The f r a c t i o n y i e l d e d 165 mg (85%) o f t h e p r o d u c t . The NMR to t h e one d e s c r i b e d  quenched  precipitate  and t h e s u p e r n a t a n t f r a c t i o n 30 mg  s p e c t r a o f b o t h f r a c t i o n s were i d e n t i c a l  above.  (15%)  186 ' ( i ) 2,4,6-Trimethoxyacetophenone  (94) with t r i t y l p o t a s s i u m .  A 25 ml f l a s k c o n t a i n i n g a s o l u t i o n o f 94 (99 mg, 0.47 mmole) i n d r y DME (10 m l ) was e q u i p p e d w i t h a m a g n e t i c  stirrer,  s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t syringe n e e d l e s , and f l u s h e d with n i t r o g e n . A s o l u t i o n o f t r i t y l p o t a s s i u m i n DME (>v0.5M) was added d r o p w i s e u n t i l a permanent r e d c o l o u r appeared i n t h e mixture. During t h e a d d i t i o n a white p r e c i p i t a t e was f o r m e d . D e u t e r i u m o x i d e (2 m l ) was added and t h e c o n t e n t s o f t h e f l a s k were poured i n t o e t h e r ( 3 0 m l ) . T h e o r g a n i c phase was washed w i t h w a t e r u n t i l n e u t r a l a n d d r i e d o v e r magnesium s u l p h a t e . The s o l v e n t s were e v a p o r a t e d under r e d u c e d p r e s s u r e . I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h e p r o d u c t m i x t u r e o b t a i n e d g a v e t h e f o l l o w i n g peak r a t i o s f o r t h e peaks a s s i g n e d t o t h e a c e t o p h e n o n e : aromatic protons:methoxy  group protons:methyl group  (j) l-(2,4,6-Trimethoxyphenyl)butane-l,3-dione  protons=2:9:2.  (121) with l i t h i u m  i s o p r o p y l c y c l o h e x y l a m i d e (two e q u i v a l e n t s ) . The p r o c e d u r e d e s c r i b e d i n ( b ) was employed. T h e f o l l o w i n g r e a g e n t s were u s e d : i s o p r o p y l c y c l o h e x y l a m i n e (295 mg, 2.06 mmole), n - b u t y l l i t h i u m i n hexane (0.820 m l , 2.50M, 2.05 mmole), a n d T j n (252 mg, 1.00 mmole), I n t e g r a t i o n o f t h e NMR s p e c t r u m o f t h e p r o d u c t gave t h e f o l l o w i n g peak r a t i o s :  aromatic protons:methoxy  p r o t o n s : t e r m i n a l m e t h y l g r o u p p r o t o n s ( t o t a l k e t o and  group  enol)=2:9:2.  187 3-Methyl-5-phenylisoxazole  (191)  A solution of benzoylacetone and h y d r o x y l a m i n e  (40J (162 mg, 1.00 mmole)  h y d r o c h l o r i d e (78 mg, 1.1 mmole) i n 95% e t h a n o l  (30 m l ) was r e f l u x e d u n t i l t h e s o l u t i o n g a v e a n e g a t i v e f e r r i c c h l o r i d e t e s t (^3 h o u r s ) . The e t h a n o l was e v a p o r a t e d under  reduced  p r e s s u r e and t h e r e s u l t i n g m i x t u r e was poured i n t o e t h e r (30 m l ) . The o r g a n i c p h a s e was washed w i t h w a t e r (3 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d  pressure  y i e l d e d a c r u d e p r o d u c t which was r e c r y s t a l l i z e d from  ethanol-ligroin  t o a f f o r d 191_ (138 mg, 8 7 % ) ; mp 62-65 d e g r e e s ; l i t .  mp 67 d e g r e e s ;  1 0 9  NMR 62.32 ( s , 3, m e t h y l g r o u p p r o t o n s ) , 6.34 ( s , 1, i s o x a z o l e p r o t o n ) , 7.2-8.0 (m, 5, a r o m a t i c p r o t o n s ) .  188 • 3 - M e t h y l - 5 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) i s o x a z o l e (183)  N—O  OMe  183  T h i s compound was p r e p a r e d by t h e method used i n t h e s y n t h e s i s o f 3-methyl-5-phenylisoxazole (191). The f o l l o w i n g r e a g e n t s were u s e d : 1 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t a n e - l , 3 - d i o n e ( 1 2 1 ) (490 mg, 1.94 mmole) and 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 (150 mg, 2.13 mmole). The c r u d e p r o d u c t was r e c r y s t a l l i z e d f r o m a c e t o n e - 1 i g r o i n t o a f f o r d 183 (364 mg, 7 5 % ) . A sample o f t h i s was s u b l i m e d (145 d e g r e e s , 0.04 mm) f o r a n a l y s i s ; mp 173-175 d e g r e e s ; s p e c t r a page 234; IR 1620, 1600 cm"  1  (C=C);  NMR 62.33 ( s , 3, m e t h y l g r o u p p r o t o n s ) , 3.80 ( s , 6 , o r t h o - m e t h o x y g r o u p p r o t o n s ) , 3.85 ( s , 3, p a r a - m e t h o x y g r o u p p r o t o n s ) , 6.20 ( s , 2, a r o m a t i c p r o t o n s ) , 6.25 ( s , 1, i s o x a z o l e p r o t o n ) , UV 275 my ( 1 4 , 4 0 0 ) ; Mass s p e c t r u m m/e 2 4 9 ( 1 0 0 ) , 2 0 6 ( 1 1 ) , 1 9 6 ( 6 5 ) , 1 9 4 ( 1 1 ) , 193(17), 180(11), 179(15), 178(11), 177(11), 165(10), 163(17), 152(10), 151(10), 150(10), 149(15), 137(24), 121(13), 109(11), 78(10), 69(15); Analysis calc'd f o r C H 0 N: 4  C 62.64  H 6.07  N 5.62  found:  C 62.37  H 6.21  N 5.32.  1 3  1 5  189 '. A t t e m p t e d A l k y l a t i o n o f 3 - M e t h y l - 5 - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) i s o x a z o l e (183) with ATlyl  Bromide.  (a) U s i n g n - b u t y l l i t h i u m a s b a s e . A f l a s k c o n t a i n i n g a s o l u t i o n o f 183_ (50 mg, 0.20 mmole) i n d r y THF (5 m l ) was e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , f l u s h e d w i t h n i t r o g e n , and c o o l e d t o -78 d e g r e e s i n a d r y i c e - a c e t o n e b a t h . