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Thietane 1, 1-dioxides as potential analgetics of the methadone type Leung, Chun-Cheung 1978

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THIETANE 1,1-DIOXIDES AS POTENTIAL ANALGETICS OP THE METHADONE TYPE 7-  hj Chun-Cheung Leung B.Sc.(Pharm), N a t i o n a l  Taiwan U n i v e r s i t y , 1969  M . S c , D a l h o u s i e U n i v e r s i t y , 1971  A THESIS SUBMITTED I N PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF 1  DOCTOR OF PHILOSOPHY i n the D i v i s i o n o f Medicinal  Chemistry  of the F a c u l t y  o f Pharmaceutical Sciences  We accept t h i s t h e s i s as conforming t o the required  standard  THE UNIVERSITY OF BRITISH COLUMBIA March, 1978 (§)  Chun-Cheung jteung, 1978  In  presenting  an  advanced  the I  Library  further  for  this  degree shall  agree  scholarly  by  his  of  this  written  in  at  University  the  make that  it  purposes  thesis  for  freely  may  be  It  fulfilment  of  of  Columbia,  British  available for  granted  gain  for  extensive by  the  is understood  financial  shall  copying Head  that  not  Pharmaceutical '  of  University  of  British  17  J u l y  1978  Columbia  the  be  requirements  reference  of  agree  and  of my  I  this  or  allowed  without  Sciences  for that  study. thesis  Department  copying  permission.  2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5  Date  partial  permission  representatives.  Department The  thesis  or  publication my  ii ABSTRACT  T h i e t a n e d e r i v a t i v e s c o n t a i n i n g phenyl and d i me thylaminomethyl  s u b s t i t u e n t s were s y n t h e s i z e d as  poten-  t i a l n a r c o t i c a n a l g e t i c s o f the methadone type. These compounds which are s t r u c t u r a l l y d e r i v e d from the s u l f o n e analogue  o f methadone "by j o i n i n g 0-2  t i o n a l ^ more r e s t r i c t e d  to C - 5 ,  are conforma-  than methadone and  thus may  he  u s e f u l i n e l u c i d a t i n g the c o n f o r m a t i o n o f methadone when bound to i t s r e c e p t o r (pharmacophoric c o n f o r m a t i o n ) . The p h o t o c y c l o a d d i t i o n r e a c t i o n o f t h i o b e n z o phenone and an a p p r o p i a t e o l e f i n i c n i t r i l e diphenyl-3-cy'anothietane, m e t h y l t h i e t a n e and  provided  cis-2.2-diphenyl-3-cyano-4-  trans-2.2-diphenyl-3-cyano-4-methyl-  thietane, cis-2,2-diphenyl-3-methyl-4-cyanothietane trans-2.2-diphenyl-3-methyl-4-cyanothietane. the f i r s t  three thietane d e r i v a t i v e s with  oxybenzoic  2,2-  and  Treatment o f  m-chloroper-  a c i d gave 2 , 2 - d i p h e n y l - 3 - c y a n o t h i e t a n e  1,1-  d i o x i d e , c i s - 2 , 2 - d i p h e n y l - 3 - c y a n o - 4 - n i e t h y l t h i e t a n e 1oxide, cis-2,2-diphenyl-3-cyano-4-methylthietane d i o x i d e and  1,1-  trans-2,2-diphenyl-3-cyano-4-methylthietane  1 , 1 - d i o x i d e . S u b m i t t i n g the c y a n o t h i e t a n e  1,1-dioxides  to h y d r o b o r a t i o n r e d u c t i o n gave the c o r r e s p o n d i n g  pri-  mary amines which were c a t a l y t i c a l l y d i m e t h y l a t e d w i t h formaldehyde a t room temperature to g i v e 3-dimethylaminomethylthietane  2,2-diphenyl-  1,1-dioxide,  cis-2,2-di-  iii phenyl-3-dime thylaminome thyl-4-me t h y l t h i e tane 1 , 1 - d i o x i de a n <  ^  t r a n s - 2 , 2 - d i p h e n y l - 3 - d i m e thylaminome thyl-4-me t h y l -  thietane 1,1-dioxide. Two attempts  to s y n t h e s i z e the p r e c u r s o r s o f  thietane derivatives containing a  dimethylaminomethyl  s i d e c h a i n a t t a c h e d to the carbon °< to the s u l f o n y l  group  gave unexpected r e s u l t s . The r e a c t i o n o f ( 5 - c h l o r o e t h a n e s u l f o n y l c h l o r i d e and acyclic  sulfone,  dime t h y l amino s t y r e n e g e n e r a t e d an  o(-(vinylsulfonyl)-£>-dimethylaminostyrene,  i n s t e a d o f the expected c y c l i c  adduct,  2-phenyl-3-dimethyl-  a m i n o - 4 - c h l o r o m e t h y l t h i e t a n e 1 , 1 - d i o x i d e . The r e p o r t e d r e a c t i o n o f methoxyallene  and thiobenzophenone  diphenyl-3-methoxy-4-methylenethietane  to g i v e 2,2-  was found to p r o -  ceed i n a d i f f e r e n t c o u r s e . The r e a c t i o n was proved t o o c c u r t h e r m a l l y as opposed to a p h o t o c h e m i c a l  reaction.  D u r i n g the c o u r s e o f the s t u d i e s , s e v e r a l r e a c t i o n s were performed  on, 2 , 4 - d i p h e n y l t h i e t e 1 , 1 - d i o x i d e  w i t h a hope o f g e n e r a t i n g 2 , 4 - d i p h e n y l t h i e t a n - 3 - o n e  1,1-  dioxide f o r antiinflammatory studies: T r e a t i n g 2,4-diphenylthiete 1,1-dioxide with sodium h y d r o x i d e r e s u l t e d i n the c l e a v a g e o f the t h i e t a n e r i n g and f o r m a t i o n o f d i b e n z y l  s u l f o n e . The expected  product, 2,2-diphenyl-3-hydroxythietane 1,1-dioxide l i k e l y formed dibenzyl  was  hut r a p i d l y underwent r i n g c l e a v a g e to g i v e  sulfone. The r e a c t i o n o f 2 , 2 - d i p h e n y l t h i e t e 1 , 1 - d i o x i d e  with  concentrated  sulfuric  two r a r e compounds,  a c i d r e s u l t e d i n formation  of  3,c_-5-diphenyl-l,r-2-oxathiacyclo-  penta-3-ene 2-oxide and  3,j;-5-diphenyl-l,r-2-oxathiacyclo-  penta-3-ene 2-oxide. T h i s r e a c t i o n d i d not occur w i t h phenylthiete  2-  1 , 1 - d i o x i d e and 2 - p h e n y l - 4 - m e t h y l t h i e t e -1,1-  dioxide. Hone o f three compounds t e s t e d showed a n a l g e s i c a c t i v i t y i n an i n v i t r o  significant  experiment based on the  inhibition  o f the c o n t r a c t i o n s o f e l e c t r i c a l l y  stimulated  guinea-pig  i l e u m by n a r c o t i c a n a l g e t i c s . I n an i n v i v o  experiment, the compounds were a l s o unable to modify the p a i n t h r e s h o l d o f a r a b b i t towards e l e c t r i c a l on t o o t h - p u l p .  The r e s u l t s i n d i c a t e the e x a c t i n g  ment f o r b i n d i n g o f methadone to the n a r c o t i c  Signature  stimulation  of Supervisor  require-  receptor.  V TABLE OF CONTENTS  PAGE ABSTRACT  .  i i i  LIST OF TABLES  .  x  LIST OF FIGURES ..  .  xi  INTRODUCTION  1  THIETANE CHEMISTRY  2 6  SYNTHETIC APPROACH  60  DISCUSSION  63  1.  S y n t h e s i s o f c y a n o t h i e t a n e s by photoc y c l o a d d i t i o n o f thiobenzophenone w i t h olefinic nitriles  2.  Synthesis of cyanothietane 1,1-dioxides  3.  S y n t h e s i s o f 3-aminomethylthietane dioxides  ...  76  1,1-  4«  Synthesis o f 3-dimethylaminomethylthietane 1 , 1 - d i o x i d e s  5«  Synthesis of 2,2-diphenyl-3-dimethylaminome t h y l t h i e t a n e  6.. Attempted s y n t h e s i s o f t h i e t a n e d e r i v a t i v e s w i t h °<-dime thylaminome t h y l s i d e chain 7.  63  Chemical r e a c t i o n s o f , 2 , 4 - d i p h e n y l t h i e t e 1 , 1 - d i o x i d e and attempted s y n t h e s i s o f 2,4-diphenylthietan-3-one 1,1-dioxide  84 92 100  105  118  PHARMACOLOGICAL TESTING  143  PARTITION STUDIES  150  STRUCTURE-ACTIVITY CONSIDERATIONS  159  ANALYTICAL METHODS EXPERIMENTAL 1.  ...  1 6 6 '  S y n t h e s i s o f thiobenzophenone (9^)  1^7 167  vi PAGE 2.  S y n t h e s i s o f 2,2-diphenyl-3-cyanot h i e t a n e (155)  3.  1  6  7  S y n t h e s i s o f 2,2-diphenyl-3-cyanothietane 1,1-dioxide (l60)  169  S y n t h e s i s o f 2,2-diphenyl-3-aininomethy1thietane 1 , 1 - d i o x i d e ( l 6 l )  170  Synthesis of 2,2-diphenyl-3-dimethyl- . aminomethylthietane 1 , 1 - d i o x i d e (J32) ..  174  6.  