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Synthesis of 4-alkyl-1, 4-dihydropyridines and related compounds ; Synthesis and thermolysis of β-cyclopropyl-⍺,… Lau, Cheuk Kun 1978

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SYNTHESIS OF 4-ALKYL-l,4-DIHYDROPYRIDINES AND RELATED COMPOUNDS. SYNTHESIS AND THERMOLYSIS OF 3-CYCLOPROPYL-a,3-UNSATURATED KETONES AND RELATED COMPOUNDS.  by  B.Sc,  CHEUK KUN|LAU McMaster U n i v e r s i t y ,  1974  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY  in  THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY)  We accept t h i s t h e s i s as conforming the r e q u i r e d standard  to  THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 1978 CHEUK KUN/LAU, 1978  In  presenting  an  advanced  the I  Library  further  for  his  of  this  written  shall  agree  thesis  in  at  University  the  make that  it  thesis  purposes  for  partial  freely  permission may  representatives.  for  University  gain  Chemistry of  British  2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5  of  Columbia,  British  by  Columbia  for  the  is understood  financial  of  of  extensive  be g r a n t e d  It  fulfilment  available  permission.  Department The  degree  scholarly  by  this  shall  Head  be  requirements  reference copying  that  not  the  of  copying  agree  and  of my  I  this  that  study. thesis  Department or  for  or  publication  allowed without  my  -ii-  ABSTRACT  This t h e s i s i s composed of three separate p a r t s . the synthesis of a s e r i e s of  Part I describes  l-carbomethoxy-4-alkyl(aryl)-l,4-dihydro-  p y r i d i n e s by the r e a c t i o n of p y r i d i n e w i t h l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e reagents i n the presence of methyl chloroformate.  In general,  the y i e l d s of the r e a c t i o n s were reasonably good and the r e a c t i o n s were very r e g i o s e l e c t i v e .  The e f f i c i e n c y of l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) -  cuprate reagents i n the preparation of 4 - a l k y l - l , 4 - d i h y d r o p y r i d i n e  deri-  v a t i v e s was compared w i t h that of l i t h i u m d i a l k y l ( a r y l ) c u p r a t e s . I t was found t h a t , i n most cases, the former reagents o f f e r e d no advantages over the l a t t e r reagents.  The use of e l e c t r o p h i l e s other than methyl c h l o r o -  formate was a l s o i n v e s t i g a t e d .  A c e t y l bromide gave reasonable y i e l d s of  the corresponding 4 - a l k y l - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e s but when c h l o r o t r i m e t h y l s i l a n e and diethylphosphorochloridate  were employed, the  y i e l d s of the corresponding 4 - a l k y l - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e s were f a i r l y poor.  F i n a l l y , the  l-carbomethoxy-4-alkyl-l,4-dihydropyridines  prepared as o u t l i n e d above were transformed i n good y i e l d s i n t o the corresponding 4 - a l k y l p y r i d i n e s by treatment of the former w i t h methyll i t h i u m , followed by o x i d a t i o n of the r e s u l t i n g 1 - l i t h i o - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e s w i t h 2,3-dichloro-5,6-dicyano-l,4-benzoquinone. of l-carbomethoxy-4-alkyl(aryl)-l,4-dihydropyridinesand conversion  The synthesis  t h e i r subsequent  i n t o the corresponding 4 - a l k y l p y r i d i n e s introduces a new and  f a i r l y e f f i c i e n t way of s y n t h e s i z i n g these compounds. Part I I describes the synthesis and thermal rearrangement of a number of B-cyclopropyl-a,B-unsaturated ketones and i n c e r t a i n cases, t h e i r t r i m e t h y l -  -iii-  silyl  e n o l ether d e r i v a t i v e s .  The  g-cyclopropyl-a,g-unsaturated  ketones were prepared i n good y i e l d s enones by t r e a t i n g cuprate. of  from the c o r r e s p o n d i n g  the l a t t e r w i t h l i t h i u m  The g-iodo enones were o b t a i n e d  the c o r r e s p o n d i n g g - d i k e t o n e s 'and  with triphenylphosphine d i i o d i d e .  annelated  silyl  the  g i v i n g the  yields.  expected corresponding  In the case of  a-cyclo-  of the c o r r e s p o n d i n g  spiroannelated  of the parent enones. T h i s new s p i r o  a n n e l a t i o n r e a c t i o n was a p p l i e d to the p r e p a r a t i o n of  s p i r o ketone 198,  a key i n t e r m e d i a t e  sesquiterpenes.  t r i m e t h y l s i l y l e n o l ether  The key s t e p s i n the s y n t h e s i s of  200.  Copper c a t a l y s e d  of m e t h y l magnesium i o d i d e to 2 - c y c l o h e x e n - l - o n e , the r e s u l t i n g  g-hydroxyketone  conjugate  of  the  the  addition  f o l l o w e d by t r a p p i n g  enolate anion with cyclopropanecarboxaldehyde 203 i n ^98% y i e l d .  the  f o r the s y n t h e s i s of a number of  s p i r o ketone 198 i n v o l v e d the p r e p a r a t i o n and t h e r m o l y s i s  of  reaction  p y r o l y s i s of the c o r r e s p o n d i n g t r i m e t h y l -  c y c l o p e n t e n e s than d i d p y r o l y s i s  spirovetivane  by the  g-cyclopropyl-a,g-  they underwent  rearrangement,  e n o l e t h e r s gave b e t t e r y i e l d s  cyclopentene  i n good y i e l d s  When the c y c l i c  cyclopentenes i n reasonable  propylmethylenecycloalkanones,  phenylthio(cyclopropyl)-  a-hydroxymethylenecycloalkanones  u n s a t u r a t e d ketones were t h e r m o l y z e d , vinylcyclopropane-cyclopentene  g-iodo  O v e r a l l d e h y d r a t i o n of 203,  gave  v i a base-  promoted e l i m i n a t i o n of a c e t i c a c i d from the c o r r e s p o n d i n g a c e t a t e gave a 78% y i e l d of a m i x t u r e of i n a r a t i o of 13:1, r e s p e c t i v e l y . lithium diisopropylamide,  the  g - c y c l o p r o p y l enones 155 and  Treatment of  211 156,  the l a t t e r m i x t u r e w i t h  f o l l o w e d by t r a p p i n g the r e s u l t i n g  enolates with  c h l o r o t r i m e t h y l s i l a n e gave the e n o l s i l y l e t h e r s 200 i n ^95% y i e l d . of  200,  followed  by h y d r o l y s i s  the  Pyrolysis  of the crude p r o d u c t , gave a 57% y i e l d of a  -iv-  mixture of the s p i r o enone 212 and 213, i n the r a t i o of 2.5:1, respectively.  The d e s i r e d isomer 212 was i s o l a t e d from the mixture  and was subsequently transformed i n t o the s p i r o ketone 198 v i a a s t r a i g h t f o r w a r d , four-step sequence of r e a c t i o n s . Part I I I describes the synthesis and thermal rearrangement of the t r i c y c l i c enones _39 and r e l a t e d compounds.  Reaction of l i t h i u m  phenylthio(syn-7-norcar-2-enyl)cuprate (38) w i t h 3-iodo-2-cyclohexen-lone and 3-iodo-2-cyclopenten-l-one gave the t r i c y c l i c enones 55_ and 56, respectively.  I t was thus c l e a r that the i n i t i a l l y formed enones 39  underwent f a c i l e Cope rearrangement  to give the t r i c y c l i c enones _55 or  56 during work-up and/or p u r i f i c a t i o n . Reaction of a 1:1 mixture of syn and a n t i l i t h i u m phenylthio(7-norcar-2-enyl)cuprates w i t h 3-iodo-2cyclohexen-l-one gave a 1:1 mixture of the t r i c y c l i c enones _5_5 and 57. S i m i l a r l y , r e a c t i o n of the same cuprate reagent mixture w i t h 3-iodo-2cyclopenten-l-one gave a 1:1 mixture of the enones _56_ and _58. When odichlorobenzene s o l u t i o n s of the enones _57_ and _58_ were r e f l u x e d , these compounds r e a d i l y rearranged to the t r i c y c l i c enones _5_5 and 56, respectively.  TABLE OF CONTENTS Page TITLE PAGE ABSTRACT  i i  TABLE OF CONTENTS LIST OF TABLES ACKNOWLEDGEMENTS PART I .  i  v v i i viii  SYNTHESIS OF 4-ALKYL-l,4-DIHYDROPYRIDINES AND RELATED COMPOUNDS  INTRODUCTION I. General I I . Structure I I I . Synthesis of Dihydropyridines IV. Oxidation of Dihydropyridines  1 1 2 4 25  DISCUSSION I. General I I . Reaction of L i t h i u m P h e n y l t h i o ( a l k y l or a r y l ) cuprates w i t h P y r i d i n e i n the Presence of Methyl Chlorofonnate I I I . Comparison of L i t h i u m D i a l k y l ( o r d i a r y l ) c u p r a t e s w i t h L i t h i u m P h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s i n the Synthesis of l-Carbomethoxy-4-alkyl(or aryl)-l,4-dihydropyridines IV. Reaction of L i t h i u m D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of A c e t y l Bromide V. Comparison of D i f f e r e n t E l e c t r o p h i l e s i n the Synthesis of 4 - A l k y i - l , 4 - d i h y d r o p y r i d i n e D e r i v a t i v e s from the Reaction of L i t h i u m D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of the E l e c t r o p h i l e s VI. Mechanistic Considerations V I I . Conversion of l-Carbomethoxy-4-alkyl-l,4-dihydropyridines to the Corresponding 4 - A l k y l p y r i d i n e s  27 27 28 33  37 40  45 49  EXPERIMENTAL  54  BIBLIOGRAPHY  72  -viPage PART I I . SYNTHESIS AND THERMOLYSIS OF g-CYCLOPROPYLa,g-UNSATURATED KETONES AND RELATED COMPOUNDS INTRODUCTION I. General I I . Vinylcyclopropane-Cyclopentene Rearrangement I I I . Mechanistic Considerations i n the Thermal Vinylcyclopropane-Cyclopentene Rearrangement IV. The Problem  81 81 82 92 95  DISCUSSION I. Synthesis of C y c l i c B-Iodo-a,8-Unsaturated Ketones I I . Conversion of g-Iodo-a,B-Unsaturated Ketones i n t o the Corresponding B-Cyclopropyl-a,B-Unsaturated Ketones I I I . Thermolysis of B-Cyclopropyl-a,g-Unsaturated Ketones IV. A p p l i c a t i o n of Thermal Vinylcyclopropane-Cyclopentene Rearrangement to S p i r o v e t i v a n e Synthesis  97 97 111  EXPERIMENTAL  153  BIBLIOGRAPHY  189  PART I I I .  117 136  REACTION OF LITHIUM PHENYLTHIO(7-NORCAR-2-ENYL)CUPRATES WITH CYCLIC g-IODO-a,g-UNSATURATED KETONES AND RELATED REACTIONS  INTRODUCTION I. General I I . 1,2-Divinylcyclopropane Rearrangements I I I . The Objective  199 199 199 205  DISCUSSION I. General I I . Reaction of C y c l i c g-Iodo-a,B-Unsaturated Ketones w i t h L i t h i u m Phenylthio(7-norcar-2-enyl)cuprate Reagent  206 206 207  EXPERIMENTAL  217  BIBLIOGRAPHY  224  -vii-  LIST OF TABLES  PART I Table  Page  0  I.  Reaction of L i t h i u m P h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s w i t h P y r i d i n e i n the Presence of Methyl Chloroformate.  II.  Comparison of the Use of L i t h i u m D i a l k y l ( d i a r y 1 ) c u p r a t e s w i t h the Use of L i t h i u m P h e n y l t h i o ( a l k y l or a r y l ) cuprates i n the Synthesis of l-Carbomethoxy-4-alkyl(or a r y l ) - 1 , 4 dihydropyridines.  31 35  I I I . Reaction of Lithium D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of A c e t y l Bromide.  39  IV.  Comparison of D i f f e r e n t E l e c t r o p h i l e s i n the Synthesis of 4 - A l k y l - l , 4 - d i h y d r o p y r i d i n e D e r i v a t i v e s from the Reaction of P y r i d i n e w i t h L i t h i u m Di-n-butylcuprate.  44  V.  Conversion of l - C a r b o m e t h o x y - 4 - a l k y l ( a r y l ) - l , 4 d i h y d r o p y r i d i n e s to the corresponding 4 - A l k y l ( a r y l ) pyridines.  53  PART I I Table I.  Conversion of C y c l i c g-Diketones and a-Hydroxymethylenecycloalkanones to the Corresponding g-Iodo-a,g-Unsaturated Ketones.  101  II.  The uv Absorption Maxima ( X ) of Some g-Halo Enones and t h e i r Parent g-Unsubstituted Enones.  106  m a x  I I I . Conversion of g-Iodo-a,g-Unsaturated Ketones i n t o g-Cyclopropyl-a,g-Unsaturated Ketones. IV.  Thermal Rearrangement of g-Cyclopropyl-a,g-Unsaturated Ketones and Related Compounds.  115 126  -viii-  ACKNOWLEDGEMENT  I wish to express my g r a t i t u d e to Dr. Edward P i e r s f o r h i s e x c e l l e n t guidance throughout the course of my research.  I t has  been a very rewarding experience to work under h i s d i r e c t i o n . My thanks and best wishes are extended to Dr. Isao Nagakura whose c o l l a b o r a t i o n on many problems helped to s t i m u l a t e the present work.  In a d d i t i o n , I wish to thank the other members of our research  group f o r many h e l p f u l d i s c u s s i o n s . The able typing of t h i s t h e s i s by Mrs. Anna Wong i s appreciated. Also I wish to thank Mr. Dave Herbert, Mr. Pat Jamieson, Mr. Howard Morton, Miss May Lee and Miss Josephine Yeung f o r proof reading the thesis. The f i n a n c i a l support from the N a t i o n a l Research C o u n c i l of Canada (1975-1978) i s g r a t e f u l l y  acknowledged.  -1PART I Synthesis  of 4 - A l k y l - l , 4 - d i h y d r o p y r i d i n e s and R e l a t e d Compounds  INTRODUCTION  I.  General D i h y d r o p y r i d i n e s have been known s i n c e  p u b l i s h e d the s y n t h e s i s of of  compounds.^*  the f i r s t  1882 when Hantzsch  representatives  D i h y d r o p y r i d i n e s a r e of c o n s i d e r a b l e  of  this  interest  because of t h e i r p h y s i o l o g i c a l p r o p e r t i e s and because of they p l a y i n b i o l o g i c a l systems.  class  the  role  The 1 , 4 - d i h y d r o n i c o t i n a m i d e  appears i n the reduced forms of n i c o t i n a m i d e adenine (NADH) 1_ and n i c o t i n a m i d e adenine d i n u c l e o t i d e  moiety  dinucleotide  phosphate  (NADPH), which  are v e r y important hydrogen t r a n s f e r reagents i n b i o l o g i c a l  systems.  2  1 D i h y d r o p y r i d i n e s e x h i b i t a wide v a r i e t y of p h y s i o l o g i c a l For example,  s e v e r a l analogs  of  activities.  3,5-diethoxycarbonyl-l,4-dihydro-2,4,63  t r i m e t h y l p y r i d i n e _2 were found to have p o r p h y r i a i n d u c i n g a c t i v i t y . Other p h y s i o l o g i c a l p r o p e r t i e s o f d i h y d r o p y r i d i n e s i n c l u d e a n t i t u m o r activity,^coronary  d i l a t i n g p r o p e r t i e s , ^ hypertensive  activity,^  9 analgesic,  s p a s m o l y t i c and l o c a l a n e s t h e t i c a c t i v i t y .  p y r i d i n e s have found use as h e r b i c i d e s and  defoliants  Some d i h y d r o -  -2-  Dihydropyridines are important intermediates i n c e r t a i n r e a c t i o n s 11 12 of p y r i d i n e s , f o r example, n u c l e o p h i l i c s u b s t i t u t i o n s , reductions, 13 and a c y l a t i o n s i n the presence of p y r i d i n e . Dihydropyridines which are r e a d i l y c o n v e r t i b l e to p y r i d i n e s a l s o serve as important precursors o f 14 the l a t t e r . Studies d i r e c t e d towards understanding  the nature of the hydrogen  t r a n s f e r mechanism of the coenzyme NADH (or NADPH) have s t i m u l a t e d the synthesis of a wide v a r i e t y of model d i h y d r o p y r i d i n e s , e s p e c i a l l y , 1,4dihydropyridines.  A l a r g e number of h i g h l y s u b s t i t u t e d dihydropyridines  have been synthesized by the Hantzsch and r e l a t e d r i n g c l o s u r e methods and by the r e d u c t i o n of the p y r i d i n e r i n g by complex hydrides."''"' Grignard reagents and organolithium reagents react w i t h simple p y r i d i n e s to give dihydropyridines i n which the 1,2 isomer i s always the major product."'""'  U n t i l r e c e n t l y , i t has been q u i t e d i f f i c u l t to synthesize  simply s u b s t i t u t e d II.  1,4-dihydropyridines.  Structure T h e o r e t i c a l l y , dihydropyridines can e x i s t i n f i v e isomeric forms,  (3_-7) , but almost a l l known dihydropyridines have e i t h e r the 1,2- or the 1,4-dihydrostructure  (3 and h_, r e s p e c t i v e l y ) ."''"' This can be explained  by the p a r t i c i p a t i o n of the unshared p a i r of e l e c t r o n s on n i t r o g e n i n the IT e l e c t r o n system o f these two isomers. 2 the highest number o f sp - h y b r i d i z e d centers.  The isomers 3_ and 4_ have  -34  H  ' N' I H  1  A  -N-  •N-  I  A  1  The s t r u c t u r e of d i h y d r o p y r i d i n e s has been the subject of much research and controversy.  The i n c o r r e c t s t r u c t u r a l assignment of  the 1,4-dihydropyridine d e r i v a t i v e 2_ obtained from the r e a c t i o n of e t h y l acetoacetate, acetaldehyde, and ammonia as a 2,3-dihydropyridine d e r i v a t i v e by Hantzsch^ r e s u l t e d i n a l o t of confusion i n subsequent studies concerning the s t r u c t u r e of d i h y d r o p y r i d i n e s , p a r t i c u l a r l y w i t h regard to the d i s t i n c t i o n between 1,2 and 1,4 isomers.  This was  p a r t i c u l a r l y s e r i o u s i n the case of the coenzyme NADH, 1_, which was erroneously i d e n t i f i e d as a 1 , 2 - d i h y d r o p y r i d i n e ^ u n t i l i t s s t r u c t u r e 17 18 was unambiguously e s t a b l i s h e d by deuterium l a b e l l i n g .  '  Now,  modern  spectroscopic methods can r e a d i l y d i s t i n g u i s h between the two types of isomers and unambiguous assignment of s t r u c t u r e i s r e l a t i v e l y s t r a i g h t forward . The r e l a t i v e s t a b i l i t i e s of 1,2- and 1,4-dihydropyridines appears s t i l l to be somewhat open to question. HMO  c a l c u l a t i o n s on the ir systems  of the d i h y d r o p y r i d i n e r i n g systems i n d i c a t e that the 1,2 isomer i s more 19 20 stable. However, s t u d i e s on hydrogen-transfer r e a c t i o n s and e q u i l i 19 21 bration ' i n d i c a t e that the 1,4-dihydropyridines are thermodynamically more s t a b l e than the corresponding 1,2  isomers.  Dihydropyridines are, i n general, very r e a c t i v e compounds.  They  22 23 are very s u s c e p t i b l e to o x i d a t i o n by a i r ' and most of them decompose 24 r e a d i l y when l e f t i n contact w i t h a i r .  For example, the d i h y d r o p y r i d i n e  d e r i v a t i v e 8_ was a i r - o x i d i z e d to the s u b s t i t u t e d p y r i d i n e 9^ i n ca. 20h  -4-  (eq.l).  23  When e l e c t r o n - w i t h d r a w i n g s u b s t i t u e n t s  capable of  resonance  R  R'.  J  H  (1)  air ca.20h  interaction  N  N  8  9  (COR, CO2R, CN, M ^ ) a r e p r e s e n t on the 3 and 5  the d i h y d r o p y r i d i n e system i s substituted case.  c o n s i d e r a b l y more s t a b l e  On the o t h e r h a n d ,  positions,  than the u n -  electron-donating substituents  at  25 these p o s i t i o n s  destabilize  these compounds.  n i t r o g e n has a m i l d s t a b i l i z i n g e f f e c t ,  A l k y l s u b s t i t u t i o n on  while a g l y c o s y l  substituent  on n i t r o g e n appears to have a r e m a r k a b l e s t a b i l i z i n g e f f e c t . example, d i h y d r o p y r i d i n e 10_ can be r e c r y s t a l l i z e d from a c e t i c 26 water i n the  form o f p a l e y e l l o w n e e d l e s .  p y r i d i n e s seem to be l e s s r e a c t i v e t h i s may be due, a t l e a s t  i n p aPh rt,  For acid-  Highly substituted  dihydro-  than those t h a t a r e u n s u b s t i t u t e d ; to s t e r i c  reasons.  10 III.  Synthesis  of Dihydropyridines  There a r e two b a s i c m e t h o d o l o g i e s  for preparing dihydropyridines;  one i n v o l v i n g the a d d i t i o n o f v a r i o u s r e a g e n t s  to a p y r i d i n e r i n g and  -5-  the other i n v o l v i n g d i r e c t formation from a l i p h a t i c reagents, as i n the Hantzsch and r e l a t e d syntheses. A.  Hantzsch Synthesis and Related Condensations The o r i g i n a l Hantzsch synthesis of dihydropyridines i n v o l v e d the  condensation ammonia.  of e t h y l acetoacetate w i t h an aldehyde i n the presence o f  The product o f t h i s r e a c t i o n was the h i g h l y s u b s t i t u t e d 1,4-  d i h y d r o p y r i d i n e 11, as shown i n eq.2.^  This method has been widely used 27-29  f o r the preparation of the dihydropyridines 1_1, 30-32 30 31 33 aromatic o r h e t e r o c y c l i c residue. ' '  P  ri  EtO^N  ^  where R i s an a l i p h a t i c ,  o  o  ,/N)Er  ^  \y  O  EtO-^Y|f^OEt  ( 2 )  11 (a) R=CH ; (b) R=C H N0 ; (c) R=H; (d) R=C H ; (e) R=CH CN 3  6  4  2  6  5  2  The Hantzsch s y n t h e s i s , as o r i g i n a l l y devised, has been modified i n a great v a r i e t y of ways.  The aldehyde component has been replaced  , , „ 34,35 . .. . ,36,37 , ... . , 38 by ketones, glyoxylic acid and p r o p i o l i c a c i d . Ammonium 25 39 40 41 42 43 acetate, formamide, hexamethylenetetramine, ' primary amines ' 44 45 and hydrazine  '  source of n i t r o g e n .  have been used as s u b s t i t u t e s f o r ammonia as the F i n a l l y , the a c t i v e methylene component has been  modified most e x t e n s i v e l y . The o r i g i n a l l y employed e t h y l acetoacetate 46 47 25 has been s u b s t i t u t e d by 1,3-diketones ,' and w-cyanoacetophenone to give 3 , 5 - d i a c y l - l , 4 - d i h y d r o p y r i d i n e s 12_ and  2,6-diphenyl-3,5-dicyano-l,4-  dihydropyridines 13, r e s p e c t i v e l y , as shown i n eq.3 and 4.  S i m i l a r l y , the  phenylthioether 2A_ r e a c t s w i t h benzaldehyde and ammonium acetate to give  -6-  d i h y d r o p y r i d i n e 15 (eq.5) R  A  25  H  O  t /  O (3)  !  NH,  H 12  Y  NCPh-  R N'C\ X  NH OAc , HOAc  H /CN  (4)  Ph'  4  13  H Ph PhS^JXl^SPh  'SPh  PhS  P h / ^ 14  NH,OAc 4 HOAc  O-  XX  -Ph  (5)  I  H 15  Enamines can a l s o be used to replace e t h y l acetoacetate.  For  example, enamines of general s t r u c t u r e 1_6_ r e a c t w i t h aldehydes to give 9 31 48 the dihydropyridines 17_ (eq.6). '  '  1,5-Diketones preformed from  the r e a c t i o n of an aldehyde w i t h an a c t i v e methylene compound another v a r i a t i o n on the Hantzsch s y n t h e s i s .  provide  For example, diketone 18,  derived from condensation of e t h y l acetoacetate and formaldehyde, reacts 49 w i t h ammonia to give the d i h y d r o p y r i d i n e 11c.  In a similar fashion,  the bis-enamine 19_ formed from the r e a c t i o n of 3-aminocrotononitrile w i t h an aromatic aldehyde was c y c l i z e d to the dihydropyridine 20 (eq.8).~^ Aldehydes can a l s o condense w i t h a c t i v e methylene compounds to give a, 8 unsaturated ketones such as 21. These l a t t e r compounds can react w i t h an  enamine o r w i t h a ketone and ammonia, to give the unsymmetrical 1,4 •dihydropyridines 22 (eq.9).^^ H +  RCHO  r  -NH, -  R'  2  y  R  !AM>\r1 H 17  16  17(a) R=aryl, R ^ a l k y l , X=CC> Et; (b) R^CHg, X=CN; (c) R ^ A r , X=CN 2  CH COCH C0 Et + 3  2  2  EUMH ^ HCHO --2 i?  NH  18  3  OEt  Et  11c  -8B.  Preparation from P y r i d i n e D e r i v a t i v e s  1.  Reduction w i t h Complex Hydrides A number of dihydropyridine d e r i v a t i v e s have been prepared by  reduction of the corresponding  p y r i d i n e s or pyridinium s a l t s w i t h  complex metal hydrides. Sodium borohydride  reduces p y r i d i n e and pyridinium s a l t s , u s u a l l y 12 52  to an isomeric mixture of 1,2-, 1,4- and/or 1,6-dihydropyridines.  '  Depending on the conditions o f the r e a c t i o n s and on the type of subs t i t u e n t s present on the p y r i d i n e r i n g , the dihydropyridines formed by the i n i t i a l attack of the hydride i o n may undergo f u r t h e r reduction to tetrahydropyridines o r may be i s o l a t e d without f u r t h e r r e d u c t i o n . For example, the p y r i d i n i u m s a l t 23_ was reduced by sodium borohydride i n methanolic sodium hydroxide to the corresponding  mixture of 1,2- and  1,6-dihydropyridines, which were i s o l a t e d as s t a b l e t r i c a r b o n y l chromium 53 complexes 24_ and 25, r e s p e c t i v e l y (eq.10).  I n a more recent  study,  i t was reported that the p y r i d i n i u m s a l t Z3 could be reduced by sodium borohydride  i n a two phase system ( e t h y l ether, aqueous methanol c o n t a i n i n g  sodium hydroxide) to the corresponding  1,2-dihydropyridine  only, and i n good  54 yield.  In c o n t r a s t , reduction  borohydride  o f the pyridinium s a l t 26^ by sodium  gave a mixture of the corresponding  tetrahydropyridine 27  and the p i p e r i d i n e 28_ ( e q . l l ) . ^ ^ 1. NaBH ,CH OH,NaOH 4  3  Cr(CO)  > 2. (CH CN) Cr(CO) 3  3  3  Cr(CO) (10)  +  3  3  25  -9-  26  27  28  P y r i d i n e i t s e l f can a l s o be reduced by sodium borohydride i n the presence of an e l e c t r o p h i l e to give N-substituted d i h y d r o p y r i d i n e s .  '  Thus, r e d u c t i o n o f p y r i d i n e by sodium borohydride i n the presence of methyl chloroformate a f f o r d e d a mixture of the 1.4- and 1 , 2 - d i h y d r o p y r i d i 29 and 30 ( e q . 1 2 ) ,  56  C£C0„Me (12) C0 Me  CO,Me  29  30  2  3-Cyanopyridine 31_, when reduced by sodium borohydride i n an a p r o t i c solvent ( f o r example, diglyme), produced the corresponding 1,4-dihydro58 p y r i d i n e 32_.  I n p r o t i c s o l v e n t s ( f o r example, ethanol) f u r t h e r r e d u c t i o n 58  to the t e t r a h y d r o p y r i d i n e 33_ occurred.  S i m i l a r l y , the 3-cyanopyridinium  s a l t 34a was reduced by sodium borohydride i n methanol to a mixture of the corresponding d i - and t e t r a h y d r o p y r i d i n e s 36a and 37a, respectively.^»61 In a l k a l i n e sodium borohydride, the corresponding 1,2- and 1,6-dihydropyridines 35a and 36a, respectively,were formed i n s t e a d . ^ > ^  j  n  c o n t r a s t , the p y r i -  dinium s a l t 34b was reduced by sodium borohydride i n methanol to the corresponding d i h y d r o p y r i d i n e s 35b and 36b without being f u r t h e r reduced to t e t r a h y d r o p y r i d i n e s . ^  Reduction of the nicotinamide d e r i v a t i v e s 34c  and 34d by sodium borohydride afforded mainly the corresponding 1,6-dihydrop y r i d i n e s 36c and 36d, r e s p e c t i v e l y .  65  -10-  CN  NaBH,  • CN NaBH,  diglyme  A  (13)  ->  EtOH  •N-  31  CN  32  33  NaBH, (14)  -N  I  R 34  I  R 35  R  R  37 36 34 (a) R=CH , Y=I, X=CN; (b) R=2,6-Cl C H CH , Y=Br, X=CN; (c) R=CH , Y=MeOS0 X=C0NH ; (d) R=n-Pr, Y=I, X=C0NH P y r i d i n e s and p y r i d i n i u m s a l t s having electron-withdrawing 3  2  2  6  3  2  3  2  s u b s t i t u e n t s on both the 3 and 5 p o s i t i o n s , can be reduced r e a d i l y by sodium borohydride to the corresponding d i h y d r o p y r i d i n e s .  These  l a t t e r compounds are l e s s s u s c e p t i b l e to f u r t h e r r e d u c t i o n than t h e i r monosubstituted or unsubstituted counterparts. p y r i d i n e s 38a, 38b, 3 8 c  5 2 > 6  ^ ^  8  Thus, the d i s u b s t i t u t e d  and the p y r i d i n i u m s a l t 4 1  6 9  were  reduced by sodium borohydride to the corresponding mixtures of dihydrop y r i d i n e s as shown i n eq. 15 and 16.  NaBH,  X>  X  (15)  4 38  40  38(a) X=CN; (b) X=C0 Me; (c) X=C0 Et, (d) X=C0CH 2  2  3  3  -11-  The r a t i o of 1,4 was  to 1,2  isomers formed i n the reduction r e a c t i o n s  found to be h i g h l y solvent dependent, ranging from 87:13  i n pyridine  52 to 37:63 i n a c e t o n i t r i l e f o r the d i e s t e r 38c.  In c o n t r a s t , sodium  cyanoborohydride reduced 38b, 38c and 38d to the corresponding  pure  52 1,4-dihydropyridines.  The r e g i o s e l e c t i v i t y of the reduction a l s o  depends on the p o s i t i o n of a l k y l s u b s t i t u e n t s on the r i n g . borohydride  Thus, sodium  reduction of 3,5-dicyano-4-methylpyridine 44 and 3,5-dicyano-2,  6-dimethylpyridine -] 67,70 txvely.  46_ afforded only the dihydropyridines 45_ and 47_ respec-  (17) H 45  44  (18)  O c c a s i o n a l l y , reduction of f u n c t i o n a l groups present on the s u b s t i t u e n t s by sodium borohydride d i e s t e r 48_ was  may become a serious problem.  reduced mainly to the monoester 4 9 ^  was reduced mainly to the d i o l 5_1. the corresponding  For example, the and the diketone _50_  In each case only small amounts of  dihydropyridine was  formed.  -12-  0  O (19) NT 50  51  Lithium aluminum hydride, a very strong reducing agent, reduces pyridine or i t s a l k y l d e r i v a t i v e s l e s s s e l e c t i v e l y than the milder reducing agent, sodium borohydride.  For example, a - p i c o l i n e 5_2 was  reduced by l i t h i u m aluminum hydride to a mixture of the tetrahydropyridine 53 and the p i p e r i d i n e 5_4.  71  S i m i l a r l y , 1,3-dimethylpyridinium iodide 26_  72 was reduced e x c l u s i v e l y to the tetrahydropyridine 27 . LiAlH, (20)  52  53  54  (21)  26  27  Very o f t e n , when l i t h i u m aluminum hydride i s employed, f u n c t i o n a l groups present on the substituents are reduced more r e a d i l y than the 12 aromatic r i n g . For example, methyl n i c o t i n a t e underwent r e a c t i o n with l i t h i u m aluminum hydride with exclusive reduction of the ester function 73 (eq.22).  The only p r e p a r a t i v e l y u s e f u l r e a c t i o n i s that of 3,5-  dicyanopyridine  i n which the r i n g i s reduced more r e a d i l y than the n i t r i l e  -13-  groups  (eq.23).  67  _  r  n  ..  LiA£H.  CH OH 2  (22)  •N 55  56 LLAHH (23) N  2.  A d d i t i o n of Organometallic  N I H 40a  Reagents  C e r t a i n organometallic compounds r e a c t w i t h p y r i d i n e , p y r i d i n i u m s a l t s and p y r i d i n e oxides to form d i h y d r o p y r i d i n e s . A l k y l l i t h i u m or a r y l l i t h i u m reagents r e a c t w i t h p y r i d i n e and a l k y l p y r i d i n e s to give 2-substituted l - l i t h i o - l , 2 - d i h y d r o p y r i d i n e s which can be hydrolysed to the corresponding 1,2-dihydropyridines or r e a c t w i t h an e l e c t r o p h i l e to give N-substituted (eq.25) ,  (eq.24)  74-79  1,2-dihydropyridines  7 8  R'Li  (24)  -14-  P y r i d i n i u m s a l t s and t h e i r a l k y l d e r i v a t i v e s  react with  alkyl-  or a r y l l i t h i u m reagents and w i t h G r i g n a r d reagents to g i v e m a i n l y corresponding 1,2-dihydropyridines  For example,  the  the p y r i d i n i u m s a l t  80 60 r e a c t s w i t h p h e n y l l i t h i u m to g i v e the d i h y d r o p y r i d i n e 61_ and .j. . , „ 81 , , 8 2 - 8 4 . ,,85,86 . . „ . p y r i d m x u m s a l t s j)2_, 64_ and bo_ react with Grignard reagents to g i v e the 2 - s u b s t i t u t e d  1,2-dihydropyridines  63,  65 and 67,  respectively. PhLi  (26)  -> I  I Me  x-  Mc  60  H  Ph  61  RMgBr (27)  62  R=Et, Ph  PhCH MgX 2  (28)  -> CHjPh 65  R'MgX  (29)  ->  COjEt 67 R e a c t i o n of p y r i d y l ketones 68_ w i t h G r i g n a r d reagents a f f o r d s  the  -15-  87 88 corresponding 1,4-dihydropyridines 69_. '  However, quaternary  salts  of n i c o t i n i c e s t e r s or n i t r i l e s 70_ react w i t h Grignard reagents to give mainly the corresponding 1,6-dihydropyridines _7_1, accompanied 89 90 by minor amounts of the 1,2-dihydro isomers 7_2. ' H  , R C0  Ph  1) PhMgBr  COR  ->  2) H 0  (30)  2  I  H 68  69  (31)  70  71 70 (a) Y=C00R  2  J_2  ; (b) Y=CN  Normally, Grignard reagents react w i t h p y r i d i n e molecules c o n t a i n i n g electron-withdrawing groups a t the 3 and 5 p o s i t i o n s to give a mixture of 1,2- and 1,4-dihydropyridines.  For example the d i s u b s t i t u t e d p y r i d i n e s  38a, 38b and 38c r e a c t w i t h methyl magnesium i o d i d e to a f f o r d a mixture of the corresponding d i h y d r o p y r i d i n e s 73 and 74, r e s p e c t i v e l y (eq.32)  27 37 68 ' ' '  (32)  38(a) X=CN; (b) X=C0 Me; (c) X=C0 Et; (d) X=C0CH 2  2  3  -16-  In some cases, the Grignard reagent attacks the s u b s t i t u e n t s r a t h e r than the r i n g moiety.  I n the case o f 38d, f o r example, the  major product of the r e a c t i o n i s the d i o l formed by a t t a c k of the Grignard reagent on the carbonyl group.  Recently, i t was found that  organocadmium reagents, formed from the r e a c t i o n of cadmium c h l o r i d e w i t h Grignard reagents, give good y i e l d s of r i n g a d d i t i o n without concommitant a d d i t i o n to the carbonyl s u b s t i t u e n t s on the p y r i d i n e 86 ring.  For example, the p y r i d i n i u m s a l t 75 reacts w i t h phenyl  magnesium bromide to give the corresponding  dihydropyridines _76 and  77 together w i t h a f a i r amount of the d i p h e n y l - 3 - p y r i d y l c a r b i n o l 78. With the phenyl cadmium reagent, none of the p y r i d y l c a r b i n o l was i s o l a t e d  (33)  3.  COPh  COPh  COPh  75  7_6  _77  78  M = MgBr  13%  49%  15%  M = Cd  19%  61%  0%  A d d i t i o n of Other Nucleophiles P y r i d i n e and p y r i d i n i u m s a l t s a l s o react w i t h a wide v a r i e t y of  other nucleophiles to give dihydropyridine d e r i v a t i v e s . For example, 94 sodium hydrazide r e a c t s w i t h 2 , 6 - l u t i d i n e  to give the adduct J9_ and  sodium methoxide reacts w i t h 4-methoxy-3,5-dinitropyridine  to give the  95 compound ^0_.  S i m i l a r l y , pyridinium s a l t s react with a wide range of  nucleophiles such as carbanions  derived from ketones, d i e t h y l malonate,  -17-  m a l o n o n i t r i l e , cyanoacetic esters and nitromethane to give 1,496—99 dihydropyridine d e r i v a t i v e s .  For example, the p y r i d i n i u m s a l t  81 reacts w i t h acetone i n the presence o f strong base to give the 1,4-dihydropyridine 82_ (eq.36) and p y r i d i n i u m s a l t 8^3 reacts w i t h the enolate anion derived from d i e t h y l malonate to give the dihydropyridine 99 84, which was then c y c l i z e d to the dihydropyridine 235. (eq.37). NHNH NaNHNH, y  2  (34)  ->  'N'  OMe  NaOMe (35)  H CH COCH 3  CH COMe 2  3  (36)  OH CXnCHAr  CX=CHAr 81  82 H  C 0 N H  83  + X CH R 2  2  CH(C0 Et) 2  -CH(C0^Et) 2 >y 84 2 C H  CONH  2  2  -EtOH  (37)  R  D i t h i o n i t e reduction of p y r i d i n i u m s a l t s to dihydropyridines a l s o proceeds by n u c l e o p h i l i c attack to form the intermediate sodium s u l f i n a t e d e r i v a t i v e ( f o r example 87) which then decomposes i n a c i d to the c o r r e s ponding dihydropyridine ( e q . 3 8 ) . ' A  number of 3-substituted and  -18-  3,5-disubstituted dihydropyridines have been prepared  l K R  s  II „-0 .CONH-)  R  86  R'V'^H CONH,  t  (38) SO,  R  88  87  24,89,102-105  V Li) •N I  H  r  R  t h i s way.  89  Cyanide i o n , which has a lower n u c l e o p h i l i c i t y than the reagents discussed above, r e a c t s only w i t h the more e l e c t r o n - d e f i c i e n t p y r i d i n i u m s a l t s , p r e f e r a b l y those that have electron-withdrawing s u b s t i t u e n t s on the 3 and 5 p o s i t i o n s , to give the corresponding dines.  1,4-dihydropyri-  . -j. • , For example,pyridinium s a l t 90_ reacts w i t h  21,75,106-109  cyanide  i o n i n dimethyl s u l f o x i d e to give the adduct 91, which was i s o l a t e d . " ' 7  However, the formation o f the 1,4-dihydro n i t r i l e adduct i s u s u a l l y reversible"*""^ and the adducts are u s u a l l y very unstable.  For example,  the cyanide adducts 92, which have been detected s p e c t r o s c o p i c a l l y , were not i s o l a t e d but were r e a d i l y transformed  to cyanopyridines 93 (eq.40).^"^ H  CN  .CONH -CN  CONH,  2  (39)  DMSO I  Me  l -  90 H  91 CN  COX (40)  I OR 92  93  -19-  4.  Other Methods Dihydropyridines can also be prepared by reduction of pyridines  or pyridinium s a l t s with metals.  Thus, reduction of 4-alkylpyridines 94  by zinc i n e i t h e r a c e t i c anhydride or an acid chloride gave the corres112 ponding 1,4-dihydropyridines 95_. With unsubstituted p y r i d i n e , the AQr r A • * A H3-115 dimer 96 was formed instead.  COR' Zn, R*COC£ (41)  Zn,(RCO) 0 2  ROC —N  (42)  N—COR  E l e c t r o l y t i c reduction of the pyridinium s a l t 90_ at c o n t r o l l e d potentials allowed  the i s o l a t i o n of e i t h e r the dihydropyridine 97_ or  ,. 116,117 the dimer 98. ' n Q  CONH <—  HjNOC  ^CONHo „ -  2  N Me  N  N  I  98  Me  Me  90  C a t a l y t i c hydrogenation For example, hydrogenation  -1.8V  -1.2V  ,CONH  +  2  (43)  N Me  97  can also be used to prepare dihydropyridines.  of the d i s u b s t i t u t e d pyridines 38a, 38b,  38c  -20-  and 38d y i e l d e d i n each case a mixture of the corresponding 1,2- and 1,4d i h y d r o p y r i d i n e s , w i t h the 1,2 isomer  1 mole of H  predominating.  1 1 8  '  1 1 9  r  (44)  Pd  ^ N-  I  I  H  H  38  40  39 X = CN, C0 Me, C0 Et, C0CH 2  2  3  C a t a l y t i c s i l y l a t i o n of p y r i d i n e by t r i m e t h y l s i l a n e gave a complex 22 120 mixture from which the d i h y d r o p y r i d i n e s 100 and 101 were i s o l a t e d .  '  Methanolysis of 101 l i b e r a t e d the parent, 1,4-dihydropyridines 105 (eq.46)  + N-  Me SiH/Pd 3  SiMe  I  102  5.8%  I  SiMe,  a  <25% 100 SiMe  •f Si Me.  103  SiMe  3  12% 99  Si Me.  N  I  I  +  (45)  35% 101  3  Me«5i-N  N—SiMe,  25% 104  0.2%  CH 0H 3  + Si Me*  CH OSiMe, 3  (46)  H  101 105 A l k y l p y r i d i n e s have been reduced by l i t h i u m i n ammonia.121  In  the presence of an e l e c t r o p h i l e ( f o r example, an a l k y l h a l i d e ) , the N-substituted 1,4-dihydropyridine 107 was i s o l a t e d (eq.47).  -21-  1. Li.'NH ,EtOH (47)  2. R X 1  N  106 R = H,CH„  R =CH , Et, n-Pr 3  Diborane reduces the d i e s t e r 38c to the corresponding mixture of 52 1,4-and 1,2-dihydropyridines (eq.48). dependent.  The r e d u c t i o n i s s o l v e n t  I n p y r i d i n e , the 1,4 isomer i s the major product w h i l e i n  tetrahydrofuran, the 1,2 isomer  predominates.  C y c l o a d d i t i o n r e a c t i o n s have a l s o been a p p l i e d to the preparation of d i h y d r o p y r i d i n e s . Thus, dimethyl a c e t y l e n e d i c a r b o x y l a t e 108 reacts w i t h the S c h i f f  base 109 to g i v e the 1,2-dihydropyridine 110 (eq.49). ' 1  Similarly,l-dimethylamino-3-methyl-2-azabutadiene  111 reacts w i t h the  123 d i e s t e r 112 to give the 1,4-dihydropyridine 113. Q Me 2  Me0 CECC0 Me + C H CH=NR 2  2  108  6  MeOjC  C0 Me 2  5  109 R  110  H  (49)  -22-  (50)  + -C0 Me  — -  >  CQ Me 2  2  NMe«  111  112  113  Dihydropyridines have a l s o been prepared from other h e t e r o c y c l i c compounds.  For example, p y r o l y s i s of the homoazepine 114 afforded  l - e t h o x y c a r b o n y l - 2 - v i n y l - l , 2 - d i h y d r o p y r i d i n e 115 (eq.51)  124  Pyrolysis  of d i e t h y l 2-azo-2-benzyloxycarbonyl-l,3-dimethylbicyclo [3.1.0]-hex-3ene-4,6-dicarboxylate 116 gave the 1,2-dihydropyridine 117  125  Hydrogen  h a l i d e s react w i t h the 4H-azepine 118 to give the d i h y d r o p y r i d i n e 119 126 (eq.53)." Oxidation of the t r i c y c l i c compound 120, followed by spontaneous n i t r o g e n e x t r u s i o n from the intermediate 121,afforded the 127 N-substituted 1,4-dihydropyridine 122 (eq.54). A  (51)  114  E  t  ° 2 \  /"  / \  E ,  °2  C  (52) N'  I  COjEt  C0 CH Ph 2  116  2  117  -23-  (54) R  120  121  122  R = C H S0 ; C H 6  C.  5  2  6  5  ; Me ; C ^ C ^ C H .  R e g i o s e l e c t i v e Synthesis of Simply Substituted  1,4-Dihydropyridines.  Objectives of the Work Described i n t h i s Thesis. Of the v a r i e t y of methods which can be employed i n the synthesis of d i h y d r o p y r i d i n e s , the Hantzsch type synthesis has been the most productive. Indeed, hundreds of s u b s t i t u t e d dihydropyridines have been prepared v i a t h i s method. However, r e l a t i v e l y few simple dihydropyridines have been prepared, since the Hantzsch synthesis works best f o r the preparation of dihydropyridines that have electron-withdrawing  s u b s t i t u e n t s on both  the 3 and 5 p o s i t i o n s . Furthermore, r e d u c t i o n of pyridinium s a l t s by sodium borohydride  i s s u c c e s s f u l only i f s t r o n g l y electron-withdrawing  groups are present on the p y r i d i n e r i n g .  Almost no success has been  achieved w i t h the reduction of the f r e e base. The major d i f f i c u l t i e s l i e i n the ease w i t h which the p a r t i a l l y reduced p y r i d i n e s are f u r t h e r reduced to tetrahydropyridines and p i p e r i d i n e s , and the readiness w i t h which the dihydropyridines isomerize, o x i d i z e and polymerize.  A d d i t i o n of organo-  m e t a l l i c reagents to p y r i d i n e s gives mainly 1,2-dihydropyridines which are not very u s e f u l as model compounds f o r probing the mode of a c t i o n of enzymes that bear a 1,4-dihydropyridine  s t r u c t u r e . A d d i t i o n of other  nucleophiles to p y r i d i n e a l s o leads to h i g h l y s u b s t i t u t e d d i h y d r o p y r i d i n e s . In view of these f a c t s , i t appeared that  there was s t i l l a need f o r  b e t t e r methods of making simply s u b s t i t u t e d 1,4-dihydropyridines.  Catalytic  -24-  s i l y l a t i o n of p y r i d i n e or a l k y l p y r i d i n e s does give simple 1,4-dihydropyridines, but a complex mixture of side products always accompanies the desired product. In 1974,  our research group had developed a new, r e g i o s e l e c t i v e  method f o r s y n t h e s i z i n g 4-substituted pyridine with l i t h i u m dialkylcuprates  1,4-dihydropyridines by r e a c t i n g i n the presence of c h l o r o f ormate."128  Thus,addition of methyl chloroformate to a s o l u t i o n of p y r i d i n e and the d i a l k y l (or a r y l ) cuprate reagent i n ether, afforded i n good y i e l d a mixture of the corresponding 1,4- and 1,2-dihydropyridines,  i n which  the 1,4 isomer predominated (> 89% of the product)(eq.55).  The present  s e c t i o n of t h i s t h e s i s i s concerned w i t h r e s u l t s obtained  from a c o n t i n u a t i o n  R CuLi 2  N-  C£C0 CH 2  C0 Me 2  123 R= (a) CH ; (b) CH CH ; (c) n-Bu; (d) ^-Bu; 3  3  2  (55)  +  3  I  C0 Me 2  124 (e) i - P r ; ( f ) C ^ ;  (g) v i n y l  of that work. 128 In the e a r l i e r work,"""'"" i t was found that l i t h i u m d i a l k y l c u p r a t e reagents are q u i t e e f f i c i e n t i n t r a n s f e r r i n g a primary a l k y l group to the 4 - p o s i t i o n of the p y r i d i n e r i n g . However, the r e a c t i o n was not very e f f e c t i v e i n the case of cuprate reagents containing secondary and t e r t i a r y a l k y l groups.  I n work described  i n t h i s t h e s i s , mixed cuprates  [ l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s ] were i n v e s t i g a t e d and compared with l i t h i u m d i a l k y l c u p r a t e s i n the aforementioned type of r e a c t i o n .  -25-  E l e c t r o p h i l e s other than chloroformate were also i n v e s t i g a t e d . the 4-substituted  Finally,  1,4-dihydropyridines synthesized were converted to  the corresponding 4-substituted p y r i d i n e s . Thus, t h i s work provided new IV.  a  synthesis of simple 4 - a l k y l and 4 - a r y l p y r i d i n e s . Oxidation of  Dihydropyridines  According to one author, "the most important r e a c t i o n of  dihydro14  p y r i d i n e s i s t h e i r o x i d a t i o n to the corresponding p y r i d i n e s . "  This i s  understandable i n view of the important r o l e of NADH i n hydrogen t r a n s f e r processes i n b i o l o g i c a l systems and the r o l e dihydropyridines intermediates  play as  i n the r e a c t i o n s of p y r i d i n e s .  