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.130 m l , 2.00M, 0.260 mmole) was added and t h e 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 a t -78 d e g r e e s f o r 45 m i n u t e s . A f t e r t h i s t i m e , a l l y ! bromide (0.020 m l , 0.23 mmole) was added and t h e r e a c 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 45 m i n u t e s a t -78 d e g r e e s . A f t e r e t h e r (10 m l ) had been added t c t h e f l a s k , N h y d r o c h l o r i c a c i d was added u n t i l t h e aqueous phase was a c i d i c . T h e o r g a n i c phase was washed w i t h water (3 X 5 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e y i e l d e d 49 mg o f a compound whose t i c and NMR s p e c t r u m i n d i c a t e d i t t o be r e t u r n e d s t a r t i n g m a t e r i a l .  (b) U s i n g l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i d e a s b a s e . A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i n e (30 mg, 2.1 mmole) i n d r y THF -was e q u i p p e d w i t h a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.130 m l , 2.00M, 0.260 mmole) was added and t h e m i x t u r e was s t i r r e d f o r 10 m i n u t e s a t room t e m p e r a t u r e  before  190 • a solution of 183 (50 mg, 0.20 mmole) in dry THF (2 ml) was added. After the resulting solution had been stirred for 1 hour, a l l y l bromide (0.020 ml, 0.23 mmole) v/as added. The reaction was stirred for 45 minutes at room temperature before the contents of the flask were transferred via a stainless steel cannula to a rapidly stirred mixture of saturated aqueous ammonium chloride solution (10 ml) and ether (50 ml). The organic phase was washed with water (3 X 10 ml) and dried over magnesium sulphate. Evaporation of the solvents under reduced pressure afforded 47 mg of a compound whose t i c and NMR. spectrum indicated i t to be returned starting material.  2,3-Dimethyl-5-(2,4,6-trimethoxyphenyl)isoxazolium fluorosulphonate (202)  Methyl fluorosulphonate (1.50 g, 13.2 mmole) was added to a solution of 3-methyl-5-(2,4,6-trimethoxyphenyl)isoxazole  (183)  (0.490 g, 1.97 mmole) in dry methylene chloride (20 ml). A white precipitate formed gradually for 10 minutes after the addition. The mixture was stirred at room temperature for 2 hours before the  191 ' p r e c i p i t a t e was c o l l e c t e d on a f i l t e r and d r i e d i n v a c u o t o a f f o r d 202 (0.486 g , 68%).  A sample was p u r i f i e d f o r a n a l y s i s by d i s s o l v i n g  i t i n a c e t o n i t r i l e and p r e c i p i t a t i n g i t w i t h e t h e r . T h i s p r o c e s s was r e p e a t e d t w i c e and t h e sample was d r i e d i n v a c u o (90 0.2 mm);  mp 235-240; s p e c t r a page IR (KBr) 1625, 1580 cm" NMR  3.98  degrees,  235; 1  (C=C and  ON);  (CD CN) 62.60 ( s , 3, C-3 methyl g r o u p p r o t o n s ) , 3  ( 2 s , 9 t o t a l , m e t h o x y g r o u p p r o t o n s ) , 4.16  g r o u p p r o t o n s ) , 6.38  ( s , 3, N-methyl  ( s , 2, a r o m a t i c p r o t o n s ) , 7.19  ( s , 1, i s o x a z o l e  proton); UV 332 my  Attempted  (24,200);  Analysis calc'd for C ^ H ^ N F S ;  C 46.28  H 4,99  N 3.85  found:  C 45,84  H 5,20  N 3,45,  Condensation  of  2,3-Dimethyl-5-(2,4,6-trimethoxyphenyl)=  i s o x a z o l i u m f l u o r o s u l p h o n a t e (202) w i t h A c e t o p h e n o n e ,  A m i x t u r e o f a c e t o p h e n o n e (31 mg, 0.25 mmole), 202 (91  mg,  0.25 mmole), and p i p e r i d i n e (25 mg, 0.29 mmole) i n a b s o l u t e ethanol (5 ml) was h e a t e d t o r e f l u x . M o s t o f t h e s a l t d i s s o l v e d on h e a t i n g . the  A f t e r b e i n g r e f l u x e d f o r 16 hours t h e m i x t u r e was c o o l e d and  s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e . The p r o d u c t was d i s s o l v e d i n a c e t o n i t r i l e and p r e c i p i t a t e d w i t h e t h e r . The p r e c i p i t a t e was c o l l e c t e d on a f i l t e r and d r i e d i n v a c u o . I t s NMR i d e n t i c a l to t h a t of the s t a r t i n g m a t e r i a l .  spectrum  was  192 " Attempted A c y l a t i o n o f 2,3-Dimethyl-5-(2,4,6-trimethoxyphenyl)isoxazolium  fluorosulphonate  (202) w i t h Benzoyl  Chloride.  (a) In d i o x a n e . A m i x t u r e o f b e n z o y l c h l o r i d e (50 mg, 0.35 mmole), 202 (91 mg, 0.25 mmole), and t r i e t h y l a m i n e  (35 mg, 0.35 mmole) i n  d r y d i o x a n e (4 m l ) was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s . A f t e r t h i s time t h e m i x t u r e was f i l t e r e d and t h e p r e c i p i t a t e was washed w i t h e t h e r and d r i e d i n v a c u o . I t s NMR s p e c t r u m was i d e n t i c a l to that o f the s t a r t i n g  material.  A s i m i l a r e x p e r i m e n t i n w h i c h t h e m i x t u r e was r e f l u x e d f o r 60 hours had i d e n t i c a l r e s u l t s .  (b) In a c e t o n i t r i l e . A s o l u t i o n o f b e n z o y l c h l o r i d e (50 mg, 0.35 mmole), 202 (91 mg, 0.25 mmole), and t r i e t h y l a m i n e  (35 mg, 0.35 mmole) was  s t i r r e d a t room t e m p e r a t u r e f o r 24 h o u r s . A f t e r t h i s t i m e , e t h e r (10 was added and t h e 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 on a f i l t e r . I t was r e d i s s o l v e d  i n a c e t o n i t r i l e and a g a i n p r e c i p i t a t e d w i t h  e t h e r , and c o l l e c t e d on a f i l t e r . I t was d r i e d i n v a c u o t o a f f o r d a compound whose NMR s p e c t r u m was i d e n t i c a l t o t h a t o f t h e s t a r t i n g material.  