S e p a r a t i o n o f c i s - "and 2-butenenitriles  177  7.  Synthesis of cis-2,2-diphenyl-3c y a n o - 4 - m e t h y l t h i e t a n e (156) and cis-2,2-diphenyl-3-methyl-4-cyanot h i e t a n e (158)  4. 5.  8.  Synthesis o f c i s-2.2-diphenyl-3c y a n o - 4 - m e t h y l t h i e t a n e 1-oxide (178)  10.  .  179  ..  180  Synthesis o f cis-2.2-diphenyl-3-aminomethyl-4-methyl-thietane 1,1-dioxide. (179)  11.  Synthesis of c i s-2,2-diphenyl-3-dime thylaminome thyl-4-me t h y l t h i e tane , 1 , 1 - d i o x i d e (33)  12.  13. .  15.  178  Synthesis of cis-2,2-diphenyl-3cyano-4-methylthietane 1,1-dioxide (174) .'.  9.  14.  trans-  181  183  Synthesis of trans-2,2-diphenyl-3c y a n o - 4 - m e t h y l t h i e t a n e (157) and t r a n s 2,2-diphenyl-3-methyl-4-cyanot h i e t a n e (li9_)  185  Synthesis o f trans-2,2-diphenyl-3cyano-4-methylthietane 1,1-dioxide (176)  186  Synthesis of trans-2,2-diphenyl-3aminome t h y l - 4 - m e t h y l t h i e tane 1 , 1 - d i oxide (180)  187  Synthesis of trans-2,2-diphenyl-3-dimethylaminomethyl-4-methylthietane 1,1d i o x i d e (34) ..........>.'  1  190  vii PAGE 16. 17. 18.  19. 20.  21.  Synthesis of 2,2-diphenyl-3-dime thylaminome t h y l t h i e tane (19,1)  191  S y n t h e s i s o f ¥,N-dimethylallylamine (200)  194  Attempted p h o t o c y c l o a d d i t i o n o f t h i o benzophenone (95) to N,N-dimethyla l l y l a m i n e (200)  195  Synthesis of P—chloroethanesulfonyl c h l o r i d e (212) ....  196  R e a c t i o n of (a-chloroe thane s u l f o n y l c h l o r i d e (212) and (5-dimethylaminos t y r e n e (2117  197  S y n t h e s i s o f methyl p r o p a r g y l e t h e r (218)  199  22.  S y n t h e s i s o f methoxyallene (113)  199  23.  S y n t h e s i s o f 2,2-diphenyl-3-methoxy-4-methylenethietane (114) Attempted h y d r o x y l a t i o n o f 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide (22J) w i t h sodium h y d r o x i d e . I s o l a t i o n of d i b e n z y l s u l f o n e (234)  24.  25.  26.  R e a c t i o n o f 2 , 4 - d i p h e n y l t h i e t e 1,1dioxide- (227) w i t h s u l f u r i c a c i d . I s o l a t i o n Of 3 , 5 - d i p h e n y l - l , 2 - o x a t h i a c y c lopenta-3-ene 2-oxide (243, 244)  200  202  203  Attempted h y d r o h o r a t i o n of 2 , 4 - d i p h e n y l t h i e t e 1 , 1 - d i o x i d e (227)  206  Synthesis of 2,2-dichlorophenyla c e t y l c h l o r i d e . (282),  2 0 7  Synthesis of M,N-diethyl-2.2-dic h l o r o p h e n y l a c e t a m i d e (283;  207  29.  S y n t h e s i s o f N,N-diethyl-<*,/5-dic h l o r o - / l - s t y r y l a m i n e (284)  208  30.  Synthesis of  27. 28. '  N,N-diethylphenyl-  viii PAGE  31. 32.  ethynylamine (285)  208  Synthesis of 2,4-diphenyl-3-diethyla m i n o t h i e t e 1 , 1 - d i o x i d e (231)  209  Attempted h y d r o l y s i s o f 2 , 4 - d i p h e n y l 3 - d i e t h y l a m i n o t h i e t e 1,1-dioxide (231)  210  BIBLIOGRAPHY ..  212  XX  LIST OF  TABLES  TABLE I. II. III. IV. V. VI.  PAGE A n a l g e s i c a c t i v i t i e s of methadone and i t s s u l f o n e analogue i n mice  12  V i c i n a l c o u p l i n g ' c o n s t a n t s J(Ha-Hb) of 2 , 2 - d i p h e n y l t h i e t a n e d e r i v a t i v e s  97  V i c i n a l coupling constants of t h i etane d e r i v a t i v e s Chemical amines  s h i f t s of s u l f o n y l  Chemical  s h i f t s of s u l t i n e s  qo  en'  Rm v a l u e s o f t h i e t a n e 1 , 1 - d i o x i d e s a t Qffo methyl e t h y l ketone c a l c u l a t e d from r e g r e s s i o n l i n e s  I l l 135  153  LIST OF FIGURES  FIGURE I. II.  PAGE A n a l g e s i c r e c e p t o r s u r f a c e proposed byB e c k e t t and Casy  17  Pmr spectrum o f 4-methylthietane GD.C1  79  cis-2,2-diphenyl-3-cyano1,1-dioxide d i s s o l v e d i n  3  III.  17.  I n h i b i t i o n of contractions of e l e c t r i c a l l y s t i m u l a t e d g u i n e a - p i g i l e u m by methadone .and t h i e t a n e 1 , 1 - d i o x i d e s  148  E f f e c t o f methadone, t h i e t a n e l l - d i o x i d e s and naloxone on g u i n e a - p i g ileum contractions  149  ?  xi  ACKNOWLEDGEMENTS  The a u t h o r i s i n d e b t e d t o Dr. Frank S. A b b o t t f o r h i s guidance, encouragement and u n d e r s t a n d i n g  through-  out the c o u r s e o f t h i s work.  F i n a n c i a l support from the M e d i c a l Research Council i sgratefully  acknowledged.  xii  DEDICATION  To my  wife,  Li-Tchou  INTRODUCTION  Thousands o f m o r p h i n e - l i k e compounds have appeared i n the l i t e r a t u r e . To date, the m a j o r i t y  of synthetic  anal-  g e s i c s which a r e as a c t i v e as morphine i n r e l i e v i n g p a i n a r e a l l a s s o c i a t e d w i t h t o l e r a n c e and a d d i c t i o n . E x t e n s i v e of m e d i c i n a l  efforts  c h e m i s t s a r e needed t o d e s i g n an a n a l g e s i c  c u l e w i t h o u t these u n d e s i r a b l e  mole-  properties.  1  2  Morphine (1) i s a d e r i v a t i v e o f phenanthrene (2) bridged  by oxygen and n i t r o g e n a c r o s s  the 4, 5 and 9, 13  p o s i t i o n s r e s p e c t i v e l y . The n a t u r a l morphine, i s o l a t e d  from  opium, o c c u r s as a l e v o isomer. The p i p e r i d i n e r i n g D adopts  *  3" OH  2  a c h a i r conformation, boat form w i t h a C/D c i s - f u s e d . The a x i a l C-13  while  the cyclohexene r i n g G i s i n a  r i n g j u n c t i o n t r a n s , r i n g s G and B  being  p h e n o l i c r i n g A i s connected to r i n g D by  bond and  an a x i a l C-9  methylene b r i d g e .  Expanding  the phenanthrene u n i t o f morphine l e a d s to a s e r i e s o f a n a l g e s i c s . The  best known example i s e t o r p h i n e  an  potent  (7,8-.di- .  hydro-7- ( l - ( R ) r - h y d r o x y - l - m e t h y l b u t y l ) -O^-methyl-6,14-endoethenomorphine (J3)) which i s 8600 times the  activity  3  o f morphine i n guinea p i g s a f t e r subcutaneous a d m i n i s t r a t i o n (1-3)• U n f o r t u n a t e l y ,  as the a n a l g e s i c a c t i v i t y  the p h y s i c a l dependence l i a b i l i t y the compound r i s e I t has  in  the  other side e f f e c t s  been g e n e r a l l y a c c e p t e d  a r e the most c r i t i c a l  t h a t the  properly  the p r o p e r l y s i t u a t e d p h e n o l i c components to a n a l g e s i c  s t r u c t u r e of morphine. The  4-phenylpiperidine  o f morphine a f f o r d s a t e r t i a r y amino group separated carbons(C-13, C-15 nucleus.  and  Almost a l l the  used c l i n i c a l l y  of  commensurately.  o r i e n t e d p i p e r i d i n e r i n g and nucleus  and  increases,  G-l6)  from a hydrophobic  activity system by 3  aromatic  s t r o n g n a r c o t i c a n a l g e s i c s which a r e  have these  structurally  similar features  (4,5).  3 Removing the e t h e r b r i d g e o f morphine g i v e s a s e r i e s o f potent  a n a l g e s i c s c a l l e d morphinans. The best (3-hydroxy-N-methylmorphinan  known example i s l e v o r p h a n o l  (A))  which i s used c l i n i c a l l y i n t h i s c o u n t r y and i s more  4  potent  and l o n g e r a c t i n g than morphine. Levorphanol  and o t h e r  morphinan d e r i v a t i v e s have the main s k e l e t o n o f the morphine s t r u c t u r e , l a c k i n g only a hydrofuran  r i n g and an a l l y l i c  hydroxy system i n r i n g G. A p p a r e n t l y ,  n e i t h e r the h y d r o f u r a n  r i n g , n o r the o l e f i n i c a l c o h o l system i s n e c e s s a r y  f o r the  a n a l g e s i c a c t i v i t y . The r i n g j u n c t i o n s i n l e v o r p h a n o l a r e a l s o i d e n t i c a l t o those i n the n a t u r a l morphine, C/D and G/B  ring  j u n c t i o n s b e i n g t r a n s - and c i s - f u s e d r e s p e c t i v e l y . The o r i e n t a t i o n o f r i n g G i s a l s o not important  i n the a n a l g e s i c a c t i v -  (3-hydroxy-N-methylisomorphinan  ityv  N-methylisomorphinan  (5)),  an isomer o f l e v o r p h a n o l w i t h r i n g C and D b e i n g c i s -  f u s e d , r e t a i n s good a n a l g e s i c a c t i v i t y  (6).  