Dihydropyridines  can be o x i d i z e d by a wide v a r i e t y of reagents.  The  o l d e s t and s t i l l most commonly used reagents are n i t r o u s or d i l u t e n i t r i c ., 1,44,48 , , 129,130 _ . . ... , ... acids, and chromic a c i d . For example,the dihydropyridine 125 was  o x i d i z e d to the corresponding p y r i d i n e 126 by 20% n i t r i c a c i d  (eq.56).^  High p o t e n t i a l quinones such as c h l o r a n i l ^  or d i c h l o r o -  7  131 dicyanoquinone 127 was  are also q u i t e commonly used.  For example, dihydropyridine  o x i d i z e d by c h l o r a n i l i n r e f l u x i n g benzene to give the corresponding  p y r i d i n e d e r i v a t i v e 128  (eq.57).^  7  S i l v e r nitrate "*"'"*"^ and i o d i n e " ^ 8  2  2  have  also been employed ( f o r example, eq.58). S u l f u r i s often used because i t 28 29 i s l e a s t l i k e l y to give side r e a c t i o n s . ' C a t a l y t i c dehydrogenation 133 13^ 133 by platinum and palladium ' have also been employed. Other reagents include p _ - n i t r o s o d i m e t h y l a n i l i n e , ^ hydrogen peroxide, diisoamyl d i s u l f i d e , carbonyls."^  7  137  mercuric acetate,  and i r o n or n i c k e l  Oxygen or a i r have been employed i n a number of  , , 23,132,139 (example, eq.1,58) 1  138  instances  0, R HC 2  N' 1  CH R  129  or I  (58)  2 RHC or AgNO ]  2  2  CH R 2  130  -27-  DISCUSSION  I.  General In s t u d y i n g the r e a c t i o n s  i n the presence  of l i t h i u m d i a l k y l c u p r a t e s with pyridine  o f methyl c h l o r o f o r m a t e , i t was found t h a t when the  l i t h i u m d i - s ^ b u t y l c u p r a t e reagent was employed, always r e p r o d u c i b l e .  the r e a c t i o n was not  T h i s l a c k o f r e p r o d u c i b i l i t y might be a t t r i b u t e d  to the low thermal s t a b i l i t y of s e c - a l k y l c u p r a t ' e s  in  g e n e r a l , a 141  c h a r a c t e r i s t i c which was r e c o g n i z e d by Posner e_t a l . to circumvent t h i s  In an attempt  l i m i t a t i o n , Posner e_t a l _ . s y n t h e s i z e d  hetero(alkyl)cuprate  reagents  a s e r i e s of  [Het(R)CuLi ( H e t = t - B u O , P h O , t - B u S , P h S , E t N ) ] 2  and compared them w i t h o t h e r organocopper reagents f o r t h e i r and e f f i c i e n c y  selectivity  i n t r a n s f e r r i n g an a l k y l group to s e v e r a l d i v e r s e types of 141  organic substrates.  I t was found that l i t h i u m p h e n y l t h i o ( a l k y l ) c u p r a t e s  PhS(R)CuLi were s u p e r i o r to other h e t e r o ( a l k y l ) c u p r a t e  reagents and l i t h i u m  d i a l k y l c u p r a t e s i n t r a n s f e r r i n g secondary a l k y l groups i n s u b s t i t u t i o n and conjugate a d d i t i o n reactions".  For example,  ii-octyl iodide  undergoes  replacement of i o d i d e by a j s - b u t y l group when t r e a t e d w i t h two of l i t h i u m p h e n y l t h i o ( s - b u t y l ) c u p r a t e alkane 131.  to g i v e a 67% y i e l d of  With l i t h i u m _t-butoxy ( s - b u t y l ) c u p r a t e ,  the c o r r e s p o n d i n g  the y i e l d of  product 131 was 52%. valents  equivalents  the c o u p l i n g  However, o n l y 7% o f 131 was i s o l a t e d when f i v e 141 o f l i t h i u m d i - s _ - b u t y l c u p r a t e were employed ( e q . 5 9 ) . R(s-Bu)CuLi n-C H g  1 7  I  > B-C H 8  solvent (a)  R PhS  (b)  t-BuO  (c)  s-Bu  1 7  131 Yield 67% 52% 7%  -±-Bu  equi-  (  5  9  )  -28-  These observations triggered our i n v e s t i g a t i o n of the r e a c t i o n of l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s with p y r i d i n e i n the presence of methyl chloroformate. II.  Reaction of Lithium P h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s with Py ridine i n the Presence of Methyl  Chloroformate.  Our i n i t i a l studies were c a r r i e d out with l i t h i u m phenylthio128 (n-butyl)cuprate 132c.  Following the procedure of P i e r s and Soucy,  a four f o l d excess of methyl chloroformate was added to a s o l u t i o n of p y r i d i n e (one equivalent) and the cuprate reagent (1.4 equivalents) i n tetrahydrofuran at -78°C.  A f t e r the r e a c t i o n mixture had been s t i r r e d  for 3h at -78°C, a small amount of methanol was added.  The d i s t i l l e d  product obtained a f t e r work-up was analysed by g a s - l i q u i d chromatography (glc) and proton magnetic resonance ("*"Hnmr) spectroscopy.  I t was  found  that the major product of the r e a c t i o n was methyl phenylthioformate 133, along with some of the expected  l-carbomethoxy-4-n-butyl-l,4-dihydropyridine  128 123c  (eq.60).  An a n a l y t i c a l sample of each of the two products  obtained by preparative g l c .  The "Hlnmr spectrum of 133 was  was  identical  with that of an authentic sample of the same m a t e r i a l obtained by the r e a c t i o n of thiophenol and methyl chloroformate i n the presence of aqueous sodium hydroxide. However, when the amount of methyl chloroformate used i n the above r e a c t i o n was reduced from four equivalents to one equivalent, the desired product,  l-carbomethoxy-4-n-butyl-l,4-dihydropyridine 123c was  i n ^65% y i e l d .  obtained  Under these c o n d i t i o n s , the amount of side product, methyl  phenylthioformate 133,was reduced to VL4% of the product mixture.  No trace  -29-  of the corresponding 1,2-dihydropyridine d e r i v a t i v e was  found.  R  ClC0„CH  o  +  I  PhS(R)CuLi  +  PhSC0 Me  C0 Me  2  2  132  123  133  132(a) R=CH ; (b) R=Et; (c) R=n-Bu; (d) R=s-Bu; (e) R=_t-Bu; ( f ) R=Ph  Compound 123c e x h i b i t e d the c h a r a c t e r i s t i c 1,4-dihydropyridine "Slnmr p a t t e r n .  The protons a t C-2 and C-6 resonated as a  two-proton  doublet centred a t T3.20, w i t h c o u p l i n g constant J=8 Hz. The  protons  at C-3 and C-5 gave r i s e to a two-proton doublet of doublets centred at T5.13  (J=8 Hz, J'=2 Hz).  F i n a l l y , the proton at C-4 produced a one-  proton m u l t i p l e t centred at x7.05 and the protons of the carbomethoxy group appeared as a three-proton s i n g l e t at T6.20. The i r spectrum of 123c showed a strong carbonyl absorption at 1730 cm  and two other absorption peaks a t 1633 and 1690 cm  In a s i m i l a r f a s h i o n , the aforementioned  procedure was  \ extended  to i n c l u d e the use of other l i t h i u m phenylthio(alkyl or a r y l ) c u p r a t e reagents.  Some of the r e s u l t s obtained are summarized i n Table 1. A l l  of the d i h y d r o p y r i d i n e d e r i v a t i v e s l i s t e d i n Table 1 e x h i b i t e d 'Hnmr and i r s p e c t r a which were s i m i l a r to that of compound 123c and a l l gave s a t i s f a c t o r y molecular weight determination (high r e s o l u t i o n mass spectrometry). I t was found that when l i t h i u m phenylthio(methyl)cuprate was the y i e l d of the d e s i r e d product,  employed,  l-carbomethoxy-4-methyl-l,4-dihydropyridine  -30-  123a,was merely 52% (entry 1, Table 1 ) .  Attempts to improve the y i e l d  by r a i s i n g the temperature of the r e a c t i o n mixture from -78°C to 0°C led  to the formation of methyl phenylthioformate 133 as the major  product.  Even at -50°C a considerable amount of 133 was formed as a  side product. the  I t was a l s o found that, regardless of the temperature of  r e a c t i o n mixture, a considerable amount of high b o i l i n g residue  remained a f t e r d i s t i l l a t i o n of the i n i t i a l l y i s o l a t e d crude product. S p e c t r a l evidence ("hlnmr) i n d i c a t e d that the major component of t h i s r e s i d u a l m a t e r i a l might be the dimer 134.  However, attempts to i s o l a t e  a pure sample of t h i s m a t e r i a l f a i l e d , since i t decomposed e x t e n s i v e l y  123a  134  when the d i s t i l l a t i o n residue was subjected to column chromatography  on  silica gel. I t i s important to note that compound 123a was q u i t e unstable i n air.  In f a c t , a f r e s h l y d i s t i l l e d c o l o r l e s s sample of 123a turned green  n e a r l y immediately upon contact w i t h a i r .  Indeed, a l l of the  1-carbomethoxy-  4 - a l k y l ( o r a r y l ) - l , 4 - d i h y d r o p y r i d i n e s which were synthesized during the course of our work were found to be unstable i n a i r , although they were s t a b l e f o r a few weeks i f c a r e f u l l y kept under an atmosphere of argon i n the  freezer.  An a n a l y t i c a l sample of each of the d i h y d r o p y r i d i n e d e r i v a t i v e s  was obtained from each of the r e a c t i o n product mixtures by means of p r e p a r a t i v e  -31-  Table 1. Reaction of l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s w i t h p y r i d i n e i n the presence of methyl chloroformate. R  PhS(R)CuLi  + CO Me z  132  Entry  123  Cuprate(R)  Y i e l d ( % ) of 123 3  133  Ratio of 123:133  1  CH -  52  2  C H -  70  88:11  3  CH (CH ) -  65  86:14  4  CH CH CHCH  80  89:11  5  (CH ) C-  26  50:50  6 5  24  6  3  2  5  3  2  3  2  3  C  3  3  3  H  >99:1  C  b  >99:1  (a)  The y i e l d i s based on the t o t a l m a t e r i a l recovered m u l t i p l i e d by the percentage p u r i t y as determined by g l c .  (b)  The r a t i o here i s a c t u a l l y 50% 123 to 50% of s i d e product which was a mixture of 133 plus methyl 2,2-dimethylpropanoate (135).  (c)  The major product was b i p h e n y l .  -32-  glc.  They were c h a r a c t e r i z e d by i r ,  'Hnmr, and mass s p e c t r a l a n a l y s i s  as soon as they were i s o l a t e d . When the procedure described above was c a r r i e d out employing  lithium  p h e n y l t h i o ( e t h y l ) c u p r a t e and the corresponding s ^ b u t y l reagent, the r e a c t i o n s proceeded smoothly and the products were q u i t e c l e a n .  Thus,  the corresponding products, l-carbomethoxy-4-ethyl-l,4-dihydropyridine 123b and l-carbomethoxy-4-s-butyl-l,4-dihydropyridine 123d, were formed i n y i e l d s of 70% and 80%, r e s p e c t i v e l y (see Table 1, e n t r i e s 2 and 4 ) . However, when l i t h i u m phenylthio(_t-butyl)cuprate was used under a v a r i e t y of r e a c t i o n c o n d i t i o n s , the major products formed appeared to be a mixture of methyl phenylthioformate 133 and methyl 2,2-dimethylpropanoate (eq.61).  135  These two compounds were not separable by preparative g l c but  the ''"Hnmr spectrum of the mixture was almost i d e n t i c a l w i t h an authentic 1:1 mixture of the same two m a t e r i a l s . The best r e a c t i o n c o n d i t i o n s found gave a y i e l d of approximately 26% ( g l c y i e l d ) of the d e s i r e d product, t-Bu  (61) CO Me z  133  135  123e  l-carbomethoxy-4-t_-butyl-l,4-dihydropyridine 123e.  Approximately equal  amounts of the s i d e products 133 and 135 were a l s o formed i n the r e a c t i o n (entry 5, Table 1 ) . In the case of l i t h i u m phenylthio(phenyl)cuprate (entry 6, Table 1 ) , the major product formed appeared to be biphenyl 136. The l a t t e r , along  -33-  with  some other minor i m p u r i t i e s , were separated from the desired  product 123f by f r a c t i o n a l d i s t i l l a t i o n .  Comparison of the  %nmr  spectrum of the former m a t e r i a l w i t h that of an authentic sample of biphenyl showed that t h i s m a t e r i a l was mainly biphenyl.  The presence  of biphenyl i n the r e a c t i o n product was f u r t h e r confirmed by a g l c c o i n j e c t i o n a n a l y s i s i n v o l v i n g an authentic sample of biphenyl and t h i s mixture.  The desired product  l-carbomethoxy-4-phenyl-l,4-dihydro-  p y r i d i n e 123f was formed i n only 24% y i e l d  (eq.62).  +  Ph-Ph  ( ) 62  12 3 f F i n a l l y , when l i t h i u m p h e n y l t h i o ( v i n y l ) c u p r a t e was employed, no trace of the expected product 123g was found.  l-carbomethoxy-4-vinyl-l,4-dihydropyridine  A small amount of methyl phenylthioformate  133  was  i s o l a t e d together with a considerable amount of a high b o i l i n g , u n i d e n t i f i e d residue. I l l . Comparison of Lithium D i a l k y l ( o r d i a r y l ) c u p r a t e s with Lithium P h e n y l t h i o ( a l k y l or aryl)cuprates i n the Synthesis of 1-Carbomethoxy4 - a l k y l ( o r aryl)-1,4-dihydropyridines. Since one of the o b j e c t i v e s of the work described i n t h i s part of the thesis was to i n v e s t i g a t e the e f f i c i e n c y of l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) cuprates i n t r a n s f e r r i n g an a l k y l ( o r a r y l ) group to p y r i d i n e i n the formation of 1,4-dihydropyridines, i t i s appropriate to make a comparison  -34-  of the r e s u l t s obtained by using l i t h i u m d i a l k y l ( o r d i a r y l ) c u p r a t e s w i t h those obtained by employing l i t h i u m phenylthio(alkyl or a r y l ) c u p r a t e s .  A  summary of both sets of r e s u l t s i s tabulated i n Table 2. A perusal of the r e s u l t s summarized i n Table 2 c l e a r l y shows that l i t h i u m phenylthio(s_b u t y l ) c u p r a t e 132d was superior to l i t h i u m di-s_-butylcuprate i n y i e l d i n g l-carbomethoxy-4-s-butyl-l,4-dihydropyridine  (entry 4, Table 2 ) . The  l i t h i u m di-s_-butylcuprate reagent reacted w i t h p y r i d i n e i n the presence of methyl chloroformate  to y i e l d 56% of a mixture of l-carbomethoxy-4-  s_-butyl-l, 4-dihydropyridine  123d and l-carbomethoxy-2-s_-butyl-l, 2-dihydro-  p y r i d i n e 124d i n a r a t i o of 89:11 r e s p e c t i v e l y (eq.63).  When l i t h i u m  phenylthio(s_-butyl)cuprate was employed, a mixture of the 1,4-dihydro-  R  o  —>  o  cx  I  I  CO Me  CO Me  z  123  z  (  124  (a) R=CH ; (b) R=Et; (c) R=n-Bu; (d) R=s-Bu; (e) R=_t-Bu; ( f ) R=Ph 3  p y r i d i n e 123d and methyl phenylthioformate  133 ( i n a r a t i o of 89:11,  r e s p e c t i v e l y ) was obtained, i n which the y i e l d of dihydropyridine 123d was approximately 80%. When the a l k y l group i n the cuprate reagent was methyl or primary a l k y l , l i t h i u m p h e n y l t h i o ( a l k y l ) c u p r a t e s were no b e t t e r than the corresponding  d i a l k y l c u p r a t e s . For example, the r e a c t i o n of l i t h i u m  dimethylcuprate  w i t h p y r i d i n e i n the presence of methyl  gave i n 81% y i e l d a mixture of the corresponding  chloroformate  dihydropyridine  Table 2.  Comparison of the use of l i t h i u m d i a l k y l ( d i a r y l ) c u p r a t e s w i t h the use of l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e s i n the synthesis of l-carbomethoxy-4-alkyl(or a r y l ) - 1 , 4 - d i h y d r o p y r i d i n e s  R2CuLi Entry  PhSCu(R)Li  R=  Ratio 123:124  Y i e l d of 123(%)  81°  98:2  52  67  C  96:4  70  86°  98:2  65  56  98:11  80  Product Y i e l d ( % ) a  1  CH -  2  CH CH  3  CH (CH ) -  4  t CH CH CHCH  3  3  3  2  3  5 6  7  2  2  3  C  3  (CH ) C3  C  6 5 H  CH =CH2  26  3  7 0  c,d  88  e  84:16  67  f  51:46  60 ' C  a) b) c) d) e) f) g)  90:10  g  24  <1  72:28  The y i e l d here i s based on t o t a l m a t e r i a l recovered. Same as footnote a ) , Table 1. Data obtained from E.Piers e t a l . " Cul was used to prepare the cuprate reagent. CuBr was used to prepare the cuprate reagent. D i m e t h y l s u l f i d e complex of CuBr was used to make the cuprate reagent. Tri-n-butylphosphine complex of Cul was used to prepare the cuprate reagent.  -36-  derivatives,  i n which the r a t i o of  isomer 124a was 98:2  respectively  phenylthio(methyl)cuprate  the 1 , 4 - i s o m e r 123a to the (entry 1,  was employed,  Table 2 ) .  the y i e l d of  1,2-  When l i t h i u m 1-carbomethoxy-  4 - m e t h y l - l , 4 - d i h y d r o p y r i d i n e 123a was only 50%. When the incoming group was p h e n y l , i t phenylthio(phenyl)cuprate cuprate  (entry  7,  was d e f i n i t e l y  Table 2 ) .  is  clear  i n f e r i o r to the  24% y i e l d of the d e s i r e d p r o d u c t ,  of p h e n y l l i t h i u m and cuprous i o d i d e )  to 1 , 2 - i s o m e r  However,  i t was found that  reacted  to g i v e o n l y a  (prepared from the  was employed,  (123f  and 124f,  reaction  the y i e l d of  c o r r e s p o n d i n g m i x t u r e of d i h y d r o p y r i d i n e d e r i v a t i v e s the 1 , 4 -  diphenyl-  l-carbomethoxy-4-phenyl-l,4-dihydro-  When l i t h i u m d i p h e n y l c u p r a t e  r a t i o of  lithium  Lithium phenylthio(phenyl)cuprate  w i t h p y r i d i n e i n the presence of methyl c h l o r o f o r m a t e  p y r i d i n e 123f.  that  the  was 70% and  respectively)  the  was  90:10.  the r e a c t i o n of l i t h i u m d i p h e n y l c u p r a t e  p y r i d i n e i n the presence of methyl c h l o r o f o r m a t e was not always  with  reproducible.  140 G.M. W h i t e s i d e et_ a l stable  r e p o r t e d that  they had d i f f i c u l t i e s  solutions of l i t h i u m diphenylcuprates  l i t h i u m w i t h cuprous i o d i d e .  However,  i n preparing  from the r e a c t i o n of  they a l s o r e p o r t e d that  phenyl-  the 140  problem was s o l v e d by s u b s t i t u t i n g  cuprous bromide f o r cuprous  iodide.  When t h i s method f o r p r e p a r i n g l i t h i u m d i p h e n y l c u p r a t e was f o l l o w e d the r e s u l t a n t  reagent was allowed  of methyl c h l o r o f o r m a t e  and  to r e a c t w i t h p y r i d i n e i n the presence  i n the u s u a l manner,  there was o b t a i n e d an 88%  y i e l d of a m i x t u r e of l - c a r b o m e t h o x y - 4 - p h e n y l - l , 4 - d i h y d r o p y r i d i n e and l - c a r b o m e t h o x y - 2 - p h e n y l - l , 2 - d i h y d r o p y r i d i n e  124f  i n a r a t i o of  Although l i t h i u m p h e n y l t h i o ( a l k y l o r a r y l ) c u p r a t e s 1,2-dihydropyridine derivatives reactions  123f 84:16.  produced no  w i t h these reagents were not  -37-  problem free.  In most cases, a side product, methyl  phenylthioformate  133,was formed i n approximately 10% y i e l d and, i n the case where the a l k y l group was _t-butyl, t h i s side product was formed i n >25%  yield.  Thus, the use of l i t h i u m p h e n y l t h i o l ( a l k y l ) c u p r a t e s i n the r e a c t i o n w i t h p y r i d i n e and methyl chloroformate i s complementary to the use of l i t h i u m d i a l k y l ( o r d i a r y l ) c u p r a t e s but cannot take i t s place i n the synthesis of l-carbomethoxy-4-alkyl(or a r y l ) - l , 4 - d i h y d r o p y r i d i n e s . IV.  Reaction of Lithium D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of A c e t y l Bromide The work described above c l e a r l y showed that methyl  served quite w e l l as an e l e c t r o p h i l e i n promoting with various cuprate reagents. Furthermore,  chloroformate  the r e a c t i o n of p y r i d i n e  the products (N-carbomethoxy  dihydropyridines) were s u f f i c i e n t l y s t a b l e to allow f o r i s o l a t i o n and characterization.  Nevertheless, i t was of i n t e r e s t to study the p o s s i b i l i t y  of using a l t e r n a t e e l e c t r o p h i l e s , not only to determine whether or not the r e a c t i o n would be e f f i c i e n t , but also i n order to prepare simple dihydrop y r i d i n e compounds containing a substituent on nitrogen other than a carbomethoxy group. The f i r s t  a l t e r n a t e we t r i e d was a c e t y l bromide.  The  used was e s s e n t i a l l y the same as with methyl chloroformate.  procedure For example,  a four f o l d excess of a c e t y l bromide i n ether was added to a s o l u t i o n of p y r i d i n e (1 equivalent) and l i t h i u m di-n-butylcuprate (1.2 equivalents) at -78°C.  The r e s u l t i n g mixture was s t i r r e d at -78°C f o r 30 min, warmed  to 0°C and s t i r r e d f o r an a d d i t i o n a l 30 min.  A f t e r work-up, the d i s t i l l e d  product (^73% y i e l d ) was analysed by g l c and i t was found to be pure  -38-  1-acety1-4-n-buty1-1,4-dihydropyridine  137c (eq.64).  Although the  "''Hnmr of t h i s m a t e r i a l was s l i g h t l y d i f f e r e n t from i t s N-carbomethoxy counterpart, the 1,4-dihydropyridine s t r u c t u r e was c l e a r l y present.  The  protons a t C-2 and C-6 of 137c appeared as a p a i r of doublets (J=9 Hz i n each case) centered a t x2.83 and 3.46.  The protons a t C-3 and C-5,  on the other hand, resonated as a two-proton m u l t i p l e t centered a t x5.05. F i n a l l y , the proton a t C-4 appeared as a m u l t i p l e t centred a t x7.05 and the methyl group on the a c y l group resonated as a s i n g l e t a t x7.83.  The  i r spectrum of t h i s m a t e r i a l showed a strong carbonyl absorption a t 1675 cm ^ and another f a i r l y strong absorption a t 1623 cm "'".  J]  PhS(R)CuLi CH COBr 3  (64)  ^ COMe  137 137(a) R=CH ; (b) R=Et; (c) R=n-Bu; (d) R=Ph 3  S i m i l a r r e s u l t s were obtained when l i t h i u m dimethylcuprate and l i t h i u m d i e t h y l c u p r a t e were employed,and the s p e c t r a l data ( Hnmr, i r ) }  of the corresponding products, l - a c e t y l - 4 - m e t h y l - l , 4 - d i h y d r o p y r i d i n e 137a, and l - a c e t y l - 4 - e t h y l - l , 4 - d i h y d r o p y r i d i n e 137b respectively,were q u i t e s i m i l a r to those of 1-acetyl-4-n-buty1-1,4-dihydropyridine above.  The r e s u l t s are summarized i n Table 3.  137c described  I n general, the y i e l d s of  1,4-dihydropyridine d e r i v a t i v e s were not bad and, somewhat s u r p r i s i n g l y , no trace of the corresponding 1,2-dihydropyridine d e r i v a t i v e s were found. Again, l i t h i u m diphenylcuprate posed the same problem as had been encountered  earlier.  Using cuprous i o d i d e to make the diphenylcuprate,  -39-  Table 3.  Reaction of l i t h i u m d i a l k y l c u p r a t e s w i t h p y r i d i n e i n the presence of a c e t y l bromide R CuLi 2  CH COBr  N'  3  r  CO Me  137  Entry  Cuprates(R)  1  CH -  2  CH CH -  59  3  CH (CH ) -  3  3  3  Product y i e l d ( % )  50  2  2  3  73  -40-  the r e a c t i o n gave a complex mixture of products. was  When cuprous bromide  employed to make the cuprate reagent , the r e a c t i o n was cleaner,  and the s p e c t r a l data (^Hnmr) of the crude product i n d i c a t e d that the d e s i r e d product,  l-acetyl-4-phenyl-l,4-dihydropyridine  137d, was  present i n the product mixture, along w i t h a considerable amount of unknown i m p u r i t i e s .  The r e a c t i o n was not i n v e s t i g a t e d f u r t h e r .  When  the use of l i t h i u m di-s_-butylcuprate was i n v e s t i g a t e d , again, a s y n t h e t i c a l l y useless complex mixture of products r e s u l t e d .  C l e a r l y , the above r e s u l t s  showed that a c e t y l bromide d i d not give r e s u l t s superior to those obtained from methyl chloroformate.  Therefore the r e a c t i o n w i t h a c e t y l bromide  a c t i n g as an e l e c t r o p h i l e f o r the synthesis of  1,4-dihydropyridine  d e r i v a t i v e s was not i n v e s t i g a t e d f u r t h e r . V.  Comparison of D i f f e r e n t E l e c t r o p h i l e s i n the Synthesis of 4 - A l k y l - l , 4 dihydropyridine D e r i v a t i v e s from the Reaction of L i t h i u m D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of the E l e c t r o p h i l e s . Methyl chloroformate  electrophiles. salts.  and a c e t y l bromide are both f a i r l y  strong  They both r e a d i l y react w i t h p y r i d i n e to form pyridinium  The l a t t e r , probably mainly due to the p o s i t i v e charge on the  n i t r o g e n atom and to the electron-withdrawing  group (COOMe or COMe)  attached to the n i t r o g e n , are apparently q u i t e s u s c e p t i b l e to r e a c t i o n w i t h e l e c t r o n t r a n s f e r reagents such as cuprates.  I t was of i n t e r e s t  to i n v e s t i g a t e i f weaker e l e c t r o p h i l i c reagents could serve the same purpose. In t h i s connection,  the r e a c t i o n of p y r i d i n e w i t h l i t h i u m d i - n -  butylcuprate i n the presence of c h l o r o t r i m e t h y l s i l a n e was i n v e s t i g a t e d first.  Under r e a c t i o n conditions very s i m i l a r to those used i n the case  -41-  of methyl chloroformate, the expected d i h y d r o p y r i d i n e 138 was obtained. was very unstable.  l-trimethylsilyl-4-_n-butyl-l,4-  However, i t seemed that t h i s compound  Indeed, the ^Hnmr spectrum of the crude  product  showed that i t contained a considerable amount of 4 - n - b u t y l p y r i d i n e . The presence of 4 - n - b u t y l p y r i d i n e was confirmed by comparing the "4lnmr spectra of the crude product mixture w i t h that of a pure sample of butylpyridine. as f o l l o w s .  4-n-  The "*"Hnmr spectrum of the crude product was i n t e r p r e t e d  A p a i r of doublets (J=5 Hz, J'=2  Hz) centered at x l . 5 2 , was  assigned to the protons at C-2 and C-6 of 4 - n - b u t y l p y r i d i n e , w h i l e the p a i r of doublets (J=5 Hz, J"=2  Hz) at x2.89, was due to the C-3 and  C-5  protons of 4 - n - b u t y l p y r i d i n e . A t r i p l e t (J=7 Hz) centered at x3.40, was assigned to the two methylene protons on the n-butyl group adjacent to C-4 of the r i n g of 4 - n - b u t y l p y r i d i n e . A doublet, (J=8 Hz), which appeared a t x4.07 was assigned to the protons a t C-2 and C-6 of the dihydropyridines 138.  Another p a i r of doublets (J=8 Hz, J'=3.5 Hz)  centered at x5.57, was assigned to the C-3 and C-5 protons of the d i h y d r o p y r i d i n e 138.  F i n a l l y , a m u l t i p l e t centered at x3.00 was  assigned  to the proton at C-4 of the d i h y d r o p y r i d i n e 138. Since the l - t r i m e t h y l s i l y - 4 - r i - b u t y l - l , 4 - d i h y d r o p y r i d i n e 138  was  quite unstable, i t was not i s o l a t e d i n pure form f o r c h a r a c t e r i z a t i o n . Instead, the crude product mixture obtained from the r e a c t i o n described above was treated f i r s t w i t h methanolic potassium hydroxide ( i n order to cleave the N - t r i m e t h y l s i l y l group) and then w i t h 2,3-dichloro-5,6dicyano-l,4-benzoquinone  ( i n order to o x i d i z e the r e s u l t a n t 1,4-dihydro-  p y r i d i n e ) . This procedure afforded a 33% i s o l a t e d y i e l d of 4-n-butylpyridine  (eq.65).  -42n-Bo  n-Bo  l)n-Bu CuLi  1) KOH/MeOH  0  2)ClSiMe  ->  (65)  2) DDQ  3  Si Me.  138 ' Next, the use of diethylphosphorochloridate as an e l e c t r o p h i l e was i n v e s t i g a t e d . When the r e a c t i o n was attempted under the usual r e a c t i o n c o n d i t i o n s ( a d d i t i o n of diethylphosphorochloridate to a s o l u t i o n of p y r i d i n e and l i t h i u m d i - n - b u t y l c u p r a t e ) , none of the expected product, 1,4-dihydropyridine d e r i v a t i v e 139 was i s o l a t e d . However, a d d i t i o n of a s o l u t i o n of diethylphosphorochloridate i n excess p y r i d i n e to a s o l u t i o n of l i t h i u m d i - n - b u t y l c u p r a t e i n ether a t -78°C d i d give the expected product, although the y i e l d was very low (^17%) (eq.66).  The d i s t i l l e d product of the r e a c t i o n was analysed by t i c  and was shown to be the pure d i h y d r o p y r i d i n e 139. The "'"Hnmr of t h i s m a t e r i a l showed the c h a r a c t e r i s t i c 1,4-dihydropyridine s t r u c t u r e . A two proton m u l t i p l e t between T3.56 and 3.93 was assigned to the protons  at  C-2 and C-6 w h i l e the protons a t C-3 and C-5 were found to resonate a t x5.10-5.46 as a two-proton m u l t i p l e t . one-proton m u l t i p l e t a t x6.90-7.23.  The C-4 proton resonated as a This m a t e r i a l a l s o showed strong  absorption a t 1680, 1620, 1290 and 1270 cm \ i n the i r spectrum. n-Bu O  (66)  + O ^ P — OEt  139 Although the l a s t two e l e c t r o p h i l e s t r i e d d i d give the corresponding  -43-  dihydropyridine d e r i v a t i v e s , methyl chloroformate and a c e t y l bromide were d e f i n i t e l y b e t t e r choices i n terms of g i v i n g b e t t e r y i e l d s and cleaner crude products.  Table 4 summarizes and compares the r e s u l t s  of the four e l e c t r o p h i l e s i n the r e a c t i o n of l i t h i u m d i - n - b u t y l c u p r a t e w i t h p y r i d i n e . In the presence of methyl chloroformate, p y r i d i n e r e a c t s w i t h l i t h i u m d i - n - b u t y l c u p r a t e reagent to give an 86% y i e l d of a mixture of the corresponding 1,4 and 1,2-dihydropyridine, 123c and 124c, i n a r a t i o of 98:2 r e s p e c t i v e l y (entry 2, Table 4 ) .  With a c e t y l bromide,  the y i e l d of the corresponding 1,4-dihydropyridine 137c was 73% and no trace of the corresponding 1,2-dihydropyridine was detected (entry 1, Table 4).  When d i e t h y l p h o s p h o r o c h l o r i d a t e was employed, the y i e l d of the cor-  responding 4 - n - b u t y l - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e 139 was a mere 17% (entry 3, Table 4 ) .  With chlorotrimethylsilane, the crude product  a mixture of the expected  was  l-trimethylsilyl-4-n-butyl-l,4-dihydropyridine  138 and the corresponding o x i d i z e d product., 4—n-butylpyridine (entry 4, Table 4 ) . Although the study j u s t described was very b r i e f , i t appeared that the use of c h l o r o t r i m e t h y l s i l a n e and d i e t h y l p h o s p h o r o c h l o r i d a t e as e l e c t r o p h i l e s was of l i m i t e d s y n t h e t i c value i n the r e a c t i o n of p y r i d i n e with lithium dialkylcuprates. not i n v e s t i g a t e d f u r t h e r .  Therefore the use of these reagents  was  -44-  Table 4.  Comparison of d i f f e r e n t e l e c t r o p h i l e s i n the synthesis of 4 - a l k y l - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e s from the r e a c t i o n of p y r i d i n e w i t h l i t h i u m di-n-butylcuprate. n-Bo  I  E  Entry  Electrophile  1  CH COBr  2  CJcC0 CH  73  3  C£PO(OC H )  4  C£Si(CH )  3  2  Product y i e l d ( % )  86  3  2  3  5  3  2  a  17 >33  b  (a) The product was a mixture of l-carbomethoxy-4-n-butyl-l,4dihydropyridine and l-carbomethoxy-2-n-buty1-1,4-dihydrop y r i d i n e i n the r a t i o of 98:2. (b) The product was a mixture of l - t r i m e t h y l s i l y l - 4 - n - b u t y l 1,4-dihydropyridine and 4-ri-butylpyridine.  -45-  VI.  Mechanistic Considerations Although we have not done any mechanistic s t u d i e s on the r e a c t i o n s  of organocuprate reagents w i t h p y r i d i n e i n the presence of methyl chloroformate, separate c o n t r o l experiments showed that the cuprate 128 reagents d i d not r e a c t w i t h p y r i d i n e d i r e c t l y .  For example, when a  s o l u t i o n of p y r i d i n e and l i t h i u m dimethylcuprate i n ether was s t i r r e d a t 0°C f o r l h and was then worked up without a d d i t i o n of methyl chloroformate, 128 p y r i d i n e could be recovered i n greater than 80% y i e l d .  These r e s u l t s  i n d i c a t e d that the products were probably formed by r e a c t i o n of the cuprate reagent w i t h the i n i t i a l l y formed p y r i d i n i u m s a l t 140. cr COoMe  140 As was already mentioned e a r l i e r , p y r i d i n e and a l k y l p y r i d i n e s undergo n u c l e o p h i l i c a t t a c k by a l k y l l i t h i u m or a r y l l i t h i u m reagents to give 274-79 substituted-l-lithio-l,2-dihydropyridines.  1-Carbomethoxypyridinium  c h l o r i d e r e a c t s w i t h Grignard reagents to a f f o r d mainly  l-carbomethoxy-2-  85 86 alky1-1,2-dihydropyridine (eq.29).  '  The high r e g i o s e l e c t i v i t y i n v o l v e d  i n the conjugate a d d i t i o n of cuprate reagents to p y r i d i n e i n the presence  of methyl chloroformate i n d i c a t e d that t h i s r e a c t i o n probably goes v i a a  -46-  mechanism d i f f e r e n t from that involved i n the reactions employing Grignard or a l k y l l i t h i u m reagent.  Conjugate a d d i t i o n of 142-145  cuprate reagents to a,g-unsaturated enones are w e l l documented. The N-carbomethoxypyridinium s a l t system 140 can be considered as an analogue equivalent of an a,B-unsaturated ketone i n which the nitrogen atom replaces the oxygen atom i n the enone system, as shown below.  The carbon-  COjMe  140  141  nitrogen double bond C=N+ i s s i m i l a r to the carbonyl f u n c t i o n a l i t y (JX=0) and the other double bond on the pyridinium r i n g i s analogous to the double bond conjugated to the carbonyl function i n the enone system. Although the mechanism of conjugate a d d i t i o n of organocuprate reagents to a,3-unsaturated enones i s s t i l l open to question, the e l e c t r o n transfer hypothesis proposed by H. 0. House e_t a l . i s c u r r e n t l y 144 145 the most w e l l accepted. ' 145 146 presently a v a i l a b l e  '  The l i m i t e d s t r u c t u r a l information  suggests that the l i t h i u m d i a l k y l c u p r a t e  reagents probably e x i s t as dimers ( R ^ C ^ L ^ ) i n ether s o l u t i o n w i t h a c y c l i c structure having approximately D  0  symmetry - structure 142. The  charge t r a n s f e r mechanism suggests an i n i t i a l transfer of an e l e c t r o n from the cuprate reagent to the unsaturated substrate 143 to form r a d i c a l anion 144 (Scheme 1 ) . Subsequent t r a n s f e r of an organic r a d i c a l from a t r a n s i e n t species l i k e 145 would complete the a d d i t i o n sequence.  -47R—Li —R I  J  <}"  Y  |  R—Li—R  I  Cu  * \  e l e c t r o n  , [ _  •  ?"  +  R Cu Li J-+ 4  2  I  |  coupling  - C = C - C -  2  >  transfer 143  142 R—Li —R 7N  |  - C - C - C -  144  °  u  i  L I  <jfc-C-C = C -  R-Li-R  145  >  R  l  l  - C - C= C -  -,+  r  +[R Cu Li ] 3  2  2  L  ,  i Li  SCHEME I  +  +^4^12  Observations i n d i c a t i n g that there i s a r e l a t i o n s h i p between the r e d u c t i o n p o t e n t i a l s of various unsaturated carbonyl compounds and t h e i r a b i l i t y to r e a c t w i t h cuprate reagents has l e n t support to 144 the mechanism proposed.  Such a c o r r e l a t i o n a l s o allows a f a i r l y  r e l i a b l e p r e d i c t i o n to be made as to whether or not an unsaturated substrate w i l l undergo conjugate a d d i t i o n .  Various other s t u d i e s  d i r e c t e d towards the e l u c i d a t i o n of the mechanism o f conjugate a d d i t i o n of cuprate reagents to unsaturated carbonyl compounds have shown that i n most cases, an a n i o n - r a d i c a l i s indeed an intermediate 144 i n these r e a c t i o n s . Analogously, a s i m i l a r mechanism can be postulated f o r the formation of 4 - a l k y l - l , 4 - d i h y d r o p y r i d i n e d e r i v a t i v e s from the r e a c t i o n of p y r i d i n e w i t h cuprate reagents i n the presence of an e l e c t r o p h i l e . Thus i t can be proposed that the cuprate reagent t r a n s f e r s an e l e c t r o n to the p y r i d i n i u m r i n g to form an e l e c t r o n - t r a n s f e r complex 146 which then couples w i t h the cuprate reagent to form a t r a n s i e n t intermediate 147.  Subsequent t r a n s f e r o f an a l k y l group from the copper atom of the  intermediate to the d i h y d r o p y r i d i n e r i n g would give the corresponding product (Scheme 2 ) .  + RCu  -48-  R Cu Li 4  2  j^^X.  electron t r a n s f e r  2  *  [ W a  coupling  (Ml  J 146  R—Li—R I Cu  +  R—Li —R  [  R Cu Li ] 3  2  2  Li + RCu + +  H  2 4 2 2 R  SCHEME 2  C U  L I  Reactions i n v o l v i n g e l e c t r o n transfer to pyridine are not new. Certain metals ( f o r example, sodium) transfer one e l e c t r o n to p y r i d i n e to form the r a d i c a l anion 148 which dimerizes 149  (eq.67).  r e a d i l y to t e t r a h y d r o b i p y r i d y l  147  * O~O  Na  H  N'  148 Charge-transfer  H  (67)  149  complexes of pyridinium s a l t s were known as early  as 1955. E.M. Kosower et a l .investigated the spectra of s u b s t i t u t e d 1-methylpyridinium iodides i n aqueous s o l u t i o n and obtained for the presence of a charge-transfer  evidence  complex, the p r i n c i p a l c o n t r i b u t i n g  forms of which may be depicted as 150 and 151148  Kosower also found  that  V Me  150 nucleophiles which form charge-transfer  Me  151 complexes e a s i l y , or which might  be expected to do so, add to the pyridinium s a l t a t the 4-position, while  -49-  those nucleophiles which probably do not form complexes' or do so only 149 to a very l i m i t e d extent, add a t the 2 - p o s i t i o n .  These l a t t e r  f i n d i n g s are i n p e r f e c t accord w i t h our mechanistic proposal. The mechanism suggested above i s very t e n t a t i v e and based only on analogy.  We, have no experimental b a s i s to substantiate our p o s t u l a t i o n .  Therefore, more work should be done i n t h i s area i f the nature of the r e a c t i o n i s to be understood more f u l l y . VII.  Conversion of l-Carbomethoxy-4-alkyl-l,4-dihydropyridiries  to the  Corresponding 4 - A l k y l p y r i d i n e s . As has been mentioned p r e v i o u s l y , one of the most important reactions of dihydropyridine  d e r i v a t i v e s i s t h e i r o x i d a t i o n to the corresponding  p y r i d i n e compounds. By o x i d i z i n g the. p y r i d i n e s synthesized  l-carbomethoxy-4-alkyl-l,4-dihydro-  v i a the r e a c t i o n of p y r i d i n e w i t h organocuprate  reagents i n the presence of methyl chloroformate,  we have provided  a  new route to the synthesis of simple 4 - a l k y l p y r i d i n e s . Synthesis of 4 - a l k y l p y r i d i n e s from p y r i d i n e i t s e l f has been a f a i r l y d i f f i c u l t task.  Most a v a i l a b l e methods y i e l d a mixture of 4 - a l k y l p y r i d i n e s  and 2 - a l k y l p y r i d i n e s .  For example, the thermal rearrangement of the  p y r i d i n i u m s a l t s 152 i n the Ladenburg rearrangement r e a c t i o n gave i n each case a mixture of the corresponding 2- and 4 - a l k y l (or a r y l ) p y r i d i n e s (eq.68).150,151  C a t a l y t i c a l k y l a t i o n of p y r i d i n e by the r e a c t i o n of the  l a t t e r w i t h an a l i p h a t i c a c i d i n the presence of the corresponding lead s a l t and a c a t a l y s t a l s o a f f o r d s a mixture of 2- and 4 - a l k y l p y r i d i n e s , 152 together with d i a l k y l a t e d product (eq.69).  When p y r i d i n e i s heated  w i t h a d i a c y l peroxide i n the presence of the corresponding a l i p h a t i c c a r b o x y l i c a c i d , a mixture of the corresponding 2- and 4 - a l k y l p y r i d i n e i s  -50-  4 - A l k y l p y r i d i n e s can be synthesized d i r e c t l y from p y r i d i n e by the Wibaut-Arens a l k y l a t i o n .  The o v e r a l l synthesis i n v o l v e s the  r e a c t i o n of p y r i d i n e w i t h an a c i d anhydride i n the presence of zinc (Dimroth r e a c t i o n ) , thermal rearrangement of the r e s u l t a n t dimeric product 96^ to a 1 , 4 - d i a c y l - l , 4 - d i h y d r o p y r i d i n e 153 and f i n a l l y , reduction of the l a t t e r to a 4 - a l k y l p y r i d i n e (eq.71).1^4,155  153  -51-  A more e f f i c i e n t synthesis of 4 - a l k y l p y r i d i n e s uses 4-picoline s t a r t i n g m a t e r i a l . 4 - P i c o l i n e i s f i r s t treated with sodium or p o t a s s i amide and the r e s u l t a n t anion i s allowed to react with various a l k y l halides to give the corresponding  4-alkylpyridines  (eq.72). "^ 1  (72)  As had been mentioned p r e v i o u s l y , dihydropyridines serve as important intermediates i n several reactions of p y r i d i n e .  In f a c t , a large number  of p y r i d i n e d e r i v a t i v e s may be obtained by o x i d i z i n g the corresponding dihydropyridine d e r i v a t i v e s synthesized by the Hantzsch and r e l a t e d syntheses.  By o x i d i z i n g the  l-carbomethoxy-4-alkyl-l,4-dihydropyridines  synthesized from the r e a c t i o n of p y r i d i n e with cuprate reagents i n the presence of methyl chloroformate, we have developed a f a i r l y e f f i c i e n t method f o r s y n t h e s i z i n g simple 4 - a l k y l p y r i d i n e s . Our i n i t i a l studies were c a r r i e d out w i t h l-carbomethoxy-4-nbutyl-1,4-dihydropyridine. In general, the dihydropyridine d e r i v a t i v e was f i r s t treated with three equivalents of methyllithium i n order to remove the N-carbomethoxy group,and the r e s u l t i n g l i t h i u m p i p e r i d i d e d e r i v a t i v e was then o x i d i z e d i n s i t u by a d d i t i o n of an appropriate o x i d i z i n g agent (eq.73).  p_-Benzoquinone was the f i r s t reagent t r i e d i n  -52-  the oxidation step,but a d i s a p p o i n t i n g l y low y i e l d (48%) of 4-n-butylp y r i d i n e was obtained.  When tetrachloro-1,4-benzoquinone was employed,  the y i e l d of 4-n-butylpyridine improved to 65%. that 2,3-dichloro-5,6-dicyano-l,4-benzoquinone s a t i s f a c t o r y y i e l d (73%) of 4-n-butylpyridine.  F i n a l l y , i t was found (DDQ) gave the most This type of procedure  was extended to include other 1,4-dihydropyridine d e r i v a t i v e s and the r e s u l t s are summarized i n Table 5.  In general, 4 - a l k y l p y r i d i n e s obtained  from the o x i d a t i o n were e s s e n t i a l l y pure a f t e r d i s t i l l a t i o n from the crude products.  In each case, the product was analyzed by g l c and  characterized by i r and "*Hnmr spectroscopy.  The s p e c t r a l data ( i r , "^Hnmr)  of each product was compared with those of an authentic sample a v a i l a b l e commercially or w i t h those reported i n the l i t e r a t u r e . As can be seen from the r e s u l t s summarized i n Table 5, the y i e l d s of 4 - a l k y l ( a r y l ) p y r i d i n e s were f a i r l y good. For example, the y i e l d of 4e t h y l p y r i d i n e was 89% and the y i e l d of 4-s-butylpyridine was 79% (entry 2 and 4 r e s p e c t i v e l y , Table 5).  The only exception was 1-carbomethoxy-  4-methyl-l,4-dihydropyridine which gave only a 58% y i e l d of 4-picoline (entry 1, Table 5). The low y i e l d of the l a t t e r product may be a t t r i b u t e d to mechanical loss owing to i t s v o l a t i l i t y . Compared with most other methods f o r synthesizing simple 4 - a l k y l p y r i d i n e s , the combined synthesis of l - c a r b o m e t h o x y - 4 - a l k y l ( a r y l ) - l , 4-dihydropyridines and t h e i r subsequent conversion to the corresponding 4 - a l k y l p y r i d i n e s opens a new, clean and f a i r l y e f f i c i e n t way of synthesizing these compounds.  -53-  Table 5.  