193 ' l-(2,4,6-trimethoxyphenyl)hept-6-ene-l,3-dione (205)  A 10 ml f l a s k c o n t a i n i n g a s o l u t i o n o f i s o p r o p y l c y c l o hexylamine  (285 mg, 2.02 mmole) i n d r y THF (5 m l ) was e q u i p p e d w i t h  a m a g n e t i c s t i r r e r , s t o p p e r e d w i t h a serum c a p , f i t t e d w i t h n i t r o g e n i n l e t and o u t l e t s y r i n g e n e e d l e s , and f l u s h e d w i t h n i t r o g e n . A s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (0.825 m l , 2.50M, 2.06 mmole) was added and t h e 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 a t room  temperature  f o r 10 m i n u t e s . A f t e r t h i s t i m e , a s o l u t i o n o f l - ( 2 , 4 , 6 - t r i m e t h o x y phenyl ) b u t a n e - l , 3 - d i o n e (121) (252 mg, 1.00 mmole) i n d r y THF (2 m l ) was added and t h e s o l u t i o n was s t i r r e d f o r lh hours a t room t e m p e r a t u r e ' b e f o r e a l l y ! bromide (0.085 m l , 1.00 mmole) v/as added. A f t e r b e i n g s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s t h e c o n t e n t s o f t h e f l a s k were t r a n s f e r r e d v i a a s t a i n l e s s s t e e l c a n n u l a t o a r a p i d l y s t i r r e d m i x t u r e o f M h y d r o c h l o r i c a c i d (10 m l ) and e t h e r (50 m l ) . T h e o r g a n i c phase was washed w i t h N h y d r o c h l o r i c (2 X 5 m l ) and w a t e r (3 X 10 m l ) , and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a m i x t u r e w h i c h showed two s p o t s on t i c . The minor one o f t h e s e c o r r e s p o n d e d t o s t a r t i n g m a t e r i a l . T h e  194 NMR  spectrum spectrum o f the crude product mixture i n d i c a t e d t h a t  i t c o n s i s t e d m a i n l y o f 205 (^90%). T h i s e s t i m a t e was based on i n t e g r a t i o n o f t h e peaks d e s c r i b e d below w i t h r e s p e c t t o t h e peaks a t 62.11 and 2.25 a s s i g n e d t o t h e t e r m i n a l m e t h y l g r o u p i n t h e e n o l and k e t o t a u t o m e r s o f s t a r t i n g m a t e r i a l 121. NMR  ( a s s i g n m e n t s and i n t e g r a t i o n s i m p l i f i e d by i g n o r i n g  the presence of 121 i n the mixture)  62.20-2.75 (m, 4,  methylene  group p r o t o n s ) , 3.75 ( 2 s , 9 t o t a l , methoxy g r o u p p r o t o n s ) , 4.7-5.2 (m, 3, t e r m i n a l v i n y l g r o u p p r o t o n s ) , 5.73 ( s , <1, v i n y l p r o t o n o f e n o l t a u t o m e r ) , 6.13  ( s , 2, a r o m a t i c p r o t o n s ) .  5-Hydroxy-5-phenyl-l-(2,4,6-trimethoxyphenyl)hexane-l,3-dione  (206)  206  T h i s compound was p r e p a r e d by t h e same p r o c e d u r e a s t h a t employed i n t h e p r e p a r a t i o n o f 5 - h y d r o x y - l - p h e n y l - 5 - ( 2 , 4 , 6 - t r i methoxyphenyl)hexane-l,3-dione  ( 1 5 8 ) . The f o l l o w i n g r e a g e n t s were  u s e d : i s o p r o p y l c y c l o h e x y l a m i n e (285 mg, 2.02 mmole), n - b u t y l l i t h i u m  195 i n hexane (0.825 m l , 2.50M, 2.06 mmole), l - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) butane-1,3-dione  (121) (252 mg, l.OOmmole), and a c e t o p h e n o n e  (120  1.00 mmole). The p r o d u c t was s e p a r a t e d f r o m some r e t u r n e d s t a r t i n g m a t e r i a l s by p r e p a r a t i v e t i c on s i l i c a g e l (2 p l a t e s ) . A m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (2:1 v / v ) was used t o d e v e l o p t h e p l a t e s . The band l y i n g a t  0.2-0.3 v/as removed and e x t r a c t e d  w i t h c h l o r o f o r m . The s o l v e n t was removed under r e d u c e d p r e s s u r e t o a f f o r d c r u d e 206 (220 mg, 5 9 % ) . The NMR s p e c t r u m o f t h i s p r o d u c t i n d i c a t e d t h a t i t c o n t a i n e d some (^20%) o f d i h y d r o p y r o n e 207 ( s e e below). IR 3500 ( 0 - H ) , 1650-1560 cm" NMR  1  (C=0 and  C=C);  ( a s s i g n m e n t s i m p l i f i e d by i g n o r i n g t h e p r e s e n c e  o f 207 i n t h e m i x t u r e )  <S2.50, 2.60 ( 2 s , 3 t o t a l , c a r b i n o l c a r b o n  m e t h y l g r o u p p r o t o n s i n k e t o and e n o l t a u t o m e r s ) , 2.7-3.5 (m, 2, p r o t o n s on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n i n k e t o and e n o l t a u t o m e r s ) , 3.75 ( s , 6, o r t h o - m e t h o x y g r o u p p r o t o n s ) , 3.80 ( s , 3, para-methoxy  g r o u p p r o t o n s ) , 5.68 ( s , ^0.5, v i n y l p r o t o n o f e n o l  t a u t o m e r ) , 6.10 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 7.1-7.6 (m, 5, p r o t o n s on p h e n y l r i n g ) .  mg,  196 2,3-Dihydro-2-methyl-2-phenyl-6-(2,4,6-trimethoxyphenyl)-4H-pyran4-one (207)  O  MeO  207  T h i s compound was p r e p a r e d f o l l o w i n g t h e p r o c e d u r e employed i n t h e p r e p a r a t i o n o f 2 , 3 - d i h y d r o - 2 , 6 - d i p h e n y l - 2 - m e t h y l 4H-pyran-4-one ( 1 2 8 ) . The c r u d e a l c o h o l 206 (135 mg, 0.354 mmole) d e s c r i b e d above was u s e d . A f t e r w o r k u p , 207 (120 mg, 94%) was o b t a i n e d as a c r u d e o i l ; IR 1655 (C=0), 1600 cm"  1  (C=C);  NMR 61.80 ( s , 3, m e t h y l g r o u p p r o t o n s ) , 2.83 ( d , J=17 c p s , 1, m e t h y l e n e p r o t o n ) , 3.05 ( d , J=17 c p s , 1, m e t h y l e n e p r o t o n ) , 3.75 ( s , 6, o r t h o - m e t h o x y g r o u p p r o t o n s ) , 3.82 ( s , 3,  para-methoxy  g r o u p p r o t o n s ) , 5.55 ( s , 1, v i n y l p r o t o n ) , 6.16 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 7.2-7.7 (m, 5, p r o t o n s on p h e n y l r i n g ) .  