A free phenolic  hydroxy group, however, i s r e q u i r e d f o r h i g h a n a l g e s i c potency  4  5  i n morphinan  d e r i v a t i v e s , as i t i s i n morphine ( 7 ) .  That r i n g C o f morphine analgesic  a c t i v i t y can be r e a l i z e d from 6,7-benzomorphan  derivatives. morphinan  i s not important f o r the  In t h i s class of analgesics,  structure  i s replaced  p o s i t i o n s now r e f e r r e d  the r i n g C o f the  by two a l k y l s u b s t i t u e n t s  at  t o a s C-5 and C-9 o f 6,7-benzomorphan  (£>). A simple example i s 2'-hydroxy-2-methyl-5,9-dimethyl6,7-benzomorphan (7,8). Isomers h a v i n g 5,9-dimethyl  = a l k y l or H = H or a l k y l '=• a l k y l  6  substi-  5  7  ( J3 isomer)  8 (d isomer)  t u e n t s i n a c i s ( p isomer) o r t r a n s ( ^ i s o m e r ) r e l a t i o n s h i p w i t h r e s p e c t t o the p i p e r i d i n e r i n g have been i s o l a t e d . A potent  a n a l g e s i c a c t i v i t y i s found  racemates. I n a n i m a l s while  i n both / ( * ) and p(±)  the d racemate i s a s a c t i v e as morphine  the p racemate i s even more p o t e n t . L i k e the s i t u a t i o n s  i n morphine and morphinan, the a n a l g e s i c a c t i v i t y r e s i d e s l a r g e l y i n the l e v o a n t i p o d e s  o f «/ and p d i a s t e r e o i s o m e r s ( 8 ) .  The  cL isomer i s r e l a t e d  s t e r i c a l l y t o morphine and morphinans  and  the p isomer t o i s o m o r p h i n a n ( _ 5 ) . I n monkey i t has been  shown t h a t complete d i s s o c i a t i o n o f the u n d e s i r e d liability  dependence  from a n a l g e s i a c a n be o b t a i n e d i n 6,7-benzomorphan  derivatives. Unfortunately, t h i s highly a t t r a c t i v e can not be observed a n a l g e s i c s having  i n humans ( 9 ) . N e v e r t h e l e s s ,  property  effective  l e s s s i d e e f f e c t s than morphine have been  o b t a i n e d i n t h e 6,7-benzomorphan s e r i e s . Phenazocine hydroxy-2-phenethyl-5,9-dimethyl-6  (oC-2 1  ,7-benzomorphan (_9), f o r  example, i s about t h r e e times a s potent  as morphine and causes  l e s s c i r c u l a t o r y d e p r e s s i o n and o t h e r s i d e e f f e c t s . The d e v e l opment o f t o l e r e n c e i s slower and the a d d i c t i o n l i a b i l i t y i s  6 H (—CH  3 GH  3  OH 9  l e s s a l t h o u g h the The  p o t e n t i a l f o r the abuse s t i l l  exists  (10).  h y d r o a r o m a t i c r i n g B i n morphine, morphinan,  benzomorphan d e r i v a t i v e s s e r v e s to l o c k the system i n t o a r i g i d u n i t  so t h a t  4-phenylpiperidine  the p i p e r i d i n e r i n g i s con-  s t r a i n e d to a c h a i r c o n f o r m a t i o n and  the phenyl r i n g to  an  a x i a l o r i e n t a t i o n w i t h the a r o m a t i c p l a n e p a s s i n g through and  G-4  o f the p i p e r i d i n e r i n g . T h i s a x i a l - p h e n y l - c h a i r  f o r m a t i o n o f the seem to be rigid  G-2  con-  4 - p h e n y l p i p e r i d i n e moiety, however, does not  absolutely  required  f o r analgesic  activity.  Non-  c y c l i c d e r i v a t i v e s i n which the phenyl r i n g can not  constrained t i v i t y and  to an a x i a l o r i e n t a t i o n / , r e t a i n the a n a l g e s i c the u n d e s i r e d t o x i c i t y o f morphine. The  examples are m e p e r i d i n e  (10)..and </-prodine (11).  11  0  be ac-  best known  These  H  10  and  two  7 simple p i p e r i d i n e d e r i v a t i v e s p o s s e s s an e q u a t o r i a l  phenyl  c h a i r c o n f o r m a t i o n . M e p e r i d i n e has about one f i f t h the p o t e n cy o f morphine. I n / - p r o d i n e a the  e t h o x y c a r b o n y l group  propionoxy ; f u n c t i o n  replaces  o f JLO and r e s u l t s i n potency  </-Prodine, which i s about two  rise.  times a s a c t i v e a s morphine, i s  one o f the two racemic d i a s t e r e o i s o m e r s o f p r o d i n e . I t has a trans  3-methyl / 4 - p h e n y l c o n f i g u r a t i o n  and i s about  3 times  l e s s a c t i v e than the second form, (5-prodine (12), which has a c i s - 3-methyl/4-phenyl dine d e r i v a t i v e s  configuration  (11). I n o t h e r p o t e n t pro<  such as ^-promedol,  the p h e n y l group  resides  I  0  p r e f e r e n t i a l l y i n the a x i a l c o n f o r m a t i o n (19). Modification  o f the m e p e r i d i n e  ated a potent a n a l g e s i c ,  fentanyl  s t r u c t u r e has  gener-  (13), i n which the phenyl  13  and the a c y l groups a r e s e p a r a t e d from the p i p e r i d i n e  ring  by a n i t r o g e n atom. In man  f e n t a n y l i s a powerful analgesic,  about 100 times more p o t e n t than morphine  (11).  A l t h o u g h the 4 - p h e n y l p i p e r i d i n e moiety appears to be the most fundamental component o f morphine, benzomorphan, m e p e r i d i n e  morphinan,  and t h e i r d e r i v a t i v e s , the p i p e r i -  dine r i n g i s not c o n t a i n e d i n the s t r u c t u r e s o f a s e r i e s o f a c y c l i c a n a l g e s i c s r e p r e s e n t e d by methadone (14), (15.), dextromoramide  16  (JL6)  and dextropropoxyphene  17  diampromide (17). These  9 acyclic  compounds a r e s t r u c t u r a l l y r e l a t e d and p o s s e s s good  analgesic a c t i v i t y .  The potency o f diampromide  t h a t o f morphine i n r a t s tency tha t. a t  approaches  (12). Dextromoramide p o s s e s s e s a po-  dose o f 5 mg  i s e q u i v a l e n t to 10 mg  f o r the treatment o f p o s t - o p e r a t i v e p a i n (13)-  o f morphine  Dextropropoxy-  phene has been used e x t e n s i v e l y f o r the treatment o f m i l d to moderate p a i n a l t h o u g h i t s potency i n man i n and codeine  f a l l s between a s p i r -  (14). The potency o f methadone i s twice t h a t  of morphine and 10 times t h a t o f meperidine but i t s t o x i c i t y i s 3 to 10 times g r e a t e r than t h a t o f morphine (11). The </methyl isomer o f methadone, isomethadone  (18), and the n o r -  methyl d e r i v a t i v e , normethadone (19), a r e a l s o e f f e c t i v e  anal-  g e s i c s a l t h o u g h l e s s p o t e n t than methadone (14). The c a r b o n y l group  o f methadone has been c o n v e r t e d t o the a l c o h o l and i t s  a c e t y l e s t e r . The a l c o h o l d e r i v a t i v e , methadol  (20), i s l e s s  p o t e n t w h i l e the a c e t y l d e r i v a t i v e , a c e t y l m e t h a d o l (21), i s more p o t e n t and l o n g e r a c t i n g than methadone (15). R e p l a c e ment o f the p r o p i o n y l group  o f methadone by hydrogen,  hydroxy,  1 0  a c e t o x y o r p r o p i o n o x y has r e s u l t e d i n a decrease o r a l a c k o f analgesic  activity  ( 1 1 ) . I t has been proposed t h a t an e l e c -  t r o n i c i n t e r a c t i o n between the amino n i t r o g e n and the c a r b o n y l carbon e x i s t s and l o c k s the methadone m o l e c u l e i n a p i p e r i d i n e - l i k e c o n f o r m a t i o n (22) that: may account f o r t h e ' a n a l g e s i c  2 3  / CH^  Wii  3  \ CH^  22  activity  (16,  1 7 ) . The two p h e n y l groups i n methadone a r e a l s o  important and removal i n analgesic  potency  o f one o f them causes a sharp decrease (18). I t i s p o s s i b l e t h a t  r e s i d u e h e l p s t o m a i n t a i n the p r o p i o n y l  second p h e n y l  group o f methadone i n  1 1  a p o s i t i o n to s i m u l a t e  the a l i c y c l i c  Replacement o f the c a r b o n y l a s u l f o n y l f u n c t i o n has  r i n g of morphine  (11).  