Entry  Conversion o f l-carbomethoxy-4-alkyl(aryl)-l,4-dihydropyridines to the corresponding 4 - a l k y l ( a r y l ) p y r i d i n e s  0  Y i e l d ( % ) of 4 - a l k y l ( o r  I C0 CH^ R = CH -  p-benzoquinone  9  1 2  CH CH -  3  CH (CH ) -  4  CH CH CHCH  5  C  3  6 5 H  2  2  DDQ 58 89  2  3  3  tetrachloro-1,4benzoquinone  55  3  aryl)pyridines  48  3  3  65  73 79 73  -54-  EXPERIMENTAL  General  Information Melting points,  apparatus,  determined w i t h a F i s h e r - J o h n s m e l t i n g  and b o i l i n g p o i n t s  are u n c o r r e c t e d .  Ultraviolet  s p e c t r a were o b t a i n e d w i t h a Cary 15 spectrophotometer solution.  point  (uv)  i n methanol  I n f r a r e d ( i r ) s p e c t r a were o b t a i n e d w i t h a P e r k i n - E l m e r  710 i n f r a r e d s p e c t r o p h o t o m e t e r , solution.  N u c l e a r magnetic  as l i q u i d f i l m s or i n c h l o r o f o r m  resonance  ("Hlnmr) s p e c t r a were  w i t h V a r i a n T - 6 0 , HA-100 a n d / o r XL-100 s p e c t r o m e t e r s , solution,  with tetramethylsilane  as i n t e r n a l s t a n d a r d .  mass s p e c t r a were r e c o r d e d w i t h a V a r i a n / M A T CH4B mass  obtained  i n deuterochloroform Low r e s o l u t i o n spectrometer.  High r e s o l u t i o n mass s p e c t r a were r e c o r d e d w i t h a K r a t o s / A E I MS50 mass spectrometer.  M i c r o a n a l y s e s were performed by M . P . B o r d a , M i c r o a n a l y t i c a l  L a b o r a t o r y , U n i v e r s i t y of B r i t i s h Columbia, Vancouver. l i q u i d chromatography Gas  ( g l c ) was performed on a Hewlett Packard HP5830A  Chromatography u n i t connected  following  columns were used:  chromosorb w (80-100 mesh); chromosorb w (80-100 mesh).  to a HP18850A GC t e r m i n a l .  w (60-80 mesh); 80 mesh);  The  (A) 6 f t x 0.125 i n . , 5% OV-210 on HP (B) 6 f t x 0.125 i n . , P r e p a r a t i v e gas l i q u i d  was performed on a V a r i a n Aerograph the f o l l o w i n g columns:  A n a l y t i c a l gas  5% OV-17 on HP chromatography  Model 90-P gas chromatograph,  using  (C) 10 f t x 0.25 i n . , 10% OV-210 on chromosorb  (D) 10 f t x 0.25 i n . ,  10% 0V-17 on chromosorb w (60-  (E) 10 f t x 0.25 i n . , 15% Versamide 900 on chromosorb w (60-80  mesh) . All  reactions  i n v o l v i n g organocopper reagents were performed i n  -55-  three-necked  round-bottomed f l a s k s equipped w i t h a serum stopper, an  argon i n l e t tube, and a glass-covered magnetic s t i r r i n g bar.  Prior <  to the i n t r o d u c t i o n of solvent or any reagent, the apparatus was d r i e d w i t h a bunsen flame w h i l e being evacuated and was then f i l l e d w i t h argon. A s l i g h t p o s i t i v e pressure of argon was maintained  throughout the r e a c t i o n .  S t a r t i n g M a t e r i a l s and Reagents S o l u t i o n s of m e t h y l l i t h i u m i n ether, e t h y l l i t h i u m i n benzene, n - b u t y l l i t h i u m i n hexane, s ^ b u t y l l i t h i u m i n cyclohexane,  _t-butyllithium  i n pentane and p h e n y l l i t h i u m i n benzene were obtained from A l f a Inorganics Inc., and were standardized by the procedure of Gilman e t al\^ l i t h i u m , which i s no longer commercially follow.  158  Vinyl-  a v a i l a b l e , was prepared as  To a s t i r r e d s o l u t i o n of t e t r a v i n y l t i n  159  (6.8 g, 30 mmol)  i n pentane (150 ml) i n a flame-dried 500 ml three-necked  f l a s k equipped w i t h  a mechanical s t i r r e r and an argon i n l e t tube was added v i a a syringe a s o l u t i o n of r i - b u t y l l i t h i u m i n hexane (2.1M, 28.6 ml, 60 mmol) over a period of 10 min.  The s o l u t i o n was concentrated by blowing a r a p i d  stream of argon across the surface of the s o l u t i o n f o r 40 min.  The pre-  c i p i t a t e d v i n y l l i t h i u m was f i l t e r e d under argon, washed twice w i t h pentane and d i s s o l v e d i n 80 ml of anhydrous ether. by the procedure of Gilman e t al."*"^  The s o l u t i o n was then standardized  7  Commercial samples of cuprous i o d i d e and cuprous bromide were p u r i f i e d by d i s s o l v i n g them i n a saturated aqueous s o l u t i o n of the appropriate h a l i d e (potassium i o d i d e o r potassium bromide, r e s p e c t i v e l y ) followed by treatment of the s o l u t i o n w i t h c h a r c o a l , f i l t r a t i o n and d i l u t i o n w i t h water to reprec i p i t a t e the copper(I)halide.'''^  Phenylthiocopper was prepared by r e f l u x i n g  a mixture of cuprous oxide (9g, 60 mmol) and thiophenol (16g, 136 mmol) i n  -56-  absolute ethanol (500ml) f o r seven days. "" " 1  phenylthiocopper  1  The b r i g h t yellow s o l i d  obtained by f i l t r a t i o n of the r e s u l t a n t mixture was  washed thoroughly with ethanol and then dried under vacuum.  The y i e l d  was e s s e n t i a l l y q u a n t i t a t i v e . Anhydrous ether, obtained from Mallinckodt L t d . , was used from f r e s h l y opened 1 l b cans without f u r t h e r treatment. was d i s t i l l e d from l i t h i u m aluminum hydride immediately  Tetrahydrofuran p r i o r to use.  P y r i d i n e and triethylamine were d i s t i l l e d from potassium hydroxide and stored over potassium hydroxide.  A c e t o n i t r i l e was d i s t i l l e d from  phosphorous pentoxide. 162 General Procedure f o r the Preparation of Lithium D i a l k y l c u p r a t e s To a s l u r r y of cuprous iodide (572 mg, 3 mmol) i n cold  (temperature  v a r i e s with d i f f e r e n t cuprates) dry ether (25 ml) was added a s o l u t i o n of the appropriate commercial a l k y l l i t h i u m reagent (6 mmol).  The r e s u l t i n g  mixture was s t i r r e d at the appropriate temperature f o r 30 to 60 min (temperature details).  and time vary w i t h d i f f e r e n t cuprates, see r e f . 162 f o r  A s o l u t i o n containing 3 mmol of the appropriate l i t h i u m  dialkylcuprate resulted. General Procedure f o r the Preparation of Lithium P h e n y l t h i o ( a l k y l or 161 aryljcuprates To a suspension of phenylthiocopper  (726 mg, 4.2 mmol) i n cold  (-20°C) tetrahydrofuran (25 ml) was added a s o l u t i o n of the appropriate a l k y l - or a r y l l i t h i u m reagent (4.2 mmol).  The mixture was s t i r r e d at  -20°C (0°C when methyllithium was used) f o r 30 min.  A s o l u t i o n containing  4.2 mmol of the appropriate l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e resulted.  -57-  General Procedure f o r the Reaction of L i t h i u m P h e n y l t h i o l a l k y l ( o r a r y l ) c u p r a t e s w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate.  To a cold (-78°C) s t i r r e d s o l u t i o n of the appropriate l i t h i u m p h e n y l t h i o ( a l k y l or a r y l ) c u p r a t e (4.2 mmol) i n about 30 ml of t e t r a hydrof uran (under argon) was added 3 mmol (237 mg) of p y r i d i n e . A s o l u t i o n of methyl chloroformate (3 mmol) i n tetrahydrofuran (25 ml) was added dropwise over a period of 15 min. The r e s u l t i n g mixture was s t i r r e d a t -78°C f o r the appropriate time, warmed t o an appropriate temperature and s t i r r e d f o r an a d d i t i o n a l length of time.  Methanol  (3 ml) and ether (15 ml) was added to the r e a c t i o n mixture, the l a t t e r was s t i r r e d f o r a few seconds, and then f i l t e r e d  through a short column  (4 cm diameter) of f l o r i s i l (35 g, 60-80 mesh).  The column was e l u t e d  w i t h an a d d i t i o n a l 350 ml o f ether.  Evaporation of the ether, followed  by d i s t i l l a t i o n of the r e s i d u a l o i l ( a i r bath) gave the f i n a l products. Reaction of L i t h i u m Phenylthio(methyl)cuprate w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate.  Following the general procedure o u t l i n e d above, 4.2 mmol of l i t h i u m phenylthio(methyl)cuprate was allowed to react w i t h 3 mmol of p y r i d i n e and 3 mmol of methyl chloroformate a t -78°C f o r l h , and a t 0°C f o r an a d d i t i o n a l 2h. Normal work-up followed by d i s t i l l a t i o n  (air-bath  temperature V50°C, 0.1 Torr) of the crude product afforded 241 mg (52%) of l-carbomethoxy-4-methyl-l,4-dihydropyridine  123a.  This m a t e r i a l was  pure by g l c a n a l y s i s (column A, 90°C) and e x h i b i t e d i r ( f i l m ) v  m a x  1730,  1690, 1630 cm" ; "Shimr, x3.25 (d,2H, =CH-N-CH=, J=8Hz), 5.17 (d of d, 2H, 1  =CH-CH(CH )-CH=, J=8Hz, J'=3.5 Hz), 6.20 ( s , 3H, -C0 CH ), 7.00 (m, IH, 3  2  -CH(CH )), 8.93 (d, 3H, -CH(CH ), J=7 Hz). 3  3  3  Mol. Wt. Calcd. f o r  -58-  CgH^NO^: 153.0789.  Found (high r e s o l u t i o n mass spectrometry):  153.0760.  A f a i r amount of high b o i l i n g o i l remained a f t e r a l l the 1-carbomethoxy4-methyl-l,4-dihydropyridine  had been d i s t i l l e d .  The "hinmr of t h i s  m a t e r i a l i n d i c a t e d that a major component of t h i s m a t e r i a l could be 163 the dimer 134,  but t h i s m a t e r i a l was not i n v e s t i g a t e d f u r t h e r .  Reaction of Lithium P h e n y l t h i o ( e t h y l ) c u p r a t e w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate.  Following the general procedure o u t l i n e d above, 4.2 mmol of l i t h i u m p h e n y l t h i o ( e t h y l ) c u p r a t e was allowed to react with p y r i d i n e (3 mmol) and methyl chloroformate  (3 mmol) at -78°C f o r 3h.  The r e a c t i o n was  then  quenched w i t h methanol. Normal work-up followed by d i s t i l l a t i o n ( a i r - b a t h temperature V50°C, 0.2 Torr) of the crude o i l afforded 400 mg of a colorless o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l (column A, 90°C) showed  the presence of one major component (88%) and a minor one (11%). major component was shown to be 123b  (70% y i e l d ) .  l-carbomethoxy-4-ethyl-l,4-dihydropyridine  An a n a l y t i c a l sample of the l a t t e r , obtained by pre-  p a r a t i v e g l c (column C, 110°C), e x h i b i t e d i r ( f i l m ) v 1636  1727,  max -11 ' cm ; Hnmr, x3.20 (d, 2H, =CH-N-CH=, J=8 Hz), 5.17  =CH-CH(CH )-CH)=, J=8 Hz, J'=3.5 Hz), 6.20 3  -CH(CH CH )), 8.75 2  (m, 2H, -CH CH ), 9.14  3  2  Calcd. f o r CgH^ N0 : 167.0946. 3  The  2  3  1690,  (d of d,  (s, 3H, -C0 CH ), 7.13 2  3  ( t , 3H, J=7.0 Hz).  Mol.  2H, (m, IH, Wt.  Found (high r e s o l u t i o n mass spectrometry)  :167.0909. An a n a l y t i c a l sample of the minor component was a l s o obtained preparative g l c (column C, 110°C) and was formate 133.  by  shown to be methyl phenylthio-  An authentic sample of t h i s compound was  prepared by  the  -59-  reactionof thiophenol and methyl chloroformate aqueous sodium hydroxide.  i n the presence of  Comparison of the ^"Hnmr spectra of  the authentic m a t e r i a l with that of the same m a t e r i a l i s o l a t e d from the r e a c t i o n mixture and a g l c c o i n j e c t i o n a n a l y s i s of the authentic m a t e r i a l with the same m a t e r i a l i s o l a t e d from the r e a c t i o n mixture confirmed  the i d e n t i t y of the minor component.  Reaction of Lithium Phenylthio(n-butyl)cuprate with Pyridine i n the Presence of Methyl  Chloroformate.  Following the general procedure o u t l i n e d above, 4.2 mmol of l i t h i u m phenylthio(n-butyl)cuprate was allowed to react with p y r i d i n e (3 mmol) and methyl chloroformate  (3 mmol) at -78°C for 3h. Normal work-up followed  by d i s t i l l a t i o n (air-bath temperature ^80°C, 0.2 Torr) of the crude o i l afforded 444 mg of c o l o r l e s s o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l (column  A, 110°C) i n d i c a t e d that i t was a mixture of  l-carbomethoxy-4-n-butyl-l,4-  dihydropyridine 123c (86%) and methyl phenylthioformate  (14%).  An a n a l y t i c a l  sample of the former, obtained by preparative g l c (column C, 110°C), exhibited i r (film) v  -1 1 ' 1730, 1693, 1633 cm ; Hnmr, T3.20 (d, 2H, =CH-N-CK=,J=8 Hz), —  max  5.13 (dof d,2H, =CH-CH(n-Bu)-CH=, J=8 Hz, J'=3.5 Hz), 6.20 (s, 3H, -C0 CH ), 2  i  3  t  7.05 (m, IH, -CH(n-Bu), 8.68 (unresolved m, 6H, -CH-CH CH CH -), 9.12 2  2  2  (unresolved m, 3H, -CH -CH ); y i e l d , 65%. Mol. Wt. Calcd. f o r C^H^NO^ 2  195.1253.  3  Found (high r e s o l u t i o n mass spectrometry): 195.1259.  Reaction of Lithium Phenylthio(s-butyl)cuprate w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate.  Following the general procedure o u t l i n e d above, l i t h i u m phenylthio(sbutyl)cuprate (4.2 mmol) was allowed to react with pyridine (3 mmol) and  -60-  methyl chlorofornate (3 mmol) a t -78°C f o r l h , and a t 0°C f o r an a d d i t i o n a l 2h. Normal work-up followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^75°C, 0.1 Torr) of the crude o i l afforded 519 mg of a colorless o i l .  A g l c a n a l y s i s (column C, 155°C) of t h i s m a t e r i a l  i n d i c a t e d that i t was a mixture of l-carbomethoxy-4-s_-butyl-l dihydropyridine 123d (89%) and methyl phenylthioformate  ,4-  (11%).  An  a n a l y t i c a l sample of the former, obtained by preparative g l c (column C, 155°C), e x h i b i t e d i r ( f i l m ) v 1730, 1690, 1632 cm^^Hnmr, T3.15 max (d, 2H, =CH-N-CH=, J=8 Hz), 5.22 ( d o f d , 2 H , =CH-CH(s Bu)-CH=, J=8 Hz, r  J'=3.5 Hz), 6.20(s, 3H, -C0 CH_ ), 7.02 (m, IH, -CH(s_-Bu)). 2  of 123d was 80%. Mol. Wt. Calcd. f o r C ^ H ^ N C y r e s o l u t i o n mass spectrometry):  The y i e l d  3  195.1255.  Found (high  195.1250.  Reaction of Lithium P h e n y l t h i o ( t - b u t y l ) c u p r a t e w i t h P y r i d i n e i n the Presence of Methyl Chloroformate Following the general procedure o u t l i n e d above, l i t h i u m phenylthio (_tb u t y l ) c u p r a t e (4.2 mmol) was allowed to react w i t h p y r i d i n e (3 mmol) and methyl chloroformate for an a d d i t i o n a l l h .  (3 mmol) a t -78°C f o r l h , warmed to -20°C and s t i r r e d Normal work-up followed by d i s t i l l a t i o n ( a i r - b a t h  temperature ^80°C, 0.2 Torr) of the crude o i l afforded 273 mg of c o l o r l e s s oil.  A g l c a n a l y s i s (column A, 110°C) of t h i s m a t e r i a l showed the presence  of two components i n the r a t i o of approximately  1:1. An a n a l y t i c a l sample  of each component was obtained by preparative g l c (column C, 150°C). One of the components was shown to be  l-carbomethoxy-4-_t-butyl-l,4-dihydro-  p y r i d i n e 123e (^26% y i e l d ) and i t e x h i b i t e d i r ( f i l m ) v  1730, 1690,  max 1635  cm ; -"-Hnrnr, T3.22 (d, 2H, =CH-N-CH=, J=8 Hz), 5.12 (d ofd,2H, =CH-CH-CH=, -1  -61-  i  J=8 Hz, J'-4 Hz), 6.26 ( s , 3H, -C0 CH ), 7.40 (m, IH, -CH(t-Bu)), 9.18 2  3  (s, 9H, - C ( C H ) ) . 3  The  3  'Hnmr data obtained from the other component i n d i c a t e d that  i t could be a mixture of methyl phenylthioformate 133 and methyl 2,2dimethylpropionate 135, but t h i s m a t e r i a l was not i n v e s t i g a t e d f u r t h e r . Reaction of L i t h i u m Phenylthio(phenyl)cuprate w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate.  Following the general procedure o u t l i n e d above, l i t h i u m p h e n y l t h i o (phenyl)cuprate (4.2 mmol) was allowed to r e a c t w i t h p y r i d i n e (3 mmol) and methyl chloroformate (3 mmol) a t -20°C f o r 30 min, and a t room temperature f o r an a d d i t i o n a l 20h. Normal work-up, followed by f r a c t i o n a l d i s t i l l a t i o n of the crude o i l gave two f r a c t i o n s . temperature up to 95°C, 0.1 carbons (250 mg).  F r a c t i o n one ( a i r - b a t h  Torr) contained a complex mixture of hydro-  There was no carbonyl nor C-N absorption i n the i r  spectrum of t h i s m a t e r i a l . Comparison of the "4lnmr s p e c t r a of t h i s m a t e r i a l w i t h that of an authentic sample of biphenyl showed that the major c o n s t i t u e n t of t h i s m a t e r i a l could be b i p h e n y l .  This was confirmed  by a g l c c o i n j e c t i o n a n a l y s i s i n v o l v i n g a pure sample of b i p h e n y l and the above mixture.  This m a t e r i a l was not i n v e s t i g a t e d f u r t h e r .  ( a i r bath temperature M.20°C, 0.1 Torr) was pure 1,4-dihydropyridine 123f (152 mg, 24% y i e l d ) . (film) v  F r a c t i o n two  l-carbomethoxy-4-phenyl-  This m a t e r i a l e x h i b i t e d i r  1725, 1690, 1632 c m ; Hnmr, T2.79 (m, 5H, phenyl), 3.12 -1  1  (d, 2H, =CH-N-CH=, J=8 Hz), 5.07 (d of d, 2H, =CH-CH(phenyl)CH=, J=8 Hz, J'=3.5 Hz), 5.90 (m, IH, -CH-phenyl), 6.22 ( s , 3H, -C0 CH ). 2  Calcd. f o r C H N 0 : 215.0943. 13  215.0931.  13  2  3  Mol. Wt.  Found (high r e s o l u t i o n mass spectrometry):  -62-  Preparation of Lithium Divinylcuprate-Dimethyl Sufide Complex ((jg^^CuLi'Me^S)"'"^^ and i t s Reaction with P y r i d i n e i n the Presence of Methyl  Chloroformate.  To a cold (-50°C) s o l u t i o n of Me,,S*CuBr (615 mg, 3 mmol) i n ether (5 ml) and dimethyl s u l f i d e (4 ml) was added a s o l u t i o n of v i n y l l i t h i u m i n ether (10 ml, 0.6 M, 6 mmol). -50°C f o r 15 min.  The r e s u l t i n g s o l u t i o n was s t i r r e d a t  To t h i s s o l u t i o n was added 2.5 mmol (198 mg) of p y r i d i n e  followed by the dropwise a d d i t i o n of a s o l u t i o n of methyl (15 mmol) i n ether (10 ml) over a period of 15 min.  chloroformate  The r e s u l t i n g black  s o l u t i o n was s t i r r e d at -50°C f o r 2h, warmed to 0°C and s t i r r e d f o r an a d d i t i o n a l 30 min. column of  This s o l u t i o n was then f i l t e r e d through a short  f l o r i s i l (35 g, 60-80 mesh).  a d d i t i o n a l 300 ml of ether.  The column was eluted with an  Evaporation of solvent and d i s t i l l a t i o n ( a i r -  bath temperature ^50°C, 0.1 Torr) of the r e s i d u a l o i l afforded 253 mg (61%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column A, 100°C) of t h i s m a t e r i a l  i n d i c a t e d that i t was a mixture of l-carbomethoxy-4-vinyl-l,4-dihydrop y r i d i n e 123g and l-carbomethoxy-2-vinyl-l,2-dihydropyridine 124g i n the r a t i o of ca. 1:1. An a n a l y t i c a l sample of each compound was obtained by preparative g l c (column C, 130°C). The former exhibited i r ( f i l m ) v max 1730, 1690, 1635 cm ; Hnmr, T3.19 (d, 2H, =CH-N-CH=, J=8 Hz) 3.9-4.40 -1  1  (m, IH, ^ = ^ ) , 4.84-5.26 ( d i f f u s e , 4H, =CH-CH(vinyl)CH= and § ^ = C ) > H  6.20 ( s , 3H, -C0 CH 3 1, 6.42 (m, IH, =CH-CH-CH=). 2  C H N0 :165.0790. 9  11  2  Mol. Wt. Calcd. f o r  Found (high r e s o l u t i o n mass spectrometry): 165.0790.  The l a t t e r e x h i b i t e d i r ( f i l m ) v 1720, 1645, 1585 cm" ; Hnmr max 1  1  T3.27 (d, IH, =CH-N-, J=7 Hz), 3.91-4.99 ( d i f f u s e , 7H), 6.21 ( s , 3H, -CO^R^l  Mol. Wt. Calcd. f o r CgH^NO^. 165.0790.  mass spectrometry): 165.0790.  Found (high r e s o l u t i o n  -63-  Reaction of L i t h i u m Diphenylcuprate w i t h P y r i d i n e i n the Presence of Methyl  Chloroformate. To a s o l u t i o n of l i t h i u m diphenylcuprate (6 mmol prepared from 140  cuprous bromide and p h e n y l l i t h i u m  ) i n anhydrous ether (25 ml) a t  -78°C under an atmosphere of argon was added 5 mmol of p y r i d i n e . A s o l u t i o n of methyl chloroformate (20 mmol) i n ether (25 ml) was added dropwise over a period of 15 min.  The r e s u l t i n g mixture was s t i r r e d a t  -78°C f o r l h , warmed to 0°C and then s t i r r e d f o r an a d d i t i o n a l 1.25h. F l o r i s i l (3 g) was added to the r e a c t i o n mixture, the l a t t e r was s t i r r e d for a few seconds, and then f i l t e r e d through a short column of f l o r i s i l (35 g).  The column was e l u t e d w i t h an a d d i t i o n a l 350 ml of ether.  Evaporation of the ether, followed by f r a c t i o n a l d i s t i l l a t i o n ( a i r - b a t h ) of the r e s i d u a l o i l gave two f r a c t i o n s .  The f i r s t f r a c t i o n ( a i r - b a t h  temperature up to 110°C, 0.2 Torr) was a complex mixture.  "''Hnmr of  t h i s m a t e r i a l showed that the major component i n t h i s mixture was probably b i p h e n y l , but t h i s was not i n v e s t i g a t e d f u r t h e r .  The second  f r a c t i o n ( a i r - b a t h temperature VL25°C, 0.2 Torr; 897 mg, 89% y i e l d ) was shown by g l c a n a l y s i s (column C, 170°C), to be a mixture of 1-carbomethoxy4-phenyl-l,4-dihydropyridine 123f and  l-carbomethoxy-2-phenyl-l,2-  dihydropyridine 124f i n the r a t i o of 84:16. A n a l y t i c a l samples of each compound was obtained by p r e p a r a t i v e g l c (column C, 180°C). S p e c t r a l data ('''Hnmr, i r ) o f the former was i d e n t i c a l w i t h that of authentic 128 m a t e r i a l prepared e a r l i e r by M. Soucy.  The very small amount of  the l a t t e r obtained e x h i b i t e d i r ( f i l m ) v 1720, 1645, 1590 cm" ; max ' • ' 1  "''Hnmr, T2. 30-3.00 (5H, m, phenyl), 3.0-3.37 (m, IH,), 4.0-4.94 (m, 4H), 6.28 ( s , 3H, -C0 CH ). 2  3  -64Reaction of L i t h i u m D i a l k y l c u p r a t e s w i t h P y r i d i n e i n the Presence of A c e t y l Bromide. General Procedure To a s o l u t i o n of the appropriate l i t h i u m d i a l k y l c u p r a t e (6 mmol) i n dry ether (25 ml) a t -78°C under an atmosphere of argon was added 5 mmol of p y r i d i n e .  A s o l u t i o n of a c e t y l bromide (20 mmol) i n dry  ether (25 ml) was added dropwise over a period of 15 min.  The r e s u l t i n g  mixture was s t i r r e d a t -78°C f o r 30 min, warmed to 0°C and then s t i r r e d f o r an a d d i t i o n a l 30 min. mixture.  F l o r i s i l (3 g) was added to the r e a c t i o n  The l a t t e r was s t i r r e d f o r a few seconds, and then f i l t e r e d  through a short column of f l o r i s i l (35 g). an a d d i t i o n a l 350 ml of ether.  The column was e l u t e d w i t h  Evaporation of the ether, followed by  d i s t i l l a t i o n of the r e s i d u a l o i l gave the corresponding  l-acetyl-4-alkyl-  1,4-dihydropyridine. Reaction of L i t h i u m Dimethylcuprate  w i t h P y r i d i n e i n the Presence of  A c e t y l Bromide. Following the general procedure o u t l i n e d above, 6 mmol of l i t h i u m dimethylcuprate was allowed to react w i t h 5 mmol of p y r i d i n e and 20 mmol of a c e t y l bromide.  Normal work-up followed by d i s t i l l a t i o n ( a i r bath  temperature ^65°C, 0.1 Torr) of the crude o i l afforded 404 mg (59%) of a colorless o i l .  A g l c a n a l y s i s (column C, 140°C) of t h i s m a t e r i a l  showed that i t was pure l - a c e t y l - 4 - m e t h y l - l , 4 - d i h y d r o p y r i d i n e 137a and i t e x h i b i t e d i r ( f i l m ) v 1680, 1637 cm" ; Hnmr, x2.90 (d, IH, max =CH-N-, J=9 Hz), 3.52 (d, IH, =CH-N-, J=9 Hz), 5.10 (m, 2H, =CH-CH-CH=), » t i 1  7.00  (m, IH, -CH(CH )), 7.85 ( s , 3H, 3  Mol. Wt. Calcd. f o r C H, ,N0: S  137.0840.  1  (d, 3H, -CH-CH , J=7 Hz). 3  Found (high r e s o l u t i o n mass  -65-  spectrometry): 137.0836.  None o f the corresponding  1,2-dihydropyridine  d e r i v a t i v e was detected. Reaction of L i t h i u m Diethylcuprate w i t h P y r i d i n e i n the Presence of A c e t y l Bromide. Following the general procedure o u t l i n e d before, 6 mmol of l i t h i u m d i e t h y l c u p r a t e was allowed to r e a c t w i t h 5 mmol of p y r i d i n e i n the presence of 20 mmol of a c e t y l bromide.  Normal work-up, followed by  d i s t i l l a t i o n ( a i r - b a t h temperature ^85°C, 0.2 Torr) of the crude o i l gave 386 mg (51%) of a c o l o r l e s s l i q u i d .  A g l c a n a l y s i s (column C,  145°C) of t h i s m a t e r i a l showed that i t was pure l-acetyl-4-ethy1-1,4dihydropyridine and i t e x h i b i t e d i r ( f i l m )  1670, 1625 cm  v  "*"Hnmr,  x2.87 (d, I H , =CH-N-, J=9 Hz), 3.48 (d, IH, =CH-N-, J=9 Hz), 5.13 (m, 2H, =CH-CH-CH=Q, 7.13 (m, IH, -CH(CH CH )), 7.99 ( s , 3H, -C0CH_ ) , 8.37-8.77 2  3  3  (m, 2H, -CH(CH CH )), 9.16 ( t , 3H, -CH(CH CH )). 2  3  C H N0: 151.0997. g  13  2  3  Mol. Wt.Calcd. f o r  Found (high r e s o l u t i o n mass spectrometry): 151.0993.  None of the corresponding 1,2-dihydropyridine d e r i v a t i v e was detected. Reaction o f L i t h i u m Di-n-butylcuprate w i t h P y r i d i n e i n the Presence of A c e t y l Bromide. Following the general procedure o u t l i n e d above, 6 mmol of l i t h i u m di-ri-butylcuprate was allowed to r e a c t w i t h 5 mmol of p y r i d i n e i n the presence o f 20 mmol of a c e t y l bromide.  Normal work-up, followed by  d i s t i l l a t i o n ( a i r - b a t h temperature M.10°C, 0.1 Torr) of the crude o i l gave 653 mg (73%) o f a c o l o r l e s s l i q u i d .  A g l c a n a l y s i s (column C, 140°C)  of t h i s m a t e r i a l showed that i t was pure 1-acety1-4-n-buty1-1,4-dihydrop y r i d i n e and i t e x h i b i t e d i r ( f i l m ) v 1675, 1632 cm" ; Hnmr, T2.83 max ' 1  f  i  1  «•  (d, IH, =CH-N-, J=9 Hz), 3.46 (d, IH, -N-CH=, J=9 Hz), 5.05 (m, 2H, =CH-CH-CH  -66-  7.05 (m, IH, -CH(n-Bu)), 7.83 ( s , 3H, -COCH^), 8.45-8.90 ( d i f f u s e , 6H, -CH(CH CH CH CH )), 9.10 ( t , 3H, - ( C H ^ C H ^ , J=7 Hz). Mol. Wt. Calcd. 2  2  2  3  for C^H^NO: 179.1309. 179.1307.  Found (high r e s o l u t i o n mass spectrometry):  None o f the corresponding  1,2-dihydropyridine  d e r i v a t i v e was  detected.  Synthesis of l - T r i m e t h y l s i l y l - 4 - n - b u t y l - l , 4 - d i h y d r o p y r i d i n e and i t s Conversion i n t o 4-n-Butylpyridine To a c o l d s o l u t i o n of l i t h i u m d i - n - b u t y l c u p r a t e (6 mmol) i n dry ether (25 ml) a t -78°C under an atmosphere of argon was added 5 mmol of pyridine.  A s o l u t i o n of c h l o r o t r i m e t h y l s i l a n e (702 mg, 6.5 mmol) i n  ether (25 ml) was added dropwise over a period of 15 min.  The r e s u l t i n g  mixture was s t i r r e d a t -78°C f o r 2h, warmed to 0°C and then s t i r r e d f o r an a d d i t i o n a l 30 min. F l o r i s i l (3 g) was added to the r e a c t i o n mixture, the l a t t e r was s t i r r e d f o r a few seconds, and then f i l t e r e d through a short column of f l o r i s i l (35 g ) . The column was eluted w i t h an a d d i t i o n a l 350 ml of ether.  Evaporation of the ether afforded 520 mg of crude product.  A  glc a n a l y s i s (column A, 110°C) of t h i s m a t e r i a l i n d i c a t e d the presence of two components i n the r a t i o of ca. 1:1 ^"Hnmr i n d i c a t e d that t h i s m a t e r i a l was a mixture of l - t r i m e t h y l s i l y - 4 - n - b u t y l - l , 4 - d i h y d r o p y r i d i n e 138 and 4 - n - b u t y l - p y r i d i n e .  The presence of 4-n-butylpyridine i n the  mixture was confirmed by comparing the "'"Hnmr spectrum of the mixture w i t h the ''"Hnmr of an authentic sample of 4-n-butylpyridine.  The "'"Hnmr spectrum  of the product mixture was i n t e r p r e t e d as f o l l o w s : xl.52 (d of d, J=5 Hz, J'=2Hz, protons a t C-2 and C-6 of 4 - n - b u t y l p y r i d i n e ) , 2.89 (d of d, J=5 Hz, J'=2 Hz, protons a t C-3 and C-5 of 4 - n - b u t y l p y r i d i n e ) , 7.40 ( t , J=7 Hz, CH (CH )CH 2  2  3>  -67-  4-n-butylpyridine), 4.07 (d, J=8 Hz, protons at C-2 and C-6 of the dihydropyridine 138), 5.57 (d of d, J=8 Hz, J'=3.5 Hz, protons a t C-3, C-5 of the dihydropyridine 138), 3.00 (m, proton a t C-4 of the dihydropyridine 138). Because of the i n s t a b i l i t y of the dihydropyridine 138, t h i s m a t e r i a l was not i s o l a t e d f o r c h a r a c t e r i z a t i o n . Instead, the crude product mixture obtained above was subjected to o x i d a t i o n . mixture was dissolved i n 20 ml of dry ether. to -78°C under an atmosphere of argon.  The crude  This s o l u t i o n was cooled  A s o l u t i o n of 0.1% potassium  hydroxide i n methanol (1.5 ml) was added.  The mixture was s t i r r e d f o r  10 min, and a s o l u t i o n of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (1.25 g, 5.5 mmol) i n tetrahydrofuran (25 ml) was added dropwise over a period of 10 min.  The r e s u l t i n g mixture was warmed to 0°C,  stirred  for 2h a t that temperature, warmed to room temperature and then s t i r r e d for an a d d i t i o n a l l h . The product mixture was poured i n t o an aqueous s o l u t i o n of sodium hydroxide (10%, 60 ml). thoroughly with ether.  The aqueous layer was extracted  The combined ether extracts were d r i e d over  anhydrous magnesium s u l f a t e .  Removal of solvent followed by d i s t i l l a t i o n  (air-bath temperature ^95°C, 16 Torr) of the r e s i d u a l o i l afforded 233 mg (33%) of pure 4-n-butylpyridine, [ l i t . bp. 84°C, 8 T o r r ] . m a t e r i a l exhibited i r ( f i l m ) v 1602 cm ; max 1  1 5 4  '  1 5 5  '  1 6 6  This  ^Hnmr, t l . 5 2 (d of d,2H,  =CH-N=CH, J=5 Hz, J'=2 Hz), 2.89 (d of d,2H, =CH-C=CH, J=5 Hz, J'=2 Hz), 7.40  ( t , 2H, =C-CH (CH ) CH , J=7 Hz), 8.00-9.30 ( d i f f u s e , 7H) . 2  2  2  3  Conversion of l-Carbomethoxy-4-alkyl(or a r y l ) - l , 4 - d i h y d r o p y r i d i n e s to the Corresponding 4-Alkyl(or a r y l ) p y r i d i n e s . A.  Using p-Benzoquinone as Oxidant Conversion of l-Carbomethoxy-4-roethyl-l,4-dihydropyridine to 4-Methylpyridine  -68-  To a cold (-5°C) s o l u t i o n of  l-carbomethoxy-4-methyl-l,4-  d i h y d r o p y r i d i n e (306 mg, 2 mmol) i n dry ether (10 ml) under an atmosphere of argon was added dropwise a s o l u t i o n of m e t h y l l i t h i u m (6 mmol) i n ether over a period of 10 min.  The r e s u l t i n g mixture  was s t i r r e d f o r 15 min, and a s o l u t i o n of p-benzoquinone (216 mg, 2 mmol) i n ether (10 ml) was added dropwise over a period of 10 min. The r e s u l t i n g mixture was s t i r r e d a t 0°G f o r l h and then poured i n t o an i c e - c o l d 50% aqueous s o l u t i o n of ammonium hydroxide (50 ml).  The  aqueous s o l u t i o n was e x t r a c t e d thoroughly w i t h ether and the combined ether e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e .  Evaporation  of the ether, followed by d i s t i l l a t i o n of the r e s i d u a l o i l ( a i r - b a t h temperature ^65°C, 16 Torr) afforded 102 mg (55%) of pure 4-methylpyridine. A g l c a n a l y s i s (column E, 110°C) of t h i s m a t e r i a l , by c o i n j e c t i o n w i t h an authentic sample obtained commercially, and comparison of s p e c t r a l data w i t h that of the authentic sample confirmed the i d e n t i t y of t h i s m a t e r i a l . Conversion of l-Carbomethoxy-4-n-butyl-l,4-dihydropyridine  to 4-n-Butyl-  pyridine. Following a procedure i d e n t i c a l w i t h that described above f o r 1carbomethoxy-4-methyl-l,4-dihydropyridine,  a s o l u t i o n of 390 mg (2 mmol)  of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine i n 10 ml of dry benzene was treated f i r s t w i t h m e t h y l l i t h i u m (6 mmol) and then w i t h p-benzoquinone (2 mmol).  Normal work-up, followed by d i s t i l l a t i o n ( a i r bath  temperature  ^90°C, 16 Torr) of the crude product afforded 126 mg (48%) of 4-nbutylpyridine.  A g l c a n a l y s i s (column E, 130°C) of t h i s m a t e r i a l show  that i t was 95% pure.  S p e c t r a l data ( i r ^ H n m r ) of t h i s m a t e r i a l was  i d e n t i c a l w i t h the authentic m a t e r i a l prepared  earlier.  -69-  B.  Using Tetrachloro-l,4-benzoquinone as Oxidant Conversion o f l-Carbomethoxy-4-n,-butyl-l,4-dihydropyridine to 4-ji-Butylpyridine To a cold (-5°C) s o l u t i o n of l-carbomethoxy-4-n-butyl-l,4-dihydro-  p y r i d i n e (195 mg, 1 mmol) i n dry benzene (10 ml) was added a s o l u t i o n of m e t h y l l i t h i u m (3 mmol) i n ether. for 15 min.  The r e s u l t i n g mixture was s t i r r e d  A s o l u t i o n of tetrachloro-l,4-benzoquinone (246 mg, 1 mmol)  i n benzene (20 ml) was added dropwise over a period of 15 min. r e s u l t i n g mixture was r e f l u x e d  The  f o r 3.5h, cooled to room temperature and  then poured i n t o an i c e - c o l d 50% aqueous s o l u t i o n of ammonium hydroxide (80 m l ) .  The aqueous s o l u t i o n was extracted thoroughly w i t h benzene and  the combined benzene e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the benzene, followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^90°C, 16 Torr) of the r e s i d u a l o i l afforded 87.7 mg (65%) of pure 4-n-butylpyridine. C.  Using 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) as Oxidant. General Procedure To a cold (-78°C) s o l u t i o n of the appropriate l-carbomethoxy-4-  a l k y l ( o r a r y l ) - 1 , 4 - d i h y d r o p y r i d i n e (2 mmol) i n tetrahydrofuran (10 ml) under an atmosphere of argon was added dropwise a s o l u t i o n of m e t h y l l i t h i u m (6 mmol) i n ether over a period of 10 min. to s t i r a t -78°C f o r 45 min.  The r e s u l t i n g mixture was allowed  A s o l u t i o n of DDQ (500 mg, 2.2 mmol) i n t e t r a -  hydrofuran (10 ml) was added dropwise over a period of 10 min.  The r e s u l t i n g  mixture was s t i r r e d a t -78°C f o r 2h, warmed to room temperature and then s t i r r e d f o r an a d d i t i o n a l l h . The .reaction mixture was poured i n t o an i c e  -70c o l d 10% aqueous s o l u t i o n of sodium hydroxide (60 ml). s o l u t i o n was extracted thoroughly w i t h ether.  The aqueous  The combined ether  e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent followed by d i s t i l l a t i o n ( a i r - b a t h , 16 Torr) of the r e s i d u a l o i l gave the corresponding 4 - a l k y l ( o r a r y l ) p y r i d i n e . Conversion of l-Carbomethoxy-4-methyl-l,4-dihydropyridine  to 4-Methylpyridine  Following the general procedure o u t l i n e d above, 306 mg (2 mmol) of l-carbomethoxy-4-methyl-l,4-dihydropyridine  was allowed to r e a c t f i r s t w i t h  6 mmol of m e t h y l l i t h i u m and then w i t h 2.2 mmol of DDQ.  Normal work-up,,  followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^65°C, 16 Torr) of the crude o i l gave 108 mg (58%) of pure 4-methylpyridine. Conversion of l-Carbomethoxy-4-ethyl-l,4-dihydropyridine to 4 - E t h y l p y r i d i n e Following the general procedure o u t l i n e d above, 334 mg (2 mmol) of l-carbomethoxy-4-ethyl-l,4-dihydropyridine was allowed to r e a c t f i r s t w i t h 6 mmol of m e t h y l l i t h i u m and then w i t h 2.2 mmol of DDQ.  Normal work-up,  followed by d i s t i l l a t i o n ( a i r - b a t h temperature MJ5°C, 16 Torr) of the r e s i d u a l o i l afforded 190 mg (89%) of 4 - e t h y l p y r i d i n e . Comparison of the s p e c t r a l data obtained from the product w i t h that of the commercially a v a i l a b l e authentic sample and a c o i n j e c t i o n experiment  involving glc  (column E, 100°C) confirmed the i d e n t i t y . Conversion of l-Carbomethbxy-4-ri-buty 1-1,4-dihydropyridine to 4-ii-Butylpyridine Following the general procedure o u t l i n e d above,390 mg (2 mmol) of l-carbomethoxy-4-n-butyl-l,4-dihydropyridine was allowed to r e a c t f i r s t w i t h 6 mmol of m e t h y l l i t h i u m and then w i t h 2.2 mmol of DDQ.  Normal work-up,  followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^90°C, 16 mm) of the r e s i d u a l  -71-  i o i l afforded 197 mg  (73%) of pure 4-n-butylpyridine.  Conversion of l-Carbomethoxy-4-s.-butyl-l  ,4-dihydropyridirie to  4-s-  Butylpyridine Following the general procedure o u t l i n e d above, 390 mg l-carbomethoxy-4-s_-butyl-l,4-dihydropyridine  (2 mmol) of  was allowed to r e a c t f i r s t  w i t h 6 mmol of m e t h y l l i t h i u m and then w i t h 2.2 mmol of DDQ.  Normal  work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^70°C, 36 afforded 214 mg  Torr)  (79%) of 4 - s b u t y l p y r i d i n e [ l i t . bp 197°C, 765 T o r r ] .  This m a t e r i a l e x h i b i t e d i r ( f i l m ) v =CH-N=CH-, J=5 Hz, J'=2  Hz), 2.92  1601 cm  max  -11 : Hnmr xl.50 (d of d, '  (d of d, 2H, =CH-C=CH-, J=5 Hz, J'=2  7.10-7.77 (m, IH, =C-CH(C H )), 7.83-9.00 (m, 2H, -CHCH CH ), 8.77 2  5  2  3  i  CH -CH-, J=7 Hz), 9.18 3  1 6 6  r  ( t , 3H, -CH -CH , J=7 2  3  Hz), (d, 3H,  Hz).  Conversion of l-Carbomethoxy-4-phenyl-l,4-dihydrbpyridine  to 4-Pheriylpyridine  Following the general procedure o u t l i n e d above, 430 mg l-carbomethoxy-4-phenyl-l,4-dihydropyridine  2H,  (2 mmol) of  was allowed to react f i r s t with  6 mmol of m e t h y l l i t h i u m and then w i t h 2.2 mmol of DDQ.  Normal work^up  followed by d i s t i l l a t i o n of the r e s i d u a l o i l ( a i r bath temperature M.3Q°C, 0.5 Torr) afforded 220 mg [ l i t . mp.  69-73°C].  (71%) of pure 4-phenylpyridine, mp 70-72°C  The s p e c t r a l data ( i r , "Si nmr)  of t h i s m a t e r i a l  were i d e n t i c a l w i t h those obtained from a commercially sample.  a v a i l a b l e authentic  -72-  BIBLIOGRAPHY  1.  A. Hantzsch. Ann. 215, 1 (1882).  2.  Reviews on the s t r u c t u r e , synthesis, stereochemistry and hydrogen t r a n s f e r r e a c t i o n s of the p y r i d i n e nucleotides are given i n the f o l l o w i n g : (a) T.P. Singer and E.B. Kearney. Advan. 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Abstr. 44, 5396g (1950).  See also reference 14b.  153.  S. Goldschmidt and M. Minsinger. Chem. Ber. 87, 956 (1954).  154.  J.P. Wibaut and J.F. Arens. Rec. t r a v . Chim. 60, 119 (1941).  155.  J.F. Arens and J.P. Wibaut, Rec. trav. Chim. 61, 59 (1942).  156.  A.E. Chichibabin.  157.  H. Gilman and F.K. Cartledge, J . Organometal.  158.  D. Seyferth and M.L. Weiner, J . Am. Chem. Soc. 83, 3583 (1961).  159.  T e t r a v i n y l t i n i s commercially a v a i l a b l e , but t h i s compound was  B u l l . Soc. Chim. [5] 3_, 1607 (1936). Chem. 2, 447 (1964).  prepared i n our laboratory from the r e a c t i o n of v i n y l magnesium bromide and stannic c h l o r i d e , f o l l o w i n g the procedure of G.J.M. Van der Kerk. Organic Synthesis C o l l e c t i v e V o l . 4_, 881 (1963).  -80-  160. G.B. Kauffman and L.A. Teter. Inorg. Synth. 7_, 9 (1963). 161. G.H. Posner, D.J. B r u n e l l e and L. Sinoway. Synthesis, 662 (1974). 162. C.R. Johnson and G.A. Dutra. J . Am. Chem. Soc. 95, 7777 (1973). 163. P.M. A t l a n t i and J.F. Biellman. C.R. Acad. S c i . Ser. C, 271, 688 (1970). 164. Farbenfabriken Bayer A-G. Neth. A p p l . 6,408,287 ( C l . C07C), Jan. 21, 1965. Chem. Abstr.  63, 11440 (1970).  165. H.O. House, C.Y. Chu, J.M. W i l k i n s and M.J. Umen. J . Org. Chem. 40, 1460  (1975).  166. C.T. Kyte, G.H. J e f f e r y and A.I. Vogel, J . Chem. Soc. 4454 (1960).  -81PART I I Synthesis and Thermal Rearrangement of B-Cyclopropyl-a,B-unsaturated Ketones and Related Compounds INTRODUCTION  I.  General The occurrence of five-membered r i n g s i n an i n c r e a s i n g number of  n a t u r a l products of b i o l o g i c a l importance has r e c e n t l y stimulated the development of a wide v a r i e t y of new s y n t h e t i c methods f o r the preparation of cyclopentane r i n g s . acid 1  1  For example, the a n t i b i o t i c sesquiterpenes h i r s u t i c  2 3 and c o r i o l i n 2 , the l i p o p h i l i c a n t i b i o t i c pentalenolactone 3^ , 4  the sesterterpene r e t i g e r a n i c acid 4^ , the t r i c y c l i c sesquiterpenes capnellane 5^ and zizaene 6^, a l l contain two or more fused cyclopentane rings.  Most of the more r e c e n t l y developed methods f o r c o n s t r u c t i n g cyclopentane r i n g s are based on intramolecular r i n g closure of a c y c l i c precursors.  7-15  . , - . . ... , . 16-18 A few novel methods that involve r i n g c o n t r a c t i o n  and r i n g expansion^"  9  ^  of c y c l i c compounds have been reported. Cyclo21—26  a d d i t i o n reactions have a l s o been employed.  I t was not u n t i l quite  r e c e n t l y that the w e l l e s t a b l i s h e d vinylcyclopropane-cyclopentene rearrange27-30 ment has received considerable a t t e n t i o n as a v i a b l e and s y n t h e t i c a l l y  -82-  valuable method f o r cyclopentane r i n g synthesis,  II.  Vinylcyclopropane-Cyclopentene Rearrangement The thermal rearrangement of vinylcyclopropane to cyclopentene 31  was f i r s t reported by Overberger and Borchert i n 1960 ( e q . l ) . then, this process has received considerable attention.  Since  A wide v a r i e t y  of substituted vinylcyclopropanes having the general structure 1_ have been thermally rearranged to cyclopentenes of tne general structure 8^ (eq. 1).  (1)  a) b) c)  32,33 3  34  R =R =Me 1  35  , R^, Rg—C£  R , R,=C£ 5 6  2  c  R =Et  R =CH0  2  5  d)  R =R =C0 Et R =C0 Me, R  36,37  5  2  e) f) g) h)  36  R -C-C H 3  37-39 Rl  38,39  =CH , 3  P)  R =X^> 3  r)  3  s) R  2  5  or R =C0 Me 6  2  R  R =CH , R =X-^Q3  2  2  R =R.=CH 3 4 3' 5 '  5  q) 2  40  3  6  , R =C-C H 3  3  47 48  R  5  or R =N(CH ) 6  3  2  R or R =0CH_ j o J R =0CH c  48  4  48  R  5  3  or Rg=Ph  5  R.=CH„ 4 3  In general, the y i e l d s of i s o l a b l e cyclopentene products i n these reactions are f a i r l y high,except when the cyclopropyl group i s c i s to a  -83-  methyl group across the double bond.  For example,the rate of thermolysis  of compound 7_f was comparable to that of the other members of ]_, but only a small amount of cyclopentene amount of polymer. cyclopropane  product 8f_ was obtained along with a large  I t was also found that s u b s t i t u t i o n i n the v i n y l -  system, both on the r i n g and around the double bond, exerts  considerable influence on the rate of the r e a c t i o n and plays a r o l e i n 2 determining the course of the thermal rearrangement i n t o a  cyclopentene.  These s u b s t i t u t i o n e f f e c t s w i l l be discussed i n more d e t a i l l a t e r on when the mechanism of the rearrangement i s considered. Stepwise vinylcyclopropane rearrangements occur i n compounds 9 and 12 which g i v e , i n a d d i t i o n to the monocyclized  products ]_0 and L3, the  d i c y c l i z e d products 11_ and L4, r e s p e c t i v e l y (eq. 2 and 3 ) . " ^ ' ^  In  these examples, the i n c o r p o r a t i o n of a p o r t i o n of the v i n y l c y c l o p r o p y l moiety into a c y c l i c s t r u c t u r e does not i n t e r f e r e with the r e a c t i o n . f a c t , these transformations represent the f i r s t examples of  In  cyclopentene  annelation v i a vinylcyclopropane rearrangement.  The idea of using the rearrangement of vinylcyclopropanes as a method for f i v e membered r i n g annelation has been expanded recently by S t o r k ^ , 9  -84-  T r o s t ^ ^ ' ^ , Corey"^ and Monti"^. 1  By i n c o r p o r a t i n g appropriate substituents  on the cyclopropane r i n g or on the v i n y l i c double bond, the newly constructed r i n g may contain a f a i r l y wide v a r i e t y of f u n c t i o n a l groups. For example, compound 1_5_ rearranges smoothly at 360°C to the annelated 49 cyclopentene 16_ (eq.4).  The siloxyvinylcyclopropanes _20, which were  prepared from the cycloalkanones 17_ v i a the oxaspiropentanes  18^, undergo  50  thermal rearrangement to give the enol s i l y l ethers 21 i n over 90% y i e l d . Hydrolysis of the enol s i l y l ethers 21 unmasked the carbonyl groups to give the corresponding cyclopentanones  _22 (Scheme 1).  