197 5-(2,6-Dimethoxyphenyl)-5-hydroxy-l-(2,4,6-trimethoxyphenyl)hexane1 , 3 - d i o n e (208)  MeO  208  In t h e f o l l o w i n g p r e p a r a t i o n s o f t h i s compound t h e p r o c e d u r e f o l l o w e d was t h e same as t h a t employed i n t h e p r e p a r a t i o n of 5-hydroxy-l-phenyl-5-(2,4,6-trimethoxyphenyl)hexane-l,3-dione  (158),  (a) U s i n g one e q u i v a l e n t ' o f d i a n i o n . The f o l l o w i n g r e a g e n t s were u s e d : i s o p r o p y l c y c l o h e x y l a m i n e (143 mg, 1.02 mmole), n - b u t y l l i t h i u m i n hexane (0.430 m l , 2.50M, 1.07 mmole), l - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) b u t a n e - l , 3 - d i o n e (121) (126 mg, 0.500 mmole), and 2 , 6 - d i m e t h o x y a c e t o p h e n o n e (39) .(90 mg, 0.50 mmole) i n d r y THF (7 ml t o t a l v o l u m e ) . The p r o d u c t was s e p a r a t e d f r o m r e t u r n e d s t a r t i n g m a t e r i a l s by p r e p a r a t i v e t i c on s i l i c a g e l (2 p l a t e s ) . A m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (2:1 v / v ) was used t o d e v e l o p t h e p l a t e s . The band l y i n g a t R  f  0.0-0.1 was  removed and e x t r a c t e d w i t h c h l o r o f o r m . E v a p o r a t i o n o f t h e s o l v e n t u d e r r e d u c e d p r e s s u r e a f f o r d e d 208 (44 mg, 20%) as a c l e a r o i l ; s p e c t r a as d e s c r i b e d i n ( d ) .  198 (b) W i t h t h e a d d i t i o n o f z i n c c h l o r i d e . The q u a n t i t i e s o f r e a g e n t s o u t l i n e d i n ( a ) were  employed  i n t h i s e x p e r i m e n t a n d a s o l u t i o n o f a n h y d r o u s z i n c c h l o r i d e i n THF (3.0 m l , 0.35M, 1.0 mmole) was added a t t h e same t i m e a s t h e 2,4-dimethoxyacetophenone.  The t i c o f t h e crude product mixture  i n d i c a t e d t h e p r e s e n c e o f s u b s t a n t i a l amounts o f s t a r t i n g m a t e r i a l s and an amount o f p r o d u c t a p p r o x i m a t e l y t h e same a s i n ( a ) .  ( c ) W i t h t h e a d d i t i o n o f magnesium  bromide.  The q u a n t i t i e s o f r e a g e n t s g i v e n i n ( a ) were  employed  i n t h i s e x p e r i m e n t and powdered a n h y d r o u s magnesium b r o m i d e ( 2 0 0 mg, 1.06 mmole) was added a t t h e same t i m e a s t h e  2,6-dimethoxyacetophenone.  Separation o f t h e product from r e t u r n e d s t a r t i n g m a t e r i a l s , as i n ( a ) , a f f o r d e d 208 (84 mg, 3 9 % ) ; s p e c t r a l d a t a a s i n ( d ) .  (d) U s i n g f i v e e q u i v a l e n t s o f d i a n i o n . The f o l l o w i n g q u a n t i t i e s o f r e a g e n t s were u s e d : i s o p r o p y l c y c l o h e x y l a m i n e (720 mg, 5.11 mmole), n - b u t y l 1 i t h i u m i n hexane ( 2 . 1 5 m l , 2.50M, 5.36 mmole), l - ( 2 , 4 , 6 - t r i m e t h o x y p h e n y l ) hexane-l,3-dione acetophenone  ( 1 2 1 ) (630 mg, 2.50 mmole), and 2 , 6 - d i m e t h o x y -  ( 3 9 ) (90 mg, 0.50 mmole) i n d r y THF (30 ml t o t a l  volume).  The p r o d u c t was s e p a r a t e d from r e t u r n e d 121 by p r e p a r a t i v e t i c on s i l i c a g e l (5 p l a t e s ) u s i n g a m i x t u r e o f c a r b o n t e t r a c h l o r i d e a n d e t h e r (1:1 v / v ) a s d e v e l o p i n g s o l v e n t . No r e t u r n e d 3 £ was o b s e r v e d . The band a t R  f  0.4-0.6 was removed and e x t r a c t e d w i t h c h l o r o f o r m ,  e v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d  199 121 (401 mg, 8 0 % o f t h e o r e t i c a l e x c e s s ) . E x t r a c t i o n o f t h e band at R  f  0.1-0.2 a f f o r d e d 208 (220 mg, 100%) as a c l e a r o i l ; s p e c t r a  page 236; IR 3550 ( 0 - H ) , 1650-1560 cm"  1  (C=C and C=0);  NMR 61.60, 1.72 ( 2 s , 3 t o t a l , c a r b i n o l c a r b o n m e t h y l g r o u p p r o t o n s i n e n o l and k e t o t a u t o m e r s ) , 2.87 ( d , J=14 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.07 ( d , J=14 c p s , 1, p r o t o n on m e t h y l e n e g r o u p a t o c a r b i n o l c a r b o n ) , 3.70, 3.78 ( 2 s , 15 t o t a l , methoxy g r o u p p r o t o n s ) , 5.70 ( s , <1, v i n y l p r o t o n o f e n o l ) , 6.07 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 6.50-7.40 (m, 3, p r o t o n s on d i m e t h o x y p h e n y l r i n g ) ; UV 272-305 mp ( b r o a d ) ( 8 2 2 0 ) ; Mass s p e c t r u m ( a ) low r e s o l u t i o n m/e 4 1 4 ( 2 0 ) , 3 8 4 ( 1 0 ) , 383(41), 253(14), 252(60), 238(16), 237(65), 222(21), 221(70), 218(14), 207(10), 205(12), 197(23), 196(66), 195(100), 193(22), 182(18), 181(76), 180(58), 179(16), 178(16), 177(11), 169(15), 168(52), 167(13), 166(19), 165(71), 164(13), 163(59), 162(12), 161(14), 152(35), 151(26), 150(30), 149(10), 148(13), 147(19), 139(20), 138(12), 137(42), 136(11), 135(38), 133(10), 122(21), 121(19), 109(16), 107(32), 106(10), 105(28), 103(14), 92(14), 91(32), 79(23), 78(16), 77(37), 69(28), 66(11), 65(18), 63(16), 55(22), 53(16), 51(17); (b) h i g h r e s o l u t i o n c a l c ' d f o r £ 3 2 6 ^ 7 ( ~ ^ ) » C  414.168 amu, f o u n d 414.171 m/e.  