group o f methadone w i t h  l e d to an a n a l g e s i c  sulfone.  This  s u l f o n e analogue o f methadone (23) i s as a c t i v e as methadone  23  and  c a r r i e s the resemblance to the l a t t e r i n t h a t the  analge-  s i c a c t i v i t y m a i n l y r e s i d e s i n the R-isomer. L i k e methadone, the R-isomer o f the  s u l f o n e analogue p o s s e s s e s a potency  times t h a t of the S-antipode  (Table I ) . A p r e f e r r e d conforma-  t i o n s i m i l a r to t h a t of methadone was for  the a n a l g e s i c a c t i v i t y o f _23 I t has  been w i d e l y  18  a l s o proposed to account  (16).  accepted  that n a r c o t i c  i n t e r a c t with  some s p e c i f i c r e c e p t o r s i n the  the a n a l g e s i c  e f f e c t s . A number o f attempts have been made to  l o c a l i z e the GNS.  The  techniques  and  to t r i g g e r  s i t e s of a c t i o n of n a r c o t i c a n a l g e s i c s w i t h i n t h a t have been employed i n v o l v e  j e c t i o n of n a r c o t i c a g o n i s t s areas,  OTS  analgesics  observation  or a n t a g o n i s t s  microin-  into various  o f the i n h i b i t i o n of n o c i c e p t i v e  t i o n s o f a g o n i s t s o r examination o f the a c t i o n o f  the  brain reac-  antagonists  Table Analgesic i n mice  a c t i v i t i e s o f methadone and i t s s u l f o n e analogue _23_  (19)  Isomer  Methadone  Sulfone  analogue o f  methadone (23)  a  I  (i)-methadone = 100  Configuration  Activity  +  R  180  -  S  10  +  R  180  S  10  -  a  13 against  the e f f e c t s o f systemic  a d m i n i s t r a t i o n of a g o n i s t s .  Studies  o f p r e c i p i t a t i o n o f the withdrawal syndrome i n mor-  phine-dependent a n i m a l s or a u t o r a d i o g r a p h i c  studies of  d i s t r i b u t i o n of r a d i o a c t i v e a n a l g e s i c s i n the GNS  the  have a l s o  been employed. The  s i t e s o f a c t i o n o f o p i a t e s have been found  to o c c u r w i t h v e r y  considerable  r e s u l t s presented agreement. The  r e g i o n a l v a r i a t i o n s , and  from d i f f e r e n t l a b o r a t o r i e s are not  the  in  l o c a l i z a t i o n of these c e n t r a l s i t e s has  been  a s c r i b e d to the a n t e r i o r thalamus (20), p o s t e r i o r hypothalamus (21), p e r i v e n t r i c u l a r - p e r i a q u e d u c t a l r e g i o n of m i d b r a i n  (22,  23), and  He-  the a r e a  surrounding  the t h i r d v e n t r i c l e (24).  p o r t s from a group r e p r e s e n t e d ever, have p r e s e n t e d  by Herz and  d i s p a r a t e r e s u l t s . They showed t h a t  s t r u c t u r e s e a s i l y reached from the pons and  Teschemacher, how-  4th v e n t r i c l e  the  (medulla,  lower p a r t of m i d b r a i n ) were the main s i t e s of a c t i o n  of a n a l g e s i c s  (25-27). The  d i s c r e p a n c i e s i n the c e n t r a l l o c a l -  i z a t i o n of o p i a t e r e c e p t o r s Unfortunately,  o b v i o u s l y needs to be  the i n v i t r o b i n d i n g  agonists or antagonists  resolved.  studies with narcotic  have not p r o v i d e d  an unambiguous  ans-  3  wer.  Regional  study o f s t e r e o s p e c i f i c b i n d i n g o f H -naloxone  to b r a i n homogenate o b t a i n e d revealed was  from d i f f e r e n t a r e a s o f r a t b r a i n  t h a t the g r e a t e s t amount o f s t e r e o s p e c i f i c b i n d i n g  found i n the corpus s t r i a t u m . The  stem e x h i b i t e d o n l y o n e - q u a r t e r and much s t e r e o s p e c i f i c b i n d i n g i c b i n d i n g was  m i d b r a i n and  the  brain  o n e - e i g h t h r e s p e c t i v e l y as  (28). T h i s p a t t e r n of s t e r e o s p e c i f -  a l s o g e n e r a l l y observed i n monkey and human  b r a i n s by u s i n g H -dihydromorphine  (29). The  g r e a t e s t amount  14 o f s t e r e o s p e c i f i c b i n d i n g was  observed i n amygdala,  d u c t a l area of midbrain,  hypothalamus, thalamus and  nucleus.  found to be v e r y low  The  surrounding Hertz  b i n d i n g was the  i n the  periaquecaudate area  4th v e n t r i c l e , i n c o n t r a s t to the r e s u l t s  et a l . (25-27). On  the o t h e r hand, G o l d s t e i n and  of  his  coworkers (30) demonstrated a set of s t e r e o s p e c i f i c b i n d i n g 3 H -levorphanol  of  i n mice which o c c u r r e d p r e d o m i n a n t l y i n the  b r a i n stem, e s p e c i a l l y i n medulla-pons a r e a . T h i s set o f s t e r e o s p e c i f i c b i n d i n g was ent from those two  shown to p o s s e s s p r o p e r t i e s d i f f e r -  o f naloxone b i n d i n g  (28). I t was  groups of workers were d e a l i n g w i t h d i f f e r e n t  o p i a t e b i n d i n g r e c e p t o r s which were r e l a t e d but somewhat i n s t r u c t u r e and be and  argued t h a t  f u n c t i o n (30). The  s e t s of  different  s i t u a t i o n can  c l a r i f i e d u n t i l the v a r i o u s o p i a t e r e c e p t o r s are studied i n d i v i d u a l l y . Nevertheless,  t h e r e has  not  separated  been a common  f i n d i n g i n t h a t the o p i a t e r e c e p t o r b i n d i n g s are a s s o c i a t e d with neuronal  membranes, m a i n l y w i t h microsomal and  mitochondrial  f r a c t i o n s (28,  29,  30-32). An  crude  H-^-etorphine-  macromolecule complex has  been r e c e n t l y i s o l a t e d when the  membrane f r a c t i o n prepared 3  from r a t b r a i n homogenate was  ed w i t h H - e t o r p h i n e . macromolecule may The  I t was  represent  treat-  shown t h a t t h i s i s o l a t e d bound the p h a r m a c o l o g i c a l  receptor  e x i s t e n c e of o p i a t e r e c e p t o r s has been  (33).  supported  by the r e c e n t i s o l a t i o n of some endogenous substances w i t h opiate a c t i v i t i e s stance  (34-39). Hughes (40,  41)  i d e n t i f i e d a sub-  i n the b r a i n s o f p i g s , cows, g u i n e a p i g s , r a t s , r a b b i t s  and mice, t h a t mimicked the  effect  of morphine to i n h i b i t  con-  15 t r a c t i o n s o f guinea p i g i l e u m . T h i s substance which i s c a l l e d e n k e p h a l i n and has a m o l e c u l a r weight  o f 1000 was found t o be  a .mixture.-o'f two c l o s e l y : related..pentapepti.des h a v i n g the- " following  sequence: Tyr-Gly-Gly-Phe-Met  (Methionine-Enkephalin)  Tyr-Gly-Gly-Phe-Leu  (Leucine-Enkephalin)  S i m i l a r p e p t i d e s were a l s o i s o l a t e d by Snyder and T e r n i u s 35,  39,  42, 4 3 ) -  (34,  G o l d s t e i n i d e n t i f i e d a n o t h e r p e p t i d e from  p i t u i t a r y g l a n d , h a v i n g a m o l e c u l a r weight  o f 1800. He  thought  t h a t t h i s p e p t i d e may be t h e p r e c u r s o r o f e n k e p h a l i n (44, 45)• I t i s i n t e r e s t i n g t o note t h a t e n k e p h a l i n has a tyramine moiety  ( t y r o s i n e minus G00H group) i n the t e r m i n a l p o r t i o n , which  i s a common f e a t u r e o f many o p i a t e a g o n i s t s and a n t a g o n i s t s (46,  47). The c o n f o r m a t i o n o f met-enkephalin  has been  proposed  on the b a s i s o f s t r u c t u r a l s i m i l a r i t i e s w i t h morphine and r e lated analgesics  ( 6 4 - 6 7 ) .  