The enol s i l y l  ethers 21_ may also be transformed i n t o a s p e c i f i c enolate , which may then be a l k y l a t e d to introduce f u r t h e r a l k y l groups.  For example,  treatment of 2lb with methyllithium followed by methyl iodide gave the perhydroazulene  d e r i v a t i v e 23 (eq.5)."^ (4) 16 OLi  I^^Y©  [>-SPh KOH  17_  OSiMe  2  BF (CH ) 2  Me SiCJl  iN(i-pr),  4  _ >  n  3  (CHJ, 2n y  18  a) n=0 b) n=2 c) n=l  <CH)n  2  3  19  OSiMe  3  H  (CH ) 2  n  -85-  OSiMe  3  CH^Li  CH I  (5)  3  21b Although t h i s procedure was found to work quite w e l l with cycloalkanones,  i t f a i l e d with a,3-unsaturated cycloalkenones.  saturated Furthermore,  with cyclohexanone, the y i e l d of the siloxyvinylcyclopropane from the corresponding oxaspiropentane was f a i r l y poor.  However, these l i m i t a t i o n s  could be overcome by s u b s t i t u t i n g the s i l o x y group with a phenythio group. Tne vinyicyclopropylphenyl s u l f i d e 26_ could be prepared by the a d d i t i o n of 1 - l i t h i o c y c l o p r o p y l p h e n y l s u l f i d e to 4-_t-butylcyclohexanone 2h_, followed by dehydrat ion of the r e s u l t i n g alcohol 25. P y r o l y s i s of the v i n y i c y c l o propylphenyl s u l f i d e J26_ gave the enol thioether 27_ which could be hydrolysed to the corresponding cyclopentanone 28^ or d e s u l f u r i z e d to give the c y c l o pentene 29_ (Scheme 2)  S i m i l a r l y , a d d i t i o n of 1 - l i t h i o c y c l o p r o p y l p h e n y l  s u l f i d e to the a,8-unsaturated ketone _30^, followed by dehydration of the l a t t e r gave the cyclopropylphenyl  s u l f i d e 31. P y r o l y s i s of t h i s compound,  followed by h y d r o l y s i s of the r e s u l t i n g enol t h i o ether _32 afforded the cyclopentenone 33. ™  S  SPh  A  \ / SOC£ ,pyridin 2  24  25  26  -86-  Th e l a s t few examples mentioned above demonstrated that the thermal rearrangement of vinylcyclopropane systems which incorporate the carbon-carbon double bond i n a r i n g a f f o r d s y n t h e t i c a l l y u s e f u l y i e l d s of the corresponding cyclopentane d e r i v a t i v e s (annelation products).  S i m i l a r r e s u l t s have been obtained when the  cyclopropane  r i n g i s fused to another c y c l i c s t r u c t u r e . For example, p y r o l y s i s of the enol s i l y l ethers 3>4_, followed by h y d r o l y s i s of the products, gave the cyclopentenones  rearranged  _3_5 and 3_6_, along w i t h considerable  53 amounts of 37_ (eq.6).  However, p y r o l y s i s of the enol s i l y l ethers 38,  followed by h y d r o l y s i s of the r e s u l t i n g products, afforded i n good y i e l d s 53 the annelated cyclopentanones  39_ as the only i s o l a t e d products  (eq.7).  In a s i m i l a r f a s h i o n , compound 40 rearranged upon heating to a f f o r d the  -87-  OSiMe,  CC)  <c 2.  H 0  +  3  39 Yield 21% 99% 85%  38 a) n=0 b) n=l c) n=2  ketone 41_.  The l a t t e r was transformed  (7)  i n t o the aldehyde 4^3, which  served as an intermediate i n the synthesis of  11-deoxyprostaglandin  52 E  2 —  (Scheme 4) .  I t i s i n t e r e s t i n g to note that compound 45_, the  deoxo d e r i v a t i v e of compound 4^), undergoes a f a c i l e intramolecular "ene" r e a c t i o n rather than the normal vinylcyclopropane rearrangement.  Thus  p y r o l y s i s of compound 4_5 afforded the o l e f i n 48_ as the major product 52a along with a small amount of the annelated  cyclopentene 4 7 (ecj.8).  Presumably, isomerization of 4_5 to 4j5 occurred, p r i o r to the rearrangement OMe  to 48.  HO ---s. H  600'C 40  H  41  H  42  CHO  43  -88-  The thermal rearrangement of vinylcyclopropane systems i s unsuccessful i f the product that would be produced i s e x t r a o r d i n a r i l y strained.  For example, i t was found that 1 - v i n y l n o r t r i c y c l e n e 49_  was recovered unchanged upon heating at 475°C f o r 25 min."*  4  I f a normal  vinylcyclopropane rearrangement had occurred, the r e s u l t i n g product (50) 55 would have been i n v i o l a t i o n of Bredt's r u l e .  49  50  Normal vinylcyclopropane rearrangement can take place even i f the e n t i r e vinylcyclopropane moiety i s incorporated i n t o a c y c l i c framework, provided that there i s no excessive r i n g s t r a i n present i n the rearranged product and that there i s no competitive r e a c t i o n taking place.  For  example, at 250°C, 8-thujene _51 rearranged to a f f o r d a mixture of 52. and _53_ w h i l e at 300°C, 53 was the only observed product (eq.10).^^ The succes: of t h i s rearrangement might suggest that higher homologs would rearrange i n a s i m i l a r way.  However, p y r o l y s i s of 7-carbomethoxynorcar-2-ene 54  gave a complex mixture i n which ethylene and carbomethoxycyclopentadiene 56^were present. 55 ( e q . l l ) .  5 7  Presumably, the l a t t e r were formed v i a the intermediate  -89-  250°C  300°C (10)  51  52  53  Me0 C-  + CH=CH2 (11)  2  Me0 C 2  5  56  5  P y r o l y s i s of bicyclo[3.1.0]hex-r2-ene ene 57b and bicyclo[6.1.0]non-2-ene  57a, bicyclo[5.1.0] oct-2-  57c r e s u l t e d i n transannular hydrogen  migration to give the dienes 58a, 58b and 58c r e s p e c t i v e l y , rather than 58 59 undergoing the vinylcyclopropane-type rearrangement (eq.12).  '  The  ease of transannular hydrogen migration i n the bicyclo[6.1.0]nonene system could be diminished by incorporating additional unsaturation i n t o the system.  When t h i s was done, the vinylcyclopropane-type rearrangement  took place.  For example, p y r o l y s i s of the bicyclo[6.1.0Jnonatrienes _59  gave the corresponding dihydroindenes j>0 ( e q . 1 3 ) . ^  Similarly, pyrolysis  of the b i c y c l i c unsaturated ketone 61_ gave the cyclopentanone 65 major product (eq.14). ( 2)  bl_ as the  (12)  C H  N  (a) n=0; (b) n=2; (c) n=3  (13) 59 60 (a) R=H; (b) R=C£; (c) R=C0 Et; (d) R=CH 0H 2  2  -90-  O  (14)  Vinylcyclopropane-Cyclopentene rearrangements by means other than heat.  may also be effected  P h o t o l y s i s of the vinylcyclopropane d e r i v a t i v e  64 gave the cyclopentene 65_ as the major product  (eq.15).  Irradiation  66  of the bicycloheptene 67 i n the presence of a s e n s i t i z e r gave 66% of the 67  bicyclo[3.2.0]heptene j68 and 13% of i t s isomer ^9 (eq.16).  Similarly,  i r r a d i a t i o n of the b i c y c l i c compound 7_1 and 7_3 gave the corresponding 68  b i c y c l o [3.3. 0]octenes 12_ and 74_ r e s p e c t i v e l y (eq.17 and 18).  -91-  CD v  hv  60%  y  (18)  r  H  73  74  Treatment of l,l-dibromo-2-vinylcyclopropane 75a with methyllithium gave 86% of the cyclopentadiene 76a and 14% of the penta-l,2,4-triene, while l,l-dibromo-2-methyl-2-isopropenylcyclopropane 75b gave 95% of a mixture of the dimethylcyclopentadienes 76b  CH Li  RBr-  (eq.19). 69  3  (19)  \  Br  75 (a) R=H;  76  (b) R=CH,  T r a n s i t i o n metals have a l s o been used to catalyse the v i n y l c y c l o propane-cyclopentene rearrangement.  Thus, a s t o i c h i o m e t r i c rhodium(I)  complex of the vinylcyclopropane 7_7 rearranges r e a d i l y to the rhodium (I) complex of bicyclo[3.3.0]octa-2,6-diene ( e q . 2 0 ) .  7 1  However, i n the  absence of the c a t a l y s t , the same vinylcyclopropane 7_7 gave the b i c y c l o 72 [3.2.1]octa-2,6-diene  _79 v i a a [3,3] sigmatropic rearrangement (eq.21).  (20)  (21)  21  79  -92-  S i m i l a r l y the bicyclo[6.1.0]nona-2,4,6-triene jH) rearranged r e a d i l y and q u a n t i t a t i v e l y i n the presence of dicarbonylrhodium(I) c h l o r i d e diraer i n t o the corresponding bicyclo[4.3.0]nonatriene 81 (eq.22).  73  .CI  *  (CO) Rh^ ^Rh(CO) 2  c  2  (22) I H R  80  III.  81  Mechanistic Considerations i n the Thermal VinylcyclopropaneCyclopentene Rearrangement. The mechanism of the thermal vinylcyclopropane-cyclopentene 27 28 30  rearrangement has long been a subject of controversy.  '  '  Most of  the arguments have focused on the degree to which the process i s concerted or stepwise.  The vinylcyclopropane rearrangement can be thought to occur  v i a a mechanism i n which the rate-determining step i s the opening of the 74 75 cyclopropyl r i n g to form the d i r a d i c a l 82,  '  followed by r i n g closure  as a r e s u l t of intramolecular coupling of the d i r a d i c a l .  On the other  hand, i t can a l s o be envisaged to proceed v i a a concerted mechanism i n v o l v i n g a Cope-type t r a n s i t i o n state such as 83 (Scheme 5 ) ^ » ^ » ^ #  -93-  Scheme 5  K i n e t i c data has indicated that the rearrangement i s a unimolecular 33 76 process w i t h an a c t i v a t i o n energy of cii. 50 kcal/mol.  '  The a c t i v a t i o n  energy i s about 14 kcal/mol lower than that of ordinary cyclopropane r i n g cleavage.  The d i f f e r e n c e corresponds quite w e l l to the a l l y l i c  resonance  energy and has been interpreted i n terms of a resonance s t a b i l i z e d b i r a d i c a l intermediate. Current sentiment seems to favor the intermediacy of a d i r a d i c a l rather than a concerted process.  T h e o r e t i c a l molecular o r b i t a l c a l c u l a t i o n s ,  based on the MINDO/3 (Modified Intermediate Neglect of D i f f e r e n t i a l Overlap) semiempirical SCF-MO (Self-Consistent F i e l d Molecular O r b i t a l theory) method, 80 predicted that the rearrangement i s a "forbidden" b i r a d i c a l o i d process. Wilcott and Cargle were able to conclude, from nmr i n v e s t i g a t i o n s , that i n the thermolysis of monodeuteriovinylcyclopropane, the l o s s of stereos p e c i f i c i t y a t the deuterium-labeled s i t e i n the c y c l o p r o p y l r i n g i s at l e a s t f i v e times as f a s t as the conversion to cyclopentene, thus s u b s t a n t i a t i n g 81 the d i r a d i c a l mechanism (Scheme 6). More r e c e n t l y , the same authors have  Scheme 6  -94-  studied the degenerate rearrangement of 1 - ( 2 - d e u t e r i o v i n y l ) trans,trans-2,3-dideuteriocyclopropane  84a by nmr and have obtained  a d d i t i o n a l evidence supporting the intermediacy (Scheme 7).  of a d i r a d i c a l  82  84a  \  /  i i 4  84b  1  (84b+84c):84d=2:l  Scheme 7  Comparative k i n e t i c studies have shown that s u b s t i t u t i o n s on C-2 of vinylcyclopropane with c h l o r o ^ , m e t h o x y l ^ , phenyl^ , or a 2  8  47 dimethylamino  group (85a, 85b, 85c, 85d r e s p e c t i v e l y ) considerably  enhances the rate of rearrangement to the corresponding cyclopentene. A l s o , the products formed are e x c l u s i v e l y the 4-substituted cyclopentenes 86 rather than the 3-substituted isomers 87_ (eq.23).  The f a c i l i t y with  which these reactions take place and the s t e r e o s e l e c t i v i t y of the process have been explained by invoking a d i r a d i c a l  \  intermediate. (23)  > 87  85  86  (a) R=R -CA; (b) R or R^OCI^; (c) R or R^Ph; (e) R or R =NMe 1  2  I t i s of i n t e r e s t to note that when an a l k y l group i s located c i s to the cyclopropyl r i n g i n these vinylcylopropane  systems (for example,  -95-  as i n compounds 90_, 91_ and 93) , the r a t e of thermal rearrangement i s s t r i k i n g l y reduced and the products formed are u s u a l l y polymers or s t r u c t u r a l l y rearranged o l e f i n s (eq.24-26). the  37 49 83 ' '  I n c o n t r a s t , when  a l k y l group i s s i t u a t e d trans to the c y c l o p r o p y l r i n g , i t has no 37 83  d i m i n i s h i n g e f f e c t on the r a t e s of rearrangement. has been explained i n terms of s t e r i c i n t e r a c t i o n s .  '  This observation The c i s a l k y l  groups prevent the r i g i d a l l y l i c r a d i c a l from remaining planar i n the t r a n s i t i o n s t a t e , thereby lowering i t s a l l y l i c resonance energy, r a i s i n g the  energy b a r r i e r to r i n g c l o s u r e and hence making the r e a c t i o n pathway  towards i s o m e r i z a t i o n to o l e f i n s an e n e r g e t i c a l l y more favourable process,  450°C  Me  360°C  *~  polymer  (24)  300°C cis-trans (25) isomerization  CHzCOjR  92  (26)  390°C s> 93 IV.  The Problem Recently, our laboratory has developed an e f f i c i e n t method f o r the  preparation of c y c l i c 8-halo-ot,6-unsaturated ketones from the r e a c t i o n of  -96-  84 c y c l i c g-diketones 96_ w i t h triphenylphosphine d i h a l i d e s . These g-halo enones have been converted i n t o a v a r i e t y of g-alkyl-a,B-unsaturated ketones i n good y i e l d by t r e a t i n g the former w i t h various cuprate 85 reagents.  Thus, o v e r a l l , previous work i n our laboratory had e s t a b l i s h e d  an e f f i c i e n t s y n t h e t i c route f o r transforming a c y c l i c g-diketone of the general s t r u c t u r e 96_ to the corresponding c y c l i c g-alkyl-a,g-unsaturated ketones of the general s t r u c t u r e 98_, as shown i n the scheme below. Ph px 3  o  o  2  97.  96  98  The f i r s t o b j e c t i v e of the work described i n t h i s s e c t i o n of t h i s t h e s i s was to i n v e s t i g a t e the p o s s i b i l i t y of extending t h i s methodology to include the synthesis of c y c l i c g-cyclopropyl-a,g-unsaturated of the general s t r u c t u r e 99.  ketones  I t can r e a d i l y be seen that the l a t t e r  compounds incorporate i n t o t h e i r s t r u c t u r e s the vinylcyclopropane moiety, with the v i n y l p o r t i o n of t h i s f u n c t i o n a l i t y being part of the ketone moiety.  a,g-unsaturated  Thus, the second o b j e c t i v e of t h i s work was to i n v e s t i g a t e the  thermolysis of these compounds, to determine whether or not they could serve as precursors f o r an e f f i c i e n t cyclopentane annelation method.  F i n a l l y , the  p o s s i b i l i t y of applying t h i s methodology to the t o t a l synthesis of n a t u r a l products was a l s o considered worthy of i n v e s t i g a t i o n .  -97DISCUSSION I.  Synthesis of C y c l i c B-Iodo-a,B-Unsaturated  Ketones  The conversion of B-diketones i n t o the corresponding B-chloro-ot,Bunsaturated ketones has been achieved by t r e a t i n g the former w i t h a wide v a r i e t y of reagents: phosphorous t r i c h l o r i d e , phosphorus  oxychloride,  86 phosgene, a c e t y l c h l o r i d e and o x a l y l c h l o r i d e .  However, p r i o r to recent  work done i n our l a b o r a t o r y , the transformation of B-diketones i n t o the corresponding B-iodo-a,B-unsaturated ketones by use of analogous reagents had not been accomplished.  In f a c t , reports concerning the preparation  of t h i s c l a s s of compounds had been very scarce.  3-Iodo-2-cyclohexen-l-one  101 had been prepared by r e f l u x i n g 3-chloro-2-cyclohexen-l-one 100 with 87 sodium iodide i n acetone f o r 24h (eq.27).  However, the product of t h i s  r e a c t i o n was a mixture of B-iodo and B-chloro enones, and the B-iodo compound obtained was not f u l l y characterized. (27) 100  A24h  Recently, P i e r s and Nagakura"^ reported an e f f i c i e n t conversion of c y c l i c B-diketones i n t o the corresponding B-halo-a,B-unsaturated  ketones  by t r e a t i n g the former w i t h triphenylphosphine d i h a l i d e s i n the presence of t r i e t h y l a m i n e . or iodide (eq.28).  I t was found that the h a l i d e could be c h l o r i d e , bromide, This represented the f i r s t d i r e c t conversion of  B-diketones i n t o the corresponding B-iodo-a,B-unsaturated ketones, and, i n f a c t , represented the f i r s t general synthesis of the l a t t e r type of compound.  -98Ph PX 3  2  (28) solvent X = CI, Br, I  103  In studying the r e a c t i o n of these 6-halo enones w i t h v a r i o u s cuprate reagents, i t was found that the B-iodo enones were s u p e r i o r to the corresponding bromo or chloro d e r i v a t i v e s i n y i e l d i n g the 85 corresponding B-alkyl-a,B-unsaturated ketones.  Therefore, the B-iodo  enones were chosen to be the s t a r t i n g m a t e r i a l s to i n v e s t i g a t e the synthesis of the corresponding B-cyclopropyl-a,B-unsaturated The o r i g i n a l procedure reported f o r the conversion of i n t o the corresponding B-iodo enones was r a t h e r tedious. when 1,3-cyclohexanedione  ketones. B-diketones  For example,  104 was t r e a t e d w i t h triphenylphosphine d i i o d i d e  i n a c e t o n i t r i l e i n the presence of t r i e t h y l a m i n e at room temperature, i t took four days f o r complete conversion of the dione i n t o 84 1-one  101 (eq.29).  3-iodo-2-cyclohexen-  During the course of the work described i n t h i s t h e s i s ,  the procedure has been s i m p l i f i e d and the y i e l d s of the r e a c t i o n products have been improved considerably.  Thus, the dione 104 was converted i n t o  the corresponding B-iodo enone 101 i n 87% y i e l d by r e f l u x i n g the former w i t h 1.1 equivalents of triphenylphosphine d i i o d i d e i n a c e t o n i t r i l e i n the presence of 1.1 equivalents of t r i e t h y l a m i n e f o r 9h. 101 was found to be a low m e l t i n g s o l i d : mp 15-16°C.  The B-iodo enone  I t e x h i b i t e d a strong  absorption i n the uv spectrum at 258 nm, w i t h e=9000(ir->-ir* t r a n s i t i o n of a,B-unsaturated  ketone).  Two strong absorption bands at 1675 and 1595  i n the i r spectrum of t h i s compound a l s o i n d i c a t e d the presence of an unsaturated carbonyl f u n c t i o n a l i t y .  cm a,B-  The o l e f i n i c proton of t h i s compound  gave r i s e to a one-proton t r i p l e t at T3.20 (J=2HZ) i n the "hlnmr spectrum.  -99-  The s t r u c t u r e of the enone 101 was f u r t h e r Confirmed by a s a t i s f a c t o r y elemental a n a l y s i s .  112 n=l, R=H 113 n=l, R=CH  116 n=2  114  3  S i m i l a r transformations were c a r r i e d using the g-diketones 105-108, i n c l u s i v e , and the hydroxymethylenecycloalkanones materials.  The r e s u l t s are summarized i n Table 1.  109 and 110 as s t a r t i n g In each case, the  product e x h i b i t e d s p e c t r a l data ( i r , ^Hnmr) i n f u l l accord w i t h the assigned  Ph PI 3  .-  0  104  2  (29)  Et N,CH CN 3  3  r . t . 4 days  101  s t r u c t u r e , and gave a s a t i s f a c t o r y elemental a n a l y s i s and/or a molecular  -100-  weight determination  (high r e s o l u t i o n mass  spectrometry).  Although the data summarized i n Table 1 are r e l a t i v e l y s t r a i g h t forward, i t i s appropriate to make a few comments.  I t was  the conversion of cyclopentanediones 106 and 107 i n t o the  found that corresponding  3-iodo enones 112 and 113, r e s p e c t i v e l y , required a s h o r t e r r e a c t i o n time (3h) than d i d t h e i r six-membered r i n g counterparts 104 and  105  ( e n t r i e s 3 and 4 vs e n t r i e s 1 and 2, Table 1). I t i s of i n t e r e s t to note that attempted conversion of the dione 108 (prepared from a D i e l s - A l d e r r e a c t i o n between 1,3-cyclopentadiene and 1,3-cyclopentenedione) i n t o the corresponding  0-iodo enone 114 under  r e a c t i o n c o n d i t i o n s i d e n t i c a l w i t h those used f o r other cyclopentanediones gave only a 30% y i e l d of the desired product 114. y i e l d of the r e a c t i o n by extending result.  Attempts to improve the  the r e a c t i o n time to 72h gave the same  A d d i t i o n of hexamethylphosphoramide as cosolvent, i n the hope  that a more p o l a r solvent might improve the r e a c t i o n , showed no e f f e c t . Previous studies i n our laboratory by Dr. I . Nagakura had shown that the conversion of 2-hydroxymethylenecyclohexanone corresponding  110 i n t o the  8-iodo enone 116 under conditions i d e n t i c a l w i t h those  employed f o r the c y c l i c 8-diketones ( r e f l u x i n a c e t o n i t r i l e ) gave a very low y i e l d of the desired product. which was  I t was suspected that the 8-iodo enone  formed i n t h i s r e a c t i o n might not be s t a b l e enough to s u r v i v e  the high temperature of the r e a c t i o n mixture. shown that the conversions  Previous s t u d i e s had a l s o  of 8-diketones i n t o the corresponding  8-iodo enones were  more e f f i c i e n t when the r e a c t i o n s were c a r r i e d out i n a c e t o n i t r i l e r a t h e r 84 than i n benzene,a l e s s p o l a r solvent.  Thus i t was hoped that by  the  a d d i t i o n of hexamethylphosphoramide, a very polar s o l v e n t , to a c e t o n i t r i l e as cosolvent, might improve the e f f i c i e n c y of the conversions  of the  -101-  Table 1.  Conversion of c y c l i c 6-diketones and a-hydroxymethylenecycloalkanones to the corresponding 8-iodo-a,g-unsaturated ketones  Entry  Starting material (1,3-dicarbonyl compounds)  Reaction Condition 3  8-Iodo enone p r o d u c t ( y i e l d )  1.  104  B  101  (87%)  2.  105  B  111  (73%)  3.  106  A  112  (85%)  4.  107  A  113  (92%)  5.  108  A  114  (31%)  6.  109  C  115  (73%)  7.  110  C  116  (94%)  Reaction c o n d i t i o n A: 1.1 equiv. of P h ^ P ^ was used w i t h a c e t o n i t r i l e as solvent.  Time of r e f l u x was 3h"; B: a c e t o n i t r i l e was the s o l v e n t ;  time of r e f l u x was 9h; C: acetonitrile/HMPA i n the r a t i o of 6:1 was the s o l v e n t , r e a c t i o n was c a r r i e d out at r . t . f o r 15h. The y i e l d was based on d i s t i l l e d pure products.  b  -102-  a-hydroxymethylenecycloalkanones  i n t o the corresponding 0-iodo enones.  This was indeed found to be the case. The conversions of the a-hydroxymethylenecycloalkanones  109 and  110 i n t o the corresponding 3-iodo enones 115 and 116, r e s p e c t i v e l y , were c a r r i e d out i n a manner s i m i l a r to that used f o r the 8-diketones, except that a 6:1 mixture of a c e t o n i t r i l e and hexamethylphosphoramide was used as solvent, and the reactions were c a r r i e d out at room temperature f o r 15h (entries 6 and 7, Table 1). Both of the reactions were h i g h l y r e g i o s e l e c t i v e and s t e r e o s e l e c t i v e , since, i n each case, only a s i n g l e 8-iodo enone was formed.  On the b a s i s of "4lnmr s p e c t r a l data (see below), i t  appeared that i n both of the products the iodine atom was trans t o the carbonyl group. The general p r i n c i p l e used i n assigning the stereochemistry of the a-halomethylenecycloalkanones 117 and 118 was based on the e m p i r i c a l observations that, i n the ^Hnmr spectrum, the 8 - o l e f i n i c protons c i s to the carbonyl group i n enones of t h i s type resonate downfield from t h e i r 88 89 trans counterparts. ' For example, the 8 - o l e f i n i c proton of compound 119 gives r i s e t o a s i g n a l at T3.55, whereas the corresponding proton i n 89 the isomer 120 resonates at T2.65.  However, since our reactions were  completely s t e r e o s e l e c t i v e , we had only one of the two possible isomers a v a i l a b l e , and therefore, a d i r e c t comparison could not be made.  117  119  118  120  115  -103-  Our assignments  are based on the f o l l o w i n g arguments.  The  88 protons a to the heteroatom  i n v i n y l c h l o r i d e 121  and v i n y l i o d i d e  90 122  resonate at T3.72 and T3.52, r e s p e c t i v e l y .  The d i f f e r e n c e i n  chemical s h i f t s of the two protons caused by changing the a - s u b s t i t u e n t on the ethylene d e r i v a t i v e s from c h l o r o to iodo (AT) was 0.2.  Comparison  of the AT value of the B - o l e f i n i c protons of compounds 120 and  115  (AT=0.26) w i t h that of 119 and 115 (AT=1.16) i n d i c a t e s that compound 115 should have the same stereochemistry as compound 120, s i n c e the AT value, of t h e i r B - o l e f i n i c protons (AT=0.26) i s c l o s e r to that between v i n y l c h l o r i d e and v i n y l i o d i d e (AT=0.2) than the AT value between compound 119 and 115.  Furthermore, both compounds 115 and 120 have  s i m i l a r molecular s t r u c t u r e s , and the chemical s h i f t s of t h e i r  B-olefinic  protons are q u i t e s i m i l a r . More evidence comes from the observation that the c i s and trans B - o l e f i n i c protons i n 2-methylenecyclohexanone 123 89 resonate at T4.28 andT4.96 r e s p e c t i v e l y .  The d i f f e r e n c e i n chemical  s h i f t s between the c i s and trans B - o l e f i n i c proton (AT) i n 123 was  0.68.  Thus, t a k i n g i n t o account the AT value caused by the change of a-substituent on the methylene group from c h l o r o to iodo (0.2T u n i t s ) , the d i f f e r e n c e i n chemical s h i f t of the B - o l e f i n i c protons of 119 and 115 would be to be c l o s e to 0.9T u n i t s .  The observed d i f f e r e n c e was 1.16,  expected  thus p r o v i d i n g  e x c e l l e n t evidence f o r the stereochemistry of 115 as assigned. The same type of argumentation can be a p p l i e d to the B-iodo enone 116.  -104-  Heathcock e_t  a l . reported that the """Hnmr spectrum of the 8-chloro enone 88  124 showed a 8 - o l e f i n i c proton resonance at T3.0 that of the 8-iodo enone 116 by 0.7x u n i t .  which d i f f e r s from  The d i f f e r e n c e would appear  to be too l a r g e f o r the two compounds to have the same stereochemistry. Furthermore,  the chemical s h i f t of the B - o l e f i n i c proton of enone 116  (T2.30) i s q u i t e close to those of compounds 115 (T2.39) and 120 (T2.65). By analogy, i t i s c l e a r that compound 116 should possess the stereochemistry as shown. I t has been w e l l e s t a b l i s h e d that the conjugation of a double bond w i t h a carbonyl group leads to intense absorption i n the u l t r a v i o l e t 91 spectrum (TT-MT* transition).  I t i s a l s o w e l l known that there i s a  regular and s i g n i f i c a n t v a r i a t i o n i n the wavelength at which the absorption maximum (Amax ) occurs, depending upon the s u b s t i t u t i o n pattern on the chromophore.  The magnitude of these s h i f t s can be predicted by a set of  r u l e s f i r s t formulated by Woodward 92 and l a t e r modified by F i e s e r 93 and 91 by Scott.  For example, according to the Woodward r u l e s , an a - a l k y l  substituent causes a bathochromic s h i f t (a s h i f t of the absorption maximum towards higher wavelength) of ^10 nm.  S i m i l a r l y , a 8-chloro substituent  causes an increment of ^12 nm and a B-bromo substituent i s supposed to 91 cause an increment of "^30 nm.  However, since no c y c l i c B-iodo-a,B-  unsaturated ketones had been f u l l y characterized p r i o r to our i n v e s t i g a t i o n , nothing was known about the e f f e c t of a B-lodo substituent on the p o s i t i o n of the T T - H T * absorption maximum of an a,B-unsaturated  ketone.  Based on the  uv data of the l i m i t e d number of 3-iodo-2-cycloalken-l-ones and a-iodomethylenecycloalkanones prepared i n t h i s l a b o r a t o r y , i t was hoped that the extent of the bathochromic s h i f t caused by a 8-iodo substituent could be e s t a b l i s h e d .  -105-  Table 2 l i s t s the  TT->TT*  a b s o r p t i o n maxima of a number of parent  2-cycloalken-l-ones and 2-methylenecycloalkanones, along w i t h those of some of the corresponding B-halo compounds.  The d i f f e r e n c e s between  the a b s o r p t i o n maxima of the B-halo enones and that of t h e i r parent unsubstituted enones are a l s o l i s t e d i n Table 2.  C l e a r l y , the data  summarized i n the t a b l e showed that the uv absorption maxima of the B-chloro-a,B-unsaturated ketones 130-132 f o l l o w the Woodward r u l e s f a i r l y c l o s e l y ( e n t r i e s 7-9, Table 2). For example, 3-chloro-5,5-dimethyl-299 cyclohexen-l-one 130 showed an absorption maxima at 238 nm  which was  12 nm higher than that of the parent 2-cyclohexen-l-one 125 ( e n t r i e s 1 and 7, Table 2 ) . The magnitude of t h i s increment was as expected, since the Woodward r u l e s p r e d i c t e d a ^12 nm bathochromic s h i f t caused by a 91 B-chloro s u b s t i t u e n t .  S i m i l a r l y , 3-chloro-2,5,5-trimethyl-2-cyclohexen-  1-one 131 had an a b s o r p t i o n maximum at 244 nm''^ which was 10 nm higher than that of 2-methyl-2-cyclohexen-l-one ( e n t r i e s 2 and 8, Table 2 ) . The difference i n X between the B - c h l o r o enones 131 and 130 was 6 nm, which max was c l o s e to that p r e d i c t e d by the Woodward r u l e s f o r the e f f e c t of an a-alkyl substituent. I t was q u i t e unexpected to f i n d that the p o s i t i o n s of the uv absorption maxima of the three B-bromo enones 133-135 shown i n Table 2 d i d not agree w i t h those p r e d i c t e d by the Woodward r u l e s ( e n t r i e s 10-12). A l l three compounds showed a b s o r p t i o n maxima much lower than those c a l c u l a t e d by the Woodward r u l e s .  Compared w i t h the corresponding a, 8-  unsaturated ketones, a l l of them showed a bathochromic s h i f t .  However,  the magnitude of the s h i f t f e l l q u i t e short of the 30 nm expected f o r a B-bromo s u b s t i t u e n t .  For example, 3-bromo-2-methyl-2-cyclohexen-l-one  134  Table  2.  The uv  a b s o r p t i o n maxima  (X  )  of  some  8-halo  enones  and  their  a,B-Unsaturated Entry  Ketones  parent  B-unsubstituted  Difference in X Observed  X ^ t n m ) (e)  Calculated *  m a  ^ l  n m  )  B-halo parent  enones  m a x  and  enones  between their  Reference  B-unsubstituted  enones  226  (10400)  94  125  234  95  126  6  213  (9500)  226  (8550)  231  (7550)  96  127  &  97  128  98  123  6  \_J  2 3 0  ( °) 740  98  129  |[ 130  238  (113500)  238  12  99  8  9  10  11  12  13  14  244  (1300)  241  (16000)  246  (13400)  246  (13060)  243  (12302)  258  (9000)  258  (9504)  256  (8377)  246  10  100  238  15  101  256  20  99,102  264  12  103  256  17  104  c i 32  105  24  105  32  103  26  106  15  16  260  17  249  (11353)  31  105  248  (11520)  22  105  253  (9900)  35  105  265  (7198)  34  105  261  (7110)  30  105  112  18 113s'  19 114  1  20 116.  21 138  o oo i 22  257  (6681)  26  105  276  (9170)  45  105  263  (shoulder)  33  139  6^  23  115  The  X  max  (calc.)  unsubstituted parent  enone.  (6-bromo +  was c a l c u l a t e d  enone, For  for a  example,  substituent)=256  3 0 nm ( 8 - b r o m o  using  8-chloro the ^  m 3 J C  t h e Woodward substituent (calc.)  a d d 12  for  nm, whereas t h e X max s u b s t i t u e n t )' = 2 6 4 n m .  rules:  nm a n d f o r a  8-bromo  (calc.)  for an a - a l k y l  of  enone  8-bromo  133 w o u l d  8-bromo  substituent,  enone  a d d 1 0 nm t o  substituent  a d d 3 0 nm t o  b e 2 2 6 nm ( p a r e n t 134 w o u l d  the  enone  r  the  125)  b e 2 3 4 nm ( p a r e n t  parent  +  3 0 nm  enone  126)  -109-  had a A  max  at 246 nm.  On the b a s i s of Woodward's r u l e s , the X  t h i s compound should be around 264  for  max  nm.  Another s i g n i f i c a n t d e v i a t i o n from the Woodward r u l e s was  the  observation that the absorption maxima of both 3-bromo-5,5-dimethyl-2cyclohexen-l-one 133 and 3-bromo-2-methyl-2-cyclohexen-l-one i d e n t i c a l ( e n t r i e s 10 and 11, Table 2 ) .  134 were  They were p r e d i c t e d to have a  d i f f e r e n c e i n a b s o r p t i o n maximum by ^10 nm due to the presence of an e x t r a a - a l k y l s u b s t i t u e n t on enone 134. the 3-iodo analogs.  This anomaly was a l s o found i n  For example, 3-iodo-2-cyclohexen-l-one 101 and  3-iodo-2-methyl-2-cyclohexen-l-one absorption maximum at 258 nm  111 were shown to have the same  ( e n t r i e s 13 and 14, Table 2 ) .  absorption maxima of 3-iodo-2-cyclopenten-l-one 112 and  A l s o , the  3-iodo-2-methyl-  2-cyclopenten-l-one 113 occurred at n e a r l y the same wavelength  ( e n t r i e s 17  and 18, Table 2). I t i s unfortunate that very l i t t l e uv data regarding c y c l i c g-bromoa,B-unsaturated ketones have been reported i n the l i t e r a t u r e .  Because of  t h i s l a c k of data, i t i s not c e r t a i n whether or not there i s a general trend f o r the abnormal behaviour described above.  In any case, i t i s  c l e a r that one has to be c a r e f u l when applying the Woodward r u l e s i n p r e d i c t i n g the a b s o r p t i o n maxima of B-bromo-a,B-unsaturated  ketones.  Concerning the bathochromic e f f e c t of a B-iodo s u b s t i t u e n t , a p e r u s a l of the uv data obtained from the B-iodo enones l i s t e d i n Table 2 showed that there was no r e g u l a r p a t t e r n i n the bathochromic s h i f t s .  Owing to  these i r r e g u l a r i t i e s and to the l i m i t e d data a v a i l a b l e , i t i s not p o s s i b l e at t h i s moment to e s t a b l i s h a d i s c r e t e value f o r the bathochromic  shift  caused by a B-iodo s u b s t i t u e n t . In g e n e r a l , the p r e p a r a t i o n of c y c l i c B-iodo-a,8-unsaturated ketones  -110-  from the corresponding 1,3-dicarbonyl compounds could be c a r r i e d out i n a simple manner.  Furthermore, the products obtained were c l e a n and the  y i e l d s of products were good. and easy to handle.  The 8-iodo enones were found to be s t a b l e  The a-iodomethylenecycloalkanones, though not as  s t a b l e as the e n d o c y c l i c analogs, could be stored under an atmosphere of argon i n a f r e e z e r f o r a few months without s u b s t a n t i a l decomposition. However, i f exposed to a i r at room temperature, these compounds darken i n c o l o r and decompose f a i r l y r a p i d l y ( i n a day or two).  I t i s also  i n t e r e s t i n g to note that the a-iodomethylenecycloalkanones are apparently considerably more s t a b l e than t h e i r c h l o r o counterparts. For example, 2-chloromethylenecyclohexanone  140 has been reported to undergo decom-  p o s i t i o n even at -20°C under n i t r o g e n . ^ 1  7  140 The 8-iodo enones, i n g e n e r a l , are e a s i e r to prepare than t h e i r chloro and bromo counterparts. This i s mainly because, i n the p r e p a r a t i o n of the triphenylphosphine d i h a l i d e reagents, iodine c r y s t a l s are much e a s i e r to handle than noxious c h l o r i n e gas or the l i q u i d bromine.  The  8-iodo enones are a l s o e a s i e r to handle (higher molecular weight, l e s s v o l a t i l e ) and are more r e a c t i v e i n c e r t a i n r e a c t i o n s ( f o r example, 85  r e a c t i o n w i t h cuprate reagents  ) than the corresponding chloro or bromo  compounds. g-chloro-a,B-unsaturated carbonyl compounds have i n the past become 86  i n c r e a s i n g l y u s e f u l as intermediates i n organic s y n t h e s i s .  Since i t now  appears that the corresponding 8-iodo enones can be r e a d i l y prepared and  -111-  since these iodo enones are e a s i e r to handle and are more r e a c t i v e i n c e r t a i n r e a c t i o n s , i t i s c l e a r that t h i s new c l a s s of compounds might a l s o f i n d i n c r e a s i n g use as intermediates i n organic s y n t h e s i s .  II.  Conversion of g-Iodo-a,g-Unsaturated g-Cyclopropyl-a,g-Unsaturated  Ketones i n t o the  Corresponding  Ketones.  Although a wide v a r i e t y of f u n c t i o n a l i z e d vinylcyclopropanes have been synthesized, g-cyclopropyl-a,g-unsaturated prepared.  3-Cyclopropyl-2-cyclohexen-l-one  ketones have r a r e l y been  142 has been prepared by the Michael  a d d i t i o n of the enamine 141 to methyl v i n y l ketone, followed by i n t r a m o l e c u l a r 108 c y c l i z a t i o n of the r e s u l t i n g intermediate (eq.30). (30)  Recently, the a d d i t i o n of a l l y l - y l i d e s of a,B-unsaturated  ketones to  Michael acceptors has provided an e f f i c i e n t route to g-cyclopropyl-a,gunsaturated ketones  (eq. 31) .  \  (31)  0II 0II X=SMe , SMe , SMe(NMe ); E=CN, COR, 2  2  2  CHO,  C0 R, N0 2  2  For example, the y l i d e 143 reacted c l e a n l y w i t h methyl v i n y l ketone to give the vinylcyclopropane 144 i n 75% y i e l d  (eq.32).  110  -112-  r.t.  (32)  75%  113 More r e c e n t l y , Marino et al_  t  u t i l i z e d the conjugate a d d i t i o n  reactions of l i t h i u m dicyclopropylcuprate to B-halo, B-alkoxy and B-acetoxy enones i n preparing B-cyclopropyl-a,8-unsaturated  ketones.  For example, the B-chloro enone 100 reacted with l i t h i u m d i c y c l o p r o p y l cuprate to give the corresponding B-cyclopropyl enone 142 i n 80% y i e l d (eq.32a). (c^-C H ) CuLi 3  5  2  (32a)  80% 100  142  The conjugate a d d i t i o n of l i t h i u m dicyclopropylcuprate to a c e t y l e n i c carbonyl compounds to give B-cyclopropyl-a,B-unsaturated been reported 113  For example, treatment of the a c e t y l e n i c ketone 146  with l i t h i u m dicyclopropylcuprate gave the corresponding enone 147, i n >95% y i e l d  THPO-CH -CHC-G0Me + 2  ketones also has  (eq.33a).  (c-C H > 5  CuLl  -78°C 0.5h >95%  146  B-cyclopropyl  THPO-  :CHCOMe  (33a)  147  THP=Tetrahydropyran  In e a r l i e r work i n our laboratory, i t had been found that c y c l i c B-halo-a,B-unsaturated  ketones reacted with various cuprate reagents to  produce the corresponding  B-alkyl-a,B-unsaturated ketones i n high y i e l d 85  -113-  The 3-halo enones can be prepared e a s i l y from the r e a c t i o n of the corresponding  c y c l i c g-diketones w i t h triphenylphosphine d i h a l i d e s  (described e a r l i e r i n t h i s t h e s i s ) .  84  I t was t h e r e f o r e of i n t e r e s t to  i n v e s t i g a t e whether or not t h i s procedure could be a p p l i e d to the preparation of c y c l i c g-cyclopropyl-a,B-unsaturated  ketones.  r e s u l t , a s e r i e s of c y c l i c B-cyciopropyl-a,B-unsaturated prepared by the r e a c t i o n of B-iodo-a,B-unsaturated p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (eq.33 and 34).  As a  ketones were  ketones w i t h l i t h i u m  Some of the r e s u l t s a r e  summarized i n Table 3.  I, 101 111 112 113  R  y-"  PhS(c-C H )CuLi  ^  THF  " ( 2)n-  3  5  ( 3 3 )  CH  n=2, R=H n=2, R=CH_ n=l, R=H n=l, R=CH  142 n=2, R=H 146 n=2, R=CH 147 n-1, R=H 148 n-1, R=CH  PhS(c-C,H )CuLi (34) 115 lib  n-1 n=2  150 n=2  A t y p i c a l procedure f o r the conversion of ketones i n t o the corresponding  B-iodo-a,B-unsaturated  B - c y c l o p r o p y l enones f o l l o w s .  To a  s o l u t i o n of l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (4.5 mmol) i n t e t r a hydrofuran a t -78°C was added a s o l u t i o n of 3-iodo-2-cyclohexen-l-one 101 (3 mmol) i n tetrahydrofuran. f o r 2.5h.  The r e s u l t i n g mixture was s t i r r e d at -78°C  Methanol was added t o quench the r e a c t i o n and the r e a c t i o n  -114-  mixture was f i l t e r e d through a short column of f l o r i s i l .  Evaporation  of the s o l v e n t , f o l l o w e d by d i s t i l l a t i o n of the r e s i d u a l o i l gave 335 mg (82%) of pure 3-cyclopropyl-2-cyclohexen-l-one 142.  The s p e c t r a l data 90  of t h i s m a t e r i a l were i d e n t i c a l w i t h those reported i n the l i t e r a t u r e . S i m i l a r l y , the fcS-iodo enones 111-116 were transformed i n t o the c o r r e s ponding 8 - c y c l o p r o p y l enones 146-150, r e s p e c t i v e l y . summarized i n Table 3.  The r e s u l t s are  A l l of the products l i s t e d i n Table 3 e x h i b i t e d  s p e c t r a l data i n f u l l accord w i t h the assigned s t r u c t u r e s .  Each of the  new compounds a l s o gave a s a t i s f a c t o r y elemental a n a l y s i s and/or molecular weight determination (high r e s o l u t i o n mass spectrometry). Although the data summarized i n the t a b l e are l a r g e l y s e l f explanatory, there are a few minor p o i n t s that need to be d i s c u s s e d i n more detail.  For simpler 8-iodo enones, l i k e 3-iodo-2-cyclohexen-l-one  101  and 3-iodo-2-cyclopenten-l-one 112, complete conversion i n t o the c o r r e s ponding 8-iodo enones needed only 1.5 e q u i v a l e n t s of cuprate reagent, and the r e a c t i o n was c a r r i e d out at -78°C f o r 2.5h Table 3).  ( e n t r i e s 1 and 3,  However, f o r 8-iodo enones 111 and 113, which contained a  methyl group at the a - p o s i t i o n , a higher r e a c t i o n temperature (0°) more cuprate reagent (2 e q u i v a l e n t s ) were required to e f f e c t  and  complete  conversion of the s t a r t i n g m a t e r i a l i n a reasonable time ( e n t r i e s 2 and 4, Table 3 ) .  Apparently, the a-methyl group caused a c e r t a i n amount of s t e r i c  congestion, thus impeding the conjugate a d d i t i o n of the cuprate reagent to the g - p o s i t i o n . S i m i l a r l y , f o r 2-iodomethylenecycloalkanones 115 and 116, higher temperatures (-20°C and 0°C r e s p e c t i v e l y ) than those needed f o r enones 101 and 112 were required f o r complete conversion of the s t a r t i n g m a t e r i a l  -115-  Table 3.  Conversion of 8-iodo-a,B-unsaturated ketones i n t o B-cyclopropyl-a,B-unsaturated ketones.  B-iodo enones  Entry  Reaction Condition  3  B-cyclopropyl enones  ( Y i e l d %)  1.  101  A  142  (82%)  2.  111  C  146  (88%)  3.  112  A  147  (97%)  4.  113  C  148  (84%)  5.  115  D  149  (65%)  116  B  150  (82%)  b  6.  Reaction c o n d i t i o n A: 1.5 eq. of PhS(c_-C.jH^)CuLi was used at -78°C f o r 2.5h; B: 1.5 eq. of PhS(c-C.jH,-)CuLi was used at 0°C f o r 2.5h; C: 2 eq. of PhS(c_-C.jH,.)CuLi was used at 0°C f o r 2.5h; D: 1.5 eq. of PhS(c-C H )CuLi was used at -78°C f o r l h , at -20°C f o r 2h. 3  5  Reaction was performed by Dr. I . Nagakura.  -116-  i n a reasonable time ( e n t r i e s 5 and 6, Table 3).  A c a r e f u l a n a l y s i s of  the r e a c t i o n products obtained from these r e a c t i o n s showed t h a t , i n each case, transformation of the 2-iodomethylenecycloalkanone  i n t o the  corresponding 8-cyclopropyl enone was h i g h l y s t e r e o s e l e c t i v e . only one product was obtained from each r e a c t i o n .  Essentially,  The stereochemistry of  the products 149 and 150 could r e a d i l y be assigned as shown on the b a s i s of the "Sinmr s p e c t r a . The argument employed here was s i m i l a r to that used i n determining the stereochemistry of 2-iodomethylenecyclohexanone (described e a r l i e r ) and was based on the e m p i r i c a l observation that i n the "Slnmr s p e c t r a , the f i - o l e f i n i c protons c i s to the carbonyl group of c e r t a i n a-alkylmethylenecyclo89 hexanones resonate downfield from t h e i r trans counterparts. f o r 2-methylenecyclohexanone  152  153  For example,  123,  154  155  the proton c i s to the carbonyl group resonated at x4.28 w h i l e the proton 89 trans to the carbonyl group gave r i s e to a s i g n a l at T4.96.  A l s o , the  8 - o l e f i n i c proton of compound 151 resonated at x3.53-3.55 whereas the 8' analogous proton of i t s isomer 152 gave r i s e to a s i g n a l at x4.30-4.35.  -117-  In a r e l a t e d study described i n a subsequent part of t h i s t h e s i s we were able to i s o l a t e the two p a i r s of isomers 153 + 154 and 155 + 156. The B - o l e f i n i c protons of compounds 153 arid 155 resonated at x3.92 and 4.02, r e s p e c t i v e l y .  On the other hand, the analogous protons of the  isomeric p a i r of compounds (154, 156) gave r i s e to s i g n a l s at T5.08 and 5.16.  Since compounds 153 and 155 had the B - o l e f i n i c proton  resonances  downfield from t h e i r isomeric counterparts (154, 156), they should have the s t r u c t u r e as assigned.  As f o r compounds 149 and 150, we had only  one of the two p o s s i b l e isomers a v a i l a b l e , and t h e r e f o r e , a d i r e c t comparison w i t h t h e i r isomeric counterparts could not be made. a comparison of the chemical s h i f t s of the B - o l e f i n i c proton  However,  resonances  of these two compounds w i t h those of compounds 153 and 155, c l e a r l y i n d i c a t e s that 149 and 150, possess the stereochemistry shown. In g e n e r a l , the transformation of B-iodo enones i n t o the corresponding B - c y c l o p r o p y l enones i s a very c l e a n process and the y i e l d s are h i g h . more, i n no case were we able to detect a product r e s u l t i n g from a d d i t i o n of a second c y c l o p r o p y l group. by the aforementioned  Further-  conjugate  F i n a l l y , a l l the products obtained  procedure were s t a b l e and could be stored i n d e f i n i t e l y  i f they were kept under argon i n a f r e e z e r .  III.  Thermolysis of B-Cyclopropyl-a,B-Unsaturated Ketones As already mentioned, c y c l i c 3-cyclopropyl-2-cycloalken-l-ones and  2-cyclopropylmethylenecycloalkanones are b a s i c a l l y v i n y l c y c l o p r o p a n e derivatives.  I t was t h e r e f o r e of i n t e r e s t to determine whether or not  thermolysis of these compounds would r e s u l t i n a cyclopentene-type a n n e l a t i o n processes, as depicted by the f o l l o w i n g schemes.  -118-  A  ->  (CH ) W 2  i r  A  Two general procedures (A and B) were employed i n the i n v e s t i g a t i o n of the thermal rearrangement of the aforementioned type of compounds.  A  d e t a i l e d d e s c r i p t i o n of the general procedure A f o l l o w s . A pyrex tube, 1.2 (i.d.)x32 cm, f i l l e d with glass h e l i c e s ( i . d . 4.76 nm) was washed successively with water, acetone and n-hexane.  The column was conditioned  by placing i t i n a furnace and heating i t at ^450"C f o r 3h. During  this  period of time, the column was thoroughly purged with a stream of nitrogen. A n-hexane s o l u t i o n of the appropriate g-cyclopropyl enone (200 mg i n 20 ml of n-hexane) was added dropwise over a period of 1.5h to the top of the v e r t i c a l l y held, heated tube (^450°C). stream of nitrogen was discontinued.  During t h i s period of time, the  The pyrolysate from the bottom of  the column was cooled by having i t pass through a water condenser connected to the bottom of the p y r o l y s i s tube, and was c o l l e c t e d i n a two-necked f l a s k , equipped with a drying tube and immersed i n a cold (-78°C) bath (see diagram 1) A f t e r a d d i t i o n of the s o l u t i o n was complete, the hot column was washed with a f u r t h e r 30 ml of n-hexane.  Removal of the hexane from the pyrolysate,  followed by d i s t i l l a t i o n (air-bath) of the r e s i d u a l o i l , gave the thermolysis product . Thermolysis of 3-cyclopropyl-2-cyclopenten-l-one  147 under the conditions  described above (.procedure A), gave an 80% y i e l d of a c o l o r l e s s o i l . a n a l y s i s of t h i s m a t e r i a l showed the presence of four major components  A glc  -119Argon needle v a l v e  f  N, stopcock  heating tape asbestos glass wool glass helices  glass h e l i c e s - furnace pyrex-tube(1.2x32cm)  pyrex-tube (1.2x100cm)  water i n l e t drying tube lceone bath Diagram 1  Diagram 2 drying tube  dry i c e acetone bath  -120-  together with small amounts of minor i m p u r i t i e s (^2% ) which were not identified.  The major components were shown to De the ketone 157  (^46%), the enone 158 (M.4%), the dienone 159 (^20%) and the dienone 160 (M.8%)(eq.34).  (34)  An a n a l y t i c a l sample of each major component was obtained by preparative g l c .  The structures assigned to the thermolysis products  157-160 were supported by spectroscopic data. 158 (^  max  The uv spectrum of enone  237 nm, e=ll,370) agreed w e l l with that expected (Woodward's  r u l e s ) f o r a compound possessing t h i s s t r u c t u r e .  The i r spectrum also  indicated the presence of a conjugated ketone system (  v m a x  1690, 1630 cm  1  F i n a l l y , the ''"Hnmr spectrum of 158 showed only a complex m u l t i p l e t at T7.10-7.80, thus c l e a r l y i n d i c a t i n g the absence of o l e f i n i c protons. The i r spectrum of ketone 157 i n d i c a t e d that the compound was a saturated five-membered r i n g ketone (v 1740 cm ^ ) . max  The only o l e f i n i c J  proton present appeared as a one-proton m u l t i p l e t at T4.58 i n the Hnmr 1  spectrum.  The l a t t e r also showed a one-proton m u l t i p l e t between T6.57  and 6.88, which could r e a d i l y be a t t r i b u t e d to the t e r t i a r y bridgehead proton adjacent to the carbonyl group.  When compound 157 was passed  through a short column of b a s i c alumina, i t isomerized q u a n t i t a t i v e l y to the enone 158. The observed absorption maximum (268 nm, e=18,630) i n the uv spectrum  )  -121-  of the conjugated dienone 160 agreed w e l l w i t h that expected f o r a compound possessing t h i s s t r u c t u r e . t i o n s at 1640 and 1570 cm . 1  The i r spectrum e x h i b i t e d the expected absorpI n the ^Hnmr spectrum of compound 160, the  o l e f i n i c proton a to the carbonyl group produced a s i g n a l at x4.09 as a broad, one-proton s i n g l e t .  One of the two o l e f i n i c protons on the  propenyl s i d e chain appeared as a one-proton doublet (J=16 Hz) a t x3.44, whereas the other (a to the t e r m i n a l methyl group) appeared as a one-proton doublet of quartets (J=16 Hz, J'=6 Hz) at x3.7U.  The l a r g e coupling constant  between the two o l e f i n i c protons c l e a r l y i n d i c a t e d that they are trans to each other.  The terminal methyl group of the s i d e chain gave r i s e to a  three-proton doublet (J=6 Hz) at x8.10. Both the uv absorption maximum (226 nm, e=14,090) of the dienone 159 and the i n f r a r e d spectrum (v 1705, 1610 cm ^) of t h i s compound i n d i c a t e d max the presence of a conjugated cyclopentenone system.  The "Slnmr spectrum of  159 e x h i b i t e d a two-proton m u l t i p l e t between x4.70 and 5.10, r e a d i l y a t t r i b u t a b l e to the terminal o l e f i n i c protons of the v i n y l group, and a two-proton m u l t i p l e t between x3.92 and 4.40, which could be assigned to the other two o l e f i n i c protons i n the molecule.  The methylene group  of the a l l y l side chain appeared as a two-proton doublet (J=6.5 Hz) at x6.88.  Isomerization of the dienone 159 to the isomeric compound 160  was e f f e c t e d by passing the former through a short column of b a s i c alumina.  The s p e c t r a l data obtained from the isomerized product were  i d e n t i c a l w i t h that of the dienone 160 obtained e a r l i e r . Thermolysis of 3-cyclopropyl-2-cyclohexen-l-one 142 under conditions very s i m i l a r t o those described above (procedure A ) , afforded a 78% y i e l d of a c o l o r l e s s o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l i n d i c a t e d that i t was  -122a mixture of the ketone 161 (^3%), the enone 162 (M34%) and the dienone 163 (^11%), along w i t h a number of minor, u n i d e n t i f i e d i m p u r i t i e s (^2%). An a n a l y t i c a l sample of each of the three thermolysis products was obtained by p r e p a r a t i v e g l c , and each compound was c h a r a c t e r i z e d by i r and "'"Hnmr spectroscopy.  Enone 162 e x h i b i t e d the c h a r a c t e r i s t i c six-membered  O  •Oo-  (35)  +  161  142  ring  162  163  a,B-unsaturated carbonyl absorptions i n the i r spectrum (  v m a x  1660, 1630 cm "*").  The "'"Hnmr spectrum of t h i s compound e x h i b i t e d only a complex m u l t i p l e t between T7.2 and 8.3. The melting point [252°C (dec)] of the 2 , 4 - d i n i t r o p h e n y l hydrazone d e r i v a t i v e of t h i s m a t e r i a l agreed very w e l l w i t h that reported 114  i n the l i t e r a t u r e (251.5°C). The i r spectrum of ketone 161 i n d i c a t e d that the compound was a saturated six-membered  r i n g ketone ( v 1718 cm "'"). max  The only o l e f i n i c  proton present appeared as a broad one-proton s i n g l e t a t T4.57.  This  m a t e r i a l a l s o showed a one-proton m u l t i p l e t centered a t x6.63, which could r e a d i l y be a t t r i b u t e d to the t e r t i a r y bridgehead to the carbonyl group.  proton adjacent  When compound 161 was passed through a short column  of b a s i c alumina, i t isomerized t o the enone 162. The i r spectrum of the dienone 163 a l s o i n d i c a t e d the presence of an a,B-unsaturated carbonyl f u n c t i o n a l i t y (  v m a x  1670, 1642, 1590 cm ^ ) .  The s i n g l e o l e f i n i c proton a t o the carbonyl group gave r i s e t o a s i n g l e t at T4.16 i n the "''Hnmr spectrum, w h i l e the two o l e f i n i c protons on the side chain appeared as a m u l t i p l e t a t T3.82.  The t e r m i n a l methyl group gave  r i s e t o a three-proton doublet (J=5 Hz) a t x8.14. These s p e c t r a l data were i d e n t i c a l w i t h those p r e v i o u s l y reported f o r t h i s compound."'"'''"'  -123Although the thermolysis of 3-cyclopropyl-2-cyclohexen-l-one 142 at ^450°C gave a s a t i s f a c t o r y y i e l d of the annelated products 161 and 162, p y r o l y s i s of 3-cyclopropyl-2-cyclopenten—1-one 147 gave s i g n i f i c a n t amounts of the dienones 159 and 160.  Since i t was d e s i r a b l e to minimize the  formation of these undesired s i d e products, i t was decided to i n v e s t i g a t e d i f f e r e n t thermolysis c o n d i t i o n s .  I t was hoped that by lowering the  thermolysis temperature and i n c r e a s i n g the contact time (by i n c r e a s i n g the length of the thermolysis tube), the thermolysis r e a c t i o n might be improved and the formation of open-chain dienones might be reduced. A new p y r o l y s i s apparatus w i t h a longer p y r o l y s i s tube was constructed (as shown i n diagram 2).  A general experimental procedure (procedure B)  employing t h i s set-up f o l l o w s .  A pyrex tube (1.2x100 cm) f i l l e d w i t h  glass h e l i c e s (.i.d. 4.76 mm) was washed s u c c e s s i v e l y w i t h saturated aqueous sodium bicarbonate s o l u t i o n , water, acetone and n-hexane.  By  means of a heating tape which had been wrapped around i t , the column was heated to the desired thermolysis temperature and was kept at t h i s temperature f o r at l e a s t 3h.  During t h i s time, the column was thoroughly  purged w i t h a r a p i d flow of argon.  A n-hexane s o l u t i o n of the appropriate  8-cyclopropyl enone (200 mg i n 20 ml n-hexane) was added dropwise, over a period of 1.5h, to the top of the v e r t i c a l l y held column.  During t h i s  p e r i o d , a very slow flow of argon (^5 ml/min) was passed through the column.  The pyrolysate from the bottom of the column was cooled by  a l l o w i n g i t to pass through a water condenser attached to the bottom of the p y r o l y s i s tube, and was c o l l e c t e d i n a two-necked f l a s k which was equipped w i t h a drying tube and was immersed i n a c o l d (-78°C) bath. A f t e r the a d d i t i o n of the s o l u t i o n was complete, the hot column was washed w i t h a f u r t h e r 30 ml of ri-hexane. The combined hexane s o l u t i o n was concentrated and the r e s i d u a l o i l was d i s t i l l e d to g i v e the p y r o l y s i s product.  -124-  3-Cyclopropyl-2-cyclbhexen-l-one 142 was chosen as the substrate to study the new thermolysis c o n d i t i o n s i n some d e t a i l .  Pyrolysis  of t h i s m a t e r i a l at ^425°C (procedure B) gave a 98% y i e l d of a c o l o r l e s s oil.  A g l c a n a l y s i s of t h i s m a t e r i a l showed that i t was a mixture of  the ketone 161 (^31%) and the enone 162 (^67%), along w i t h very s m a l l amounts of u n i d e n t i f i e d i m p u r i t i e s (^2%).  This m a t e r i a l was passed  through a short column of b a s i c alumina.  The column was e l u t e d w i t h  ether.  Removal of the ether and a n a l y s i s of the r e s i d u a l o i l by g l c  and i r showed that the ketone 161 had isomerized completely to enone 162. The above procedure  was repeated at 322°C, 400°C and 450°C.  r e s u l t s are summarized i n Table 4 ( e n t r i e s 2b-e). had taken place.  The  At 322°C, no r e a c t i o n  At 400°C, some rearrangement occurred, although a  considerable amount of s t a r t i n g m a t e r i a l was recovered (V37%).  At 450°C,  the annelated cyclopentenes c o n s t i t u t e d ^96% of the product and no s t a r t i n g m a t e r i a l was recovered.  However, the y i e l d was considerably lower than  that obtained from thermolysis a t 425°C and i t thus appeared that the l a t t e r p y r o l y s i s temperature was the p r e f e r r e d one.  In no case was there  any of the dienone 163 detected. In comparison w i t h the o l d procedure (procedure A ) , t h i s new procedure (B) showed a dramatic improvement i n terms of g i v i n g b e t t e r y i e l d s and l e s s undesired side-products.  The use of t h i s new procedure was extended  to i n c l u d e the thermolysis of other B-cyclopropyl-a,B-unsaturated ketones. Some of these r e s u l t s are summarized i n Table 4 and w i l l be discussed i n more d e t a i l l a t e r .  A l l of the products l i s t e d i n Table 4 e x h i b i t e d spectral-  data i n f u l l accord w i t h the assigned s t r u c t u r e s , and a l l new compounds gave s a t i s f a c t o r y elemental a n a l y s i s and/or molecular weight determinations (high r e s o l u t i o n mass spectrometry).  -125-  A p r e l i m i n a r y study, performed by Dr. I . Nagakura of our l a b o r a t o r y , showed that thermolysis of 2-methyl-3-cyclopropyl-2-cyclohexen-l-one (procedure A) gave the dienones 165 and 166 as the major products.  146 Only  a very small amount of the d e s i r e d annelated cyclopentene 164 was formed (eq.36).  (36)  146  164 ^10%  These r e s u l t s were not t o t a l l y unexpected.  165 M.8.4%  166 ^50%  We had mentioned e a r l i e r i n  the i n t r o d u c t i o n , that when an a l k y l group i s placed c i s to the c y c l o p r o p y l r i n g across the double bond on a vinylcyclopropane system (as i n compound 146), the r a t e of thermal rearrangement i s u s u a l l y much lower than the r a t e of rearrangement of u n s u b s t i t u t e d cases, and the products formed are 37 49 83 u s u a l l y polymers or s t r u c t u r a l l y rearranged o l e f i n s .  '  '  In a r e l a t e d  study described i n a subsequent part of t h i s t h e s i s , i t was found that the thermal rearrangement of the t r i m e t h y s i l y l enol ether d e r i v a t i v e s of 2cyclopropylmethylenecycloalkanones gave better y i e l d s of the corresponding spiroannelated products than d i d the corresponding parent enones (eq.37). I t was hoped that p y r o l y s i s of the t r i m e t h y s i l y l enol ether d e r i v a t i v e of  (37)  enone 146 might a l s o give a b e t t e r y i e l d of the annelated product 164'.  Thus,  Table 4.  Thermal rearrangement of 8-cyclopropy1-a,B-unsaturated ketones and r e l a t e d compounds  Entry Substrate 1.  Reaction Condition  147 ^450°C(A)  2. a. b. c. d. e.  142 ^450°C(A) ^322°C(B) ^400°C(B) ^425°C(B) ^450°C(B)  Products and Products R a t i o ( % )  157 ^46%  158 ^14%  159 ^20%  160 M.8%  161 V3%  162 ^84%  163 ^11%  142  V37% ^31% ^5%  171  ^425°C(C)  4.  167  ^425°C(B)  170(^75%)  5.  172  -v450°C(A)  173(^75%)  6.  150  ^450°(A)  175 ^44%  176 ^9%  ^450°(A) ^425°(B)  185 ^74% ^84%  186  ^450°(A) ^425°(B)  187 ^39% ^33%  188 «V31% ^50%  ^425°(C)  ^94%  184  a. b. 8  -  d  149  a. b. 9.  191  Yield Unidentified impurities ^2% ^2%  ^100% ^37%  -V15Z ^67% ^91%  3.  7.  b  3  ^76%  174(^16%)  189 ^9%  80%  *11% ^2% ^5%  78% 100% 100% 98% 71%  ^24%  67%  ^25%  50%  ^9%  30%  177 ^38%  74%  190 M5%  149 ^9%  C  VL2% VL6%  74% 85%  ^6% ^8%  90% 85%  A-6%  56%  I  P y r o l y s i s was c a r r i e d out i n a v e r t i c a l pyrex tube (1.2x32 cm) using procedure A (see t e x t ) . P y r o l y s i s was c a r r i e d out i n a v e r t i c a l pyrex tube (1.2 cm x 1 m) under a very slow flow of argon (procedure B) (see t e x t ) . P y r o l y s i s was c a r r i e d out i n the same way as (B), the crude p y r o l y s i s product was hydrolysed by 1:1 methanol and 1 N aq. HC1. ^Product r a t i o was based on g l c a n a l y s i s of d i s t i l l e d p y r o l y s a t e . c Y i e l d i s based on the t o t a l weight of d i s t i l l e d pyrolysate recovered. ^This data was obtained from Dr. I . Nagakura of our laboratory.  -128-  the t r i m e t h y l s i l y l enol ether 167 was prepared, by treatment of the enone 146 with l i t h i u m diisopropylamide i n 1,2-dimethoxyethane, followed by trapping of the r e s u l t a n t enolate anion with c h l o r o t r i m e t h y l s i l a n e i n the presence of triethylamine (eq.38).  The s t r u c t u r e of the s i l y l  enol ether 167 was supported by the "'"Hnmr spectrum of the compound  OSiMej  l.i-pr NLi,DME 2  2. Et N,C£SiMe 3  (38) 3  which showed a t r i m e t h y s i l y l group at T9.91 as a nine-proton s i n g l e t . The o l e f i n i c proton gave r i s e to a s i g n a l at  T5.20  i n the form of a  t r i p l e t , while the v i n y l methyl group appeared as a broad s i n g l e t at T8.20.  The i r spectrum of t h i s m a t e r i a l showed two weak bands at 1650  and 1600 cm \ When the s i l y l ether 167 was pyrolysed (procedure B), the major product formed was _o-cyclopropyltoluene 170 (entry 4, Table 4).  Pre-  sumably, the s i l y l encl ether 167 had undergone two successive [1,5] sigmatropic hydrogen migrations to give the intermediate 169.  Elimination  of (CH ) Si0H from 169 could then give O-cyclopropyltoluene 170 (eq.39). 3  3  Si Me,  (39)  167  168  169  170  -129-  In c o n t r a s t , p y r o l y s i s (procedure B) of the t r i m e t h y l s i l y l enol ether of 3-cyclopropyl-2-cyclohexen-l-one 171, followed by h y d r o l y s i s and work-up, gave a 67% y i e l d of a mixture of the annelated cyclopentene 162 0W6%)  and a number of u n i d e n t i f i e d i m p u r i t i e s (^24%)(entry 3, Table 4)  (40)  The only a c y c l i c 8-cyelopropyl-a,B-unsaturated ketone i n v e s t i g a t e d during the course of the work described i n t h i s t h e s i s was compound 172. Thermolysis of t h i s compound at ^450°C (procedure A) gave a mixture of the ketone 173 (^75%) and m-xylene 174 (vL6%) i n a t o t a l y i e l d of ^30% (eq.41, entry 5, Table 4). 450  c  +  30% 172  173 75%  The i n i t i a l s t u d i e s i n v o l v i n g thermal rearrangement  (41) 174 16%  of 2 - c y c l o p r o p y l -  methylenecycloalkanones were performed on the short thermolysis column, using the o l d procedure (procedure A). methylenecyclohexanone  Thermolysis of 2 - c y c l o p r o p y l -  150 at ^450°C gave a 74% y i e l d of a mixture of  the spiroketone 175 (^44%), the dienone 176 (^9%) along w i t h a s m a l l amount (^9%) (entry 6, Table 4).  and t e t r a l i n 177 (^38%),  of minor i m p u r i t i e s which were not  identified  -130-  (42) 150  175  176  177  The spiroketone 175 e x h i b i t e d an i n t e r e s t i n g """Hnmr spectrum.  From  a s t r u c t u r a l point of view, the two o l e f i n i c protons were c l e a r l y nonequivalent and were expected to have d i f f e r e n t chemical s h i f t s .  I t was  therefore s u r p r i s i n g to f i n d that these two protons appeared as a sharp two-proton s i n g l e t a t T4.24.  The r e s t of the protons showed up as a  f i v e - p r o t o n m u l t i p l e t a t T7.40-7.82 and a seven-proton m u l t i p l e t a t T7.97-8.60.  In order to determine whether or not i t was p o s s i b l e to  d i s t i n g u i s h between the two o l e f i n i c protons by ''"Hnmr, the spectrum of 175 was r e i n v e s t i g a t e d i n the presence of a s h i f t reagent: Eu(FOD) . ^ 2 7 • Under these c o n d i t i o n s , the o l e f i n i c protons appeared as two sets of doublets of t r i p l e t s a t T3.58 and 3.94. Each set had coupling constants, J=6 Hz and J'=2 Hz. Furthermore, the o r i g i n a l f i v e - p r o t o n m u l t i p l e t at T7.40-7.80 was transformed i n t o a three-proton m u l t i p l e t a t x6.44-6.84 and a two-proton m u l t i p l e t a t x7.14-7.50. m u l t i p l e t was s h i f t e d to x7.62-8.12.  The o r i g i n a l seven-proton  I n a decoupling experiment ( i n  the presence of the s h i f t reagent), i r r a d i a t i o n a t x7.29 (the s i g n a l due to the two protons a t o the double bond) caused the two doublets of t r i p l e t s at x3.58 and 3.94 to c o l l a p s e t o an AB p a i r of doublets (J=5.6 Hz), as would be expected. To f u r t h e r confirm the p o s i t i o n of the double bond i n the s p i r o compound 175, the "''Hnmr spectrum of the isomeric spiroketone 178 ( k i n d l y supplied by Dr. R. D. Sands o f A l f r e d U n i v e r s i t y , A l f r e d , New York"'"'"^) was compared w i t h that of compound 175.  As expected, the two o l e f i n i c  -131-  protons of compound 178, which were s t r u c t u r a l l y e q u i v a l e n t , appeared as a s i n g l e t .  However, the chemical s h i f t of these protons (T4.50)  was s l i g h t l y d i f f e r e n t from that of the o l e f i n i c protons i n compound 175.  178 Further evidence f o r the s t r u c t u r e of the s p i r o enone 175 was 13 supplied by the  Cnmr spectrum (proton decoupled) of t h i s  compound.  The spectrum showed the presence of two nonequivalent o l e f i n i c carbon atoms at <5(ppm) 132.4b and 133.35, a carbonyl carbon atom at 211.48 and a quaternary carbon atom at 64.06.  The r e s t of the carbon centers  appeared at 6(ppm) 22.96, 27.67, 31.28, 32.29, and 39.89 (2 carbons). F i n a l l y , i n order to confirm the s p i r o carbon s k e l e t o n of ketone 175, t h i s m a t e r i a l was hydrogenated (10% Pd/C i n methanol) to the saturated spiroketone 179.  The s p e c t r a l data ( i r , "4frimr) of the l a t t e r  were i d e n t i c a l w i t h those of an authentic sample of 179 prepared from 117 the p i n a c d rearrangement of the d i o l 180. The d i o l 180 was prepared from the d i m e r i z a t i o n of cyclopentanone using aluminum and mercuric 101 chloride.  179 The  180  Hnmr spectrum of the dienone 176 i n d i c a t e d that i t was a  mixture of c i s and trans isomers.  The t e r m i n a l methyl groups of the  isomers resonated a t x8.99 and 9.02.  Exhausive hydrogenation of the  -132-  mixture gave a s i n g l e product, 2-n-butylcyclohexanone.  Spectral  data ( i r , ^"Hnmr) of the l a t t e r were i d e n t i c a l to those reported i n the S a d t l e r Index. The formation of follows.  t e t r a l i n 177 may be r a t i o n a l i z e d as  Homolysis of the cyclopropane  d i r a d i c a l 181.  r i n g would give the  Ring c l o s u r e to give the b i c y c l i c . d i r a d i c a l  intermediate 182, followed by hydrogen m i g r a t i o n would a f f o r d the d i e n o l 183.  Dehydration  of the l a t t e r would then give t e t r a l i n 177 (Scheme 8 ) .  150  181  182  1,4 hydrogen shift  183  177 Scheme 8  Although the thermolysis of 2-cyclopropylmethylenecylohexanone 150 d i d give the expected s p i r o ketone 175, a considerable amount of the undesired t e t r a l i n 177 was a l s o formed.  Since, as postulated above,  the formation of t e t r a l i n probably involved the carbonyl f u n c t i o n a l i t y , i t seemed reasonable to p o s t u l a t e that masking the carbonyl group would e l i m i n a t e the formation of t e t r a l i n . ether of enone 150 was prepared.  Thus, the t r i m e t h y l s i l y l enol  The t r i m e t h y l s i l y l enol ether 184 was  obtained b y f i r s t t r e a t i n g the enone 150 w i t h l i t h i u m diisopropylamide i n 1,2-dimethoxyethane, followed by the a d d i t i o n of c h l o r o t r i m e t h y l s i l a n e  -133-  i n the presence of t r i e t h y l a m i n e (eq.43).  The s t r u c t u r e of the enol  ether 184 was supported by s p e c t r a l data.  In the ''"Hnmr spectrum, the  o l e f i n i c proton on the e x o c y c l i c cyclopropylmethylene group resonated as a doublet at x4.92, with coupling constant = 9.5 Hz. The other o l e f i n i c proton on the six-membered r i n g gave r i s e to a t r i p l e t at T5.04 w i t h J=4.5 Hz. A nine-proton s i n g l e t due to the t r i m e t h y l s i l y l group appeared at T9.87.  The i r spectrum showed two weak absorption  bands a t 1680 and 1660 cm "*".  trans-l-phenyl-l-butene 186 (^14%), and small amounts of u n i d e n t i f i e d minor i m p u r i t i e s (^12%). Table 4).  No t e t r a l i n was detected (eq.44, entry 7a,  An a n a l y t i c a l sample of each of the two major components war-  obtained by preparative g l c and t h e i r s t r u c t u r e s were confirmed by the s p e c t r a l data.  The ''"Hnmr spectrum of compound 185 e x h i b i t e d a one-  proton t r i p l e t (J=4 Hz) at T5.28, r e a d i l y a t t r i b u t a b l e to the o l e f i n i c proton of the enol s i l y l ether group.  A one-proton m u l t i p l e t between  T4.24 and 4.37 and another one-proton m u l t i p l e t between T4.45 and 4.60  -134-  could be assigned to the other two o l e f i n i c protons i n the  molecule.  The t r i m e t h y l s i l y l group gave r i s e to a nine-proton s i n g l e t at x9.93. The i r spectrum of t h i s m a t e r i a l showed a strong absorption at 1655 cm  \  In the "4lnmr spectrum of compound 186, a f i v e - p r o t o n m u l t i p l e t at T2.60-3.00 i n d i c a t e d the presence of a monosubstituted  benzene r i n g .  The two o l e f i n i c protons gave r i s e to a m u l t i p l e t between x3.55 and  4.00.  The two a l l y l i c methylene protons appeared as a m u l t i p l e t at x7.64-8.00, whereas the t e r m i n a l methyl group showed up as a three-proton at x8.95 w i t h J=7 Hz.  triplet  These data were e s s e n t i a l l y the same as  those  118 reported i n the l i t e r a t u r e . I t was  thus q u i t e c l e a r that i n terms of the y i e l d of s p i r o a n n e l a t i o n  product, the thermolysis of the t r i m e t h y l s i l y l enol ether 184 showed cons i d e r a b l e improvement over the thermal rearrangement of the parent enone 150.  The thermolysis (procedure A) of the enol ether 184 was  on a l a r g e r s c a l e (l.Og).  The crude thermolysis product was  repeated hydrolyzed  i n a 1:1 mixture of methanol and IN aqueous h y d r o c h l o r i c a c i d and hydrolyzed product was subjected to column chromatography. y i e l d of the pure s p i r o ketone 175 was  the  A 50% o v e r a l l  isolated.  The thermolysis of the t r i m e t h y l s i l y l enol ether 184 was  later  improved f u r t h e r by employing the new procedure (procedure B) using the long p y r o l y s i s column.  Thus p y r o l y s i s of the enol ether 184 at ^425 C U  gave an 85% y i e l d of one major product, the s p i r o enol ether 185  (^84%),  along w i t h a s m a l l amount of minor i m p u r i t i e s (^16%) which were not identified  (entry 7b, Table 4 ) .  No t r a n s - l - p h e n y l - l - b u t e n e was  detected.  A p r e l i m i n a r y study by Dr. I . Nagakura of our l a b o r a t o r y showed that thermolysis of 2-cyclopropylmethylenecyclopentanone  149 at ^450°C  -135-  \  (procedure A) gave a f a i r l y low y i e l d of the desired product, the s p i r o ketone 187. A considerable amount of the undesired dienones 188, 189 and indane 190 was a l s o formed (eq.45, entry 8a, Table 4 ) .  I n an attempt  to improve t h i s r e a c t i o n , the c y c l o p r o p y l enone 149 was pyrolysed a t ^425°C under the new procedure (procedure B)(entry 8b, Table 4).  Although the  r e a c t i o n product was somewhat cleaner, the y i e l d of the s p i r o ketone 187 had not been improved.  (45)  191 F i n a l l y , the t r i m e t h y l s i l y l enol ether 191 was prepared v i a a procedure i d e n t i c a l w i t h that employed f o r the enol ether 184. Thermolysis of the enol ether 191 at ^425°C (procedure B) followed by h y d r o l y s i s of the crude p y r o l y s i s product gave a 56% y i e l d of a c o l o r l e s s o i l .  A g l c a n a l y s i s of  t h i s m a t e r i a l showed the presence of e s s e n t i a l l y one product (^94%), the s p i r o ketone 187 (entry 9, Table 4).  However, the i r spectrum of t h i s  m a t e r i a l showed the presence of both saturated and a,g-unsaturated compounds.  carbonyl  Therefore, t h i s m a t e r i a l was subjected to column chromatography.  E v e n t u a l l y , a 38% o v e r a l l y i e l d of the s p i r o ketone 187 was i s o l a t e d .  The  low y i e l d of the l a t t e r may be a t t r i b u t e d p a r t l y to i t s v o l a t i l i t y and t o mechanical l o s s e s . analysis. ^ max V  The s t r u c t u r e of s p i r o ketone was confirmed by s p e c t r a l  Tne i r spectrum showed the presence of a five-membered r i n g ketone c m  ^' * * n t  ie  ^Hnmr spectrum, the two o l e f i n i c protons gave r i s e  to two sets of m u l t i p l e t s at x4.10 and 4.55-  -136-  In general, the thermolysis of the c y c l i c  8-cyclopropyl-a,6-  unsaturated ketones described so f a r gave reasonable y i e l d s of the expected annelated cyclopentenes.  Since the r e a c t i o n s were simple to  perform and the desired products were f a i r l y easy to i s o l a t e , t h i s procedure should f i n d more a p p l i c a t i o n s i n the f u t u r e as a s y n t h e t i c method f o r cyclopentene  annelation.  Of p a r t i c u l a r i n t e r e s t i s the  s p i r o a n n e l a t i o n r e a c t i o n i n v o l v i n g the thermolysis of 2-cyclopropylmethylenecycloalkanones or the corresponding  enol s i l y l ethers.  For  example, the thermolysis of 2-cyclopropylmethylenecyclohexanone 150 or i t s t r i m e t h y l s i l y l e n o l ether d e r i v a t i v e afforded a spiro[4.5]decane  system  and i t i s thus c l e a r that t h i s r e a c t i o n could serve as a key step i n the synthesis of a wide v a r i e t y of n a t u r a l l y occuring  spiro[4.5]decane  sesquiterpenes, f o r example, the s p i r o v e t i v a n e s .  The p o s s i b i l i t y of  applying t h i s s p i r o a n n e l a t i o n method to the synthesis of s p i r o v e t i v a n e s was i n v e s t i g a t e d and c o n s t i t u t e s the next p o r t i o n of t h i s t h e s i s .  IV.  A p p l i c a t i o n of Thermal Vinylcyclopropane-Cyclopentene  Rearrangement  to Spirovetivane Synthesis The r a p i d l y i n c r e a s i n g number of known spirovetivane-type s e s q u i t e r penoids have i n common the s t r u c t u r a l l y i n t e r e s t i n g carbon skeleton 192. Representatives of the s p i r o v e t i v a n e s i n c l u d e 8-vetivone 193, a - v e t i s p i r e n e 119 194, g - v e t i s p i r e n e 195, h i n e s o l 196, and anhydro-8-rotunol  197.  -137-  The i n t e r e s t i n the spirovetivane c l a s s of sesquiterpenoids as constituents of e s s e n t i a l o i l s , as s t r e s s metabolites, and as proposed intermediates i n terpene biogenesis has stimulated considerable s y n t h e t i c 121-132 e f f o r t s d i r e c t e d towaras the preparation of these compounds.  The 120  f i r s t e f f o r t s i n t h i s area were reported by Marshall and coworkers  ,  who had e a r l i e r shown that 8-vetivone i s a member of t h i s group rather than a hydroazulene d e r i v a t i v e as o r i g i n a l l y reported.  Due i n part to  the widely v a r i a n t o x i d a t i o n s t a t e at carbons 1,2,6,7,8,11,12 and 14 throughout the s e r i e s , e a r l i e r s y n t h e t i c e f f o r t s had concentrated on the 121—128 construction of s p e c i f i c spirovetivanes-  Recently, the emphasis  has s h i f t e d toward the construction of one or more intermediates which could serve as a s y n t h e t i c precursor of a number of n a t u r a l products 129-132 belonging to t h i s c l a s s of sesquiterpenes. Among the few syntheses 129-l'-i2 that employed t h i s approach  , i t i s of i n t e r e s t to note that those  129 132 reported by Caine anc Buchi have involved the use ot the s p i r o o l e f i n i c ketone 198 as a key intermediate. So f a r , the l a t t e r has been converted i n t o (±)-a-vetispirene 194129 , ( i ) - B - v e t i v o n e 193132 , and (±)132 h i n e s o i acetate 199.  Here we report a convenient a l t e r n a t i v e preparation  of the s y n t h e t i c intermediate 198 based on the new thermal s p i r o a n n e l a t i o n method developed e a r l i e r , as described i n the previous s e c t i o n of t h i s thesis, O  199 As described p r e v i o u s l y , the s p i r o enone 175 could  be prepared i n  good y i e l d by the thermal rearrangement of the enol s i l y l ether 184, followed by the h y d r o l y s i s of the i n i t i a l l y formed product 185 (Scheme 9).  -138-  Th e success of these e a r l i e r e f f o r t s encouraged us to i n v e s t i g a t e the p o s s i b i l i t y of applying t h i s methodology to the synthesis of spirovetivanes.  Scheme 9 Since the s y n t h e t i c intermediate 198 employed by C a i n e  X Z y  and Buchi" ""^ 1  had the p o t e n t i a l of serving as a synthetic precursor of a f a i r l y l a r g e number of s p i r o v e t i v a n e s , i t was decided to make t h i s compound our synthetic goal.  The key step to compound 198 would then be to synthesize  a spiroL4.5]decane  system that contained both a methyl group at carbon 10  and a s u i t a b l e f u n c t i o n a l i t y on the f i v e membered r i n g which subsequently could be r e a d i l y converted to a carbonyl group at carbon 2.  One p o s s i b l e  candidate was the s p i r o enol s i l y l ether 201, which on the b a s i s of the previous work, should be obtainable by thermal rearrangement of the enol s i l y l ether 200 (eq.46).  Hopefully, mainly f o r s t e r i c reasons, the methyl  group on the six-membered r i n g of 200 would, during the thermolytic rearrangement, d i r e c t bond formation i n the required manner so that the s p i r o compound 201 would be produced s t e r e o s e l e c t i v e l y .  Thus, the i n i t i a l  synthetic o b j e c t i v e was to prepare the enol s i l y l ether 200 and to carry out the thermal rearrangement of t h i s compound.  (46)  200  201  -139-  The conjugate a d d i t i o n of l i t h i u m diorganocuprate reagents to a,8-unsaturated intermediate  carbonyl compounds produces, p r i o r to h y d r o l y s i s , a n 133 w i t h the p r o p e r t i e s of a metal enolate.  This r e a c t i o n  intermediate reacts w i t h a v a r i e t y of e l e c t r o p h i l i c reagents, such as 134 carbonyl compounds, to g i v e a l d o l products , Michael a d d i t i o n acceptors 135 to form Michael adducts , and r e a c t i v e a l k y l h a l i d e s to form a l k y l a t e d 136 ketones.  Thus, i t was expected that the a d d i t i o n of l i t h i u m d i m e t h y l -  cuprate to 2-cyclohexen-l-one, followed by trapping the r e s u l t i n g enolate w i t h cyclopropanecarboxaldehyde, would give the k e t o l 203 r e g i o s e l e c t i v e l y , Dehydration of the k e t o l 203 would then g i v e the desired 6-cyclopropyl enone 155 and/or 156 (scheme 10). CTM+  Me CuLi 2  N^.c-C H CH0 3  5  202 Scheme 10 Cyclopropanecarboxaldehyde, which i s not commerically a v a i l a b l e , can be prepared by a wide v a r i e t y of methods, i n c l u d i n g r e d u c t i o n of N,N-dimethyl137 cyclopropylcarboxamide w i t h diethoxyaluminohydride and o x i d a t i o n of c y c l o 138 p r o p y l c a r b i n o l by p y r i d i n i u m chlorochromate , chromium t r i o x i d e and s u l f u r i c 139 a c i d i n dimethylformamide , N-chlorosuccinimide and d i m e t h y l s u l f i d e140 , or 141 manganese d i o x i d e i n pentane.  A l l of these methods were t r i e d , but none of  them gave s a t i s f a c t o r y i s o l a t e d y i e l d s of the pure aldehyde.  F i n a l l y , i t was  found that the method which gave the most s a t i s f a c t o r y r e s u l t s (71% i s o l a t e d y i e l d of pure cyclopropanecarboxaldehyde) involved e e r i e ammonium n i t r a t e 142 o x i d a t i o n of c y c l o p r o p y l c a r b i n o l .  The l a t t e r , though commercially a v a i l a b l e ,  was prepared from cyclopropanecarboxylic a c i d .  E s t e r i f i c a t i o n of the a c i d w i t h  -140-  ethanol i n r e f l u x i n g benzene containing a c a t a l y t i c amount of s u l f u r i c 143 acid , followed by l i t h i u m aluminum hydride reduction of the r e s u l t i n g 144 e s t e r , gave a 55% o v e r a l l y i e l d of the c y c l o p r o p y l c a r b i n o l  (Scheme 11).  I t was found that d i r e c t reduction of cyclopropanecarboxylic a c i d by diborane i n tetrahydrofuran f a i l e d to give an acceptable y i e l d of c y c l o propylcarbinol. "' 14  COjH  EtOH, Bz  H2S04  ->  A  ^  DjB  LiA£H, ^ . Ether  2( N H  HjOH  4  }  2 (V H0 C e (N  6> - C H O  2  Scheme 11 A d d i t i o n of 2-cyclohexen-l-one  to a cold (0°C) ether s o l u t i o n of  l i t h i u m dimethylcuprate, followed by trapping of the r e s u l t i n g enolate anion with one equivalent of cyclopropanecarboxaldehyde a colorless o i l .  gave a 60% y i e l d of  A g l c a n a l y s i s of t h i s m a t e r i a l showed the presence of a  major component (^70%) and two minor compounds (VL4% and 7% r e s p e c t i v e l y ) . An a n a l y t i c a l sample of each component was obtained by preparative g l c . The major component was i d e n t i f i e d as the enone 153, the regioisomer of the expected product 155. spectral analysis.  The s t r u c t u r a l assignment of enone 153 was based on  The 6 - o l e f i n i c proton of enone 153 e x h i b i t e d a doublet  of t r i p l e t s ( J = l l Hz, J'=2 Hz) a t T3.92 i n the "4inmr spectrum rather than a doublet of doublets as would be expected from the desired regioisomer 155. One of the minor components (^7%) was i d e n t i f i e d as the geometrical isomer 154 of the enone 153.  The ^Hnmr spectrum of the enone 154 a l s o  exhibited a doublet of t r i p l e t s ( J = l l Hz, J'=2 Hz) f o r the B - o l e f i n i c proton, the chemical s h i f t of which was a t  T5.08.  The assignment of stereo-  chemistry to the two isomers, 153 and 154 had been discussed e a r l i e r i n t h i s  -141thesis and w i l l not be repeated here. l.Me CuLi 2  L^JJ  2.C-C H-CHO  * 153  154  F i n a l l y , the other minor isomer (^14%) was found to be  3-methyl-  cyclohexanone by comparing the ^Hnmr spectrum of t h i s m a t e r i a l with that of an authentic sample obtained commercially. In order to show c o n c l u s i v e l y that the major component obtained from the cuprate r e a c t i o n was indeed compound 153 and not 155, a s p e c i f i c synthesis of compound 153 was c a r r i e d out.  Thus, a d d i t i o n of 3-methylcyclo-  hexanone to an ethereal s o l u t i o n of l i t h i u m diisopropylamide, k i n e t i c a l l y 146 generated enolate anion 204. propanecarboxaldehyde,  Trapping t h i s enolate anion w i t h c y c l o -  followed by dehydration of the intermediate k e t o l ,  gave a 23% y i e l d of 2-cyclopropylmethylene-5-methylcyclohexanone  153 (eq.48).  The s p e c t r a l data obtained from t h i s m a t e r i a l were i d e n t i c a l with those of the major component obtained from the cuprate r e a c t i o n described above.  I t was apparent that, i n the cuprate a d d i t i o n r e a c t i o n to 2-cyclohexen-lone, e q u i l i b r a t i o n and isomerization of the intermediate enolate anion must have occurred p r i o r to the condensation with the aldehyde g i v i n g enones 153 and 154 as the r e s u l t i n g products. The condensation of the s p e c i f i c enolate 202 with e t h y l formate was also investigated.  E t h y l formate was chosen because the r e s u l t i n g 2-hydroxy-  -142-  methylene-3-methylcyclohexanone  205, i f formed, could be r e a d i l y t r a n s -  formed i n t o 2-cyciopropylmethylene-3-methylcyclohexanone  155 v i a the  corresponding g-iodo enone 139 as described e a r l i e r i n t h i s t h e s i s f o r 2-hydroxymethylenecyclohexanone 110 (Scheme 12).  Scheme 12 The condensation r e a c t i o n of e t h y l formate w i t h the s p e c i f i c enolate generated by the cuprate a d d i t i o n to 2-cyclohexen-l-one would a l s o give r i s e to an ethoxide anion (Scheme 13).  The l a t t e r could  abstract a proton from the i n i t i a l l y formed product 205 to form ethanol. The ethanol could then serve as a source of protons to a l l o w the k i n e t i c a l l y generated enolate 202 to e q u i l i b r a t e .  202  205 Scheme 13  I t was t h e r e f o r e proposed to add potassium hydride to the r e a c t i o n mixture so that a s i g n i f i c a n t concentration of ethanol could be avoided. In t h i s way, i t was hoped t h a t , i n absence of s i g n i f i c a n t amounts of a proton source, e q u i l i b r a t i o n of the intermediate enolate anion would be n e g l i g i b l e and hence the r e a c t i o n might be r e g i o s e l e c t i v e .  This idea was  t r i e d out as f o l l o w s . To a cold s o l u t i o n (0°C) of l i t h i u m dimethylcuprate  -143-  (1.5 eq.) i n ether was added one equivalent of 2-cyclohexen-l-one.  Then  two equivalents of potassium hydride were added, followed by the a d d i t i o n of two equivalents of e t h y l formate.  The r e s u l t i n g s o l u t i o n was s t i r r e d  at 0°C f o r l h . A f t e r work-up, a 41% y i e l d of a 1:1 mixture of 2-hydroxymethylene-3-methylcyclohexanone  205 and  hexanone 206 was obtained (eq.49).  2-hydroxymethylene-5-methylcyclo-  The '''Hnmr of t h i s mixture showed the  (49) 205  206  presence of two o l e f i n i c protons at xl.30 and 1.36 i n the r a t i o of ^1:1, corresponding to the two B - o l e f i n i c protons on the a-hydroxymethylene groups of the two compounds 205 and 206. Although i t was c l e a r that the above r e a c t i o n was not r e g i o s e l e c t i v e , as had been hoped, i t was nevertheless decided to transform the two compounds, 205 and 206 i n t o the corresponding B-cyclopropyl enones, so that the l a t t e r could be compared w i t h the B-cyclopropyl enones obtained e a r l i e r by condens a t i o n of 202 w i t h cyclopropanecarboxaldehyde.  