H  p  200 5-(2,6-Diiiiethoxyphenyl )-l-(2,4,6-trimethoxyphenyl )hex-4-ene-l,3dione  (216)  H 216E  216Z  (a) U s i n g hydrogen c h l o r i d e i n c h l o r o f o r m . C h l o r o f o r m (20 ml) was s a t u r a t e d w i t h hydrogen c h l o r i d e by b u b b l i n g t h e a n h y d r o u s g a s t h r o u g h t h e s o l v e n t f o r 15 m i n u t e s . A s o l u t i o n of  5-(2,6-dimethoxyphenyl)-5-hydroxy-l-(2,4,6-trimethoxy-  phenyl)hexane-l,3-dione  (208) (84 mg, 0.19 mmole) i n c h l o r o f o r m  (1 ml) was added and t h e r e s u l t i n g s o l u t i o n v/as s t i r r e d a t room t e m p e r a t u r e f o r 40 m i n u t e s b e f o r e b e i n g v/ashed w i t h w a t e r (4 X 10 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e y i e l d e d 80 mg o f a m i x t u r e whose t i c showed f o u r s p o t s , none o f which c o r r e s p o n d e d t o s t a r t i n g m a t e r i a l . The  sample  was r e d i s s o l v e d i n c h l o r o f o r m s a t u r a t e d w i t h hydrogen c h l o r i d e and t h e 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 20 hours b e f o r e b e i n g worked up as above. The c r u d e p r o d u c t m i x t u r e was s e p a r a t e d i n t o t h r e e components by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) u s i n g a m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (1:1 v/v) as d e v e l o p i n g s o l v e n t .  201 The major component was i d e n t i f i e d from i t s NMR s p e c t r u m ( s e e ( e ) ) as v e r y c r u d e 216 (31 mg, 3 9 % ) .  (b) U s i n g p a r a - t o i u e n e s u l p h o n i c a c i d i n benzene. A m i x t u r e o f 208 (60 mg, 0.15 mmole) and p a r a - t o l u e n e s u l p h o n i c a c i d (^1 mg) i n d r y benzene (5 m l ) was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s . A f t e r t h i s t i m e , t h e s o l v e n t was e v a p o r a t e d t o y i e l d a m i x t u r e w h i c h w a s s e p a r a t e d i n t o t h r e e components by p r e p a r a t i v e t i c on s i l i c a g e l a s d e s c r i b e d i n ( a ) . The m a j o r component was i d e n t i f i e d f r o m i t s NMR s p e c t r u m a s 216 (34 mg, 5 9 % ) .  (c) Attempt u s i n g p o l y p h o s p h o r i c a c i d . P o l y p h o s p h o r i c a c i d [^1 g ) was added t o a s o l u t i o n o f 208 (24 mg, 0.056 mmole) i n c h l o r o f o r m and t h e m i x t u r e was a l l o w e d t o s t a n d a t room t e m p e r a t u r e f o r 16 h o u r s . A f t e r t h i s t i m e , t h e t i c o f t h e m i x t u r e showed s i x s p o t s , one o f w h i c h c o r r e s p o n d e d t o starting material.  (d) A t t e m p t u s i n g h y d r o g e n c h l o r i d e i n e t h e r . A sample o f 208 (20 mg, 0.046 mmole) v/as d i s s o l v e d i n ether s a t u r a t e d with hydrogen c h l o r i d e as d e s c r i b e d i n ( a ) . A f t e r b e i n g s t i r r e d f o r 4 hours a t room t e m p e r a t u r e t h e r e a c t i o n was worked up f o l l o w i n g t h e p r o c e d u r e employed  i n ( a ) . T h i s y i e l d e d 19 mg o f  a m i x t u r e showing s e v e n s p o t s on t i c . The NMR s p e c t r u m o f t h e c r u d e m i x t u r e had t h e f o l l o w i n g peak r a t i o : methoxy g r o u p  protons=2:5.  total aromatic protons:total  202 (e) 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 . Boron t r i f l u o r i d e e t h e r a t e [^1 ml) was added t o a s o l u t i o n o f 208 (28 mg, 0.065 mmole) i n a n h y d r o u s e t h e r (4 m l ) . A p r e c i p i t a t e w h i c h formed i m m e d i a t e l y d i s s o l v e d a f t e r 2 m i n u t e s . A f t e r \\ hours t h e s o l u t i o n was p o u r e d i n t o e t h e r (20 ml) and w a t e r (10 m l ) . The o r g a n i c phase was washed w i t h w a t e r (3 X 5 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f the s o l v e n t under reduced p r e s s u r e a f f o r d e d 216 (22 mg, 82%) as an o r a n g e foam; s p e c t r a page 237; IR 1650-1500 cm"  1  (C=C and  C=0);  NMR 62.11, 2.59 ( 2 d , J=2 c p s , 3 t o t a l , v i n y l m e t h y l g r o u p p r o t o n s i n E and Z i s o m e r s r e s p e c t i v e l y ) , 3.8 ( s e v e r a l s, 15 t o t a l , methoxy g r o u p p r o t o n s ) , 5.9-6.3 (m, ^4, v i n y l p r o t o n , v i n y l p r o t o n o f e n o l , p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 6.4-7.4 (m, 3, p r o t o n s on d i m e t h o x y p h e n y l  ring);  Mass s p e c t r u m m/e 4 1 4 ( 1 0 ) , 3 8 4 ( 5 ) , 3 8 3 ( 1 5 ) , 2 3 8 ( 5 ) , 2 3 7 ( 2 3 ) , 1 9 6 ( 1 2 ) , 1 9 5 ( 1 0 0 ) , 1 8 1 ( 5 ) , 180(5) 1 6 8 ( 6 ) , 7 9 ( 2 5 ) , 7 7 ( 4 0 ) .  U n s u c c e s s f u l A t t e m p t s t o C y c l i s e 216.  (a) W i t h b o r o n t r i f l u o r i d e e t h e r a t e . A sample o f 208 was t r e a t e d w i t h b o r o n t r i f l u o r i d e e t h e r a t e i n t h e manner d e s c r i b e d f o r t h e s y n t h e s i s o f 216. The s o l u t i o n was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s . The m i x t u r e o f compounds o b t a i n e d a f t e r workup showed f i v e s p o t s on t i c , t h e m a j o r one c o r r e s p o n d i n g t o 216. The NMR s p e c t r u m o f t h e m i x t u r e showed  203 no e v i d e n c e t h a t i t c o n t a i n e d a n y c y c l i s e d p r o d u c t (no a r o m a t i c methyl  singlet).  (b) U s i n g hydrogen  chloride.  