O p i a t e r e c e p t o r s a r e a l s o l o c a t e d i n the p e r i p h e r a l nervous  t i s s u e s o f c e r t a i n animal  s p e c i e s . The t r a n s m i s s i o n  from the m y e n t e r i c p l e x u s t o the l o n g i t u d i n a l muscle i s dep r e s s e d by morphine i n g u i n e a p i g s (48, 49). The t r a n s m i s s i o n from v a g a l nerve  t o s i n o a t r i a l node i s morphine s e n s i t i v e i n  r a t s and r a b b i t s  (50). As f a r as a d r e n e r g i c autonomic j u n c -  t i o n s a r e concerned,  the n i c t i a t i n g membrane o f c a t s and the  vas d e f e r e n s o f mice a r e morphine s e n s i t i v e The  (24,  51-53)..  d e p r e s s a n t a c t i o n s o f n a r c o t i c a n a l g e s i c s on the  guinea p i g i l e u m have been i n t e n s i v e l y i n v e s t i g a t e d i n r e c e n t years  (28, 48, 49, 54-62). Morphine and o t h e r potent  narcotics  16  s t e r e o s p e c i f i c a l l y produce depressant e f f e c t s on the e l e c t r i c a l l y evoked c o n t r a c t i o n s o f g u i n e a p i g i l e u m i n the concen—R t r a t i o n range o f 10"  —Q t o 10"^ M (49). The p o t e n c i e s  t i c a g o n i s t s and a n t a g o n i s t s  of narco^  i n the i n h i b i t i o n o f c o n t r a c t i o n s  have been demonstrated t o p r e d i c t a c c u r a t e l y the a n a l g e s i c potencies  o f these drugs i n a n i m a l s and i n man  (63).  Tolerance  to a c t i o n s o f n a r c o t i c a n a l g e s i c s and withdrawal e x c i t a t i o n s p r e c i p i t a t e d by u s i n g n a r c o t i c a n t a g o n i s t s  such as naloxone  have a l s o been demonstrated i n t h i s t i s s u e (49, 6 l ) . now been w i d e l y  accepted  model f o r a n a l g e s i c  I t has  that guinea p i g ileum i s a r e l i a b l e  s t u d i e s . I t s u s e s i n the i n v e s t i g a t i o n o f  n a r c o t i c a n a l g e s i c s have c e r t a i n advantages. E f f e c t s o f abr-:/_ sorption, d i s t r i b u t i o n , biotransformation drugs a r e l i m i t e d o r almost c o m p l e t e l y  and e x c r e t i o n o f the  excluded. I n the stud-  i e s of s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p of n a r c o t i c  analgesics  i n whole a n i m a l s , s e r i o u s d i f f i c u l t i e s i n the i n t e r p r e t a t i o n of r e s u l t s have a r i s e n due t o the c o n s i d e r a b l e v a r i a t i o n i n the l i p o p h i l i c i t y o f n a r c o t i c a n a l g e s i c drugs and t h e r e f o r e in their ability  to p e n e t r a t e  the b l o o d b r a i n b a r r i e r . I t has  been known t h a t , i n whole a n i m a l s , r e l a t i v e l y h y d r o p h i l i c n a r c o t i c s such as morphine a r e more a c t i v e a f t e r i n t r a v e n t r i c u l a r than i n t r a v e n o u s  a d m i n i s t r a t i o n , w h i l e no s i g n i f i c a n t  ence i s found f o r more l i p o p h i l i c The  compounds ( 2 6 ,  differ-  6 8 , 69).  n a t u r e o f o p i a t e r e c e p t o r s has been demonstrated  to be p r o t e i n (33, 7 0 ) , p h o s p h o l i p i d  (71, 72) and p r o t e o l i p i d  (73, 74). I t i s l i k e l y t h a t the o p i a t e r e c e p t o r s a r e membrane bound complexes whose s t e r e o s p e c i f i c b i n d i n g i s dependent on  17 the i n t e g r i t y o f hoth p r o t e i n s and  phospholipids  {13).  The  shape of the o p i a t e r e c e p t o r has "been proposed by B e c k e t t Gasy (17) a c c o r d i n g c o t i c a n a l g e s i c s and  to the common s t r u c t u r a l f e a t u r e s of studies of s t r u c t u r e - a c t i v i t y  drugs. A r e c e p t o r s u r f a c e was  formulated  l a t e r modified  (19) to .accommodate the r i g i d  s k e l e t o n of  I).  The  o t h e r c y c l i c and  r e c e p t o r was  acyclic analgesics  proposed to c o n s i s t of three  nar-  relation-  s h i p s on these  r a l morphine and  and  and natu-  (Figure  essential  Figure I A n a l g e s i c r e c e p t o r s u r f a c e proposed by B e c k e t t  and  Gasy  (17,  19).  sites: a flat o r aromatic  s u r f a c e which a l l o w s b i n d i n g w i t h  nucleus  the  phenolic  o f the a n a l g e s i c m o l e c u l e , an a n i o n i c  site  18 which a s s o c i a t e s w i t h  the p o s i t i v e l y charged ammonium group of  the drug m o l e c u l e , and i n g C(15)-C,(l6)  a c a v i t y which accommodates  .the p r o j e c t -  p o r t i o n o f p i p e r i d i n e r i n g i n morphine  other a n a l g e s i c molecules.  The  stereochemical  and  requirements  f o r the a n a l g e s i c a c t i v i t i e s of morphine, morphinan, 6,7-benz— omorphan and  t h e i r d e r i v a t i v e s have been a t t r i b u t e d to  s p a c i a l c o n s t r a i n t of the b i n d i n g s i t e s on the r i g i d s u r f a c e . I n the e x p l a n a t i o n acyclic  receptor  of a n a l g e s i c a c t i v i t i e s of c e r t a i n  compounds such as methadone, methadol,  acetylmethadol  and  diampromide e t c . , Portoghese has  one  b i n d i n g mode can o c c u r i n the i n t e r a c t i o n o f these  b l e drugs w i t h  the  Recently, to e x i s t i n two  the  p o s t u l a t e d t h a t more than  same a n a l g e s i c r e c e p t o r  (75,  flexi-  76).  the o p i a t e r e c e p t o r has been proposed  i n t e r c o n v e r t i b l e s t a t e s which are  f o r t r i g g e r i n g the a g o n i s t i c and  (5)  responsible  antagonistic a c t i v i t y  respec-  t i v e l y . Sodium i o n i s thought to modulate the i n t e r c o n v e r s i o n of the two  s t a t e s by a c t i n g on the a l l o s t e r i c  s i t e of the r e -  c e p t o r . Under the p r e v a i l i n g sodium c o n c e n t r a t i o n i n the b r a i n , the o p i a t e r e c e p t o r i s c o n s i d e r e d  to e x i s t p r e d o m i n a n t l y i n  the a n t a g o n i s t i c s t a t e . As mentioned p r e v i o u s l y , ' t h e a n a l g e s i c a c t i v i t y methadone was  a t t r i b u t e d to the p i p e r i d i n e - l i k e  of  conformation  r e s u l t i n g from an i n t r a m o l e c u l a r i n t e r a c t i o n between the n i t r o g e n atom and  the c a r b o n y l  carbon (16). T h i s e l e c t r o n i c  i n t e r a c t i o n appears to be p r e s e n t  i n the c r y s t a l ' s t r u c t u r e of o  methadone f r e e base. A s h o r t d i s t a n c e of 2.91 two  atoms was  observed by Bye  A between the  (77). I n s o l u t i o n , the magnitude  19  Methadone  of  t h i s i n t e r a c t i o n i s c o n s i d e r a b l y weaker than what i s gener-  a l l y b e l i e v e d . S t u d i e s by c i r c u l a r d i c h r o i s m and p r o t o n magn e t i c resonance done  (78) i n d i c a t e d t h a t N...CO i n t e r a c t i o n o f meth  i slikely  p r e s e n t i n the m o l e c u l e so t h a t i n CDCl^  s o l u t i o n t h r e e p o s s i b l e conformers, 14a, 14b and 14c were  14a  14b  14c  p r e s e n t i n a p p r o x i m a t e l y 1:1:2 r a t i o . The N...CO i n t e r n a l a s s o c i a t i o n i s p o s s i b l e i n the conformers 14a and 14c, but i t certainly  d i d n o t predominate  t o the e x c l u s i o n o f the unasso-  c i a t e d rotamer 14b. I n CD^OD s o l u t i o n a c o n f o r m e r i c d i s t r i b u t i o n o f a p p r o x i m a t e l y 1:4:5 (14a:14b:14c) o c c u r r e d . The p e r -  20 sistence  o f 14b  i n both s o l v e n t s i s s u r p r i s i n g i n l i g h t  considerable s t e r i c interactions. by  the  ish  solvation  e f f e c t of p o l a r  I t s presence was solvents,  of the  P h C C ( 0 ) E t and  ~N(CEj)  2  as r e p r e s e n t e d by  physiological  pH,  w i t h the  narcotic  the  14b  c a r b o n y l oxygen i s s t i l l  that  the  species that  the  one  and  the  proton-  interacts Gasy,  p o s i t i v e ammonium group  possible  a  (79).  