Thus, treatment of the mixture  of 205 and 206 w i t h triphenylphosphine d i i o d i d e i n a c e t o n i t r i l e - h e x a m e t h y l phosphoramide i n the presence of t r i e t h y l a m i n e gave an 82% y i e l d of a 1:1 mixture of the corresponding B-iodo enones 139 and 138, r e s p e c t i v e l y (eq.50). An a n a l y t i c a l sample of each of the products 138 and 139 was obtained by preparative g l c .  -144-  >3 2 PI  H(  + 206  CH CNHMPA, Et N 3  205  138  -6r  (50)  139 1:1 In each case, the assigned s t r u c t u r e was supported by s p e c t r a l data. 3  The i r of iodo enone 138 showed the presence of an a,B-unsaturated ketone (vmax 1690, 1570 cm ^ ) .  The "Sinmr spectrum showed the presence r  of only one o l e f i n i c proton which resonated at T2.30 as a t r i p l e t (J=2 Hz). The methyl group gave r i s e to a s i g n a l at x8.97 i n the form of a doublet (J=5.5 Hz). Compound 139 exhibited s i m i l a r s p e c t r a l data.  The i r  spectrum of compound 139 showed two strong bands at 1685 and 1565 cm \  The  s i n g l e o l e f i n i c proton showed up as a s i n g l e t at x2.51 i n the "4inmr spectrum. The methyl group gave r i s e to a doublet at x8.94 w i t h J=7 Hz.  The a l l y l i c  proton at C-3 showed up as a m u l t i p l e t at x6.64-7.02. The mixture of iodo enones 138 and 139 was converted i n t o a mixture of the corresponding B-cyclopropyl enones by t r e a t i n g the former w i t h l i t h i u m phenylthio(cyclopropyl)cuprate.  A 75% y i e l d of a mixture of the B - c y c l o p r o p y l  enones 153, 155 and 156 i n a r a t i o of 2:1:1, r e s p e c t i v e l y , was obtained (eq.51). glc.  A n a n a l y t i c a l sample of each compound was obtained by preparative  The s p e c t r a l data obtained from compound 153 was i d e n t i c a l w i t h those  "TJ- rV'  yVS  k ^ A ^ P h S (£-C H ) CuLi  138  139  3  5  (51)  +  153  of the same compound obtained as described e a r l i e r .  In the Hnmr spectrum 1  of the enone 1_55, the B - o l e f i n i c proton appeared as a doublet of doublets ( J = l l Hz, J'=l Hz) at X4.02.  The analogous proton of the isomeric compound  -145-  156 gave r i s e to a doublet of doublets (J=10.5 Hz, J'=2 Hz) a t x5.16. The assignment of stereochemistry to the two isomers, 155 and 156 had been discussed e a r l i e r . On the basis of r e s u l t s obtained from the experiments described above,it was c l e a r that a d d i t i o n of l i t h i u m dimethylcuprate to 2-cyclohexen-l-one, followed by trapping of the r e s u l t i n g enolate anion with cyclopropanecarboxaldehyde,  did not give the desired product 155.  Furthermore, although the a l t e r n a t i v e procedure i n v o l v i n g e t h y l formate as trapping agent, did eventually produce some of the desired m a t e r i a l , t h i s methodology also f a i l e d to give the desired isomer 205 r e g i o s e l e c t i v e l y . Therefore, other methods were i n v e s t i g a t e d . 147 Mukaiyama et_ a l  had reported that s i l y l enol ethers, prepared  from various carbonyl compounds, reacted with aldehydes and ketones i n the presence of titanium t e t r a c h l o r i d e under mild conditions to give crossa l d o l condensation products i n good y i e l d s .  The enol s i l y l ether 207 was  obtained from the 1,4-addition of l i t h i u m dimethylcuprate to 2-cyclohexen-lone, followed by trapping the r e s u l t i n g enolate anion with c h l o r o t r i m e t h y l 148 silane  (eq.52).  When the Mukaiyama procedure was applied to the t r i m e t h y l -  s i l y l enol ether 207 and cyclopropanecarboxaldehyde, product was obtained.  however, no condensation  Only 3-methylcyclohexanone was recovered. c-C H CHO 3  5  Me CuLi 2  TiC£, 207  -X  (52)  » 203  It i s w e l l known that s p e c i f i c enolates generated by the r e a c t i o n of methyllithium with s i l y l enol ethers of various carbonyl compounds may be  -146-  a l k y l a t e d r e g i o s e l e c t i v e l y , f o r example, eq. 5 3 . I t was therefore decided 1 4  SiMe  3  1. CH Li 3  (53) 2. RX 6  208  209  to attempt a s i m i l a r r e a c t i o n using cyclopropanecarboxaldehyde as the e l e c t r o p h i l i c trapping reagent.  I f t h i s r e a c t i o n had been s u c c e s s f u l ,  i t should have produced the k e t o l 203.  Unfortunately, when the enol  ether 207 was treated with methyllithium, followed by the a d d i t i o n of cyclopropanecarboxaldehyde, only the enone 153 was obtained a f t e r work-up. Presumably, e q u i l i b r a t i o n of the intermediate l i t h i u m e n o l a t e anion had occurred f a s t e r than condensation.  In view of e a r l i e r r e s u l t s obtained  from attempts to trap the s p e c i f i c enolate generated d i r e c t l y by cuprate a d d i t i o n to 2-cyclohexen-l-one, t h i s r e s u l t was perhaps not s u r p r i s i n g . F i n a l l y i t was found that the s p e c i f i c enolate anion generated by copper catalysed conjugate a d d i t i o n of methyl magnesium iodide to 2-cyclohexen-l-one could be trapped by cyclopropanecarboxaldehyde  regioselectively  to give the k e t o l 203 as a mixture of diastereomers i n ^97% y i e l d (Scheme 14).  I t i s important to note that when cyclopropanecarboxaldehyde  was  added to the ether s o l u t i o n of the s p e c i f i c enolate anion, a t h i c k greyish white p r e c i p i t a t e formed immediately and remained undissolved throughout the reaction.  The r e g i o s e l e c t i v i t y of the r e a c t i o n may thus be a t t r i b u t e d to the  i n s o l u b i l i t y of t h i s intermediate alkoxide anion 210. Ma*  MeMgl Cul  >  £-C H CHO 3  5  > 210  Scheme 14  203  -147-  The s t r u c t u r e of the k e t o l 203 was which showed the presence of a saturated  supported by i t s i r spectrum six-membered r i n g ketone (v max  1700  cm  and an a l c o h o l f u n c t i o n a l i t y (v  3470 cm V  A t i c analysis  max  3  of t h i s m a t e r i a l snowed the presence of two components i n approximately equal amounts (spots of equal i n t e n s i t y ) .  This m a t e r i a l underwent p a r t i a l  dehydration and r e t r o a l d o l r e a c t i o n upon d i s t i l l a t i o n . i n s t a b i l i t y , i t was  not p u r i f i e d f u r t h e r but was  Because of i t s  used d i r e c t l y i n the next  step. Dehydration of k e t o l 203 by treatment of t h i s m a t e r i a l w i t h P_t o l u e n e s u l f o n i c a c i d i n r e f l u x i n g benzene gave a 6:1 mixture of the enones 155 and 156, r e s p e c t i v e l y , i n ^50% (eq.54).  o v e r a l l y i e l d from 2-cyclohexen-l-one  A considerable amount of 3-methylcyclohexanone  Apparently, extensive r e t r o a l d o l  was  also i s o l a t e d .  r e a c t i o n occurred under these r e a c t i o n  conditions. The y i e l d of the mixture of enones 155 and 156 was  improved  considerably  (54)  + 155  203  by f i r s t converting  156  the k e t o l 203 i n t o the corresponding acetate 211  anhydride, p y r i d i n e ) .  The  a mixture of diastereomers.  '''Hnmr spectrum of the l a t t e r showed that i t was E l i m i n a t i o n of a c e t i c a c i d from the acetate  211, accomplished by treatment of the l a t t e r w i t h 5-ene (DBN)  l,5-diazabicyclo[4.3.0]non-  i n r e f l u x i n g benzene, gave an o v e r a l l 787, y i e l d of a 13:1  of enones 155 and 156,  (acetic  r e s p e c t i v e l y , from the k e t o l 203  (.eq.55).  mixture  -148-  (55) 203  211  155 13  156 :  1  Conversion of the mixture of enones 155 and 156 i n t o the corresponding t r i m e t h y s i l y l enol ethers 200 was c a r r i e d out by the standard procedure  ( l i t h i u m diisopropylamide, glyme, 0°C; c h l o r o t r i m e t h y l -  s i l a n e , t r i e t h y l a m i n e ) as described p r e v i o u s l y f o r other enones of s i m i l a r structure.  The formation of enol s i l y l ether 200 was confirmed by the  "hhimr spectrum of t h i s m a t e r i a l , which showed the presence of the o l e f i n i c proton at C-6 as a one-proton t r i p l e t (J=3 Hz) at T5.11.  The i r spectrum  of t h i s m a t e r i a l a l s o showed that the carbonyl f u n c t i o n a l i t y was  absent.  Thermolysis of the enol s i l y l ether 200 at ^380°C under argon (procedure B ) , followed by h y d r o l y s i s (1:1 mixture of IN aqueous h y d r o c h l o r i c a c i d and methanol) of the r e s u l t i n g crude product afforded a mixture (^57%  yield  from 155 and 156) of the s p i r o enones 212 and 213 i n a r a t i o of about r e s p e c t i v e l y (eq. 56).  2.5:1  The two products were separated by column chromato-  graphy of the mixture on s i l i c a g e l .  The assignment of s t r u c t u r e and  (56)  stereochemistry to compounds 212 and 213 were supported by s p e c t r a l data and by subsequent transformation of 212 i n t o compounds of known s t r u c t u r e and stereochemistry.  -149-  The spiro enone 212 was a c r y s t a l l i n e s o l i d (m.p. 35-38°C). The i r spectrum showed the presence of a saturated six-membered ring ketone (v 1705 cm max  The two o l e f i n i c protons gave r i s e to a multiplet at  T4.02-4.38 i n the ^"Hnmr spectrum.  The methyl group gave r i s e to a doublet  (J=6 Hz; at T9.10. The rest of the protons produced a multiplet at x7.16-8.60. The enone 213 also showed a saturated carbonyl absorption at 1705 cm ^ i n the i r spectrum.  The ''"Hnmr of this material showed a two-proton multiplet  at x4.02-4.40 ( o l e f i n i c protons), a three-proton doublet (J=6 Hz) at T9.14 (secondary methyl group), a four-proton multiplet between x7.42 and 7.80 and a seven proton multiplet between x7.80-8.60. There was no apparent relationship between the stereochemistry of the reactant 200 and that of the products (2l2 and 213) i n the thermolysis reaction.  The same r a t i o of products was obtained when d i f f e r e n t samples  of 200 containing varying amounts of the two geometric isomers were pyrolysed. Although the s t e r e o s e l e c t i v i t y associated with this step was not as high as had been hoped, the minor isomer 213, which had the "wrong" stereochemistry, i s not necessarily useless from a synthetic point of view, since i t i s also a potential intermediate for spirovetivane synthesis. Treatment of the enone 212 with methyllithium i n ether at 0°C afforded a 78% y i e l d of a mixture of the alcohols 214 and 215, i n a r a t i o of ^4.6:1 (eq. 57).  The two isomers were separated by column chromatography on s i l i c a  gel. OH  (57) 214 4.6  :  215 1  -150-  Compound 214 showed the presence of an a l c o h o l f u n c t i o n a l i t y i n the i r spectrum (vmax 3500 cm ) and, i n the "4lnmr spectrum, an " e x t r a " 1  methyl group ( s i n g l e t at x8.78).  This m a t e r i a l was i d e n t i c a l with an  authentic sample of the same m a t e r i a l previously prepared and k i n d l y 132 supplied by Buchi and coworkers. The minor isomer 215 exhibited s p e c t r a l data very s i m i l a r to those of compound 214.  A strong absorption band at 3490 cm  indicated the presence of an a l c o h o l f u n c t i o n a l i t y .  1  i n the i r spectrum  In the ''"Hnmr spectrum,  a three-proton s i n g l e t at T8.96 was assigned to the methyl group a to the alcohol functionality.  The other methyl group remained as a three proton  doublet (J=6.5 Hz) at T9.25.  Each of the two o l e f i n i c protons gave r i s e  to a doublet of t r i p l e t s (T4.19 and 4.48). Each s i g n a l had the same coupling constants (J=6 Hz, J'=2 Hz). Hydroboration of the o l e f i n i c a l c o h o l 214 with disiamylborane i n tetrahydrofuran ( r . t . , 21h), followed by o x i d a t i o n of the r e s u l t i n g t r i a l k y l b o r a n e with a l k a l i n e hydrogen peroxide gave a s i n g l e d i o l 216 i n 77% y i e l d (eq.58).  D i o l 216 was a c r y s t a l l i n e s o l i d (m.p. 153-155°C).  The'ir spectrum showed two a l c o h o l bands at 3480 and 3640 cm . 1  protons were observed i n the "4lnmr spectrum of t h i s m a t e r i a l .  No o l e f i n i c A one-proton  m u l t i p l e t at x 5.55-5.95 was assigned to the proton next to the newly acquired a l c o h o l f u n c t i o n a l i t y . OH  Me 214  2  - 2°2' ° H  H  216  -151-  The stereochemical assignment of compound 216 was based on s t e r i c arguments. In the more s t a b l e conformation of compound 214, one of the methyl groups and the hydroxyl group should be e q u a t o r i a l .  Since the methyl group i s  b u l k i e r than the f l e x i b l e hydroxy group, and s i n c e the l a r g e hydroborating agent should p r e f e r e n t i a l l y a t t a c k from the l e s s hindered s i d e of the carboncarbon double bond, one would expect the d i o l 216 to be the only (or at l e a s t the predominant) product. Oxidation of the d i o l 216 w i t h p y r i d i n i u m chlorochromate  i n methylene  c h l o r i d e ( r . t . l h ) afforded the k e t o l 217 i n 88% y i e l d (eq. 59).  The  s t r u c t u r e of t h i s m a t e r i a l (mp. 51-52°C) was supported by s p e c t r a l data. The i r spectrum showed the presence of both an a l c o h o l and a s a t u r a t e d carbonyl f u n c t i o n a l i t y (  v m a x  3500, 3660, 1730 cm "*").  The  nmr  showed the presence of an AB p a i r of doublets at T7.36 and 7.84 which i n t e g r a t e d f o r two protons.  spectrum (J  =19  Hz),  These were assigned to the two protons at  C - l , a to the carbonyl f u n c t i o n a l i t y .  (59)  Dehydration of 217 i n r e f l u x i n g benzene c o n t a i n i n g a c a t a l y t i c amount of j j - t o l u e n e s u l f o n i c a c i d , followed by e q u i l i b r a t i o n of the i n i t i a l l y formed dehydration products under the same c o n d i t i o n s , a f f o r d e d a 90% y i e l d of the s p i r o enones 198 and 218 i n a r a t i o of 9:1 r e s p e c t i v e l y (eq.60). enone 198 was  i s o l a t e d from the isomeric mixture by p r e p a r a t i v e t i c .  The  The  i r spectrum of t h i s m a t e r i a l showed the presence of a five-membered r i n g saturated carbonyl group at 1740 cm  The o l e f i n i c proton gave r i s e to a  -152-  m u l t i p l e t between T4.49 and 4.66 i n the '''Hnmr spectrum.  The methyl group  on the double bond showed up as a three proton s i n g l e t at T7.76.  This  m a t e r i a l was i d e n t i c a l w i t h a sample of the same m a t e r i a l p r e v i o u s l y 132 prepared by Buchi  129 and Caine.  We are g r a t e f u l f o r t h e i r assistance  i n supplying s p e c t r a l data and an authentic sample of t h i s m a t e r i a l .  pTsOH A (60) Bz 217  90%  198  218  Following a sequence s i m i l a r to that o u t l i n e d above, hydroboration of the a l c o h o l 215 with disiamylborane  i n tetrahydrofuran, followed by  o x i d a t i o n of the r e s u l t i n g d i o l (not p u r i f i e d ) by pyridinium chlorochromate i n methylene c h l o r i d e , afforded (38% o v e r a l l y i e l d from 215) the k e t o l 219 (Scheme 15).  The i r spectrum of t h i s m a t e r i a l showed the presence of both  an a l c o h o l and a carbonyl f u n c t i o n a l i t y (  v  3500, 1730 cm \ r e s p e c t i v e l y ) .  The t e r t i a r y methyl group at C-6 gave r i s e to a three-proton s i n g l e t at T8.84 i n the ''"Hnmr spectrum. as a doublet  The secondary methyl group at C-10 appeared  (J=6.5 Hz) at x9.16.  This m a t e r i a l was i d e n t i c a l with a 129  sample of the same m a t e r i a l p r e v i o u s l y prepared by Caine.  We are g r a t e f u l  to Professor Caine f o r h i s assistance i n supplying s p e c t r a l data of t h i s material.  K e t o l 219 had p r e v i o u s l y been converted i n t o the s p i r o enone  129 198. C H NCr0 HC£ 5  5  3  2. H 0 ,Na0H 2  215  2  Scheme 15  219  198  -153EXPERIMENTAL  For general information, see the experimental part of Part I of this thesis. Reagents and S t a r t i n g M a t e r i a l s .  Cyclohexane-1,3-dione, cyclopentane-1,  3-dione, and 2-methylcyclopentane-l,3-dione were obtained from A l d r i c h Chemical Company Inc. and were used without further p u r i f i c a t i o n .  2-  Methylcyclohexane-1,3-dione was prepared from cyclohexane-1,3-dione by a l k y l a t i n g the l a t t e r with methyl iodide i n aqueous dioxane containing sodium hydroxide.^®  The preparation of the t r i c y c l i c 8-diketone 108,  i n v o l v i n g a D i e l s - A l d e r r e a c t i o n between cyclopentadiene and cyclopentane1,3-dlone, was c a r r i e d out i n our laboratory by Dr. I . Nagakura.  2-Hydroxy-  methylenecyclohexanone and 2-hydroxymethylenecyclopentanone were prepared by the formylation of cyclohexanone and cyclopentanone, r e s p e c t i v e l y . ^ 1  1  152 Cyclopropyllithium was prepared by the method of D. Seyferth. To a s t i r r e d suspension of 1.5 g (214 mmol) of l i t h i u m wire (or ribbon, washed with dry benzene) i n 80 ml of cold (0°C) anhydrous ether under an atmosphere of argon was added, dropwise, a s o l u t i o n of cyclopropyl bromide (12.1 g, 100 mmol).  The mixture was s t i r r e d at 0°C f o r 1.5h. The r e s u l t i n g  s o l u t i o n of c y c l o p r o p y l l i t h i u m containing one equivalent of l i t h i u m bromide 153 was standardized by Gilman's procedure and used as such. T r i - n - b u t y l t i n Hydride was prepared by reduction of t r i - n - b u t y l t i n c h l o r i d e with l i t h i u m aluminum hydride i n ether. I.  Synthesis of B-Iodo-a,B-Unsaturated Ketones General Procedure A. -  To a s o l u t i o n of triphenylphosphine (2.88 g,  11 mmol) i n dried a c e t o n i t r i l e (50 ml) was added 2.79 g (11 mmol) of iodine crystals.  The mixture was s t i r r e d at room temperature f o r 20 min.  To the  r e s u l t i n g yellow suspension of triphenylphosphine diiodide was added successively  -154-  t r i e t h y l a m i n e (1.1 g, 11 mmol) and the appropriate c y c l i c (10 mmol).  The r e s u l t i n g s o l u t i o n was r e f l u x e d f o r 3h.  was removed under reduced pressure.  B-diketone Acetonitrile  The r e s i d u a l o i l was extracted by  s t i r r i n g and decantation w i t h f i v e 30 ml p o r t i o n s of ether.  The combined  ether e x t r a c t s were concentrated t o about 25 ml and the r e s u l t i n g s o l u t i o n was f i l t e r e d through a short column of f l o r i s i l column was eluted w i t h a f u r t h e r 75 ml of ether.  (25 g, 80-100 mesh). The Removal of solvent from  the combined eluants and d i s t i l l a t i o n of the r e s i d u a l o i l gave the corresponding B-iodo-a,B-unsaturated General Procedure B. -  ketone.  The general procedure B was e s s e n t i a l l y the  same as procedure A except that the r e a c t i o n mixture was r e f l u x e d f o r 9h instead of f o r 3h. General Procedure C. -  To a s o l u t i o n of triphenylphosphine (2.88 g,  11 mmol) i n a mixture of d r i e d a c e t o n i t r i l e (50 ml) and hexamethylphosphoramide (8 ml, f r e s h l y d i s t i l l e d from l i t h i u m aluminum hydride) was added 2.79  g (11 mmol) of i o d i n e c r y s t a l s .  temperature f o r 20 min.  The mixture was s t i r r e d at room  To the r e s u l t i n g yellow suspension of t r i p h e n y l -  phosphine d i i o d i d e was added s u c c e s s i v e l y t r i e t h y l a m i n e (1.1 g, 11 mmol) and the appropriate c y c l i c B-diketone alkanone (10 mmol). temperature f o r 15h.  (10 mmol) or a-hydroxymethylenecyclo-  The r e s u l t i n g red s o l u t i o n was s t i r r e d at room A c e t o n i t r i l e was removed under reduced pressure.  The remaining hexamethylphosphoramide s o l u t i o n was extracted by s t i r r i n g and decantation w i t h f i v e 50 ml p o r t i o n s of pentane.  The combined pentane  e x t r a c t s were washed w i t h three 30 ml p o r t i o n s of water and d r i e d over anhydrous magnesium s u l f a t e .  Removal of solvent and d i s t i l l a t i o n of the  r e s i d u a l o i l gave the corresponding  B-iodo-a,B-unsaturated  ketone.  -155-  Synthesls of 3-Iodo-2-Cyclohexen-l-one  JJ11. -  F o l l o w i n g the general  procedure B o u t l i n e d above, a mixture of cyclohexane-l,3-dione (1.12 g, 10 mmol), t r i e t h y l a m i n e (1.1 g, 11 mmol) and triphenylphosphine d i i o d i d e (11 mmol) i n a c e t o n i t r i l e (50 ml) was r e f l u x e d f o r 9h. Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature 75-85°C, 1 Torr) of the crude o i l , a f f o r d e d 1.92 g (87%) of pure 3-iodo-2-cyclohexen-l-one 101 as a c o l o r l e s s o i l .  This m a t e r i a l c r y s t a l l i z e d i n a r e f r i g e r a t o r and  e x h i b i t e d mp vL5-16°C; uv A 258nm(e=9000);ir ( f i l m ) v 1675 cm" max max (OO), 1595 cm"  1  (C-C); Hnmr, x3.20 ( t , 1H.-C-C-H, J=2 Hz), 6.90-7.23  1  1  (m, 2H, CH - C ( I ) - ) , 7.40-8.27 (m, 4H). Anal. Calcd f o r C,H..I0:C, 32.45; H, 3.17. Found: C, 32.66; H, 3.25. Synthesis of 2-Methyl-3-iodo-2-cyclohexen-l-one ILL. -  F o l l o w i n g the  general procedure B o u t l i n e d above, a mixture of 2-methylcyclohexane-l,3dione (1.26 g, 10 mmol), t r i e t h y l a m i n e (1.1 g, 11 mmol) and triphenylphosphine d i i o d i d e (11 mmol) i n a c e t o n i t r i l e (50 ml) was r e f l u x e d f o r 9h. Normal workup, followed by d i s t i l l a t i o n ( a i r - b a t h temperature 112-118°C, 11 Torr) of the crude o i l , a f f o r d e d 1.72 g (73%) of pure c r y s t a l l i n e cyclohexen-l-one 111.  2-methyl-3-iodo-2-  This m a t e r i a l e x h i b i t e d mp 57-59°C; uv X 258 nm max  (e=9500); i r (CHC1 ) v 1670, 1605 cm ; Hnmr, T6.80-7.20 (m, 2H, -CH„3 max —2 -1  1  0  C(I)=  ) , 7.36-7.70 (m, 2H, -C0CH ~ 2  ) , 7.80-8.33 (m, 2H, -CH -CH -CH -), 2  2  2  7.97(t, 3H, =C-CH , J=2 Hz). 3  Anal. Calcd f o r 0-^10: C, 36.04; H, 3.87. Found: C, 36.23; H, 4.00. Synthesis of 3-Iodo-2-cyclopenten-l-one 117. - F o l l o w i n g the generalprocedure A o u t l i n e above, cyclopentane-l,3-dione (981 mg, 10 mmol) was allowed to r e a c t w i t h triphenylphosphine d i i o d i d e (11 mmol) and t r i e t h y l a m i n e (1.1 g, 11 mmol) i n a c e t o n i t r i l e (50 m l ) . Normal work-up, followed by d i s t i l l a t i o n  (air-bath  -156-  temperature ^80°C, 0.2 Torr) of the crude o i l , a f f o r d e d 1.77 g (85%) of pure c r y s t a l l i n e 3-iodo-2-cyclopenten-l-one 112.  This m a t e r i a l ex-  h i b i t e d mp 67-68°C; uv X 249 nm (£=11350); i r ( C H C l ) v 1710, max J max 0  1570 cm" ; ^Ttamr, T3.36 ( t , 1H,-C=C-H, J=1.8 Hz), 6.84-7.10 (m, 2H), 7.441  7.66 (m, 2H). Anal. Calcd f o r C ^ I O :  C, 28.88; H, 2.42.  Found: C, 28.98; H, 2.40.  Synthesis of 2-Methyl-3-iodo-2-cyclopenten-l-one 1 1 ^ . -  F o l l o w i n g the  general procedure A, a mixture of 2-methylcyclopentane-l,3-dione (1.12 g, 10 mmol), t r i e t h y l a m i n e (1.1 g, 11 mmol) and triphenylphosphine d i i o d i d e (11 mmol) i n a c e t o n i t r i l e (50 ml) was r e f l u x e d f o r 3h. followed by d i s t i l l a t i o n  Normal work-up,  ( a i r - b a t h temperature ^50°C, 0.2 Torr) of the  crude o i l , a f f o r d e d 2.03 g (92%) of pure, c r y s t a l l i n e 2-methyl-3-iodo-2cyclopenten-l-one 113. This m a t e r i a l e x h i b i t e d mp 52-53°C; uv X 248 nm max J  r  (e=11520), shoulder at 210 nm (£=4655); i r ( C H C l - ) v 1701, 1620 j max 1  cm" ; 1  Hnmr, T6.84-7.20 (m, 2H, -CH_ -C(I)= ), 7.32-7.60 (m, 2H, -C0CH_ - ) , 2  2  8.17 ( t , 3H, -C=C-CH , J=2 Hz). 3  A n a l , Calcd f o r Cg^IO: C, 32.43; H, 3.15.  Found C, 32.36; H, 3.30.  Synthesis of the B-Iodo Enone 1_14_. - F o l l o w i n g the general procedure A, a mixture of the c y c l i c 8-diketone 108 (1.62 g, 10 mmol), t r i e t h y l a m i n e (1.1 g, 11 mmol) and triphenylphosphine d i i o d i d e (11 mmol) i n a c e t o n i t r i l e (50 ml) was r e f l u x e d f o r 3h.  Normal work-up, followed by d i s t i l l a t i o n ( a i r -  bath temperature VL20°C, 0.2 Torr) of the crude o i l , a f f o r d e d 0.83 g (V31%) of the pure, c r y s t a l l i n e iodo enone 114. This m a t e r i a l e x h i b i t e d mp 78-80°C; uv X 253 nm (£=9900); i r (CHCl-Jv 1698, 1561 cm" ; Hnmr, x3.61 max 3 max 1  1  (s, IH, -CH=C(I)-), 3.88-4.20 (m, 2H, H-C=C-H), 6.27-6.45 (m, I H ) , 6.606.80 (m, I H ) , 6.85-7.20 (m, 2H), 8.10-8.50 (m, 2H).  -157-  Anal. Calcd. f o r C^Hg'IO: C, 44.145; H, 3.333. Found: C, 44.15; H, 3.48. 103 Synthesis of 2-Iodomethylenecyclopentanone 115.  Following the general  procedure C, 2-hydroxymethylenecyclopentanone (1.02 g, 10 mmol) was allowed to r e a c t  w i t h triphenylphosphine d i i o d i d e (11 mmol) and t r i e t h y l a m i n e  (1.1 g, 11 mmol) i n a mixture of a c e t o n i t r i l e (50 ml) and hexamethylphosphoramide  (8 ml) at room temperature f o r 3 days.  Normal work-up,  followed by d i s t i l l a t i o n of the crude o i l , afforded 1.62 g (73%) of a pale yellow c r y s t a l l i n e m a t e r i a l .  This m a t e r i a l was r e c r y s t a l l i z e d from  ether and was shown to be 2-iodomethylenecyclopentanone 115. A r e c r y s t a l l i z e d sample of 115 e x h i b i t e d mp 31.5°C; uv X 276 nm (e=9170), 263 nm (shoulder); i r (CHCl-)v , IH, 3 max 1720, 1608 cm" ; "Slnmr, T2.39 (vt > > -C=C(I)-H, — J=1.8 H z')', m a x  1  7.0-8.3 (m, 6H). Mol.Wt. Calcd. f o r 0^10:221.9543.  Found (high r e s o l u t i o n  mass spectrometry): 221.9544. Synthesis of 2-Iodomethylenecyclohexanone 116- procedure C,2-hydroxymethylenecyclohexanone  Following the general  (1.26 g, 10 mmol) was allowed  to react w i t h triphenylphosphine d i i o d i d e (11 mmol) and t r i e t h y l a m i n e (1.1 g, 11 mmol) i n a mixture of a c e t o n i t r i l e (50 ml) and hexamethylphosphoramide  (8 ml) at room temperature f o r 15h. Normal work-up, followed  by d i s t i l l a t i o n  ( a i r - b a t h temperature ^65°C, 0.4 Torr) of the crude o i l  afforded 2.22 g (94%) of pure oil. uv X  2-iodomethylenecyclohexanone 116 as a c o l o r l e s s  This m a t e r i a l c r y s t a l l i z e d i n a r e f r i g e r a t o r and e x h i b i t e d mp vL5°C; 265 nm (e=7200); i r ( f i l m ) v  1695, 1570 cm ; Hnmr, T2.30 ( t , IH, -1  1  -C=C(I)H, J=2 Hz) x7.32-7.70 (m, 4H), x7.96-8.42 (m, 4H). Anal. Calcd. f o r C H I 0 : C, 35.62; H 3.84. Found: C, 35.65; H, 3.76. 7  q  -158-  Preparatlon of a 1:1 Mixture of 2-Hydroxymethylene-3-methylcyclohexanone 205 and 2-Hydroxymethylene-5-methylcyclohexanone 206 and the Conversion of the Mixture to the Corresponding g-Iodo Enones 139 and 138. R e s p e c t i v e l y . To a c o l d (0°C) s o l u t i o n of l i t h i u m dimethylcuprate (16.5 mmol, prepared from cuprous i o d i d e and m e t h y l l i t h i u m ) i n ether (75 ml) was added 1.44 g (15 mmol) of 2-cyclohexen-l-one under an atmosphere of argon.  This was  followed immediately by the a d d i t i o n of potassium hydride (1.2 g, 30 mmol) and e t h y l formate (2.20 g, 30 mmol).  The r e s u l t i n g mixture was s t i r r e d  at 0°C f o r l h . Water and i c e were added, and the r e s u l t i n g mixture was filtered.  The ether l a y e r of the f i l t r a t e was extracted w i t h a f u r t h e r  100 ml of 3% aqueous sodium hydroxide. a c i d i f i e d and extracted w i t h ether.  The combined aqueous e x t r a c t s were  The combined ether e x t r a c t s were  washed w i t h b r i n e and water and d r i e d over anhydrous sodium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n  ( a i r - b a t h temperature  95-110°C, 10 T o r r ) of the r e s i d u a l o i l , afforded 863 mg (41%) of a 1:1 mixture of the hydroxymethylenecyclohexanones 205 and 206. The mixture e x h i b i t e d "''Hnmr, xl.30 ( s , a-hydroxymethylene proton), 1.36 ( s , a-hydroxymethylene proton), T8.90 (d, methyl group), 8.93 (d, methyl group). The above mixture of the hydroxymethylene d e r i v a t i v e s 205 and 206 was converted i n t o the corresponding 6-iodo enones as f o l l o w . the  Following  general procedure C, the mixture of 205 and 206 (700 mg, 5 mmol) was  allowed to react w i t h triphenylphosphine d i i o d i d e (5.5 mmol) and t r i e t h y lamine (0.55 g, 5.5 mmol) i n a mixture of a c e t o n i t r i l e (25 ml) and hexamethylphosphoramide (4 ml) at room temperature f o r 15h. Normal work-up, followed by d i s t i l l a t i o n  ( a i r - b a t h temperature ^50°C, 0.1 Torr) of the  crude o i l , afforded 2.05 g (82%) of a c o l o r l e s s o i l .  A glc analysis  -159-  (column A, 120°C) of t h i s m a t e r i a l showed that i t  consisted of a  mixture of 2-iodomethylene-3-methylcyclohexanone 139 and 2-iodomethylene5-methylcyclohexanone 138 i n the r a t i o of approximately 1:1.  An a n a l y t i c a l  sample of each of the products 138 and 139 was obtained by p r e p a r a t i v e g l c (column C, 150°C).  The pure iodo enone 139 e x h i b i t e d uv X 257 nm max (e=6681); i r ( f i l m ) v 1685, 1565 cm ; Hnmr, T2.51(S,1H,-C=C(I)H), max — -1  1  6.64-7.02 (m, IH, -C(CH )H), 7.50-7.78 (m, 2H,-CH -C0-), 7.80-8.50 3  (m, 4H), 8.94 249.9856.  2  (d, 3H, -CH(CH ), J=7 Hz). 3  Mol.Wt. Calcd. f o r CgH.^10:  Found (high r e s o l u t i o n mass spectrometry): 249.9852.  The pure iodo enone 138 e x h i b i t e d uv X 261 nm (E=7110); i r ( f i l m ) v max max 1690, 1570 cm" ; 1  """Hnmr, T2.30 ( t , IH,-C=C(I)H, J=2 Hz), 7.04-8.90  (unresolved m, 7H), 8.97  (d, 3H, -CH(CH_ ), J=5.5 Hz). 3  Mol.Wt. Calcd.  f o r CgH^IO: 249.9856. Found (high r e s o l u t i o n mass spectrometry) :249.9857. II.  Synthesis of B-Cyclopropyl-a,g-Unsaturated Ketones from B-Iodo-a,gUnsaturated Ketones. General Procedure A. -  To a c o l d (-78°C) s l u r r y of phenylthiocopper  (779 mg, 4.5 mmol) i n dry tetrahydrofuran.(30 ml) under an atmosphere of argon was added a s o l u t i o n of f r e s h l y prepared c y c l o p r o p y l l i t h i u m (containing l i t h i u m bromide; 4.5 mmol) i n ether. to -20°C and s t i r r e d f o r 20 min.  The r e s u l t i n g mixture was warmed  A c l e a r , l i g h t brown s o l u t i o n of l i t h i u m  p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (4.5 mmol) r e s u l t e d . cooled to -78°C.  The s o l u t i o n was  To t h i s s o l u t i o n was added a s o l u t i o n of the appropriate  B-iodo-a,B-unsaturated ketone (3 mmol) i n dry tetrahydrofuran (6 ml). The r e s u l t i n g mixture was s t i r r e d at -78°C f o r 2.5h.  Methanol (2 ml) and ether  -160-  (20 ml) were added and the r e s u l t i n g mixture was warmed to room temperature and then f i l t e r e d through a short column of f l o r i s i l (30 g, 80-100 mesh). The column was eluted w i t h a f u r t h e r 300 ml of ether.  Removal of solvent  from the combined eluants and d i s t i l l a t i o n of the r e s i d u a l o i l gave the corresponding B-cyclopropyl-a,8-unsaturated ketone. General Procedure B. - Procedure B was e s s e n t i a l l y the same as procedure A except that the r e a c t i o n of the B-iodo enone w i t h the cuprate reagent was c a r r i e d out at 0°C instead of at -78°C. General Procedure C. - Procedure C was e s s e n t i a l l y the same as procedure B except that 2 equivalents (6 mmol) of cuprate reagent was used instead of 1.5 e q u i v a l e n t s . Synthesis of 3-Cyclopropyl-2-Cyclohexen-l-one 142.. -  F o l l o w i n g the general  procedure A o u t l i n e d above, 3-iodo-2-cyclohexen-l-one 101 (666 mg, 3 mmol) was allowed t o r e a c t w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (4.5 mmol) i n tetrahydrofuran at -78°C f o r 2.5h. Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature 62-75°C, 0.3 Torr) of the crude o i l afforded 335 mg (82%) of pure 3-cyclopropyl-2-cyclohexen-l-one 142 as a c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d uv A  254 nm (e=17100); i r ( f i l m ) v  max  1660, 1625, 1610  max  cm" ; """Hnmr, T4.19 (S, IH, C0C=C-H), 7.50-9.34 (m, 11H). These s p e c t r a l 1  144 108 data were i d e n t i c a l w i t h those reported i n l i t e r a t u r e .  '  Synthesis of 2-Methyl-3-cyclopropyl-2-cyclohexen-l-one 1 4 6 . general procedure C, 2-methyl-3-iodo-2-cyclohexen-l-one  F o l l o w i n g the  111 (708 mg, 3 mmol)  was allowed to react w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (6 mmol) i n tetrahydrofuran at 0°C f o r 2.5h. Normal work-up, followed by d i s t i l l a t i o n of the r e s i d u a l o i l ( a i r - b a t h temperature 65-85°C, 0.35 T o r r ) , a f f o r d e d 396 mg (88%) of pure 2-methyl-3-cyclopropyl-2-cyclohexen-l-one 146 as a c o l o r l e s s  -161oil.  This m a t e r i a l c r y s t a l l i z e d i n a r e f r i g e r a t o r and could be r e c r y -  s t a l l i z e d from an ether-hexane mixture. e x h i b i t e d mp 36-37°C; uv X r  A r e c r y s t a l l i z e d sample of 146  262 nm (£=14950); i r ( f i l m ) v  max  max  1660,  "hfamr, T8.10 (S, 3H, -C0C(CH )=CH-), 7.40-8.30 (m, 6H), 9.0-  1600 cm" ; 1  3  9.30 (m, 5H).  Mol.Wt. Calcd. f o r C^H^O: 150.1044.  mass spectrometry):  Found (high r e s o l u t i o n  150.1032.  Synthesis of 3-Cyclopropyl-2-cyclopenten-l-one procedure A, 3-iodo-2-cyclopenten-l-one  l&L. -  Following the general  112 (624 mg, 3 mmol) was allowed to  r e a c t w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (4.5 mmol) i n tetrahydrofuran at -78°C f o r 2.5h.  Normal work-up, followed by d i s t i l l a t i o n ( a i r -  bath temperature ^65°C, 0.2 Torr) of the crude o i l , afforded 355 mg (97%) of c r y s t a l l i n e 3-cyclopropyl-2-cyclopenten-l-one h i b i t e d mp 31-33°C; uv X  147.  This m a t e r i a l ex-  244 nm (e=16270); i r ( C H C l ) v 1700, 1670, J max 0  max  1600 cm" ; Hnmr, x4.12 ( t , IH, -C0C=C-H, J=1.8 Hz), 7.40-7.74 (m, 4H) , 1  1  8.00-8.32 (m, I H ) , 8.78-9.26 (m, 4H).  Mol.Wt. Calcd. f o r CgH^O: 122.0731.  Found (high r e s o l u t i o n mass spectrometry):  122.0733.  Synthesis of 2-Methyl-3-cyclopropyl-2-cyclopenten-l-one  -  Following  the general procedure C, 2-methyl-3-iodo-2-cyclopenten-l-one 113 (666 mg, 3 mmol) was allowed to react w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (6 mmol) i n tetrahydrofuran at 0°C f o r 2.5h.  Normal work-up, followed by  d i s t i l l a t i o n ( a i r - b a t h temperature ^50°'C, 0.1 Torr) of the crude o i l , afforded 343 mg (84%) of pure 2-methyl-3-cyclopropyl-2-cyclopenten-l-one 148 as a c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d uv X 254 nm (e=18580); max ir(film)v  1698, 1637 cm" ; Hnmr, T7.6-8.1 (unresolved m, 4H), 8.23 1  max  1  ( t , 3H, C=C-CH , J-1.2 Hz), 8.85-9.20 (m, 5H). 3  136.0887.  Mol.Wt. Calcd. f o r CgH^O:  Found (high r e s o l u t i o n mass spectrometry):  136.0888.  -162-  Synthesis of. 2-Cyclopropylmethylenecyclohexanone 15.0.. -  Following the  general procedure B o u t l i n e d above, 2-iodomethylenecyclohexanone  116  (708 mg, 3 mmol) was allowed to react w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) cuprate (4.5 mmol) at 0°C f o r 2.5h.  Normal work-up, followed by d i s t i l l a t i o n  ( a i r - b a t h temperature ^80°C, 0.2 Torr) of the crude o i l , afforded 369 mg (82%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column B, 120°C) of t h i s m a t e r i a l  showed that i t was approximately 96% pure.  An a n a l y t i c a l sample of compound  150, obtained by p r e p a r a t i v e g l c (column D, 150°C), e x h i b i t e d mp ^15°C; uv X 265 nm (£=11750); i r ( f i l m ) v 1680, 1600 cm ; max max -1  1  Hnmr, T3.96 (d of  t , IH, -C=CH(c-C H ), J = l l Hz, J'=2 Hz), 7.24-7.74 (m, 4H), 7.97-8.82 (m, 5H), 3  5  8.90-9.51 (m, 4H). Anal. Calcd. f o r C  1()  H 0 : C, 79.96; H, 9.39. 14  Found: C, 79.69; H,  9.35.  103 Synthesis of 2-Cyclopropylmethylenecyclopentanone 149.  -  F o l l o w i n g the  general procedure A o u t l i n e d above, 2-iodomethylenecyclopentanone 115 (666  mg,  3 mmol) was allowed to react w i t h l i t h i u m p h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e (4.5 mmol) i n tetrahydrofuran at -78°C f o r l h , and at -20°C f o r another 2.5h.  Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^95°C,  0.35 Torr) of the crude o i l , afforded 265 mg  (65%) of a c o l o r l e s s l i q u i d .  A g l c a n a l y s i s (column A, 120°C) of t h i s m a t e r i a l showed that i t was mately 94% pure.  approxi-  An a n a l y t i c a l sample of 149 was obtained by p r e p a r a t i v e  g l c (column C, 150°C) and i t e x h i b i t e d mp VL8°C; uv X 267 nm (£=14820); max ir(film)v  1706, 1640 cm ; -1  1  Hnmr, T4.05 (d of t , IH, -C=C-H, J = l l Hz,  J»=2.8 Hz), 7.15-9.50 (unresolved m, IH).  Mol.Wt. Calcd. f o r C \ g  0:  2  136.0887.  Found (high r e s o l u t i o n mass spectrometry): 136.0902. Reaction of L i t h i u m P h e n y l t h i o ( c y c l o p r o p y l ) c u p r a t e w i t h a 1:1 Mixture of the Iodo Enones 122. and 123.. - Following the general procedure B, a 1:1 mixture  -163-  of the iodo enones 138 and 139 (750 mg, 3 mmol) was allowed to react w i t h l i t h i u m phenylthio(cyclopropyl)cuprate (4.5 mmol) i n tetrahydrofuran at 0°C f o r 2.5h.  Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h tem-  perature ^73°C, 0.2 Torr) of the crude o i l , afforded 369 mg (75%) of a s l i g h t l y yellow l i q u i d .  A g l c a n a l y s i s (column A, 120°C) of t h i s  m a t e r i a l showed that i t was composed of a mixture of the 0-cyclopropyl enones 156, 155 and 153 i n the r a t i o of approx. 1:1:2, together with some minor i m p u r i t i e s (<5%). An a n a l y t i c a l sample  of each of the compounds  156, 155 and 153 was obtained by preparative g l c (column C, 145°C).  The  pure enone 156 e x h i b i t e d uv X 263 nm (e=11720); i r ( f i l m ) v 1685, 1610 max max cm" ; "''Hnmr, x5.16 (d of d, IH, -C=C-H, J=10.5 Hz, J'=2 Hz), 8.96 (d, 3H, 1  -CH(CH_ ), J=7 Hz), 7.30-9.80 (unresolved m, 12H). 3  ^11^16^  :  164*1201.  Mol.Wt. Calcd. f o r  Found (high r e s o l u t i o n mass spectrometry):  The pure B-cyclopropyl enone 155 e x h i b i t e d uv ^ ir(film)v  max  m a x  164.1206.  265 nm (e=11420);  1680, 1600 cm" ; "'"Hnmr, T4.02 (d of d, IH, -C=C-H, J = l l Hz, — 1  J'=l Hz), 6.58-6.98 (m, IH), 7.48-9.50 (m, 11H), 8.96 (d, 3H, -CH(CH ), 3  J=7 Hz). Mol. Wt. Calcd. f o r C^H^O: 164.1201.  Found (high r e s o l u t i o n  mass spectrometry): 164.1205. The pure enone 153 e x h i b i t e d mp 54-56°C; uv X 265 nm (E=9810); max ir(film)v  max  1680, 1602 cm" ; Hnmr, T3.92 (d of t , IH, -C=C-H, J = l l Hz, — 1  1  J'=2 Hz), 6.90-9.50 (unresolved m, 12H), 8.98 (d, 3H, -CH(CH ), J=6 Hz). 3  Anal. Calcd. f o r C, H.,,0: C, 80.44; H, 9.82. 11 l b 1  III.  Regioselective Synthesis of  Found: C, 80.06; H9.77.  2-Cyclopropylmethylene-5-methylcyclo-  hexanone _15_3 and 2-Cyclopropylmethylene-3-methylcyclbhexanones (155 + 156). A.  Preparation of Cyclopropanecarboxaldehyde  1.  E s t e r i f i c a t i o n of Cyclopropanecarboxylic  Acid. -  To 10 g (0.116 mol) of  -164-  cyclopropanecarboxylic a c i d was added 10 g of ethanol, 15 ml of benzene, and 0.1 ml of cone, s u l f u r i c a c i d . f o r 4.5h.  The r e s u l t i n g mixture was r e f l u x e d  The ethanol-benzene-water azeotrope was  then d i s t i l l e d o f f .  The r e s i d u a l o i l was d i l u t e d w i t h ether, and washed w i t h d i l u t e sodium bicarbonate s o l u t i o n . sulfate.  The ether s o l u t i o n was d r i e d over anhydrous magnesium  A f t e r removal of the ether, the r e s i d u a l o i l was  fractionally  d i s t i l l e d to give 10 g (73%) of e t h y l cyclopropanecarboxylate 143 l i t . reported bp 133-133.5°C ).  (bp 130-132°C;  This m a t e r i a l e x h i b i t e d i r ( f i l m ) v max  1723 cm" ; 1  8.2-9.6 (m,  ^nmr,  T5.91  (q, 2H, -CH_ CH , J=7 Hz), 8.73 2  3  ( t , 3H, -CH CH_ , J=7 2  3  Hz),  5H). 144  2.  L i t h i u m Aluminum Hydride Reduction of E t h y l To a c o l d (0°C)  Cyclopropanecarboxylate.  s l u r r y of l i t h i u m aluminum hydride (6.81 g, 0.18  mol)  i n 300 ml of anhydrous ether, i n a d r i e d three-neck f l a s k equipped w i t h a water condenser, a dropping funnel and a n i t r o g e n gas i n l e t , was dropwise a s o l u t i o n of e t h y l cyclopropanecarboxylate i n ether (50 m l ) , through the dropping f u n n e l . warmed to room temperature, and was  (18.55 g, 0.163  then r e f l u x e d f o r 17h.  7.13 3.  Normal work-  ).  This m a t e r i a l  Hnmr, T6.60 (d, 2H, -CH-OH, J=7 max —z. (br s IH, -CH 0H), 8.60-9.90 (m, 5H). -1  1  was  g (75%) of c y c l o -  p r o p y l c a r b i n o l (bp 120-122°C, l i t . reported bp 123-124°C 3350 cm ;  mol)  The r e s u l t i n g mixture  up, followed by f r a c t i o n a l d i s t i l l a t i o n , afforded 8.85  exhibited i r ( f i l m ) v  added  Hz),  2  Oxidation of C y c l o p r o p y l c a r b i n o l w i t h C e r i c Ammonium N i t r a t e . -  s o l u t i o n of c e r i c ammonium n i t r a t e (114.3 g, 0.21 mol) i n water (200 was added 7.15  g (0.1 mol) of c y c l o p r o p y l c a r b i n o l .  To a ml)  The r e s u l t i n g red  s o l u t i o n was heated on a steam bath, w i t h constant s w i r l i n g , u n t i l the red c o l o r discharged completely.  I c e - c o l d saturated sodium c h l o r i d e s o l u t i o n  -165-  (200 ml) was added to the r e s u l t i n g c o l o r l e s s s o l u t i o n . The r e s u l t i n g mixture was extracted w i t h f i v e 80 ml p o r t i o n s of methylene c h l o r i d e . The combined methylene c h l o r i d e e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e and sodium bicarbonate. removed by  The methylene c h l o r i d e was  f r a c t i o n a l d i s t i l l a t i o n and the r e s i d u a l o i l was f r a c t i o n a l l y  d i s t i l l e d t o give 5.07 g (71%) of cyclopropanecarboxaldehyde (b.p. 98°1  42  100°C, l i t . reported bp 9 7 - 9 9 ° C ) . 1710  This m a t e r i a l e x h i b i t e d i r ( f i l m ) v  cm" ; """Hnmr, T1.09 (d, IH, -CHO, J=6 Hz), 8.95 (d, 4H, - < j j i 1  , J=6 H z ) ,  T8.0-8.34 (m, IH, -CH-CHO). B.  Synthesis of 2-Cyclopropylmethylene-5-methylcyclohexanone 1 ^ . -  c o l d (0°C) s o l u t i o n of l i t h i u m dimethylcuprate  To a  (3.3 mmol) i n anhydrous ether  (18 ml) under an atmosphere of argon was added a s o l u t i o n of 2-cyclohexen-lone  (288 mg, 3 mmol) i n ether (1 ml).  f o r 10 min at 0°C.  The r e s u l t i n g mixture was s t i r r e d  Cyclopropanecarboxaldehyde (210 mg, 3 mmol) was added.  The r e s u l t i n g yellow suspension was s t i r r e d a t 0°C f o r l h .  Saturated  ammonium c h l o r i d e s o l u t i o n (15 ml) was added and the r e s u l t i n g mixture was s t i r r e d v i g o r o u s l y f o r a few min.  