Dry benzene (40 m l ) was s a t u r a t e d w i t h . h y d r o g e n c h l o r i d e by b u b b l i n g t h e a n h y d r o u s g a s d i r e c t l y t h r o u g h t h e s o l v e n t . A s o l u t i i o n o f 216 (50 mg, 0.12 mmole) i n d r y benzene (1 m l ) was added and t h e 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 a t room t e m p e r a t u r e f o r 24 h o u r s . A f t e r t h i s t i m e , i t was washed w i t h w a t e r (4 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e y i e l d e d 46 mg o f r e t u r n e d s t a r t i n g m a t e r i a l ( t i c a n d NMR). A s i m i l a r e x p e r i m e n t i n v o l v i n g a s o l u t i o n o f 216 i n c h l o r o f o r m s a t u r a t e d w i t h hydrogen c h l o r i d e had c o m p a r a b l e  results.  ( c ) With aluminum c h l o r i d e . A sample o f 216 (14 mg, 0.032 mmole) was d i s s o l v e d i n m e t h y l e n e c h l o r i d e (4 m l ) and aluminum c h l o r i d e (^50 mg) was added, a f t e r b e i n g s t i r r e d a t room t e m p e r a t u r e f o r 1 h o u r , t h e m i x t u r e was poured i n t o c h l o r o f o r m (30 m l ) and washed w i t h w a t e r ( 4 X 5 m l ) . The s o l u t i o n was d r i e d o v e r magnesium s u l p h a t e and t h e s o l v e n t s were removed under r e d u c e d p r e s s u r e . T h i s y i e l d e d 12 mg o f a m i x t u r e which showed t h r e e s p o t s on t i c , none o f w h i c h c o r r e s p o n d e d t o s t a r t i n g m a t e r i a l . The NMR s p e c t r u m o f t h e p r o d u c t showed two d o u b l e t s (J=2 c p s ) a t 62.10, 2.45. No a r o m a t i c m e t h y l s i n g l e t was o b s e r v e d . I n t e g r a t i o n gave t h e f o l l o w i n g peak r a t i o s : t o t a l d o u b l e t s : t o t a l methoxy g r o u p  protons=3:10.  204 2-Hydroxy-5-methoxy-4-methyl-l-naphthyl ketone  2,4,6-trimethoxyphenyl  (217)  MeO.  H 217  ..O  OMe  Water (5 d r o p s ) and s t a n n i c , c h l o r i d e (1 m l ) were added to a solution of 5-(2,6-dimethoxyphenyl)-l-(2,4,6-trimethoxyphenyl)h e x - 4 - e n e - l , 3 - d i o n e (216) (95 mg, 0.23 mmole) i n d r y benzene.  The  r e s u l t i n g m i x t u r e was s t i r r e d f o r 18 h o u r s a t room t e m p e r a t u r e and t h e n poured i n t o w a t e r (10 m l ) . A p r e c i p i t a t e w h i c h had formed i n t h e r e a c t i o n f l a s k was d i s s o l v e d i n c h l o r o f o r m (100 ml) and added t o t h e b e n z e n e - w a t e r m i x t u r e . The o r g a n i c phase was washed w i t h w a t e r (6 X 10 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d 85 mg o f c r u d e p r o d u c t which was p u r i f i e d by p r e p a r a t i v e t i c on s i l i c a g e l (1 p l a t e ) . A m i x t u r e o f e t h e r and c a r b o n t e t r a c h l o r i d e (3:2 v / v ) v/as used t o d e v e l o p t h e p l a t e . The band l y i n g a t  0.0-0.1 was removed  and e x t r a c t e d w i t h c h l o r o f o r m . E v a p o r a t i o n o f t h e s o l v e n t under r e d u c e d p r e s s u r e a f f o r d e d 217_ (46 mg, 52%) as b r i g h t y e l l o w c r y s t a l s .  205 A sample o f t h e s e was s u b l i m e d f o r a n a l y s i s ; mp 235-237 d e g r e e s ; s p e c t r a page 238; IR 1640 (C=0), 1600, 1540 cm"  1  (C=C a r o m a t i c ) ;  NMR 62.55 ( s , 3, m e t h y l g r o u p p r o t o n s ) , 3.8 ( s e v e r a l s , 12 t o t a l , methoxy g r o u p p r o t o n s ) , 5.8-8.0 (m, 6, a r o m a t i c p r o t o n s ) ; U V - V i s 283 ( s h o u l d e r ) , 310 ( 2 2 , 6 0 0 ) , 397 ( 6 7 , 8 0 0 ) , 415 my, (shoulder); Mass s p e c t r u m m/e 3 8 2 ( 3 7 ) , 3 6 5 ( 2 2 ) , 2 1 5 ( 2 0 ) , 2 0 0 ( 1 5 ) , 195(12), 189(30), 188(100), 177(16), 175(20), 165(15); Analysis calc'd f o r C H 0 :  C 69.10  H 5.80  found:  C 68.96  H 6.00.  2 2  2 2  6  206 2-{3,5-Dimethoxy-4-(4,6-dioxo-2-hydroxy-6-2',4',6'-trimethoxyphenylhex-2-yl)phenyl}-2-methylpropionitrile  (122)  122 T h i s compound was p r e p a r e d f o l l o w i n g t h e employed i n t h e p r e p a r a t i o n o f 5-hydroxyphenyl)hexane-l,3-dione  procedure  l-phenyl-5-(2,4,5-trimethoxy-  ( 1 5 8 ) . The f o l l o w i n g r e a g e n t s were u s e d : .  i s o p r o p y l c y c l o h e x y l a m i n e - ( 7 2 0 mg, 5.11 mmole), n - b u t y l l i t i u m i n hexane (2.15 m l , 2.50M, 5.36 mmole),  l-(2,4,6-trimethoxyphenyl)-  h e x a n e - l , 3 - d i o n e (121) (630 mg, 2.50 mmole) and  2-(4-acetyl-3,5-  d i m e t h o x y p h e n y l ) - 2 - m e t h y l p r o p i o n i t r i l e (22) (124 mg, 0.502 mmole)i n d r y THF (30 ml t o t a l v o l u m e ) . The p r o d u c t was s e p a r a t e d f r o m u n r e a c t e d 121 by p r e p a r a t i v e t i c on s i l i c a g e l (5 p l a t e s ) . The p l a t e s were d e v e l o p e d w i t h a m i x t u r e o f c a r b o n t e t r a c h l o r i d e and e t h e r (1:1 v / v ) . The band l y i n g a t R  f  0.4-0.6 was removed and e x t r a c t e d  with chloroform. Evaporation of the s o l v e n t under reduced  pressure  a f f o r d e d 121 (395 mg, 78% o f t h e o r e t i c a l e x c e s s ) . No u n r e a c t e d  22  was o b s e r v e d on t h e p l a t e s . E x t r a c t i o n o f t h e band l y i n g a t  0.1-0.2  a f f o r d e d 122 (252 mg,  100%) as a c l e a r o i l ; s p e c t r a page 239;  207 '• IR 3550 ( 0 - H ) , 2255  (C=H),  1650-1560 cm'  1  (C=C and C=0);  NMR 61.55, 1.77, 1.70 ( 3 s , 9 t o t a l , c a r b i n o l c a r b o n methyl group p r o t o n s i n e n o l and k e t o t a u t o m e r s and gem-dimethyl group p r o t o n s r e s p e c t i v e l y ) , 2.6-3.4 (m, 2, p r o t o n s on m e t h y l e n e group a t o c a r b i n o l c a r b o n i n e n o l and k e t o t a u t o m e r s ) , 4.8 ( s e v e r a l 15 t o t a l , methoxy g r o u p p r o t o n s ) , 5.72 ( s , <1, v i n y l p r o t o n o f e n o l t a u t o m e r ) , 6.15 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 6.71 ( s , 2, p r o t o n s on d i m e t h o x y p h e n y l  ring);  UV 285-310 my ( b r o a d ) ( 8 6 5 0 ) ; Mass s p e c t r u m ( a ) low r e s o l u t i o n m/e 4 9 9 ( 2 ) , 4 8 1 ( 4 ) , 468(5), 252(45), 248(32), 232(32), 221(48), 197(10), 196(15), 195(100), 168(15), 161(9); . .  (b) high r e s o l u t i o n c a l c ' d f o r C^yH^QgN,  499.220 amu, f o u n d 499.220 m/e.  208 2-{3,5-Dimethoxy-4-(4,6-dioxo-6-2',4',6 -trimethoxyphenylhex-l-en-2-yl) 1  p h e n y l } - 2 - m e t h y l p r o p i o n i t r i l e (230)  29E  29Z  Boron t r i f l u o r i d e e t h e r a t e (^1 m l ) was added to a s t i r r e d s o l u t i o n o f 122 (232 mg, 0.465 mmole) i n a n h y d r o u s e t h e r (20 m l ) . A p r e c i p i t a t e w h i c h formed d u r i n g t h e a d d i t i o n d i s s o l v e d i n 2 m i n u t e s . A f t e r 20 m i n u t e s t h e s o l u t i o n was washed w i t h w a t e r and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s u n d e r r e d u c e d p r e s s u r e a f f o r d e d a c r u d e m i x t u r e o f 29 and 230 (223 mg, 100%)  209 as a b r i g h t o r a n g e foam; s p e c t r a page IR  240;  2255 ( C H N ) , 1650-1580 ( O C and O O ) ,  1530  cm"  1  (C=C a r o m a t i c ) ; NMR  61.72 ( s , 6, gem-dimethyl g r o u p p r o t o n s ) , 2.23,  2.55  ( 2 d , J=2 c p s , v i n y l m e t h y l g r o u p p r o t o n s i n E and Z i s o m e r s o f 2 9 ) , 3.3-3.9 ( m e t h y l e n e g r o u p p r o t o n s i n 230 and methoxy g r o u p p r o t o n s ) , 6.10 ( s , 2, p r o t o n s on t r i m e t h o x y p h e n y l r i n g ) , 6.66 ( 2 s , 2, p r o t o n s on d i m e t h o x y p h e n y l r i n g ) , 6.0-6.7 (m, v i n y l p r o t o n o f 29 and v i n y l proton of v a r i o u s enol tautomers).  U n s u c c e s s f u l A t t e m p t s t o C y c l i s e t h e M i x t u r e o f 230 and 29.  (a) W i t h s t a n n i c c h l o r i d e . A sample (150 mg, 0.301 mmole) o f t h e c r u d e m i x t u r e o f 230 and 29 d e s c r i b e d above was d i s s o l v e d i n d r y benzene (30 m l ) , Water (5 d r o p s ) and s t a n n i c c h l o r i d e (1 ml) were added. The r e s u l t i n g m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s and t h e n p o u r e d i n t o w a t e r (10 m l ) . The o r g a n i c p h a s e was washed w i t h w a t e r (4 X 10 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s y i e l d e d a c r u d e m i x t u r e w h i c h showed f o u r s p o t s on t i c . I t s NMR s p e c t r u m d i d n o t show a peak a s s i g n a b l e t o an a r o m a t i c m e t h y l g r o u p . In a n o t h e r e x p e r i m e n t t h e same p r o c e d u r e was f o l l o w e d u s i n g m e t h y l e n e c h l o r i d e as s o l v e n t . S i m i l a r r e s u l t s were o b t a i n e d ,  210 (b) With aluminum c h l o r i d e . The m i x t u r e o f 230 and 29 (50 mg, 0.10 mmole) was d i s s o l v e d i n d r y benzene (4 m l ) and aluminum c h l o r i d e (^50 mg) v/as added. The m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 4 hours b e f o r e b e i n g poured i n t o c h l o r o f o r m (25 m l ) . T h e o r g a n i c phase was washed w i t h w a t e r (5 X 5 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a c r u d e m i x t u r e  showing  s e v e n s p o t s on t i c . I t s NMR s p e c t r u m d i d n o t show an a r o m a t i c m e t h y l signal.  ( c ) With p o l y p h o s p h o r i c a c i d . The m i x t u r e o f 230 and 29 (25 mg, 0.052 mmole) was added t o p o l y p h o s p h o r i c a c i d (4 m l ) and t h e r e s u l t i n g m i x t u r e was h e a t e d on a steam b a t h f o r 2 h o u r s . A f t e r t h i s t i m e , i t was p o u r e d i n t o w a t e r (20 m l ) and e x t r a c t e d w i t h c h l o r o f o r m (5 X 5 m l ) . T h e combined e x t r a c t s were washed with' w a t e r (3 X 5 m l ) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d a m i x t u r e showing s i x s p o t s on t i c , t h e m a j o r one c o r r e s p o n d i n g t o starting materials.  (d) W i t h s u l p h u r i c a c i d . The m i x t u r e o f 230 and 29 (23 mg, 0.048 mmole) was added t o c o n c e n t r a t e d s u l p h u r i c a c i d (4 m l ) and t h e m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 1% h o u r s . A f t e r t h i s t i m e , i t was poured i n t o w a t e r (20 m l ) and e x t r a c t e d w i t h c h l o r o f o r m (4 X 10 m l ) . The combined e x t r a c t s were washed w i t h w a t e r and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s under r e d u c e d p r e s s u r e a f f o r d e d  211 a m i x t u r e showing f i v e s p o t s on t i c , t h e m a j o r one c o r r e s p o n d i n g to starting m a t e r i a l s .  (e) With hydrogen c h l o r i d e . D r y benzene (10 m l ) was s a t u r a t e d w i t h h y d r o g e n c h l o r i d e by b u b b l i n g t h e a n h y d r o u s g a s t h r o u g h t h e s o l v e n t f o r 15 m i n u t e s . A s o l u t i o n o f 230 and 29 (50 mg, 0.010 mmole) i n d r y benzene (1 m l ) was added a n d t h e 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 a t room t e m p e r a t u r e f o r 24 h o u r s . A f t e r t h i s t i m e , i t was p o u r e d i n t o c h l o r o f o r m (40 m l ) and washed w i t h w a t e r (5 X 10 m l ) . T h e s o l u t i o n was d r i e d o v e r magnesium s u l p h a t e and t h e s o l v e n t s were removed u n d e r r e d u c e d p r e s s u r e t o a f f o r d 46 mg ( 9 2 % ) o f a m i x t u r e c o n t a i n i n g p r e d o m i n a n t l y 29E and Z_ (by NMR).  2-(7-Hydroxy-5-methyl-4-m'ethoxy-8-2 ,4',6'-trimethoxybenzoyl-2-naphthyl)1  2 - m e t h y l p r o p i o n i t r i l e (27)  A sample o f t h e m i x t u r e o f 230_and 29 (212 mg, 0.440 mmole)  212 was d i s s o l v e d i n d r y benzene (50 ml) and a n h y d r o u s h y d r o g e n c h l o r i d e was b u b b l e d t h r o u g h t h e s o l u t i o n f o r 1% h o u r s . A f t e r t h i s t i m e , s t a n n i c c h l o r i d e (2 ml) and w a t e r (2 d r o p s ) were added and t h e r e s u l t i n g m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 16 h o u r s b e f o r e b e i n g p o u r e d i n t o w a t e r (20 m l ) . A p r e c i p i t a t e w h i c h had formed i n t h e r e a c t i o n f l a s k was d i s s o l v e d i n c h l o r o f o r m (100 ml) and added t o t h e b e n z e n e - w a t e r m i x t u r e . The o r g a n i c p h a s e was washed w i t h w a t e r (4 X 20 ml) and d r i e d o v e r magnesium s u l p h a t e . E v a p o r a t i o n o f t h e s o l v e n t s u n d e r r e d u c e d p r e s s u r e a f f o r d e d 187 mg o f c r u d e p r o d u c t w h i c h v/as r e c r y s t a l 1 i z e d f r o m e t h a n o l - l i g r o i n t o y i e l d 27 90 mg, 46%) as b r i g h t y e l l o w c r y s t a l s . A sample was s u b l i m e d f o r a n a l y s i s (180 d e g r e e s , 0.04 mm);  s p e c t r a page 241;  IR 2255 (C=N), 1640 (C=0), 1600, 1540 cm' *•  NMR  1  (C=C a r o m a t i c ) ;  62.70 ( s , 6, g e m - d i m e t h y l g r o u p p r o t o n s ) , 2.51 ( s , 3,  a r o m a t i c m e t h y l g r o u p p r o t o n s ) , 4.8 ( s e v e r a l s, 12 t o t a l , methoxy g r o u p p r o t o n s ) , 5.8-8.0 ( s e v e r a l s, 5 t o t a l , a r o m a t i c p r o t o n s ) ; UV 295 ( s h o u l d e r ) , 304 ( 1 8 , 0 0 0 ) , 398 ( 5 4 , 4 0 0 ) , 420 mu (shoulder); Mass s p e c t r u m m/e 4 4 9 ( 2 4 ) , 4 3 2 ( 2 8 ) , 2 8 2 ( 1 2 ) , 2 6 7 ( 1 3 ) , 266(10), 256(23), 255(100), 242(25), 240(23), 211(12), 195(49), 180(11), 168(11), 167(10), 165(11), 152(13), 149(13), 139(16), 137(14), 115(12), 109(13), 95(13), 91(17), 85(14), 83(11), 81(17), 79(13), 77(18), 71(18), 70(11), 69(26), 67(15), 63(10), 57(52), 56(23), 55(61), 53(17), 51(16), 50(13); Analysis calc'd for C H 0 N: 6  C 69.47  H 6.05  N 3.12  found:  C 69.42  H 6.15  N 3.00.  2 6  2 7  213 MB1J0GMPHY  1)  H. 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Chem., 38, 4056 ( 1 9 7 3 ) .  [121)  S.C. Watson a n d J . F . Eastham, J . Organomet. Chem. , £ , 165 ( 1 9 6 7 ) .  Columbia.  219  SPECTRAL APPENDIX  224  MeO.  S  3 MoO  OMo  68Z  6SE  50.0  i  1 1 1 1  "r  100.0 40(30-^.  3600  »•"!  1  153.0 3200  2600  i ' ' '  250.0 .200.0  300.0  M/E  FREQUENCY (CM ) 2000 1800  I 350.0 1  1  1  1  I 400.0 1  1  1  1  I ' • ' I 450.0 500.0 1  1  2400  1.0  I I I  4.0  1600  1400  1200  1000  800  6SO  228  229  232  235  238 MeO. OMe  °^  H  .-°  OM.  2)7  (Do  h-in.  _l UJ or  '  I  1 i  '  50.0  i  l  i  j  100.0  i  —r~T—i—r—|—i—i—i—i—|—i—i—i—i—|—j- -!—r*—i—]—i—i—r—n—|  200.0  250.0  300.0  3600  3200 I I  >>  !  70  i  UJ z <  t  i  50  /?  *\  80  <J 60  ;  i  :  1  !  i  I  0  !  1  I  1  j !  i i  i 1 i  1 1  I  i 1  1 1  i  !  1 * 1 1  i i  !  1  i  rt  i j  i  30  10  i  !  <  20  .i 1 1" ~r i j !  >/l 40 2 £  i  1  90  g  2800  i  J- ^~ V 1  1 1  T  ~T  ; !  i_ ! -i1  1 11  ; 1  i  i  i  1 j 1  i 1  I  j_  !  !  T  1 ' I .in  ! ! !  i "ft :  r  i  1  ;  I i j i  i  I  j iji  1  I M  j  I i  i f  r  Hi Mil  Ml 1 l  I  :  i I! i!'! I i , ! T ' • !  11 i l  i ] i ! . II ; [TH i ff] f >  f  i  i  • i i i i_ nr  ,  ;  1 : I  i  !  ! 1  •i  ii  I!  M  1  :  I '  •J  1 i  Iii!  T  \ j•Ml " 't~ tn" •j • ; .  1 i i !f ! 1i I Ii ' 1 : jl  ! | i  'j  • \ \ : i; 1  :  i  : i  II : , ; ' r~  :  -liUi : j i  1000  i ! ' j • : i l l jT'' -  M 4 T T T!TT ; 1 iJi: ir -• L-{f ~7V 1 1 ; ;i- ,  i i  !'1 i i! 1  1200  l i t LU-  1 i 1  1 •1 ill  !!  1400  !  i i I | ' 1: j ! !  i  I  ;  1  1600  |  j\ 'it  l_ H  !  i  j  ! i  !  i  i  ~ri •p*K> i  i •  1  i  1i i  ! i  li'i  T  !  1  j  i  i  j  • j  TT  -1  i  i  i i f'  i  !  f"  J  ! i  4  !  1/  450.0  I—t—p~r™  500.0  1  1800  j  400.0  (CM )  2000 j  t  :  i  1 1 !  i  I 1  i  2400  350.0  M/E  FREQUENCY 40t>0 100  • r-r1  1  r—T  150.0  M  t1  "I  ~\i  "i> : i  t|'  1h :  •  ;i:  "if-  c  H , j • ;; , ;,:  1  i:..  *|  \-  \J ; i \ .  I, Tjxi i  650  \j i=i  •rfi'  !  \  j[ r ;•  1—  "IT" *|;  800  il ::r .1  ! i  •  ', i . ' ! •• I !  vxl ij j  TTT 1 j ' !  i '  '1  Ti i  i  • • I !'""! ii ' ! I j . i • j ' I i i' • i ! : ;; : : i •: 1 ' I ! in : . . I : : 1 ! i i 11 . i i I; i ! ' • 1!; : | i : ; ! , 11 i!. Mil j . , ' i i i | j I• • Iii! !: !  : | -  .  :  s:  i  1  i  .  f.  :  240  

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