r e c e p t o r . A c c o r d i n g to B e c k e t t and  e l e c t r o n i c a t t r a c t i o n between the  In  d i s p o s i t i o n of  methadone appears as  a t e d form, which i s expected to be  dimin-  diphenylpropylamine  a n a l g e s i c s p o s s e s s e s an a n t i p e r i p l a n a r - l i k e  At  (78).  study of 5-methylmethadone i t i s b e l i e v e d  pharmacophoric c o n f o r m a t i o n s of  2  explained  which tend to  the magnitude of i n t r a m o l e c u l a r a s s o c i a t i o n  more r e c e n t  of  the  an and  piperidine-like  Methadone, p r o t o n a t e d  c o n f o r m a t i o n that (16). in was  the  f i t s the  This electronic crystalline  hypothetical  receptor s t i l l  i n t e r a c t i o n , however, was  structure  not  exists  observed  of methadone hydrobromide which  found to e x i s t i n an a n t i p e r i p l a n a r  conformation  (80).  21  0  2 A n t i p e r i p l a n a r conformation of methadone  hydrobromide  Measurements by u s i n g c i r c u l a r d i c h r o i s m and p r o t o n  magnetic  resonance methods a l s o i n d i c a t e d t h a t the presence o f such an extended  form c o u l d not be excluded  i p l a n a r c o n f o r m a t i o n was  (78). A p r e f e r r e d  antiper-  a l s o observed f o r isomethadone  and normethadone (19) i n o r g a n i c s o l u t i o n s  A l t h o u g h methadone may  (78, 81).  exist i n certain preferred  conformations i n p h y s i o l o g i c a l f l u i d ,  whether or not  such  p r e f e r r e d c o n f o r m a t i o n s can be r e l a t e d to the a n a l g e s i c ities  (18)  o f methadone i s q u e s t i o n a b l e . I t has been now  activ-  fairly  w e l l a c c e p t e d t h a t both the r e c e p t o r macromolecule and  the  22 drug molecule  can i n f l u e n c e the c o n f o r m a t i o n o f each o t h e r .  The p r e f e r r e d c o n f o r m a t i o n o f methadone may he p e r t u r b e d by the i n t e r a c t i o n f o r c e s e x i s t i n g between the drug and the r e c e p t o r . Thus the p r e f e r r e d c o n f o r m a t i o n o f methadone i n s o l u t i o n may not be the p h a r m a c o l o g i c a l c o n f o r m a t i o n , the conformation that f i t s  the p e r t u r b e d r e c e p t o r macromolecule.  To i n v e s t i g a t e the n a t u r e o f i n t e r a c t i o n between the a n a l g e s i c r e c e p t o r and the s t r u c t u r a l l y f l e x i b l e methadone m o l e c u l e , c o n f o r m a t i o n a l l y r e s t r i c t e d analogues  o f methadone seems t o be  b e t t e r s u i t e d . A few c o n f o r m a t i o n a l l y r i g i d methadone a n a l o gues, such as 2A and _25_ have been s t u d i e d . I n g e n e r a l , such  GH 24  3  25  Methadone  s t r u c t u r a l m o d i f i c a t i o n s o f methadone r e s u l t e d i n l e s s or  i n a c t i v e compounds  ( 8 2 ) . I t i s p o s s i b l e t h a t the s t e r e o -  c h e m i s t r y o f these r i g i d isfy  the r e q u i r e m e n t s  active  analogues  o f methadone does not s a t -  demanded by the o p i a t e r e c e p t o r .  T h i e t a n e 1 , 1 - d i o x i d e s such as 2G a r e c o n s i d e r e d t o be s t r u c t u r a l l y s i m i l a r to the s u l f o n e analogue  o f methadone  23 (23) which i s b e l i e v e d , as mentioned i n page 11, to i n t e r act  w i t h o p i a t e r e c e p t o r i n the same manner as t h a t o f 22.  GH.  CH-,  V  CH^  IT-  IT-  /  CH-  CH.  CH-  so,  -SO,  CH-  CH-> 23  26  S t u d i e s o f these r e l a t i v e l y new cyclic  s u l f o n e s may  diphenylpropylamine icant  degree  ( s u l f o n e analogue methadone)  and l e s s  investigated  l e a d to development o f new  potent  type a n a l g e s i c s c o n t a i n i n g a  of conformational  of  signif-  rigidity.  The p r e s e n t p r o j e c t c o n t i n u e s p r e v i o u s i n v e s t i g a t i o n s , i n our l a b o r a t o r y , o f t h i e t a n e 1 , 1 - d i o x i d e s f o r medic a l uses  (83-86).  Because o f the s y n t h e t i c d i f f i c u l t y  en-  countered i n the s y n t h e s i s o f £ 6 , Coates and Haya ( 8 4 , 8 5 ) , on the b a s i s o f c e r t a i n assumptions  and p r o p o s a l s , synthe-  sized 2,4-diphenyl-3-dimethylaminomethylthietane 1,1-dioxides (27-29) and  2-phenyl-3-dimethylaminomethylthietane  d i o x i d e s (J30, ,3_1) as an approach  to a p p l y the s e m i r i g i d  etanes to the s t u d i e s o f methadone-receptor these compounds were found ty.  I n comparison  phenyl group,  thi—  interaction. A l l  to be d e v o i d o f a n a l g e s i c a c t i v i -  w i t h the s t r u c t u r e o f _ 2 6 ^  phenyl group o n C ( 2 ) . I t  1,1-  27-31  lacks a  i s p o s s i b l e that t h i s missing  r a t h e r than the one a l r e a d y p l a c e d on  24  27  R  1  =  H,  R  2  = H  28  R  1  =  H,  R  2  = G l or  29  R  1  R  2  =  CH^,  _3_0 R = H N0  31 R =  2  the f l a t  ure I ) . I t was  two  be o f i n t e r e s t . The  the r e q u i r e d o r i e n t a t i o n  s u r f a c e o f the a n a l g e s i c r e c e p t o r  considered,  pounds 32-36, w i t h  (Fig-  t h e r e f o r e , t h a t s y n t h e s i s of com-  p h e n y l groups on the G(2)  carbon, would  h i g h s i m i l a r i t y of these compounds to  s u l f o n e analogue o f methadone (23) r e a s o n a b l y they would be potent was  3  = H  the.C(2) carbon o f t h i e t a n e r i n g , has to b i n d w i t h  CH  a n a l g e s i c s . The  d e s i r a b l e to e x p l o r e  the  32 R = H  s y n t h e s i s o f J35 and  suggestion  CH  suggested  by p r e v i o u s  3  35 c i s  33 R = GH^  cis  34 R = CH-  trans  36  trans  the  that _36  workers  (84,  8 5 ) t h a t a c l o s e a p p r o x i m a t i o n of amino s i d e c h a i n  s u l f o n e group may  be n e c e s s a r y f o r the achievement.of  s i c a l l y active thietane derivatives.  to  ahalg  26  THIETANE CHEMISTRY  Two r e v i e w a r t i c l e s on t h i e t a n e peared i n the l i t e r a t u r e  c h e m i s t r y have ap-  (87, 88). Surveys on the same s u b j e c t  i n c l u d i n g the l i t e r a t u r e to 1973 a r e found i n two d i s s e r t a t i o n s (84,  85). The m a t e r i a l p r e s e n t e d i n t h i s s e c t i o n i s a b r i e f  summary o f p u b l i c a t i o n s t h a t have not been p r e v i o u s l y w i t h emphasis on the c h e m i s t r y r e l e v a n t lem  o f the p r e s e n t  covered,  to the r e s e a r c h  prob-  project.  