The two l a y e r s were separated and the  aqueous phase was f u r t h e r extracted w i t h three 50 ml p o r t i o n s of ether. The combined ether e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e . Removal of s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l ( a i r bath temperature 115-150°C, 15 T o r r ) , afforded 293 mg (60%) of a c o l o r l e s s l i q u i d . A g l c a n a l y s i s of t h i s m a t e r i a l showed the presence of one major component A 0WO%) arid two minor components B and C (^14% and ^7% r e s p e c t i v e l y ) , together w i t h small amounts of minor i m p u r i t i e s Ov-9%).  An a n a l y t i c a l sample  of the major component A was obtained by p r e p a r a t i v e g l c (column D, 160°C) and was shown to be 2-cyclopropylmethylene-5-methylcyclohexanone 153. The  -166-  s p e c t r a l d a t a ( Hnmr, i r ) of t h i s m a t e r i a l were i d e n t i c a l w i t h those of x  the same m a t e r i a l prepared e a r l i e r by the r e a c t i o n of l i t h i u m phenylthio(cyclopropyl)cuprate w i t h the corresponding iodomethylenecyclohexanone. Small amounts of components B and C were a l s o obtained by p r e p a r a t i v e g l c (column  160°C).  S p e c t r a l data ("^Hnmr) showed that component B was  3-methylcyclohexanone, w h i l e component C was probably compound 154, the geometric isomer of the c y c l o p r o p y l enone 153. Component C e x h i b i t e d 1  Hnmr, x5.08 (d of t , IH, o l e f i n i c , J = l l Hz, J'=2 Hz), 8.98 (d, 3H,  -CH(CH ), J=6 Hz). 3  C.  Synthesis of 2-Cyclopropylmethylene-3-methylcyclohexanone 1_55_.  1.  Synthesis of 2-(1-Cyclopropyl-l-hydroxymethy1)-3-methylcyclohexanone  202.. - A 100 ml three-neck f l a s k equipped w i t h an overhead mechanical s t i r r e r and an argon i n l e t tube, and containing 437 mg (18 mmol) of magnesium t u r n i n g s , was flame-dried under a steady flow of argon. f l a s k was cooled to 0°C and dry ether (25 ml) was added.  The  To the r e s u l t i n g  s t i r r e d suspension of magnesium i n ether was added, dropwise, 2.56 g (18 mmol) of methyl i o d i d e .  The r e s u l t i n g mixture was s t i r r e d at 0°C f o r 10  min. Cuprous i o d i d e (60 mg, 0.3 mmol) was added t o t h i s s o l u t i o n of methyl magnesium i o d i d e and s t i r r i n g was continued f o r 5 min at 0°C.  After  a d d i t i o n of 2-cyclohexen-l-one (1.44 g, 15 mmol), the r e a c t i o n mixture was s t i r r e d at 0°C f o r 30 min and was then cooled to -78°C.  Cyclopropane-  carboxaldehyde (1.05 g, 15 mmol) was added dropwise w i t h vigorous s t i r r i n g . A gummy p r e c i p i t a t e formed immediately. The r e s u l t i n g mixture was warmed to 0°C, s t i r r e d f o r 30 min, warmed to room temperature and f i n a l l y s t i r r e d f o r an a d d i t i o n a l 30 min.  Saturated aqueous ammonium c h l o r i d e (30 ml) was  added and the r e s u l t i n g mixture was s t i r r e d f o r 5 min.  The aqueous l a y e r  -167-  was separated and thoroughly e x t r a c t e d w i t h four 30 ml p o r t i o n s of ether.  The combined ether e x t r a c t s were washed twice w i t h b r i n e and  d r i e d over anhydrous magnesium s u l f a t e . 2.65 g (97%) of the B-hydroxyketone (film)v  3470, 3110, 1700 cm" . 1  max  ether-hexane 0.3, 0.35)  203.  Removal of s o l v e n t , gave This m a t e r i a l e x h i b i t e d i r  A t i c a n a l y s i s ( e l u t i o n w i t h 1:1  of t h i s m a t e r i a l showed the presence of two spots (Rf =  of approximately equal i n t e n s i t y .  This m a t e r i a l underwent  p a r t i a l dehydration and r e t r o a l d o l r e a c t i o n upon d i s t i l l a t i o n as shown by t i c a n a l y s i s (5 spots) and by the i r spectrum of the d i s t i l l e d product, which showed absorptions due to the presence of both saturated and a,B-unsaturated carbonyl groups, as w e l l as absorption due to a hydroxy group ( i r ( f i l m ) v 3480, 1700, 1680, 1602 cm" ). ° max 1  Because of the f a c t that  the k e t o l 203 was q u i t e u n s t a b l e , i t was not p u r i f i e d f u r t h e r but was  used  d i r e c t l y i n the next step. 2.  Dehydration of 2-(l-Cyclopropyl-l-hydroxymethyl)-3-methylcyclohexanone  203.. a.  By R e f l u x i n g i n Benzene i n the Presence of a C a t a l y t i c Amount of _p_-  Toluenesulfonic  A c i d . - The crude B-hydroxyketone  203 (2.65 g, 14.6 mmol),  obtained as described above, was d i s s o l v e d i n benzene (60 ml) c o n t a i n i n g a c a t a l y t i c amount of oj-toluenesulf onic a c i d (33 mg) , and the r e s u l t i n g s o l u t i o n was r e f l u x e d . A Dean Stark apparatus was used to trap the water. The progress of the dehydration r e a c t i o n was followed by t i c a n a l y s i s of a l i q u o t s taken from the r e a c t i o n mixture.  I t was found t h a t , one of the  two compounds (Rf=0.35) present i n the s t a r t i n g B-hydroxyketone  mixture  dehydrated completely w i t h i n 3h to give two new compounds, w h i l e the other (Rf=0.3) dehydrated much more s l o w l y and was completely transformed to the  -168-  products only a f t e r 18h.  The benzene s o l u t i o n was washed w i t h saturated  aqueous sodium bicarbonate and d r i e d over anhydrous magnesium s u l f a t e . Removal of solvent, and f r a c t i o n a l d i s t i l l a t i o n of the r e s i d u a l o i l , gave two f r a c t i o n s .  The f i r s t f r a c t i o n (air-bath temperature up to ^50°C,  0.3 Torr) was a l i g h t c o l o r l e s s o i l (426 mg) and was shown ( i r , g l c r e t e n t i o n time on column A, 120°C) to be 3-methylcyclohexanone  (25% y i e l d ) .  A glc  a n a l y s i s (column A, 120°C) of the second f r a c t i o n (air-bath temperature ^80°C, 0.4 Torr; 1.40 g, 57% y i e l d ) showed the presence of two components i n a r a t i o of 1:6. An a n a l y t i c a l sample of each was obtained by preparative g l c (column C, 150°C).  The major component was shown to be 8-cyclopropyl  enone 155 and the minor component was shown to be the enone 156, the geometric isomer of the enone 155 (see page 163). b.  V i a Base-Promoted  Acetate. (211). -  E l i m i n a t i o n of A c e t i c Acid from the Corresponding  To a s o l u t i o n of the g-hydroxyketone 203 (1.1 g, 6 mmol)  i n pyridine (20 ml) was added 6 ml of a c e t i c anhydride.  The r e s u l t i n g  mixture was s t i r r e d at room temperature f o r 17h under an atmosphere of argon. Ether (200 ml) and water (30 ml) were added. was s t i r r e d f o r 5 min.  The r e s u l t i n g mixture  The ethereal layer was separated and washed successively  w i t h three 20 ml portions of IN hydrochloric a c i d , 20 ml of b r i n e , two 30 ml portions of saturated sodium bicarbonate and f i n a l l y 20 ml of b r i n e . A f t e r drying over anhydrous sodium s u l f a t e , the solvent was removed and the crude acetate 211 was dried under reduced pressure (vacuum pump) f o r 2h. The y i e l d of the crude acetate 211 was 1.3 g (98%). ir(film)v  1730 cm . 1  max  This m a t e r i a l exhibited  The ^Hnrnr indicated the presence of at l e a s t two  isomers (acetate methyl groups at x7.96 and 7.98) although t i c a n a l y s i s ( e l u t i o n with 1:1 ether-hexane) showed only one spot.  -169-  To a s o l u t i o n of the crude acetate 211 (1.12 benzene (80 ml) was added 930 mg (0.75 mmol) of non-5-ene (DBN).  g, 5.0 mmol) i n l,5-diazabicyclo[4.3.0]  The r e s u l t i n g mixture was r e f l u x e d f o r 17h. Ether  (250 ml) was added and the r e s u l t i n g s o l u t i o n was washed w i t h i c e - c o l d d i l u t e hydrochloric  a c i d (IN, 30 ml) and then d r i e d over anhydrous  magnesium s u l f a t e .  Removal of solvent, followed by d i s t i l l a t i o n of the  r e s i d u a l o i l , afforded  640 mg (78%)  of a c o l o r l e s s o i l .  A glc analysis  (column A, 120°C) of t h i s m a t e r i a l showed that i t was composed of enones 155 and 156 i n a r a t i o of 13:1, (<6%)  of minor i m p u r i t i e s .  IV.  Preparation  r e s p e c t i v e l y , together with small amounts  of T r i m e t h y l s i l y l Enol Ethers of g-Cyclopropyl-a,g-  Unsaturated Ketones. General P r o c e d u r e . ^ 1  methyllithium  3  - An e t h e r e a l s o l u t i o n containing  4.0 mmol of  was concentrated under reduced pressure and the r e s i d u a l  organolithium reagent was d i s s o l v e d i n 4 ml of dry 1,2-dimethoxyethane. The r e s u l t i n g s o l u t i o n was cooled to 0°C and was treated with 404 mg (4 mmol) of diisopropylamine.  To the r e s u l t a n t , s t i r r e d s o l u t i o n of  l i t h i u m diisopropylamide was added, dropwise, 3 mmol of the appropriate g-cyclopropyl-a,g-unsaturated ketone.  Meanwhile a quenching s o l u t i o n ,  prepared from 2 ml of 1,2-dimethoxyethane, 0.2 ml (^2 mmol) of t r i e t h y l a m i n e and 0.6 ml (5.1 mmol) of c h l o r o t r i m e t h y l s i l a n e dimethylaniline)  was centrifuged  amine hydrochloride.  ( f r e s h l y d i s t i l l e d from N,N-  to remove any of the i n s o l u b l e t r i e t h y l -  By use of a syringe, t h i s  chlorotrimethylsilane  s o l u t i o n was added r a p i d l y w i t h s t i r r i n g to the cold (0°C) s o l u t i o n of the l i t h i u m enolate. separate.  A f t e r a d d i t i o n was complete, a white s o l i d began t o  The r e s u l t i n g mixture was s t i r r e d at 0°C f o r 15 min.  Saturated  -170-  aqueous sodium bicarbonate (10 ml) and pentane (30 ml) were added. The aqueous s o l u t i o n was separated and extracted further with three 30 ml portions of pentane.  The combined pentane e x t r a c t s were dried over  anhydrous magnesium s u l f a t e .  Removal of the pentane, followed by  d i s t i l l a t i o n of the r e s i d u a l o i l gave the corresponding t r i m e t h y l s i l y l enol ether. Preparacion of the T r i m e t h y l s i l y l E n o l Ether of 3-Cyclopropyl-2-Cyclohexen1-one. -  Following the general procedure o u t l i n e d above, 3-cyclopropyl-2-  cyclohexen-l-one 142 (408 mg, 3 mmol) was f i r s t treated w i t h l i t h i u m diisopropylamide (4 mmol) and the r e s u l t a n t enolate anion was quenched with c h l o r o t r i m e t h y l s i l a n e (5 mmol).  Normal work-up, followed by d i s t i l l a t i o n  (air-bath temperature ^80°C, 0.1 Torr) of the crude product, afforded 550 mg of the corresponding t r i m e t h y l s i l y l enol ether 171.  A g l c a n a l y s i s (column  A, 120°C) of t h i s m a t e r i a l showed that i t was 91% pure, i n d i c a t i n g that the y i e l d of compound 171 was approximately 80%. This m a t e r i a l exhibited , 0SiMe ir(film)v 1650, 1610 cm ; Hnmr, T4.54 (broad s, IH, -C=CE-C=C- ), max — 3  5.26  (m, IH, CH -CH=C-0Si(CH ) )9.86 (broad s, 9H, Si-(CH_ ) .  intrinsic  2  3  instability  3  3  3  Due to the  of t h i s m a t e r i a l , i t was pyrolysed without f u r t h e r  p u r i f i c a t i o n or c h a r a c t e r i z a t i o n . Preparation of the T r i m e t h y l s i l y l Enol Ether of 2-Methyl-3-cyclopropyl-2cyclohexen-l-one. - Following the general procedure o u t l i n e d above, 2-methyl3-cyclopropyl-2-cyclohexen-l-one 146 (450 mg, 3 mmol) was f i r s t treated w i t h l i t h i u m diisopropylamide (4 mmol) and the r e s u l t a n t enolate anion was quenched w i t h c h l o r o t r i m e t h y l s i l a n e (5 mmol). by d i s t i l l a t i o n  Normal work-up, followed  ( a i r - b a t h temperature ^60°C, 0.05 Torr) of the crude  product, afforded 612 mg (88%) of the corresponding t r i m e t h y l s i l y l enol  -171-  ether 167 as a c o l o r l e s s o i l .  A g l c a n a l y s i s (column A, 150°C) of t h i s  m a t e r i a l showed that i t was ^96% pure.  This m a t e r i a l e x h i b i t e d i r ( f i l m )  v 1650, 1600 cm" ; Hnmr, T5.20 ( t , IH, -C=CH, J=5 Hz), 8.20 max — 1  1  s, 3H, -C=C-CH ), 9.91 (broad s, 9H, S i ( C H ) ) . 3  3  3  (broad  Due to the i n t r i n s i c  i n s t a b i l i t y of t h i s m a t e r i a l , i t waspyrolysed without f u r t h e r p u r i f i c a t i o n or c h a r a c t e r i z a t i o n . P r e p a r a t i o n of the T r i m e t h y l s i l y l Enol hexanone. -  Ether of  2-Cyclopropylmethylenecyclo-  Following the general procedure o u t l i n e d above, 2 - c y c l o p r o p y l -  methylene-cyclohexanone 150 (450 mg, 3 mmol) was f i r s t t r e a t e d w i t h l i t h i u m diisopropylamide  (4 mmol) and the r e s u l t a n t enolate anion was quenched  w i t h c h l o r o t r i m e t h y l s i l a n e (5 mmol).  Normal work-up, followed by d i s t i l l -  a t i o n ( a i r - b a t h temperature ^125°C, 16 Torr) of the crude o i l , afforded 666 mg of the corresponding  t r i m e t h y l s i l y l enol ether 184.  A glc analysis  (column B, 120°C) of t h i s m a t e r i a l showed that i t was 91% pure, i n d i c a t i n g that the y i e l d of the enol ether 184 was about 91%. ir(film)\>  max  1680 (w) , 1660 cm"  1  This m a t e r i a l e x h i b i t e d  (w); Hnmr, T4.92 (d, IH, - O C H ^ - C - H J , J _> 1  J=9.5 Hz), 5.04 ( t , IH, CH -CH=C-OSiMe , J=4.5 Hz), 7.40-7.64 (m, IH, 2  3  ),  7.72-7.96 (m, 2H, -C=CH-CH - ), 8.20-8.64 (m, 4H), 8.95-9.44 (m, 2H), 2  9.52-9.74 (m, 2H) , 9.87 222.1439 .  (broad s, 9H, S i ( C H ) ) . 3  3  Mol.Wt. Calcd. f o r C ^ H ^ O S i :  Found (high r e s o l u t i o n mass spectrometry:  222.1438 .  P r e p a r a t i o n of the T r i m e t h y l s i l y Enol Ether of 2-Cyclopropylmethylene-3methyl-cyclohexanone. - Following the general procedure o u t l i n e d above, a 1:6 isomeric mixture of the B-cyclopropyl enones 156 and 155, r e s p e c t i v e l y , (492 mg, 3 mmol) was f i r s t treated w i t h l i t h i u m diisopropylamide  (4 mmol)  and the r e s u l t a n t enolate anions were quenched w i t h c h l o r o t r i m e t h y l s i l a n e (5 mmol).  Normal work-up, followed by d i s t i l l a t i o n of the crude o i l ,  -172-  afforded 710 mg of the corresponding t r i m e t h y l s i l y l enol ethers. glc a n a l y s i s (column B, 120°C) of t h i s m a t e r i a l showed that i t was pure.  A 94%  On t h i s b a s i s , the y i e l d of the enol ether 200 was about 95%.  This m a t e r i a l exhibited i r ( f i l m ) v 1650 max  (w), 1625  T4.98 (d, IH, -C=CH(c-C H ), J=10 Hz), 5.11 3  J=3 Hz), 8.97  5  (w) cm- ; 1  "Slnmr,  ( t , IH, CH -CH=C-0Si(CH ) , 2  (d, 3H, -CH(CH_ ), J=7 Hz), 6.76-7.12 (m, IH). 3  3  Due to the  i n s t a b i l i t y of t h i s m a t e r i a l , i t was pyrolysed without further p u r i f i c a t i o n or c h a r a c t e r i z a t i o n . Preparation of the T r i m e t h y l s i l y l Enol Ether of 2-Cyclopropylmethylenecyclopentanone. -  Following the general procedure o u t l i n e d above, 2-cyclopropyl-  methylenecyclopentanone propylamide  149 (408 mg, 3 mmol) was treated w i t h l i t h i u m d i i s o -  (4 mmol) and the r e s u l t a n t enolate anion was quenched w i t h  c h l o r o t r i m e t h y l s i l a n e (5 mmol).  Normal work-up, followed by d i s t i l l a t i o n  of the r e s i d u a l o i l , afforded 562 mg enol ether 191. was pure.  (90%) of the corresponding t r i m e t h y l s i l y l  A g l c a n a l y s i s (column B, 120°C) showed that t h i s m a t e r i a l  I t exhibited i r ( f i l m ) v 1615 c m ( s ) . max  o l e f i n i c ) , 9.86  _1  Hnmr x4.90-5.32 (m, 2H,  1  (broad s, 9H, S i ( C H ) ) . Due to the i n s t a b i l i t y of t h i s 3  3  m a t e r i a l , i t was pyrolysed without f u r t h e r p u r i f i c a t i o n or c h a r a c t e r i z a t i o n . V.  Thermal Rearrangement Reactions of B-Cyclopropyl-a,B-Unsaturated  Ketones and t h e i r T r i m e t h y l s i l y l Enol Ether D e r i v a t i v e s General Procedure A. - A pyrex tube 1.2(i.d.)x32 cm, f i l l e d w i t h glass h e l i c e s ( i . d . 4.76 mm) was washed successively with water, acetone and n-hexane. The column was conditioned by p l a c i n g i t i n a furnace and heating i t at ^450°C for 3h.  During t h i s period of time, the column was thoroughly purged w i t h  a stream of n i t r o g e n . A n-hexane s o l u t i o n of the appropriate 8-cyclopropyla,B-unsaturated ketone (or the corresponding t r i m e t h y l s i l y l enol ether) (200 mg i n 20 ml of n-hexane) to be pyrolysed was added dropwise over a  -173-  period of 1.5h t o the top o f the v e r t i c a l l y held heated column (^450°C). During t h i s period of time, the stream of n i t r o g e n was discontinued. The e f f l u e n t from the bottom of the column was cooled by having i t pass through a water condenser connected to the bottom of the p y r o l y s i s tube, and was c o l l e c t e d i n a two-necked f l a s k , equipped w i t h a drying tube and immersed i n a cold (-78°C) bath (see diagram 1 ) .  A f t e r a d d i t i o n of the  s o l u t i o n was complete, the hot column was washed w i t h a f u r t h e r 30 ml of n-hexane.  Removal of the hexane, followed by d i s t i l l a t i o n of the r e s i d u a l  o i l , gave the rearranged products. General Procedure B. - A pyrex tube (1.2 x 100 cm) f i l l e d w i t h glass h e l i c e s ( i . d . 4.76 mm) was washed s u c c e s s i v e l y w i t h saturated aqueous sodium bicarbonate s o l u t i o n , water, acetone and n-hexane.  By means of a  heating tape which had been wrapped around i t , the column was heated to the  desired thermolysis temperature and was kept a t t h i s temperature f o r  at l e a s t 3h. During t h i s time, the column was thoroughly purged w i t h a r a p i d flow of argon. the  A n-hexane s o l u t i o n of the g-cyclopropyl enone (or  corresponding t r i m e t h y l s i l y l enol ether)(200 mg i n 20 ml n-hexane)  to be pyrolysed was added dropwise, over a period of 1.5h, to the top of the v e r t i c a l l y held column.  During t h i s period of time, a very slow flow  of argon (^5 ml/min) was passed through the column. The e f f l u e n t from the bottom of the column was cooled by a l l o w i n g i t t o pass through a water condenser attached to the bottom of the p y r o l y s i s tube, and was c o l l e c t e d i n a two-neck f l a s k which was equipped w i t h a drying tube and was immersed i n a cold (-78°C) bath (see diagram 2).  A f t e r a d d i t i o n of the s o l u t i o n  was complete, the hot column was washed w i t h a f u r t h e r 30 ml of n-hexane. Removal of hexane, followed by d i s t i l l a t i o n of the r e s i d u a l o i l gave the  -174-  rearranged products. General Procedure C. -  Procedure C was e s s e n t i a l l y the same as procedure  B except that the crude mixture of p y r o l y s i s products was not d i s t i l l e d but was subjected d i r e c t l y to h y d r o l y s i s . Thus, a f t e r the hexane had been removed from the p y r o l y s a t e , the r e s i d u a l o i l was taken up i n a 1:1 mixture (5 ml) of methanol and d i l u t e h y d r o c h l o r i c a c i d (IN) and the r e s u l t i n g s o l u t i o n was s t i r r e d f o r 30 min at room temperature.  The  s o l u t i o n was thoroughly e x t r a c t e d w i t h pentane and the combined pentane e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e .  Removal of solvent  and d i s t i l l a t i o n of the r e s i d u a l o i l gave the f i n a l p r o d u c t ( s ) . P y r o l y s i s of 3-Cyclopropyl-2-cyclohexen-l-one 142.. A.  At ^450°C, Procedure A. - Following the general procedure A o u t l i n e d  above, a s o l u t i o n of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n i i hexane (20 ml) was pyrolysed at ^A50°C. Normal work-up, followed by d i s t i l l a t i o n ( a i r bath temperature ^110°C, 16 Torr) of the crude o i l , afforded 156 mg  (78%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column B, 130°C)  of t h i s m a t e r i a l i n d i c a t e d that i t was a mixture of the ketone 161  (^3%),  the enone 162 (^84%) and the dienone 163 Ov-11%), along w i t h a number of minor u n i d e n t i f i e d i m p u r i t i e s (^2%).  An a n a l y t i c a l sample of each of the  three major components was obtained by p r e p a r a t i v e g l c (column D, 130°C). The pure enone 162 e x h i b i t e d i r ( f i l m ) v  1660, 1630 cm" ; 1  max  1  Hnmr, r7.2-8.3(m).  The 2,4-dinitrophenylhydrazone d e r i v a t i v e e x h i b i t e d mp 252°C (dec)(lit.mp 251.5°C). Anal.  114  (2,4-DNP d e r i v a t i v e ) Calcd. f o r C ^ ^ O ^  N, 17.71.  Found: C, 57.09; H, 5.07; N, 17.58.  C, 56.96; H,  5.10;  -175-1 1. The pure ketone 161 e x h i b i t e d i r ( f i l m ) y 1718, 1665 cm Hnmr, max T4.57 (broad s, IH, -C=C-H), 6.63(m, IH, -CO-CH-). This m a t e r i a l was passed through a short column of b a s i c alumina and the column was eluted w i t h ether.  Evaporation of the ether from the e l u a n t , followed by a n a l y s i s  of the r e s i d u a l o i l by i r , "''Hnmr and g l c showed that the ketone 161 had isomerized completely to the a,B-unsaturated enone 162. The pure dienone 163 e x h i b i t e d i r ( f i l m ) v  B.  max  1670, 1642, 1590 cm  ;  At 322°C, Procedure B. - Following the general procedure B o u t l i n e d  above, a s o l u t i o n of 3-cyclopropyl-2-cyclohexen-l-one hexane (20 ml) was pyrolysed a t 322°C.  142 (200 mg) i n n-  Normal work-up, followed by  d i s t i l l a t i o n ( a i r - b a t h temperature ^110°C, 16 Torr) of the crude o i l afforded 200 mg (100%) of a c o l o r l e s s o i l .  The i n f r a r e d spectrum and a  glc a n a l y s i s (column B, 130°C) of t h i s m a t e r i a l showed that i t was pure s t a r t i n g m a t e r i a l , the c y c l o p r o p y l enone 142. C  At 400°C, Procedure B. -  Following the general procedure B o u t l i n e d  above, a s o l u t i o n of 3-cyclopropyl-2-cyclohexen-l-one hexane (20 ml) was pyrolysed at 400°C.  142 (200 mg) i n n-  Normal work-up, followed by  d i s t i l l a t i o n of the crude o i l , afforded 200 mg (100%) of a c o l o r l e s s o i l . A g l c a n a l y s i s (column B, 130°C) of t h i s m a t e r i a l showed that i t was composed of the ketone 161 (^37%), the enone 162 (^15%) and the s t a r t i n g c y c l o p r o p y l enone 142 (^37%), along w i t h a number of minor u n i d e n t i f i e d i m p u r i t i e s (^11%).  An a n a l y t i c a l sample of each of the three major components  -176-  was obtained by p r e p a r a t i v e g l c (column D, 130°C).  I n each case, the  i d e n t i t y of the compound was confirmed by s p e c t r a l data ( i r , ^Hnmr). D.  At 425°C, Procedure B. -  Following the general procedure B o u t l i n e d  above, a s o l u t i o n of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n nhexane (20 ml) was pyrolysed at 425°C.  Normal work-up, followed by  d i s t i l l a t i o n of the crude o i l , afforded 196 mg (98%) of a c o l o r l e s s o i l . A g l c a n a l y s i s (column B, 120°C) of t h i s m a t e r i a l showed that i t was a mixture of the ketone 161 (^31%) and the enone 162 (^67%), along w i t h very small amounts of u n i d e n t i f i e d i m p u r i t i e s (^2%). passed through a short column of b a s i c alumina. w i t h ether.  This m a t e r i a l was  The column was eluted  Removal of the ether and a n a l y s i s of the r e s i d u a l o i l by g l c  (column B, 130°C) and i r showed that the ketone 161 had isomerized completely to the enone 162. E.  At 450°C, Procedure B. -  Following the general procedure B, a  s o l u t i o n of 3-cyclopropyl-2-cyclohexen-l-one 142 (200 mg) i n n-hexane (20 ml) was pyrolysed at 450°C.  Normal work-up, followed by d i s t i l l a t i o n  of the crude o i l , afforded 142 mg (71%) of a c o l o r l e s s o i l . A g l c a n a l y s i s (column B, 130°C) of t h i s m a t e r i a l showed that i t was composed of the ketone 161 (^5%) and the enone 162 (^91%), along w i t h very s m a l l amounts of u n i d e n t i f i e d i m p u r i t i e s (^4%).  The i d e n t i t i e s of the major products  161 and 162 were confirmed by a c o i n j e c t i o n experiment  involving g l c .  P y r o l y s i s of the T r i m e t h y l s i l y l E n o l Ether of 3-Cyclopropyl-2-cyclohexen1-one 221« - Following the general procedure C o u t l i n e d above, a s o l u t i o n of the enol ether 171 (200 mg, 91% pure) i n ji-hexane (20 ml) was pyrolysed  -177-  at 425°C.  Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h  temperature  ^110°C, 16 Torr) of the crude hydrolysed product, afforded 88 mg of a colorless o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l (column A, 110°C) showed  the presence of only one major product (76%) together w i t h a number of minor i m p u r i t i e s (24%).  An a n a l y t i c a l sample of the major product  was  obtained by p r e p a r a t i v e g l c (column C, 110°C) and was shown ( i r , ''"Hnmr) to be the enone 162.  The number of minor components present i n the  product mixture were not i d e n t i f i e d . P y r o l y s i s of the T r i m e t h y l s i l y l Enol Ether of  2-Methyl-3-cyclopropyl-2-  cyclohexen-l-one 167. - Following the general procedure C o u t l i n e d above, a s o l u t i o n of the enol ether 167 (200 mg, was pyrolysed at 425°C.  96% pure) i n n-hexane (20 ml)  Normal work-up, followed by d i s t i l l a t i o n  (air-bath  temperature 80-115°C, 16 Torr) of the hydrolysed product afforded 67 mg of a colorless o i l .  A g l c a n a l y s i s (column B, 110°C) of t h i s m a t e r i a l showed  the presence of one major component (75%) and a number of minor i m p u r i t i e s which were not i d e n t i f i e d .  An a n a l y t i c a l sample of the major component  was obtained by p r e p a r a t i v e g l c (column D, 115°C) and was shown to be o_cyclopropyltoluene. aromatic), 7.60  This m a t e r i a l e x h i b i t e d "''Hnmr T3.01 (broad s, 4H,  ( s , 3H, -CH ), 7.93-8.40 (m, IH, £><3  ), 8.95-9.50 (m,  4H, c y c l o p r o p y l ) . P y r o l y s i s of 3-Cyclopropyl-2-cyclopenten-l-one. JL4J. - Following the general procedure A o u t l i n e d above, a s o l u t i o n of 3-cyclopropyl-2-cyclopenten-l-one 147 (200 mg)  i n n-hexane (20 ml) was pyrolysed at ^450°C.  followed by d i s t i l l a t i o n ( a i r - b a t h temperature crude o i l afforded 160 mg  Normal work-up,  100-120°C, 16 Torr) of the  (80%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column  -178-  A, 100°C) of t h i s m a t e r i a l showed the presence of four major components together w i t h s m a l l amounts of minor i m p u r i t i e s (^2%) which were not identified.  The major components were shown to be the ketone 157  Cv46%), the enone 158 (^14%), the dienone 159 (>20%) and the dienone 160 (>18%).  An a n a l y t i c a l sample of each major component was obtained  by p r e p a r a t i v e g l c (column B, 120°C).  The pure enone 158 e x h i b i t e d uv  vmax 237 nm (E=11370); i r ( f i l m ) v max 1690, 1630 cm" ; Hnmr, x7.10-7.80 1  (m).  Mol.Wt. Calcd. f o r CgH^g 0: 122.0731.  1  Found (high r e s o l u t i o n mass  spectrometry): 122.0734. The ketone 157 e x h i b i t e d i r ( f i l m ) v 4.58  1740, 1660 cm ; "'"Hnmr, x4.401  max  (m, IH, o l e f i n i c H), 6.57-6.88 (m, IH, -C0CH-), 7.16-8.43 (m, 8H).  The ketone 157 was isomerized to the enone 158 by passing the former through a short column of b a s i c alumina. The dienone 160 e x h i b i t e d uv X 268 nm (£=18630); i r ( f i l m ) v 1640, max max 1570 cm" ; 1  """Hnrnr, x3.44 (d, IH, -C=C-CH=C-  , J=16 Hz), 3.70  (d of q,  1H,-C=C(H)CH J=16 Hz, J'=6 Hz), x4.09 (broad s, IH, C0CH=C), 7.12-7.90 3  (m, 4H), 8.10  (d, 3H,-C=C-CH_, J=6 Hz).  Mol.Wt. Calcd. f o r C H ,0: 122.0731. o  o  — j  ir  1U  Found (high r e s o l u t i o n mass spectrometry): 122.0732. The dienone 159 e x h i b i t e d uv v 226 nm (E=14090); i r ( f i l m ) v 1705, max max 1610 cm" ; 1  H), 6.88  """Hnmr, x3.92-4.40 (m, 2H, o l e f i n i c H), 4.70-5.10 (m, 2H, o l e f i n i c (d, 2H =C-CH_ -C=, J=6.5 Hz), 7.20-7.95 (m, 4H). 2  The dienone 159  was subjected to i s o m e r i z a t i o n by passing i t through a short column of b a s i c alumina.  The s p e c t r a l data obtained from the isomerized product  were i d e n t i c a l w i t h those of the dienone 160. P y r o l y s i s of the g-Cyclopropyl Enone 1J2.. - Following the general procedure 103 A o u t l i n e d above, a s o l u t i o n of the 8-cyclopropyl enone 172  (200 mg) i n  -179-  n-hexane (20 ml) was pyrolysed at ^450°C.  Normal work-up, followed by  d i s t i l l a t i o n ( a i r - b a t h temperature ^75°C, 25 Torr) of the crude o i l , afforded 60 mg  (^30%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column B,  80°C) of t h i s m a t e r i a l showed that i t was composed of the ketone 173 (^90%), m-xylene 174 impurities.  (^8%)  and small amounts of u n i d e n t i f i e d minor  The i d e n t i t y of m-xylene 174 was  confirmed by a c o n i n j e c t i o n  experiment w i t h an authentic sample i n v o l v i n g g l c and by ^Hnmr of the mixture. glc  An a n a l y t i c a l sample of the ketone 173, obtained by p r e p a r a t i v e  (column D,90°C), e x h i b i t e d i r ( f i l m ) v  T4.41 8.30  max (m, IH, CH C0CH-), 7.91  (m, IH, o l e f i n i c H), 6.60 i  3  1655  cm" ; 1  1  Hnmr,  ( s , 3H, -C0CH_ ) , 3  i  (broad , 3H, -C=C-CH_ ). s  3070, 1705,  3  These data were i d e n t i c a l w i t h those of  the same m a t e r i a l reported i n l i t e r a t u r e . P y r o l y s i s of the T r i m e t h y l s i l y l Enol Ether of pentanone 191. -  Following the general procedure C o u t l i n e d above, a s o l u t i o n  of the t r i m e t h y l s i l y l enol ether 191 at 425°C.  2-Cyclopropylmethylenecyclo-  (200 mg)  i n n-hexane (20 ml) was  pyrolysed  Normal work-up, followed by d i s t i l l a t i o n of the crude hydrolysed  product, afforded two f r a c t i o n s . ^90°C, 16 Torr) weighed 87 mg  F r a c t i o n one  (56%).  ( a i r - b a t h temperature up to  A g l c a n a l y s i s of t h i s m a t e r i a l  showed the presence of only one major compound (94%), along w i t h a number of u n i d e n t i f i e d minor i m p u r i t i e s (^6%).  The second f r a c t i o n ( a i r - b a t h  temperature up to ^110°C, 16 Torr) weighed 49 mg  (18%).  A glc analysis  of t h i s m a t e r i a l showed the presence of the same compound as i n f r a c t i o n one, along w i t h a l a r g e amount of higher b o i l i n g i m p u r i t i e s . Both f r a c t i o n s showed the presence of saturated and a,8-unsaturated carbonyl compounds i n the i r spectra.  The two f r a c t i o n s were combined and subjected to column  chromatography on s i l i c a g e l (10 g).  The column was eluted w i t h 10%  ether  -180-  i n hexane.  The major component was i s o l a t e d (52 mg, 38%) and was shown  to be the spiroketone 187.  The l a t t e r exhibited i r ( f i l m ) v  3050, 1742 max  cm 8.70  "4lnmr, T4.10 (m, IH, o l e f i n i c H), 4.55 (m, 10H).  (m, IH, o l e f i n i c H),  Mol.Wt. Calcd. f o r CgH^O: 136.0887.  7.30-  Found (high r e s o l u t i o n  mass spectrometry): 136.0925. P y r o l y s i s of 2-Cyclopropylmethylenecyclohexanone 150. -  Following the  general procedure A o u t l i n e d above, a s o l u t i o n of 2-cyclopropylmethylenecyclohexanone 150 (200 mg) i n n-hexane (20 ml) was pyrolysed at ^450°C. Normal work-up, followed by d i s t i l l a t i o n (air-bath temperature ^110°C, 16 Torr) of the crude o i l afforded 148 mg  (^74%) of a c o l o r l e s s o i l .  A glc  a n a l y s i s (column A, 100°C) of t h i s m a t e r i a l showed the presence of three major components along with small amounts 0^9%) of minor i m p u r i t i e s which were not i d e n t i f i e d .  A n a l y t i c a l samples of each of the three major  components were obtained by preparative g l c (column C, 100°C).  These  compounds were shown to be t e t r a l i n 177 (^38%), the dienone 176  (^9%)  and the spiroketone 175  (^44%).  An a n a l y t i c a l sample of t e t r a l i n 177 exhibited ''"Hnmr t2.98 (S, 4H, aromatic), 7.20-7.50 (m, 4H), 8.10-8.40 (m, 4H).  The i r and Hnmr spectra of 177 were 1  i d e n t i c a l w i t h those of commercially a v a i l a b l e t e t r a l i n . The dienone 176 e x h i b i t e d uv X 209 nm (e=10800), X 263 nm max max ir(film)v  max  3040, 1678, 1610 cm \  (e=3450);  The "''Hnmr showed the presence of two r  terminal methyl groups at T8.99 (t,-CH CH_ , J=7 Hz), and 9.02 2  3  ( t , -CH CH , 2  3  3-1 Hz) of approximately equal i n t e n s i t y , i n d i c a t i n g the presence of a mixture of c i s and trans isomers.  This m a t e r i a l was subjected to hydro-  genation (10% paladium on carbon as c a t a l y s t , methanol as solvent) and the hydrogenated product was i d e n t i f i e d ( i r , ^Hnmr) as 2-n-butylcyclohexanone.  -181-  An a n a l y t i c a l sample of the spiroketone 175 exhibited i r ( f i l m ) v max J  r  r  3080, 1710 cm" ; Hnmr T4.24 (narrow m, w, =2 Hz, 2H, o l e f i n i c H), 7.401  1  7.82 (m, 5H), 7.97-8.60 (m, 7H); Hnmr ( a f t e r a d d i t i o n of 20 mg of the 1  s h i f t reagent E u ( F 0 D ) d ) T3.58 (d of t , IH, o l e f i n i c H, J=6 Hz, J'= 3  27  2 Hz), 3.94 (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 6.44-6.84 (m, 3H), 7.14-7.50 (m, 2H), 7.62-8.12 (m, 7H).  In a decoupling  experiment,  i r r a d i a t i o n at x7.29 caused the two doublet of t r i p l e t s at x3.58 and 3.94 13 to c o l l a p s e to an AB p a i r of doublets w i t h J=5.6 Hz;  Cnmr (protons  decoupled) 6(ppm) 22.96, 27.67, 31.28, 32.29, 39.89 (2 carbons), 64.06 (quaternary carbon), 132.46 ( o l e f i n i c carbon), 133.35 ( o l e f i n i c carbon), 211.48 (carbonyl carbon). Mol.Wt.  Calcd f o r C^gH^O: 150.1044.  Found (high r e s o l u t i o n mass spectro-  metry): 150.1027. The spiroketone 175 was hydrogenated (10% Pd/C i n methanol) to the corresponding saturated spiroketone 179, which e x h i b i t e d i r (film)v 1700 cm ^; ° max 1  Hnmr, x7.50-7.76 (m, 2H), 7.76-8.78 (m, 14H).  These s p e c t r a l data were  i d e n t i c a l w i t h those of an a u t h e t i c sample of 179 prepared from the p i n a c o l rearrangement of the d i o l 1 8 0 .  1 1 7  The d i o l 180 was prepared from the  reductive d i m e r i z a t i o n of cyclopentanone by aluminum and mercuric c h l o r i d e . P y r o l y s i s of the T r i m e t h y l s i l y Enol Ether of 2-Cyclopropylmethylenecyclohexanone 184. A.  At ^450°C, Procedure A. -  Following the general procedure A o u t l i n e d  above, a s o l u t i o n of the t r i m e t h y l s i l y l enol ether 184 (200 mg, 91% pure) i n ii-hexane (20 ml) was pyrolysed at ^Ab^Z. Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^105°C, 56 Torr) of the crude o i l , afforded 148 mg of a c o l o r l e s s o i l . A g l c a n a l y s i s of t h i s m a t e r i a l  -182-  (column B, 120°C) showed the presence of two major components and a number of minor i m p u r i t i e s (^12%) which were not i d e n t i f i e d .  The  two major components were i s o l a t e d by p r e p a r a t i v e g l c (column D, 125°C) and were shown to be the s p i r o enol ether 185 (^74%) and t r a n s - l - p h e n y l 1-butene 186 (M.4%). An a n a l y t i c a l sample of the s p i r o enol ether 185 e x h i b i t e d i r ( f i l m ) v max 3060, 1655 cm ; Hnmr, x4.24-4.37 (m, IH, o l e f i n i c H), 4.45-4.60 (m, IH, -1  1  o l e f i n i c H), 5.28 ( t , IH, -CH=C-0SiMe , J=4 Hz), 7.58-7.90 (m, 2H), 7.903  8.17 (m, 2H), 8.34-8.62 (m, 6H), 9.93 ( s , 9H, - S i ( C H ) ) . 3  f o r C^ H220Si: 222.1440. 3  3  Mol.Wt. Calcd.  Found (high r e s o l u t i o n mass spectrometry):  222.1443. The s p i r o enol ether 185 was subjected to h y d r o l y s i s by s t i r r i n g i t i n 1:1 methanol - d i l u t e h y d r o c h l o r i c a c i d (IN) f o r 15 min.  A f t e r work-up,  the pure spiroketone 175 was obtained, the s p e c t r a l p r o p e r t i e s ( i r , ^Hnmr) of which were i d e n t i c a l w i t h those of the same m a t e r i a l prepared as described previously. An a n a l y t i c a l sample of trans-l-phenyl-l-butene 186 e x h i b i t e d i r ( f i l m ) vmax 3050, 1595, 955, 730, 680 cm" , Hnmr, x2.60-3.00 (m, 5H, aromatic H), 1  1  3.55-4.00 (m, 2H, o l e f i n i c H), 7.64-8.00 (m, 2H), 8.95 ( t , 3H, -CH , J=7 Hz). 3  The s p e c t r a l data l i s t e d above were e s s e n t i a l l y the same as those reported 118 i n the l i t e r a t u r e . B.  • At v-450°C Procedure C (Preparative Scale) - Following the general r  procedure C o u t l i n e d above, a s o l u t i o n of the t r i m e t h y l s i l y l enol  ether  184 (1.0 g, ^90% pure) i n n-hexane (100 ml) was pyrolysed at ^450°C. A f t e r work-up, the crude hydrolysed product was subjected to column chromatography on s i l i c a g e l (50 g, 70-270 mesh).  The column was eluted  -183w i t h pentane and 303 mg (^50%) of pure d i s t i l l e d s p i r o ketone 175 was isolated. C.  I t s i d e n t i t y was confirmed by i r and '''Hnmr data.  At 425°C, Procedure B. -  Following the general procedure B o u t l i n e d  above, a s o l u t i o n of the t r i m e t h y l s i l y l enol ether 184 (200 mg, ^90% pure) i n n-hexane (20 ml) was pyrolysed at ^425°C.  Normal work-up, followed  by d i s t i l l a t i o n ( a i r - b a t h temperature ^105°C, 56 Torr) of the crude o i l afforded 170 mg (^85%) of a c o l o r l e s s o i l .  A g l c a n a l y s i s (column B,  120°C) of t h i s m a t e r i a l showed that i t was composed of the s p i r o s i l y l enol ether 185 (^84%) and a number of u n i d e n t i f i e d minor i m p u r i t i e s (^16%). The i d e n t i t y of enol ether 185 was confirmed by the i r and "'"Hnmr spectra of t h i s m a t e r i a l . P y r o l y s i s of the T r i m e t h y s i l y l Enol Ether of methylcyclohexanone 200. A.  2-Cyclopropylmethylene-3-  At ^380°C, Small Scale. - Following the  general procedure C o u t l i n e d above, a s o l u t i o n of the t r i m e t h y l s i l y enol ether 200 (200 mg, ^90% pure) i n n-hexane (20 ml) was pyrolysed at V380°C. Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature ^70°C, 0.4 Torr) of the hydrolysed crude product afforded 119 mg of a c o l o r l e s s o i l . A g l c a n a l y s i s of t h i s m a t e r i a l showed that i t was composed of the s p i r o ketone 212 (^60%), the spiroketone 213 (^25%) and a number of u n i d e n t i f i e d minor i m p u r i t i e s (^15%). An a n a l y t i c a l sample of each of the major products was obtained by p r e p a r a t i v e g l c (column C, 110°C).  The spiroketone 212  e x h i b i t e d mp 35-38°C; uv X cm  -1  295 nm (e=237); i r (CHC1J v 3080, 1705 max 3 max 1. Hnmr, x4.02-4.38 (m, 2H, o l e f i n i c H), 7.16-8.60 (m, 11H), 9.10  (d, 3H, -CH , J=6 Hz). 3  Mol.Wt. Calcd. f o r C H u  (high r e s o l u t i o n mass spectrometry): 164.1212.  1 6  0 : 164.1201.  Found:  -184-  An a n a l y t i c a l sample of the spiroketone 213 e x h i b i t e d uv A 287 max (e=400); i r ( f i l m ) v 3090, 1705 cm" ; ""-Hnmr T4.02-4.40 (m, 2H, o l e f i n i c 1  IUcLX  H), 7.42-7.80 (m, 4H) , 7.80-8.60 (m, 7H), 9.14 (d, 3H, -CH_ , J=6 Hz). 3  Mol.Wt. Calcd. f o r C T J ^ O  164.1201.  0 2  Found (high r e s o l u t i o n mass  spectrometry): 164.1195. B.  At ^380°C, P r e p a r a t i v e Scale.  F o l l o w i n g the general procedure C  o u t l i n e d above, a s o l u t i o n of the t r i m e t h y l s i l y l enol ether 200 (8.44 g, 0.036 mol, ^90% pure) i n n-hexane (200 ml) was pyrolysed at ^380°C. A f t e r work-up, the crude hydrolysed product was subjected to column chromatography on s i l i c a g e l (350 g) and the column was e l u t e d w i t h 10% ether i n hexane.  A t o t a l of 3.35 g (0.021 mol, 57%) of the s p i r o -  ketones 212 and 213 were i s o l a t e d a f t e r d i s t i l l a t i o n ( a i r - b a t h temperature ^50°C, 0.2 T o r r ) .  P a r t i a l separation of the two isomeric spiroketones  212 and 213 was obtained.  Of the t o t a l 3.35 g i s o l a t e d products, 2.03 g  was pure spiroketone 212, 0.85 g was pure ketone 213 and the r e s t (0.47 g) was a mixture of 212 and 213  VI.  Synthesis of the Spiroketone 193. - A Key S y n t h e t i c Intermediate f o r  the Synthesis of a V a r i e t y of Spirovetivane-type Sesquiterpenoids. Reaction of the Spiroketone 211 w i t h M e t h y l l i t h i u m . - To a c o l d (0°C) s o l u t i o n of the spiroketone 212 (492 mg, 3 mmol) i n dry ether (25 ml) was added dropwise a s o l u t i o n of m e t h y l l i t h i u m (4.5 mmol) i n ether. The r e s u l t i n g mixture was s t i r r e d at 0°C f o r l h , warmed to room temperature and s t i r r e d for an a d d i t i o n a l l h .  Saturated b r i n e (20 ml) was added.  The ether  s o l u t i o n was separated from the aqueous l a y e r and the l a t t e r was e x t r a c t e d w i t h three 30 ml p o r t i o n s of ether.  The combined ether e x t r a c t s were d r i e d  -185over anhydrous magnesium s u l f a t e .  Removal of the ether, followed by  d i s t i l l a t i o n (air-bath temperaturev75°C, 0.4 Torr) of the r e s i d u a l r  o i l afforded  513 mg (95%) of a c o l o r l e s s o i l .  A g l c analysis of t h i s  m a t e r i a l showed the presence of two components i n the r a t i o of 78:22. This material was subjected to column chromatography on s i l i c a g e l (50 g). The column was eluted with 15% ether i n hexane.  The major  component (286.2 mg, 53%) was shown to be the s p i r o a l c o h o l 214 and i t exhibited i r ( f i l m ) v  3060, 3500 cm" ; Hnmr T3.93 (d of t , IH, o l e f i n i c 1  1  max H, J=6 Hz, J'=2 Hz), 4.28 (d of t , IH, o l e f i n i c  H, J=6 Hz, J'=2 Hz),  7.52-8.02 (m, 3H), 8.10-9.90 (m, 9H), 8.78 ( s , 3H, -C(0H)CH ), 9.42 (d, 3  3H, -CHCH , J=6 Hz). Mol.Wt. Calcd. f o r C^H^O: 180.1515.  Found  3  r e s o l u t i o n mass spectrometry): 180.1556.  (high  The s p e c t r a l data of a l c o h o l  214 l i s t e d above were i d e n t i c a l with those of the authentic  material  k i n d l y supplied by Dr. G. Buchi of the Massachusetts I n s t i t u t e of Technology. The minor component (62.1 mg, 11.5% y i e l d ) was shown to be the s p i r o 129 -1 1 alcohol 215 and i t exhibited i r ( f i l m ) v 3070, 3490 cm ; Hnmr x4.19 ' max (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 4.48 (d of t , IH, o l e f i n i c H, J=6 Hz, J'=2 Hz), 7.54-8.66 (m, 12H), 8.96 ( s , 3H, -C(0H)CH_ ), 9.25 (d, 3  3H, -CHCH , J=6.5 Hz). Mol.Wt. Calcd. f o r C H 0 : 180.1515. Found (high 3  12  2Q  r e s o l u t i o n mass spectrometry): 180.1515. Another 78.3 mg (<^14.5%) of a mixture of 214 and 215 was also i s o l a t e d from the column chromatography. 118 Hydroboration of the O l e f i n i c alcohol.214. with Disiamylborane.  To a cold  (0°C) s o l u t i o n of borane-tetrahydrofuran (10 mmol, 1M s o l u t i o n i n tetrahydrofuran) under an atmosphere of argon was added dropwise 1.4 g (20 mmol) of 2-methyl-2-butene.  The s o l u t i o n was s t i r r e d at 0°C f o r 2h.  To t h i s s o l u t i o n  of disiamylborane was added the o l e f i n i c a l c o h o l 214 (180 mg, 1 mmol). The  -186-  r e s u l t i n g mixture was s t i r r e d at 0°C f o r l h , warmed to room temperature and s t i r r e d f o r 21h. I t was then cooled to 0°C. sodium hydroxide  Ethanol (1 m l ) , aqueous  (3N, 7ml) and 30% aqueous hydrogen peroxide s o l u t i o n  (4 ml) were added and the r e s u l t i n g mixture was r e f l u x e d f o r 2h.  