T h i e t a n e d e r i v a t i v e s have been known to p o s s e s s nonplanar  s t r u c t u r e s . The r i n g p u c k e r i n g  v i b r a t i o n o f the t h i e t a n e  r i n g was observed i n i r (89), f a r i r ( 9 0 ) , and pmr t r a . The d e t e r m i n a t i o n  (91) spec-  of molecular structure of thietane  by e l e c t r o n d i f f r a c t i o n ,  showed t h a t the bond l e n g t h s o  C-C, and C-H were 1.84, 1.55 the bond a n g l e s o f C-S-C  (37)  o f C-S,  and 1.10 A r e s p e c t i v e l y and t h a t  and H-C-H  t i v e l y . The a n g l e o f p u c k e r i n g  were 76.8 and 112°  d e f i n e d by C2-S-C4 p l a n e and C2-  C3-C4 p l a n e was 2 6 ° (92). I n s u b s t i t u t e d t h i e t a n e s ,  37  respec-  the non-  \  bonded i n t e r a c t i o n s o f the s u b s t i t u e n t s would p a r t i c u l a r l y fa> v o u r a puckered s t r u c t u r e . I n f r a r e d s t u d i e s showed t h a t chlorothietane being  3-  p o s s e s s e d a bent r i n g w i t h the c h l o r i n e atom  equatorial  ( 9 3 ) . The x - r a y c r y s t a l l o g r a p h y  showed  that  27 (p-chlorobenzenesulfonamido )-|5-propiothiolactone was  pucker-  ed "by about 13° ( 9 4 ) . P u c k e r i n g o f the r i n g has a l s o been observed i n the t h i e t a n e 1-oxide d e r i v a t i v e s . The c r y s t a l t u r e o f c i s - 2 , 4 - d i p h e n y l t h i e t a n e trans-l-dxi.de  struc-  (38), d e t e r m i n -  ed by x - r a y c r y s t a l l o g r a p h y , p o s s e s s e d a puckered t h i e t a n e r i n g to accommodate two e q u a t o r i a l p h e n y l groups. The bond d i s t a n c e s and the bond a n g l e s were s i m i l a r to those o f unsubs t i t u t e d t h i e t a n e , the bond l e n g t h s o f S-C and G-G  being  1.85  38  o and 1.57 A r e s p e c t i v e l y ; and the bond a n g l e s o f G-S-G, and C-C-C  b e i n g 76.5, 86.9 and 93.9° r e s p e c t i v e l y  (95). The  a n g l e o f p u c k e r i n g was found to be 41.9°. The s u l f i n y l was  shown to have e q u a t o r i a l o r i e n t a t i o n  o r i e n t a t i o n of s u l f i n y l and  (95). The  S-C-G  oxygen  equatorial  oxygen was a l s o observed i n both c i s -  t r a n s - 3 - ( p - b r o m o p h e n y l ) t h i e t a n e 1-oxide ( 9 6 ) .  Thietane  1,1-dioxide d e r i v a t i v e s a l s o possess a nonplanar t h i e t a n e r i n g . Z i e g l e r e_t a l . s t u d i e d the m o l e c u l a r s t r u c t u r e o f 2,2dimethylthietane 1,1-dioxide  (39) by x - r a y methods. They show-  ed t h a t the t h i e t a n e r i n g was puckered by 23° (97). A n d r e t t i et a l . r e p o r t e d t h a t the t h i e t a n e r i n g o f c i s - 2 - c h l o r o - 3 - m o r -  28  0  39  pholino-4,4-dimethylthietane  1 , 1 - d i o x i d e was puckered by  2 6 . 6 °  (98). The  x-ray studies of  cis-2.2-diphenyl-3.4-dichloro-  t h i e t a n e and i t s o x i d a t i o n p r o d u c t ,  _cis-2,2-diphenyl-3,4-di-  c h l o r o t h i e t a n e 1 , 1 - d i o x i d e showed an i n t e r e s t i n g r e s u l t (99, 100). angles  The t h i e t a n e r i n g s i n both compounds were puckered, by o f 29 and 31.3° r e s p e c t i v e l y . The c o n f o r m a t i o n s o f C-Gl  bonds were 3 - e q u a t o r i a l and 4 - a x i a l w i t h r e s p e c t tane r i n g i n the former compound  to the t h i e -  (40). The o x i d a t i o n o f t h i e -  tane _40 t o s u l f o n e _41 r e s u l t e d i n 3 - a x i a l and  4-equatorial  40  c o n f o r m a t i o n s o f two C - C l bonds i n the t h i e t a n e  41  1,1-dioxide.  29 The  r i n g p u c k e r i n g and the p r e f e r r e d a x i a l o r i e n t a t i o n o f the  3 - s u b s t i t u e n t s were a l s o r e p o r t e d by G i s t a r o _et a l . i n t h e i r pmr study o f 3 - s u b s t i t u t e d t h i e t a n e 1 , 1 - d i o x i d e s  (101).  T h i e t a n e s a r e r e a c t i v e compounds p r o b a b l y because o f the h i g h s t r a i n o f the four-membered r i n g and t h e a v a i l a b i l i t y o f nonbonded e l e c t r o n s on s u l f u r . I n t h e presence  of acid,  t h i e t a n e s r e a d i l y undergo p o l y m e r i z a t i o n . R i n g cleavage r e a c t i o n s take p l a c e when t h i e t a n e s a r e t r e a t e d w i t h base o r e l e c -  MH CH CH GH SH. 2  2  2  t r o p h i l i c r e a g e n t s . The e l e c t r o p h i l i c r e a g e n t s  2  such a s methyl  i o d i d e p r o b a b l y form a s u l f o n i u m s a l t w i t h t h i e t a n e l e a d i n g t o the r i n g opening  +  (87, 8 8 ) .  GH I 3  I  S®I© CH  ICrI CH CH SCH 2  2  2  3  3  T h i e t a n e s can be r e a d i l y o x i d i z e d t o s u l f o x i d e s o r s u l f o n e s . U n l i k e the t h i e t a n e s , the o x i d i z e d analogues a r e more s t a b l e and u s u a l l y appear a s c r y s t a l l i n e p r o d u c t s . Thie-  S  •  SO  1  —so  2  30 tane 1 , 1 - d i o x i d e s a r e thus f r e q u e n t l y of thietanes  p r e p a r e d as d e r i v a t i v e s  f o r easy h a n d l i n g . C e r t a i n  thietanes  which can  not  he o b t a i n e d d i r e c t l y have been o b t a i n e d by r e d u c t i o n o f  the  corresponding thietane  1 , 1 - d i o x i d e s w i t h l i t h i u m aluminum  hydride.  -so2  An  e f f i c i e n t route to thietane  1 , 1 - d i o x i d e s i s the  cycloaddition of strongly nucleophilic o l e f i n s ynamines, v i n y l e t h e r s ,  (e.g. enamines,  ketene a c e t a l s and ketene a m i n a l s )  w i t h an a p p r o p i a t e s u l f e n e  generated i n s i t u by the r e a c t i o n  of s u l f o n y l c h l o r i d e and t r i e t h y l a m i n e .  These  cycloaddition H  .c=c;  -R  RCH=S0,  -SO,  Et N 3  RCH S0 C1 2  2  r e a c t i o n s have been e x t e n s i v e l y  reviewed  (84, 85, 102-107). A  b r i e f summary i s p r e s e n t e d h e r e . The  s u l f o n y l c h l o r i d e s used i n the c y c l o a d d i t i o n r e -  actions are unsubstituted c h l o r i d e s . With  or substituted  methanesulfonyl  methanesulf onyl- . c h l o r i d e , the c y c l o a d d i t i o n  r e a c t i o n r e s u l t s i n formation of 3-substituted tuted  thietane  1,1-dioxide. T r e a t i n g  or  2,3-substi-  methanesulf onyl'. c h l o r i d e  31 (42) w i t h s u b s t i t u t e d N-methyl-N-phenylvinylamines (43), f o r example, was r e p o r t e d  to generate 2 , 3 - s u b s t i t u t e d  methanesulfonyl  1 , 1 - d i o x i d e s (44) (108). With s u b s t i t u t e d  ? 3 </\\-TT-C=CHR H  Et  CH S0 C1  2  3  \ 1  >  2  2  thietane  SO, 42  43  44  R  = H, CH.  1  R^ = CH. R R X  or  = (0H )  2  2  4  c h l o r i d e s the c y c l o a d d i t i o n leads 2,3,4-substituted thietane pholino  enamines  R „2 , . / N-C=C^ , 1  , 0  +  1 , 1 - d i o x i d e s . The r e a c t i o n o f mor-  (45) w i t h s u b s t i t u t e d  R T X-CH-S0 C1 4  R  t o the f o r m a t i o n o f 2,3- o r  9  2-halomethanesulfonyl  TT Et„N 1 1 > R V  R  X r .4 R  -SO,  J  2 R^  Q  +  R  l  R  J r  R-  4 7  R  1  = H, C^H^  R  R  2  = R  X = CI, Br, I  3  = CH,  or R  2  = H, R  3  = CH  3  4  = H, CH,  z  -S0,  !  45  4  R  £  48  32 chlorides to g i v e  ( 4 6 ) « i n the presence of t r i e t h y l a m i n e , was  reported  s u b s t i t u t e d 2-halo-3-morpholinothietane 1 , 1 - d i o x i d e s  as a m i x t u r e of c i s and h a v i o r of these t h i e t a n e  t r a n s isomers  ( 4 7 ,  4 8 )  ( 1 0 9 ) .  1 , 1 - d i o x i d e p r o d u c t s towards  treatment of base was  studied  t h e i r stereochemistry  were shown to determine the  p a t h s . The  ( 1 1 0 ) .  The  4,4-dimethyl derivatives ( 4 9 ,  The  be-  the  r i n g substituents  and  reaction  5 0 ) underwent h a l o g e n  h a l i d e e l i m i n a t i o n to g i v e a t h i e t e 1 , 1 - d i o x i d e j j l upon t r e a t i n g w i t h aqueous a l c o h o l i c NaOH. I t was  hydrogen h a l i d e e l i m i n a t i o n was  proposed t h a t  the main p r o c e s s and  trans  that  i s o m e r i z a t i o n of the t r a n s isomer to the c i s form o c c u r r e d f o r e the d e h a l o g e n a t i o n . I n the case of  prebe-  2,4,4-trimethyl-3-mor-  33 pholinothietane  1,1-dioxide ( 5 2 ) ,  the  dehalogenated to g i v e j?3 w h i l e the  c i s isomer was  t r a n s isomer was  0  H-  readily unreactive  *0>  -Ir  CI  !  