Brine  (5 ml) was added and the r e s u l t i n g mixture was extracted w i t h ether.  The  combined ether e x t r a c t s were washed w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . solid.  Removal of the ether gave the d i o l 216 as a yellow  The crude d i o l was r e c r y s t a l l i z e d t o give 153 mg (77%) of pure  white c r y s t a l s which e x h i b i t e d mp 153-155°C; i r (CHCl )v  3480, 3640  0  J max -11 i l cm ; Hnmr, T8.82 (S, 3H, -C(0H)CH ) 9.07 (d, 3H, -CHCH_ , J=6 Hz), 5.553  5.95  3  (m, IH, -CHOH).  Anal.  Calcd. f o r C H 0 : C, 72.68; H, 11.18. Found: C, 72.54; H, 11.10. 1 2  2 2  2  Oxidation of the D i o l 216. to the Keto A l c o h o l 2JL7_. - To a s l u r r y of p y r i d i n i u m chlorochromate (324 mg, 1.5 mmol) i n methylene c h l o r i d e (3 ml) was added a s o l u t i o n of the d i o l 216 (198 mg, 1 mmol) i n methylene c h l o r i d e (10 ml). The r e s u l t i n g red s o l u t i o n was s t i r r e d at room temperature f o r l h . (20 ml) was added. florisil  The mixture was f i l t e r e d through a short column of  (10 g, 80-100 mesh).  of ether.  Ether  The column was eluted w i t h a f u r t h e r 50 ml  Removal of the s o l v e n t , followed by d i s t i l l a t i o n ( a i r - b a t h  temperature ^120°C, 0.2 Torr) of the r e s i d u a l o i l , afforded 176 mg (88%) of the keto a l c o h o l 217 as a c o l o r l e s s o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l  (column A, 150°C) i n d i c a t e d the presence of only one component.  This m a t e r i a l  could be r e c r y s t a l l i z e d from hexane-ether to give white c r y s t a l s , mp 51-52°C; ir(CHCl,)v  3660, 3500, 1730 cm ; """Hnmr, T7.36, 7.84 (AB system, 2H, -1  -i-CH -C0-, J ^ - 19 Hz), 8.72 (s, 3H, -C(0H)CH ), 9.18 (d, 3H, -CHCH 2  J=6.5 HZ).  3  3>  -187-  Anal. Calcd. f o r ^ ^ l o P l ' C, 73.43; H, 10.27. Found: C, 73.53; H, 10.17. Conversion of the O l e f i n i c A l c o h o l ? 1 S i n t o the Keto A l c o h o l 219 The o l e f i n i c a l c o h o l 215  (72 mg) was hydroborated under c o n d i t i o n s  i d e n t i c a l w i t h those used f o r the o l e f i n i c a l c o h o l 214 as described above. Normal work-up, followed by d i s t i l l a t i o n ( a i r - b a t h temperature up to 135°C, 0.4 Torr) afforded 92 mg of a c o l o r l e s s o i l . (column A, 150°C) of t h i s m a t e r i a l showed that i t was s t a r t i n g m a t e r i a l 215  composed of  (^32%), hydroborated product (^58%), along w i t h  a number of u n i d e n t i f i e d minor i m p u r i t i e s (10%). separated  A glc analysis  Fractional d i s t i l l a t i o n  the s t a r t i n g m a t e r i a l 214 together w i t h some minor i m p u r i t i e s  from the hydroborated product.  The l a t t e r was o x i d i z e d by treatment w i t h  pyridinium chlorochromate under c o n d i t i o n s i d e n t i c a l w i t h those used f o r the o x i d a t i o n of the d i o l 216 as described above.  Normal work-up, followed  by d i s t i l l a t i o n ( a i r - b a t h temperature ^120°C, 1 Torr) of the crude product, afforded 30 mg of a c o l o r l e s s o i l .  A g l c a n a l y s i s of t h i s m a t e r i a l (column  A, 150°C) showed the presence of only one major component (^93%) and a number of minor i m p u r i t i e s which were not i d e n t i f i e d . the keto a l c o h o l 219, e x h i b i t e d i r ( f i l m ) v (s, 3H, -C(0H)CH ), 9.16 3  max  The major component,  3500, 1730  (d, 3H, -CHCH_ , J=6.5 Hz). 3  cm" ; 1  1  Hnmr, x8.84  The s p e c t r a l data  l i s t e d above were i d e n t i c a l w i t h those of an authentic sample of the same m a t e r i a l provided by Dr. D. Caine of the Georgia I n s t i t u t e of 129 Technology.  The o v e r a l l y i e l d of 219 from 215 was  Dehydration of the Keto A l c o h o l 217_- 217  (118 mg,  acid.  38%.  To a s o l u t i o n of the keto a l c o h o l  0.6 mmol) i n benzene (20 ml) was added 15 mg of p_-toluenesulfonic  The r e s u l t i n g s o l u t i o n was r e f l u x e d f o r 87h.  The s o l u t i o n was  cooled,  -188-  s u c c e s s i v e l y washed w i t h 5 ml of saturated sodium bicarbonate s o l u t i o n and 5 ml of b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  Removal  of the solvent and d i s t i l l a t i o n ( a i r - b a t h temperature 60-65°C, 0.2 Torr) of the r e s i d u a l o i l gave 96 mg (90%) of a c o l o r l e s s o i l . A g l c a n a l y s i s (column A, 120°C) of t h i s m a t e r i a l showed the presence of only one peak (99%).  However the "'"Hnmr of t h i s m a t e r i a l i n d i c a t e d that i t was a 9:1  mixture of the isomeric keto o l e f i n s 198 and 218 r e s p e c t i v e l y .  An  a n a l y t i c a l sample of the keto o l e f i n 198, obtained by p r e p a r a t i v e t i c ( e l u t i o n w i t h 1:5 ether—hexane),  exhibited i r ( f i l m ) \ J  2980, 1740 cm  ;  max 1  H nmr T4.49-4.66 (m, IH, o l e f i n i c H), 7.76 ( s , 3H, -C=C-CH ), 9.12 (d, 3  3H, -CHCH , J=6.5 Hz). Mol.Wt. Calcd. f o r C^H^O: 178.1358. 3  (high r e s o l u t i o n mass spectrometry):  178.1360.  Found  The i r , "''Hnmr data of  the keto o l e f i n 198 l i s t e d above were i d e n t i c a l w i t h those of authentic samples of the same m a t e r i a l k i n d l y s u p p l i e d by Dr. G. Buchi of the 132 Massachusetts I n s t i t u t e of Technology and by Dr. D. Caine of the 129 Georgia I n s t i t u t e of Technology.  -189BIBLIOGRAPHY 1.  F. W. Comer, F. McCapra, I . H. Qureshi, and A. I . Scott. Tetrahedron, 23., 4761 (1967).  2.  S. Takahashl, H. Naganawa, H. Iinuma, and T. Takita.  Tetrahedron  L e t t . 1955 (1971). 3.  D. G. M a r t i n , G. Slomp, S. Mizsak, D. 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General The f a c i l e thermal Cope rearrangement of 1,2-divinylcyclopropane  systems to the corresponding cycloheptadienes has been the subject of 1 2 extensive study. '  However, most of these studies have been p r i m a r i l y  concerned with a d e l i n e a t i o n of the mechanism of the r e a c t i o n .  Little  e f f o r t has been spent on the i n v e s t i g a t i o n of the a p p l i c a b i l i t y of t h i s transformation to synthesis.  The i n c r e a s i n g number of s t r u c t u r a l l y  i n t e r e s t i n g and b i o l o g i c a l l y a c t i v e n a t u r a l products bearing a sevenmembered r i n g ( f o r example, the sesquiterpenes jaeschkeanadiol 1_, 63 4 himachalene 2^, c a r o l e n i n _3, c o r d i l i n h_ and cyclocolorenone 5) ' , has prompted recent i n v e s t i g a t i o n s regarding the p o s s i b i l i t y of applying t h i s type of transformation to the synthesis of these n a t u r a l products.  1  2  1  1  1  I I . 1,2-Divinylcyclopropane Rearrangements The thermal rearrangement of cis-1,2-divinylcyclopropane compounds to the corresponding cycloheptadiene systems i s a very f a c i l e process, presumably l a r g e l y due to the attendant r e l i e f of r i n g s t r a i n .  In f a c t ,  cis-1,2-divinylcyclopropane i t s e l f (6) has been i s o l a t e d only very recent stable at -20°C, i t rearranges to 1,4-cycloheptadiene 90 sec at 35°C.^  7_ with a h a l f l i f e  In reactions where cis-1,2-divinylcyclopropane would be  the expected product, the compound a c t u a l l y i s o l a t e d has always been 1,4-  -200-  cycloheptadiene.  For example, p y r o l y s i s of the diquaternary hydroxide 8,  y i e l d s only the diene 1_ ( e q . l ) .  Even the r e a c t i o n of diazomethane w i t h  cis-hexatriene i n the presence of cuprous c h l o r i d e at -40°C y i e l d e d the diene _7 rather than the cyclopropane 6_ ( e q . 2 ) .  <  ^^CH N(CH } OH 2  3  J  8  0  o  c  >is ^<:H N(CH3)30H v  7  (1)  *  2  8 CH N 2  2  (2)  CuC£ -40°C  9  Some d e r i v a t i v e s of c i s - 1 , 2 - d i v i n y l c y c l o p r o p a n e are s t a b l e enough to be i s o l a t e d under ordinary c o n d i t i o n s of work-up w h i l e others have been detected only as t r a n s i e n t intermediates.  For example, the b i c y c l i c  d e r i v a t i v e 1_0 has been i s o l a t e d , but i t rearranges r e a d i l y at room temperature to the b i c y c l i c compound 11.  The ketene 13_ was presumed to be the i n t e r -  mediate to account f o r the p h o t o l y t i c decomposition of the diazoketone 1_2 to the b i c y c l i c ketone 14_ (eq. 4 ) .  The l a b i l e ketene 17_ has been detected  i n the low temperature (-190°C) i r r a d i a t i o n of the methoxyketones 16 or 18 (eq. 5 ) . " ^ On warming to -70°C, the ketene spontaneously isomerizes i n a Cope process to give an e q u i l i b r i u m mixture of methoxyketones  i n which the  more s t a b l e isomer 1_8 predominates 10  r. t . 10  (3) 11  -201-  insertion  hv  THF  (4)  15  Wolff rearrangement o = c =  Cope rearrangement  MeO  o-c  o  hv  LI  hv  -70  H  ,9  (5) c  -78<  H 16 The c i s , c i s - d i v i n y l c y c l o p r o p a n e d e r i v a t i v e 1_9_ has been i s o l a t e d and i t rearranges r e a d i l y to the corresponding cycloheptadiene 20 at 75°C; the more l a b i l e c i s , t r a n s isomer 21_ rearranges i n the process of preparation and work-up ( e q . 6 ) .  11  The s t a b i l i t y of the c i s , c i s - i s o m e r ,  i n contrast to that of the c i s , t r a n s - i s o m e r or of c i s - d i v i n y l c y c l o p r o p a n e i t s e l f , has been explained by the s t e r i c i n t e r a c t i o n of the n - b u t y l group w i t h the cis-methylene hydrogen of the ring., which r a i s e s the energy requirement of the b o a t l i k e o r i e n t a t i o n necessary f o r a concerted r e arrangement. R  w W  75  c  <15°C (6)  19 Trans-1,2-divinylcyclopropane has been prepared and i s o l a t e d .  1 2  expected, i t i s much more s t a b l e than the corresponding c i s compound.  As  -202However, thermolysis of t h i s compound a l s o gives 1,4-cycloheptadiene as the major product  (eq.7)  12  Presumably, the cyclopropane r i n g undergoes  homolysis and recombination to g i v e the c i s compound which then rearranges to 1,4-cycloheptadiene _7_ been s u g g e s t e d .  13  A b i r a d i c a l intermediate l i k e 22 has a l s o  14  (7)  S i m i l a r l y , the t r a n s - d i v i n y l c y c l o p r o p a n e d e r i v a t i v e s 23a and 23b have been i s o l a t e d and thermally rearranged to the corresponding c y c l o heptadienes 24a and 24b r e s p e c t i v e l y ( e q . 8 ) . ' ^ 1 1  1  - cr 24  (a) R=n-Bu; (b) R=>=-<: H 2  (8)  5  Incorporating a p o r t i o n of the d i v i n y l c y c l o p r o p a n e moiety i n t o another c y c l i c s t r u c t u r e does not negate the p o s s i b i l i t y of rearrangement . For example,the b i c y c l i c compound 25_ rearranges to the b i c y c l i c compound 26 a t 60°C w i t h i n l h ( e q . 9 ) .  16  60°C lh  ->  (9)  -203Although the conversion of the 1,2-divinylcyclopropane systems to cycloheptadienes has long been e s t a b l i s h e d , the transformation has r a r e l y been applied to synthesis. Recently, Marino and Kaneko reported the use of thermal rearrangement of s u b s t i t u t e d 3-(2-vinylcyclopropyl)-2-cyclohexenl-one 27a and 2-methyl-3-(2-vinylcyclopropyl)-2-cyclopenten-l-one 27b f o r the preparation of the r i n g fused cycloheptadiene d e r i v a t i v e s 28a and 28b r e s p e c t i v e l y (eq. 1 0 ) . ' ^ 1 7  (CH ) 2  (10) n  27  28  (a) n=l, R=H, R =C0 Et; (b) n=o, R=CH 1  2  3>  R^CX^Et  However, the synthesis of the compounds _27_ involved rather tedious procedures.  For example, compound 27b was prepared from  3-chloro-2-methyl-  2-cyclopentenone 29_. Treatment of the l a t t e r with dimethylsulfoxonium methylide gave the sulfoxonium y l i d e 30_.  Reaction of the a l l y l y l i d e 30_  with a c r o l e i n gave the v i n y l cyclopropane _31.  Treatment of compound 3_1  with the W i t t i g reagent _32_ gave a mixture of the trans-divinylcyclopropane 27b and the rearranged product 28b (scheme 1) 17 C0 EtCH=PPh 2  CH =CHCH0 2  \  COzEt  ^^COjEt  trans 27b Scheme 1  28b  if  XHO  32  3  -204-  More r e c e n t l y , Marino  and Wender  independently reported an  improved synthesis of 27_, by the 1,2-addition of the 2 - v i n y l c y c l o p r o p y l l i t h i u m derivatives 33 to 3-alkoxy-2-cycloalken-l-ones 34 (eq. 11).  IrfcCHR  2  (11) 34(a) n=o, R=Me,R =Me, (b) n=o, R=Me, R ^ E t , (c) n=l, R=Me, R =Et, 33(a) R =H, (b) R2=SPh 2  28 ~  At about the same time, a complementary method i n v o l v i n g the synthesis and rearrangement of the b i c y c l i c systems l i k e 27_ was reported by P i e r s and 21 Nagakura.  Reaction of B-iodo-a,B-unsaturated  ketones of general s t r u c t u r e  35 and 216 w i t h l i t h i u m phenylthio(2-vinylcyclopropyl)cuprate, followed by thermal rearrangement of the r e s u l t i n g B-(2-vinylcyclopropyl)-a,B-unsaturated ketones gave the corresponding cycloheptadienes ^8_ and _3_7 r e s p e c t i v e l y , i n good y i e l d (eq. 12 and 1 3 ) .  2 1  (12)  (a) n=l, R=H; (b) n=o, R=H (c) n=lR=CH  (13) 36 (a) n=l; (b) n=o  37  -205-  III.  The Objective The aforementioned  e f f i c i e n t cycloheptadiene a n n e l a t i o n r e a c t i o n  developed i n our l a b o r a t o r y stimulated our i n v e s t i g a t i o n s of the r e a c t i o n of B-iodo-a,B-unsaturated 2-enyl)cuprate _38.  ketones w i t h l i t h i u m  phenylthio(endo-7-norcar-  I t was of s p e c i a l i n t e r e s t to i n v e s t i g a t e i f thermolysis  of the r e s u l t i n g B-alkyl-a,8-unsaturated ketones 39 would g i v e the s t r u c t u r a l l y i n t e r e s t i n g t r i c y c l i c enones 4-0_ as represented i n the f o l l o w i n g scheme:  35  38  39  40  -206-  DISCUSSION I.  General Divinylcyclopropane d e r i v a t i v e s , w i t h part of the d i v i n y l c y c l o -  propane moiety incorporated i n t o another c y c l i c s t r u c t u r e or s t r u c t u r e s , have been shown to be capable of undergoing ordinary Cope type ments.  rearrange-  For example, compounds 10_ and 13 rearranged r e a d i l y to the b i c y c l i 8 9  compounds 11 and 1_4_ r e s p e c t i v e l y (eq. 3 and 4 ) . '  The thermal  rearrange-  ment of compound 41_ to compound 43_ was i n t e r p r e t e d as a Cope rearrangement of 4T to 4_2, which was subsequently  s t a b i l i z e d i n a thermally allowed 1,5-  homodienyl hydrogen s h i f t w i t h regeneration of the aromatic system to give 43_  (eq.14).  21  The o b j e c t i v e of the work described i n t h i s part of the t h e s i s was to synthesize the d i v i n y l c y c l o p r o p a n e d e r i v a t i v e s of the general s t r u c t u r e 39 and to i n v e s t i g a t e whether or not these compounds would undergo normal Cope  -207-  type rearrangement to the corresponding  t r i c y c l i c compounds of general  (15)  (a) n=l ; (b) n=2 I I . Reaction of C y c l i c g-Iodo-ct,g-Unsaturated Phenylthio(7-norcar-2-enyl)cuprate  Ketones w i t h L i t h i u m  Reagent.  To synthesize the d i v i n y l c y c l o p r o p a n e d e r i v a t i v e 39_, the p r e v i o u s l y described methodology i n v o l v i n g the transformation of ketones to the corresponding  g-iodo-a,g-unsaturated  g-cyclopropyl enones was employed.  I t was  expected that i f the l i t h i u m phenylthio (7-norcar-2-enyl) cuprate reagent 3o\ could be prepared, i t would react w i t h c y c l i c g-iodo enones i n a manner analogous to l i t h i u m phenylthio (cyclopropyl)cuprate, and thus produce the d e s i r e d b i c y c l i c system 39_ (eq.16).  Thus, the f i r s t o b j e c t i v e was to  prepare the cuprate reagent 38.  (16)  38  35  39  (a) n=l ; (b) n=2 7,7-Dibromonorcar-2-ene 44_ was obtained i n 71% y i e l d from 1,3-cyclohexadiene by s t i r r i n g the l a t t e r w i t h bromoform i n 50% aqueous sodium  -208-  hydroxide i n the presence of a phase t r a n s f e r c a t a l y s t , t r i e t h y l b e n z y l 22 ammonium c h l o r i d e (TEBA) (eq.17). This material exhibited bp 82-85°C 22 (15 T o r r ) [ l i t bp 68-70°C (8 Torr)] , and i t s s p e c t r a l data were i d e n t i c a l 22 with those reported i n the l i t e r a t u r e . Br  (17)  Preliminary studies by Dr. I . Nagakura of our laboratory had shown that 7,7-dibromonorcar-2-ene  could be reduced by t r i - n - b u t y l t i n h y d r i d e  to a 1:1 mixture of syn and anti-7-bromonorcar-2-ene 45 and 4j5, r e s p e c t i v e l y (eq.18).  However, only the syn compound 4_5 was u s e f u l i n preparing the  (18)  M  45  46 1  cuprate reagent _38.  Therefore, methods for preparing  2-ene 4_5 s t e r e o s e l e c t i v e l y were investigated.  :  1 syn-7-bromonorcar-  I t had been reported  that  sodium cyanoborohydride reduction of 7,7-dibromonorcarane 47_ gave a mixture of syn- and anti-7-bromonorcarane 48 and 4j), i n a r a t i o of 77:21 r e s p e c t i v e l y  -209-  (eq.19).  However, when t h i s procedure was employed i n an attempted  reduction of 7,7-dibromonorcar-2-ene 44, no monobromonorcar-2-ene was obtained.  (19) 47  48  49 77  .:  21  Osborn et a l had reported that 9,9-dibromobicyclo[6.1.Ojnonane 50 could be reduced by z i n c i n a c e t i c a c i d to give a mixture of syn- and anti-9-bromobicyclo [6.1.0] nonane, 51 and 52_, i n a r a t i o of 24 9:1 r e s p e c t i v e l y (eq.20).  When t h i s method was employed i n the  reduction of 7,7-dibromonorcar-2-ene 44_, a mixture of syn and a n t i -  (20) 50  51 9  52 :  1  7-bromonorcar-2-ene 4_5 and 46, i n a r a t i o of ^9:1, r e s p e c t i v e l y was obtained i n 61% y i e l d . The assignment of stereochemistry to compound 45 and 46 was based on  -210the ''"Hnmr s p e c t r a l data.  The proton at C-7 of the syn-monobromo compound  45 gave r i s e to a t r i p l e t at x6.63 w i t h J=7 Hz w h i l e that of the a n t i compound ^6_ produced a t r i p l e t at x7.13 w i t h J=3 Hz.  I t has been w e l l  e s t a b l i s h e d t h a t , i n cyclopropane systems, the v i c i n a l . c o u p l i n g constants 25 J trans , i n g e n e r a l , are lower than Jc i.s .  I t was thus c l e a r that the  three protons on the cyclopropane r i n g of compound 4^5 were i n a c i s (  r e l a t i o n s h i p , whereas i n compound 46, the proton adjacent to the bromine atom was trans to the other two c y c l o p r o p y l protons. Compounds 4_5 and j+6 were q u i t e unstable i n a i r . the mixture turned dark brown w i t h i n  a  At room temperature,  couple of days. 1,3,5-Cycloheptat-  r i e n e _53_ was found i n the "decomposed" m a t e r i a l . bromination occurred w i t h r i n g opening (eq.21).  Presumably,  dehydro-  Attempts to separate 45  (21)  and 46_ by subjecting a mixture of the two isomers to column  chromatography  on s i l i c a g e l (eluted w i t h hexane) r e s u l t e d i n extensive decomposition to the t r i e n e 5_3, w i t h very poor separation of the s u r v i v i n g d e s i r e d compounds. E v e n t u a l l y , i t was found that pure syn-7-bromonorcar-2-ene 45 could be i s o l a t e d from the mixture of isomers by c a r e f u l l y s u b j e c t i n g the mixture to column chromatography  on 150 times i t s weight of f l o r i s i l (120 mesh,  e l u t i o n w i t h hexane). The pure isomer 45_ was employed i n preparing the cuprate reagent 38. Treatment of the monobromo compound. 4_5 w i t h two equivalents of t - b u t y l l i t h i u m  -211-  i n pentane at -78°C f o r 2h generated the syn-lithlum intermediate 5_4 stereospecifically.  A d d i t i o n of tetrahydrofuran and phenylthiocopper  to the s o l u t i o n of the l i t h i u m intermediate _54_ at -20°C gave a c l e a r brown s o l u t i o n of the cuprate reagent 38_ (scheme 2).  Scheme 2 The cuprate reagent _38 thus prepared was allowed to react w i t h 3-iodo-2-cyclohexen-l-one 35b (2h at -20°C, 2h at 0°C).  Examination of  the crude product by i r spectroscopy showed that i t was composed of a mixture of saturated and a,B-unsaturated carbonyl compounds.  A glc analysis  of t h i s m a t e r i a l showed that i t was composed of two major components  (^50%  and^/25% r e s p e c t i v e l y ) and a number of minor i m p u r i t i e s (^25%) . Treatment of t h i s m a t e r i a l w i t h sodium methoxide i n methanol caused the disappearance of the saturated carbonyl absorption i n the i r spectrum , and a s i n g l e major component (^80%) r e s u l t e d (as shown by g l c a n a l y s i s ) .  The l a t t e r m a t e r i a l  was subjected to column chromatography and the major component was  isolated  and i d e n t i f i e d as the t r i c y c l i c enone _55 (72% y i e l d s t a r t i n g from the B-iodo enone 35b).  The enone 5_5 was a white c r y s t a l l i n e s o l i d (mp 59-60°C). I t s  s t r u c t u r e was supported by s p e c t r a l evidence.  A strong absorption band at  251 nm (e=7556) i n the uv spectrum and two strong bands at 1620 and 1660 cm i n the i r spectrum indicated the presence of an a,B-unsaturated ketone. The ^Hnmr spectrum showed the presence of two o l e f i n i c protons, as a symmetrical m u l t i p l e t at x3.54-3.98.  The doubly a l l y l i c proton at one of the bridgehead  1  -212-  p o s i t i o n s gave r i s e to a m u l t i p l e t at T6.19.  The r e s t of the  protons  appeared as a t h i r t e e n - p r o t o n m u l t i p l e t spreading from x7.32 to  8.40.  I t was q u i t e c l e a r from these r e s u l t s that l i t h i u m p h e n y l t h i o ( 7 norcar-2-enyl) cuprate 3_8 had indeed reacted w i t h 1-one  3-iodo-2-cyclohexen-  35b, to give the expected product 39b, which underwent f a c i l e Cope  rearrangement to give the t r i c y c l i c ketone 40b.  The l a t t e r isomerized  p a r t i a l l y under the r e a c t i o n c o n d i t i o n s (or during work-up) to the enone _55.  Treatment of the mixture w i t h sodium methoxide i n methanol completed  the i s o m e r i z a t i o n of 40b to compound 55 (Scheme 3).  _i  MeOH  72% y i e l d  Scheme 3 In s i m i l a r f a s h i o n , r e a c t i o n of 3-iodo-2-cyclopenten-l-one  35a w i t h  the l i t h i u m phenylthio(7-norcar-2-enyl)cuprate reagent _38 gave the t r i c y c l i enone 56 i n 52% y i e l d (eq.22).  The s p e c t r a l data of t h i s m a t e r i a l agreed  w e l l w i t h the s t r u c t u r e assigned.  The i r showed the presence of an  a,3-  -213-  (22)  unsaturated ketone (v  1635, 1685 cm "*") .  A strong absorption band at  max 243 nm (e=8005) i n the uv spectrum was i n agreement with that expected f o r a compound of t h i s s t r u c t u r e .  The ^Hnmr showed the presence of two v i c i n a l  o l e f i n i c protons, each of which gave r i s e to a doublet of doublets (T3.67 and 3 . 9 8 ) .  Each set of s i g n a l s exhibited the same coupling constants,  J=9 Hz, J'=7 Hz.  A broad one-proton doublet at T6.77 w i t h J=7 Hz was  assigned to the doubly a l l y l i c proton at one of the bridgehead p o s i t i o n s . I t was found l a t e r that the anti-7-bromonorcar-2-ene  46 was also  u s e f u l i n preparing the t r i c y c l i c enones 55_ and 56. A 1:1 mixture of syn- and anti-7-bromonorcar-2-ene  (obtained from  the t r i - n - b u t y l t i n h y d r i d e r e d u c t i o n of the dibromo compound 44) was used to prepare a mixture of the cuprate reagents 38_ and 38a i n a procedure s i m i l a r to that used i n the case of the pure monobromo compound _5_5. 4).  (Scheme  Reaction of t h i s mixture of cuprate reagents w i t h 3-iodo-2-cyclohexen-  1-one, followed by treatment of the crude product w i t h sodium methoxide i n methanol, gave a mixture of the t r i c y c l i c enones 5J5 and _5_7 i n a r a t i o of ^1:1  (Scheme 4).  _  .1  1 Scheme 4  '  -214The two compounds were separated by means of column chromatography of the mixture on s i l i c a g e l . The i s o l a t e d y i e l d of each component was ^45%.  The enone _57_ was a white c r y s t a l l i n e s o l i d w i t h mp 53-54°C. I t s  s t r u c t u r e was confirmed by s p e c t r a l data.  The uv spectrum of t h i s  m a t e r i a l showed a very strong absorption at 260 nm (e=19159).  The i r  spectrum showed the presence of an a,B-unsaturated ketone (v 1655, max 1600 cm "S .  Two one-proton m u l t i p l e t s at x3.94 and 4.43 i n the "'"Hnmr  spectrum were assigned to the two o l e f i n i c protons on the i s o l a t e d double bond.  A one-proton broad s i n g l e t was assigned to the a-proton of the  unsaturated ketone f u n c t i o n a l i t y .  a,B-  The r e s t of the protons appeared as a  t h i r t e e n - p r o t o n m u l t i p l e t at T7.52-8.52. When a s o l u t i o n of the enone _57_ i n _o-dichlorobenzene was r e f l u x e d f o r 40h, compound _57 rearranged smoothly to the enone 55, i n n e a r l y q u a n t i t a t i v e y i e l d (Scheme 5 ) . Presumably, an exo -* endo i s o m e r i z a t i o n had occurred g i v i n g the e n d o c y c l i c intermediate 39b which then rearranged to the t r i c y c l i c enone 5_5 (Scheme 5).  57  39b  55  Scheme 5 In a s i m i l a r f a s h i o n , r e a c t i o n of 3-iodo-2-cyclopenten-l-one w i t h a mixture of the l i t h i u m phenylthio(7-norcar-2-enyl)cuprate reagents (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-2-ene), gave a mixture of the t r i c y c l i c enone 56_ (28% i s o l a t e d y i e l d ) and the enone _58 (^30% i s o l a t e d  -215-  yield)(eq.23).  The two compounds were separated by means of column  chromatography  of the mixture on s i l i c a g e l . The enone _58_ was a white s o l i d , mp 78-79°C. I t showed a very strong uv a b s o r p t i o n at 269 nm (e=17176). at 1695, 1595 cm  1  The two bands  i n the i r spectrum i n d i c a t e d the presence of an a, 6-  unsaturated carbonyl f u n c t i o n a l i t y .  Two one-proton m u l t i p l e t s at T3.83 and  4.39 i n the ^Hnmr spectrum were assigned to the two o l e f i n i c protons on the i s o l a t e d double bond. the  A one-proton broad s i n g l e t at T4.13 was assigned to  a-proton of the a,8-unsaturated ketone moiety. When an ^-dichlorobenzene s o l u t i o n of the enone _58 was r e f l u x e d f o r  24h, compound 5_8 rearranged to the t r i c y c l i c enone _56_.  The l a t t e r could  be i s o l a t e d i n 96% y i e l d . On the b a s i s of the r e s u l t s obtained from the experiments j u s t d e s c r i b e d , i t was c l e a r that the conversion of the 3-iodo-2-cyclohexen-l-one and 3-iodo2-cyclopenten-l-one i n t o the t r i c y c l i c enones _55 and ^56^ r e s p e c t i v e l y , d i d not r e q u i r e the use of i s o m e r i c a l l y pure cuprate reagent _38.  Thus, the  rather tedious p u r i f i c a t i o n of endo-7-bromonorcar-2-ene described e a r l i e r was unnecessary.  In p r a c t i c e , the o v e r a l l conversions could be c a r r i e d out  most e f f i c i e n t l y by the f o l l o w i n g sequence of r e a c t i o n s : (a) r e d u c t i o n of 7,7-dibromonorcar-2-ene  w i t h t r i - n - b u t y l t i n h y d r i d e to give a mixture of the  -216-  endo and exo monobromo d e r i v a t i v e s ; (b) conversion of the l a t t e r mixture i n t o a mixture of the corresponding cuprate reagents (38 + 38a); (c) r e a c t i o n of 2(8 + 38a w i t h the iodo enones; (d) thermal rearrangement of r e s u l t a n t mixtures of products i n t o the t r i c y c l i c enones _55_ and 56.  -217EXPERIMENTAL For general information, see the beginning of the experimental  part  of Part I i n t h i s t h e s i s . 22 Synthesis of 7,7-Dibromonorcar-2-ene 44.  -  To a s t i r r e d mixture of  bromoform (12.6 g, 50 mmol), 1,3-cyclohexadiene (4.0 g, 50 m m o l ) , t r i e t h y l benzylammonium  c h l o r i d e (0.1 g) and ethanol (0.2 ml) was added, dropwise,  25 ml of 50% aqueous sodium hydroxide s o l u t i o n . The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 2.5h. Water (50 ml) and pentane (50 ml) were added and the two phases were separated.  The aqueous s o l u t i o n was  extracted with three 30 ml portions of pentane. The combined pentane ext r a c t s were washed twice w i t h 15 ml of water and d r i e d over anhydrous magnesium s u l f a t e .  Removal of the solvent and d i s t i l l a t i o n of the r e s i d u a l  o i l gave 9.02 g (71%) of 7,7-dibromonorcar-2-ene 44_.  This m a t e r i a l exhibited  bp 82-85°C (15 T o r r ) [ l i t . bp 68-70°C (8 T o r r ) ] ; Hnmr, T4.08 (broad s, 2H, 2 6  o l e f i n i c H), 7.70-8.35 (m, 6 H ) .  1  26  24 Reduction of 7,7-Dibromonorcar-2-ene by Zinc i n A c e t i c A c i d .  - To a s o l u t i o n  of 7,7-dibromonorcar-2-ene 44 (12 g, 47.6 mmol) i n g l a c i a l a c e t i c acid (80 ml) was added, with s t i r r i n g , 18.56 g (280 mmol) of z i n c dust i n small portions over a period of two hours at room temperature. A f t e r the l a s t p o r t i o n of z i n c dust had been added, the r e a c t i o n mixture was s t i r r e d f o r another 30 min. Then 50 ml of brine was added and the s o l i d residue i n the r e a c t i o n mixture was removed by f i l t r a t i o n . The aqueous f i l t r a t e was extracted s i x times with 75 ml portions of pentane.  The combined pentane e x t r a c t s were washed t h r i c e  w i t h 15 ml portions of 10% aqueous sodium hydroxide s o l u t i o n , once w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e .  Removal of the solvent and  d i s t i l l a t i o n of the r e s i d u a l o i l gave 5g (61%) of a c o l o r l e s s l i q u i d : bp  -218-  80-83°C (50 T o r r ) .  A g l c a n a l y s i s of t h i s m a t e r i a l (column B, 100°C)  showed that i t was composed of a mixture of syn- and anti-7-bromonorcar-2ene (^91%), 4_5 and 46^ i n r a t i o of 9:1, r e s p e c t i v e l y , along w i t h some minor i m p u r i t i e s (M3%).  A pure sample of each of compounds h5_ and 4_6 was obtained  by column chromatography  of 2g of the mixture on 300 g of 120 mesh f l o r i s i l  ( e l u t i o n w i t h hexane).  An a n a l y t i c a l sample of 45 e x h i b i t e d i r ( f i l m ) v — max 1640 cm" ; """Hnmr, T4.20 (m, 2H, o l e f i n i c H) , 6.63 ( t , IH, -CHBr, J=7 H z ) , 1  7.40-8.65 (m, 6H). Pure compound 46 e x h i b i t e d i r ( f i l m ) v 1640 cm "; "''Hnmr, — max T3.90  (m, IH, o l e f i n i c H), 4.44 (m, IH, o l e f i n i c H), 7.13 ( t , IH, -CHBr,  J=3 Hz), 7.50-8.90 (m, 6H). Compounds 45 and 46^ were q u i t e u n s t a b l e , no elemental a n a l y s i s was obtained f o r these compounds. 27 Reduction of 7,7-Dibromonorcar-2-ene by T r i - n - b u t y l t i n h y d r i d e . (14 mmol) of 7,7-dibromonorcar-2-ene  -  To 3.53 g  44 was added, dropwise, 4.06 g (14 mmol)  of t r i - n - b u t y l t i n h y d r i d e over a period of l h . The r e s u l t i n g s o l u t i o n was s t i r r e d at room  temperature f o r 3h and then d i s t i l l e d ( a i r - b a t h temperature  60-80°, 10 Torr) to give 1.26 g (52%) of a c o l o r l e s s o i l .  A n a l y s i s of t h i s ^  m a t e r i a l by g l c (column B, 100°C) showed that i t was composed of a mixture of syn- and anti-7-bromonorcar-2-ene  (^91%) 45_ and 46^, i n a r a t i o of ^1:1,  along w i t h minor, u n i d e n t i f i e d i m p u r i t i e s (^9%). General Procedure f o r the P r e p a r a t i o n of L i t h i u m Phenylthio(7-norcar-2-enyl) cuprates. -  A flame d r i e d 50-ml three-necked f l a s k , equipped w i t h a bent  side-arm tube containing 258 mg (1.5 mmol) of phenylthiocopper, was evacuated (vacuum pump) and f i l l e d w i t h argon.  A s o l u t i o n of syn- or anti-7-bromonorcar-  2-ene (or a mixture of the two compounds)(259 mg, 1.5 mmol) i n 2 ml of anhydrous ether was t r a n s f e r r e d to the f l a s k .  The s o l u t i o n was cooled to -78°C  -219-  and a s o l u t i o n of t - b u t y l l i t h i u m i n pentane (2M, 1.5 ml, 3 mmol) was added dropwise. Tetrahydrofuran was added.  The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 2h at -78°C. (10 ml, f r e s h l y d i s t i l l e d from l i t h i u m aluminum hydride)  The phenylthiocopper  i n the s i d e arm was t r a n s f e r r e d to the  r e a c t i o n v e s s e l by r o t a t i n g the bent tube.  The mixture was warmed to  -20°C and s t i r r e d at that temperature f o r 30 min.  A c l e a r brown s o l u t i o n  containing 1.5 mmol of the appropriate l i t h i u m phenylthio(7-norcar-2enyl)cuprate r e s u l t e d and was ready f o r use. General Procedure f o r Reaction of L i t h i u m P h e n y l t h i o ( 7 - n b r c a r - 2 - e n y l ) cuprates w i t h B-Iodo-q.B-Unsaturated Ketones. - To a c o l d (-78°C) s o l u t i o n of the appropriate l i t h i u m phenylthio(7-norcar-2-enyl)cuprate 14 ml of ether-tetrahydrofuran-pentane  (under  (1.5 mmol) i n  argon) was added a s o l u t i o n  of the appropriate 8-iodo enone (1.0 mmol) i n 2 ml of dry tetrahydrofuran. The dark red s o l u t i o n which formed was warmed to -20°C and s t i r r e d at that temperature f o r 2h and then at 0°C f o r another 2h. Methanol (2 ml) was added to quench the r e a c t i o n .  The r e a c t i o n mixture was allowed to warm to  room temperature and 15 ml of ether was added.  The r e s u l t i n g mixture was  f i l t e r e d through a short column of f l o r i s i l (15 g, 80-100 mesh). was eluted w i t h another 150 ml of ether.  The column  Crude products were i s o l a t e d by  evaporation of solvent under reduced pressure. Reaction of 3-Iodo-2-Cyclohexen-l-one w i t h the Cuprate Reagent Derived from syjl-7-Bromonorcar-2-ene.  -  Following the general procedure o u t l i n e d above,  1.5 mmol of l i t h i u m phenylthio(7-norcar-2-enyl)cuprate  (derived from pure  syn-7-bromonorcar-2-ene) was allowed to react w i t h 222 mg (1 mmol) of 3iodo-2-cyclohexen-l-one.  Normal work-up gave 173 mg of crude product. The  -220-  i r spectrum of t h i s m a t e r i a l i n d i c a t e d the presence of a mixture of saturated and a,S-unsaturated carbonyl compounds.  A g l c a n a l y s i s of  t h i s m a t e r i a l showed that i t was composed of two major components (^50% and 25% r e s p e c t i v e l y ) and a number minor i m p u r i t i e s (^25%).  The crude mixture  was d i s s o l v e d i n 15 ml of methanol and a c a t a l y t i c amount of sodium methoxide was added.  The r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature f o r l h  and the methanol was then removed under reduced pressure. To the residue was added 30 ml of b r i n e and the r e s u l t i n g mixture was extracted w i t h three 50 ml portions of ether.  The combined ether e x t r a c t s were d r i e d over  magnesium s u l f a t e and evaporated under reduced pressure. The yellow o i l which remained showed no t r a c e of saturated carbonyl absorption i n the i r spectrum.  A g l c a n a l y s i s of t h i s m a t e r i a l showed that i t was composed  of a s i n g l e major component (^80%), together w i t h a number of minor unidentified impurities.  This m a t e r i a l was subjected to column  chromatography  (25 g s i l i c a g e l , e l u t i o n w i t h 25% ether i n hexane), and 134 mg (72%) of the major component was i s o l a t e d and i d e n t i f i e d as the t r i c y c l i c enone 55. The l a t t e r m a t e r i a l was r e c r y s t a l l i z e d from hexane to give white needles which e x h i b i t e d mp 59-60°C; uv X  251 nm (e=7556); i r ( C H C l ) v 1620, max 3 max 0  1660 cm" ; "Hnmr, T3.54-3.98 (m, 2H, o l e f i n i c H), 6.19 (m, IH, -C=C-CH-C=C-), 1  3  7.32-8.40 (m, 13H). Anal. Calcd. f o r C--H ,0: C, 82.94; H, 8.57. Found: C, 82.94; H, 8.46. n  Reaction of 3-Iodo-2-cyclohexen-l-one w i t h the Cuprate Reagents Derived from a 1:1 M i x t u r e of syn and anti-7-Bromonorcar-2-ene. -  F o l l o w i n g the  general procedure, 1.5 mmol of l i t h i u m phenylthio(7-norcar-2-enyl)cuprate (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-2-ene) was allowed to react w i t h 222 mg (1 mmol) of 3-iodo-2-cyclohexen-l-one. Normal work-up  -221-  followed by sodium methoxide treatment and column chromatography of the crude product on 25 g of s i l i c a g e l ( e l u t i o n with 25% ether i n hexane) afforded 86 mg (45%) of the pure t r i c y c l i c enone _55_ and 85 mg (45%) of the pure enone 57_. The enone 57_ was i n i t i a l l y obtained as a c o l o r l e s s viscous o i l .  However, t h i s m a t e r i a l could be r e c r y s t a l l i z e d (from hexane)  to give a white c r y s t a l l i n e s o l i d .  The l a t t e r e x h i b i t e d mp 53-54°C;  uv A 260 nm (e=19159); i r ( f i l m ) v 1655, 1600 cm" ; Hnmr x3.94 max max 1  1  (m, IH, o l e f i n i c H), 4.21 (broad s, IH, -C0CH=C-), 4.43 (m, IH, o l e f i n i c H), 7.52-8.52 (m, 13H). Anal. Calcd. f o r C^H^O: C, 82.94; H, 8.57. Found: C, 82.76; H, 8.65. Reaction of 3-Iodo-2-cyclopenten-l-one svn-7-Bromonorcar-2-ene. -  with the Cuprate Reagent Derived from  Following the general procedure o u t l i n e d above,  1.5 mmol of l i t h i u m phenylthio(7-norcar-2-enyl)cuprate (derived from pure syn-7-bromonorcar-2-ene) was allowed to react w i t h 208 mg (1 mmol) of 3iodo-2-cyclopenten-l-one. reaction.  A d i f f e r e n t work-up procedure was used i n t h i s  A f t e r the r e a c t i o n was complete, methanol (1 ml), ether (20 ml)  and water (10 ml) was added to the r e a c t i o n mixture.  The s o l i d m a t e r i a l  that formed was removed by f i l t r a t i o n and the f i l t r a t e was extracted thoroughly with ether.  The combined ether e x t r a c t s were d r i e d over anhydrous  magnesium s u l f a t e and evaporated under reduced pressure t o give a yellow oil.  This m a t e r i a l was subjected to column chromatography on 25 g of  s i l i c a gel.  E l u t i o n of the column w i t h 25% ether i n hexane afforded  90 mg (52%) of the pure t r i c y c l i c enone 56_. The l a t t e r was r e c r y s t a l l i z e d from hexane, y i e l d i n g white f l a k e - l i k e c r y s t a l s which e x h i b i t e d mp 70-72°C; uv A 243 nm (e=8005); i r ( C H C l ) v 1685, 1635 cm" ; Hnmr, T3.67 (d of d, max 3 max 1  1  0  IH, o l e f i n i c H, J=9 Hz, J'=7 Hz), 3.98 (d of d, IH, o l e f i n i c H, J=9 Hz, J'=7 Hz), 6.77 (broad d, IH, J=7 Hz, -C=C-CH-C=C-), 7.40 (m, IH), 7.50 (m, 2H),  -222-  7.72  (broad s, 4H), 8.05-9.40 (m,  4H).  Anal. Calcd. f o r C^rL^O: C, 82.72; H, 8.10.  Found: C, 82.93; H,  8.12.  Reaction of 3-Iodo-2-cyclopenten-l-one w i t h the Cuprate Reagents Derived from a 1:1 Mixture of syn- and anti-7-Bromonorcar-2-ene. - Following the general procedure o u t l i n e d above, 1.5 mmol of l i t h i u m phenylthio(7-norcar2-enyl)cuprate  (derived from a 1:1 mixture of syn- and anti-7-bromonorcar-  2-ene) was allowed to react w i t h 208 mg  (1 mmol) of  3-iodo-2-cyclopenten-l-  one. Normal work-up, followed by column chromatography of the crude product on 25 g of s i l i c a g e l ( e l u t i o n w i t h 25% ether i n hexane) afforded 49 (28%) of the pure t r i c y c l i c enone _56_ and 53 mg The enone ^8_, which was  (31%) of the pure enone 58.  i n i t i a l l y obtained as a c o l o r l e s s v i s c o u s o i l ,  could be r e c r y s t a l l i z e d from hexane to give white needles. e x h i b i t e d mp 78-79°C; uv X  269 nm  -1  1  The  (e=17176); i r ( f i l m ) v  max cm ;  mg  latter  1695,  1595  max  Hnmr, T3.83 (m, IH, o l e f i n i c H), 4.39  (m, IH, o l e f i n i c H),  4.13  11H).  (broad s, IH, -C=CH-C=0), 7.10-8.60 (m, i  Anal.Calcd. f o r C^H^O: C, 82.72; H, 8.10. Thermal Rearrangement of the Enone 5J_. (72 mg)  Found: C, 82.74; H,  A s o l u t ion of the enone 57  i n o-dichlorobenzene (3 ml) was r e f l u x e d f o r 40h.  under reduced pressure  8.00.  (vacuum pump) and d i s t i l l a t i o n  vL05°C, 0.4 Torr) of the r e s i d u a l o i l gave 68 mg  Removal of solvent  ( a i r - b a t h temperature  (94%) of a c o l o r l e s s o i l .  A n a l y s i s of t h i s m a t e r i a l by g l c (column B, 200°C) showed that i t was composed of the enone 5_5 (^92%) and s m a l l amount of minor i m p u r i t i e s (^8%). This m a t e r i a l was 55 was  subejcted to r e c r y s t a l l i z a t i o n (hexane), and pure enone  i s o l a t e d as white c r y s t a l s .  The s p e c t r a l data of the l a t t e r were  i d e n t i c a l w i t h those of the same m a t e r i a l obtained  earlier.  -223Thermal Rearrangement of the Enone J58_. -  A s o l u t i o n of the enone _58  (40 mg) i n o-dichlorobenzene (1.5 ml) was r e f l u x e d f o r 24h. Removal of solvent and d i s t i l l a t i o n ( a i r - b a t h temperature 'vl05°C, 0.2 Torr) of the r e s i d u a l o i l gave 38 mg (96%) of the pure c r y s t a l l i n e t r i c y c l i c enone 56. A g l c a n a l y s i s (column B, 200°C) of t h i s m a t e r i a l showed that i t was pure.  -224BIBLIOGRAPHY S. J . Rhoads and N. R. Raulins. Org. Reactions,22, 54 (1975). H. M. Frey. Advan. Phys. Org. Chem. 4_, 163 (1966). R. W. M i l l s and T. Money, "Terpenoids and S t e r o i d s , " V o l . 4, S p e c i a l P e r i o d i c a l Reports.  The Chemical S o c i e t y , London, 1974,  Chapter 2. S. M. Kupchan, M. A. Eakin, and A. M. Thomas. J . Med. Chem. 14, 1147 (1971). J . M. Brown, B. T. Golding and J . J . Stofko. J . Chem. Soc. Chem. Comm. 319 (1973). E. Vogel, K. H. Ott and K. Gajek. Ann. 644, 172 (1961). W. von E. Doering and W. R. Roth.  Tetrahedron, 18, 67 (1962).  J . M. Brown, J . Chem. Soc. Chem. Comm. 226 (1965). P. K. Freeman and D. G. Kuper.  Chem.Ind. 424 (1965).  0. L. Chapman and J . D. L a s s i l a .  J . Am. Chem. Soc. 90, 2449 (1968).  G. Ohloff and Pickenhagen. Helv. Chim. Acta. 52, 880 (1969). E. Vogel.  Angew Chem. 74, 829 (1962).  B. S. Rabinovitch, E. W. Schlag and Wiberg.  J . Chem. Phys. 28,  504 (1958). W. von E. Doering and W. R. Roth.  Tetrahedron,19, 715 (1963).  A. A l l , D. Sarantakis, and B. Weinstein. J . Chem. Soc. Chem. Comm. 940 (1971). M. S. B a i r d and C. B. Reese. J . Chem. Soc. Chem. Comm. 1519 (1970). J . P. Marino and T. Kaneko.  J . Org. Chem. 39, 3175 (1974).  J . P. Marino and T. Kaneko.  Tetrahedron L e t t . 3975 (1973).  J. P. Marino and L. J . Browne.  Tetrahedron L e t t . 3245 (1976).  P. A. Wender and M. P. F i l o s a . J . Org. Chem. 41, 3490 (1976).  -225-  21.  G. Maas and M. R e g i t z . Angew Chem. I n t . Ed. Engl. 16, 711 (1977).  22.  M. Makoza, and M. Fedorynski.  23.  R. 0. Hutchins, D. Kadasamy, C. A. Maryanoff, D. Masilamarii and  Synth. Commun. _3, 305 (1973).  B. E. Maryanoff, J . Org. Chem. 42, 82 (1977). 24.  C. L. Osborn, T. C. S h i e l d s , B. A. Shoulders, J . F. Krause, H. V. Cortez, and P. D. Gardner. J . Am. Chem. Soc. 87, 3158 (1965).  25.  D. H. W i l l i a m s , I . Fleming.  "Spectroscopic Methods i n Organic  Chemistry." McGraw-Hill Book Company (UK) L i m i t e d , 1973, p.106. 26.  D. G. Lindsay and C. B. Reese. Tetrahedron,21, 1673 (1965).  27.  H. G. K u i v i l a .  Synthesis, 499 (1970).  

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