r r~"CH-  SET-"  OH CH,  3  ©  -SO, CH  0H -SO,  CH, CH  3  3  53  £2  towards the hase p r o b a b l y because the i s o m e r i z a t i o n was p o s s i b l e i n the  t r a n s isomer. I n those d e r i v a t i v e s b e a r i n g  3,3-disubstituents  (54),  the hydrogen h a l i d e e l i m i n a t i o n  s t r u c t u r a l l y p r e v e n t e d . R i n g c l e a v a g e was  the p r e f e r r e d  t i o n l e a d i n g to f o r m a t i o n o f 5 - p h e n y l - 2 H - l , 3 - o x a t h i o l e dioxide  ( 5 6 ) and  intermediate  o t h e r a c y c l i c fragments through an  (55)•  Upon r e f l u x i n g an e t h a n o l i c  0 \Rr //  W  CI -H -SO,  RB H R = H, 54  R Et N 3  H0 2  <^~^-C=C-S0 CH Cl 2  o  ^o^  CH^  not  55  2  the was  reac3,3-  enamine  s o l u t i o n of  34 R 0  <^ "Vc=C-S0 GH Gl r  o  o  0 0  R ^ S ^  c i s - o r trans-2-chloro-3-morpholino-3-phenyl-4-me t h y l t h i e t a n e 1,1-dioxide  (.54., R=CH- ), the s u l f o n y l e n a m i n e 3  ( 5 5 . , R=CH ) form3  ed underwent i n t e r m o l e c u l a r rearrangement t o g i v e  3-(2-(2-  c h l o r o e t h o x y ) e t h y l ) - 5 - m e t h y l - 4 - p h e n y l - A ^ - t h i a z o l i n e 1,1-dioxide diate  (58) v i a the f o r m a t i o n o f a q u a t e r n a r y  ammonium  interme-  (57) (111).  The c y c l o a d d i t i o n o f an enamine i n t e r m e d i a t e  with  s u l f e n e was proposed "by Chen and Ghow (112) f o r the f o r m a t i o n  35 o f s u b s t i t u t e d t h i e t a n e 1,1-dioxides (6l) o^-aminoketoximes (59) (60)  i n the presence  i n the r e a c t i o n o f  w i t h phenylmethanesul.fonyl  chloride  o f p y r i d i n e . The amino group o f the ketox-  OH  59 n =  H  m  N— H-  1  60  2  or  C H ( C H ) CN d d d n 9  9  I---H -SO,  61  . ime (59)  was s t r a t e g i c a l l y p l a c e d a t a p o s i t i o n t o f a c i l i t a t e  r i n g c l e a v a g e . The p o s s i b l e enamine i n t e r m e d i a t e  (62)  was  formed and r e a c t e d w i t h p h e n y l s u l f e n e . I t was proposed t h a t the b u l k y groups (phenyl, p i p e r i d i n o and a l k y l ) , d u r i n g the cycloaddition process,  staggered  themselves around the r i n g t o  36 H | (GH ) 2  CH (CH )CN » 2 2 n 0  0  -H  n  -C=N  <^)-CH=S0  -SO,  H-  2  6 2  6 1  a v o i d undue s t e r i c crowding, so t h a t a l l the s u b s t i t u e n t s on the t h i e t a n e r i n g assumed a t r a n s r e l a t i o n s h i p . I t i s n o t known whether the c y c l o a d d i t i o n o f s u l f e n e s w i t h enamines i s a c o n c e r t e d p r o c e s s  (path 1) o r a two-  step r e a c t i o n i n v o l v i n g f o r m a t i o n o f z w i t t e r i o n (63) (path 2 ) . A two-step a d d i t i o n p r o c e s s has been chosen by v a r i o u s workers i n e x p l a i n i n g the n a t u r e o f product  formation  (103, 112-117)•  37  I n a study o f c y c l o a d d i t i o n r e a c t i o n s  o f a number o f TT,N-di-  substituted  ( 6 4 ) with  2-methyl-l-propenylamines  methanesulfonyl that  chlorides  the r e a c t i o n s  tuted  thietane  (§3), Truce _et a l . (118) r e p o r t e d  l e d to a m i x t u r e  1,1-dioxides  (66,  o f c i s and t r a n s  6jO.  substituent  assume  J  2  ^CHS0 C1 2  R  ^CH^  E  substi-  The c i s p r o d u c t s i n  which the amino moiety and the s u l f e n e  R  substituted  6 5  6 4  \ / N  CH  T  \/ N  3  CH.  H-  -SO,  R  CH 3  T  •CH. -SO,  R1  R< 66  CH.  (cis)  67  (trans)  \ / — \ Pr IT, 0 IT, / \—/ p ^  CH.  r  Halogen, CH, C H  3 >  Pr, C ^ ,  CH -C H , 3  6  4  N0 C H 2  6  4 >  C O C H , COEt 6  R  c  5  = H, C H  3  a l e s s thermodynamically  s t a b l e c i s r e l a t i o n s h i p , were found  to be predominant i n many r e a c t i o n s  p a r t i c u l a r l y when the s u l -  38 f e n e s used were d e r i v e d from m e t h a n e s u l f o n y l c h l o r i d e  contain-  i n g an / - p h e n y l , 06-halo o r o ^ - t o l y l s u b s t i t u e n t , o r from  ethane-  s u l f o n y l c h l o r i d e b e a r i n g an o^-chloro, o r oC-cjano moiety. s t e r i c f a c t o r s appeared not to determine the in  stereoselectivity  the f o r m a t i o n o f c i s p r o d u c t s . A r a t i o n a l e f o r t h i s observed  s t e r e o s e l e c t i v i t y was was  The  p o s t u l a t e d on the b a s i s t h a t the r e a c t i o n  a two-step p r o c e s s and proceeded v i a the f o r m a t i o n o f a  z w i t t e r i o n i n t e r m e d i a t e . The  e l e c t r o s t a t i c a t t r a c t i o n between  the p o s i t i v e and the n e g a t i v e charges o f the d i p o l a r intermediate  zwitterion  (68), which can be d e l o c a l i z e d by the amino and  GH GH  3\3  3SL  H  :c=c;  CH  ,CH, •CH-  3^ N—G^ CH. ®^c;  68  v H GH GH  CH,  3\  -CH,  3  -SO, H  ,CH  3  ^CH,  39 the phenyl m o i e t i e s r e s p e c t i v e l y was suggested  t o f a v o u r the  c i s geometry o f p r o d u c t s . T h i s e x p l a n a t i o n was supported by . the d a t a t h a t c i s p r e f e r e n c e was n o t observed r i v e d from  f o r p r o d u c t s de-  the s u l f e n e s b e a r i n g s u b s t i t u e n t s without a p p r e c i a -  bly negative character. The c y c l o a d d i t i o n o f v i n y l s u l f e n e  ( 6 9 ) w i t h morpho-  l i n o o r p i p e r i d i n o enamine (70) was r e p o r t e d (119) t o proceed w i t h no s t e r e o s e l e c t i v i t y , g i v i n g a 1:1 mixture trans t h i e t a n e 1,1-dioxide  products  i s o m e r i z a t i o n o f the c i s isomer  o f c i s and  (_71, 12). Whether the p o s t -  t o the t r a n s form o c c u r r e d was  not known. I t was r e p o r t e d t h a t 71 i s o m e r i z e d t o 72 when the former was t r e a t e d w i t h b u t y l  lithium.  CH =CHCH S0 C1 2  2  2  Et N 3  CH =CHCH=S0 2  .OH 2  H H  \  CH.  CH=CH 71  R  -CH. SO,  I  T!H 70  69  R  H^  CH. -CH.  HCH =CH-  -SO,  2  H 72  40 T h i e t a n e 1 , 1 - d i o x i d e s a r e n o t the o n l y type o f p r o d u c t s formed i n the r e a c t i o n o f s u l f e n e s w i t h enamines. I n c e r t a i n c o n d i t i o n s , s u l f e n e s r e a c t w i t h enamines to form clic  s u b s t i t u t i o n p r o d u c t s . The r e a c t i o n o f phenyl  chloride  s u l f o n e 74 (120). R e a c t i o n o f s u l f o n y l  c h l o r i d e 75 w i t h enamine 76 i n the presence a f f o r d e d a c y c l i c p r o d u c t 77 i n 86% y i e l d  of triethylamine  (121). I n the r e a c -  CH3  Et N  Et00CCHS0 C=CH C. I Et  3  EtOOCCHS0 01  o  2  E-tr  IS  sulfonyl  (60) w i t h 1 - p y r r o l i d i n o c y c l o h e x e n e (73) was r e p o r t e d  to g i v e an a c y c l i c  0H  acy-  II  76  t i o n o f enamine 78 w i t h cyanomethanesulfonyl a c y c l i c i n t e r m e d i a t e 80 was a l s o proposed i s o l a t i o n o f benzoylmethyl  chloride  to account  (79) an f o r the  cyanomethyl s u l f o n e (81) ( 8 5 ) . Cer-  t a i n ^-cyanothietanes 1,1-dioxides  (82) (122) can be  41 C=CH  2  +  CTGH S0 C1 2  78  ->  2  X  0 ^"^-C-OHgSOgCHgCU -H  1  2  80  •IK" CN  R  2  79  0>  H-  .G=CHS0 GH G1  81  -SO, R  c  82  R  = R  1  R R 1  2  CH ;  2  3  ~  generated by t h i s method depending on the e l e c t r o n i c n a t u r e >: and  the b u l k i n e s s o f the r i n g  with out  s u b s t i t u e n t s . The r e a c t i o n o f j[9_  enamine 8_3_ gave o n l y a c y c l i c product  8_5_. I t was p o i n t e d  t h a t t h i e t a n e 8_4. may be formed b e f o r e rearrangement t o 85  (117 )• I n c e r t a i n r e a c t i o n s the f o r m a t i o n  (GH ) J 2  CN  Et.N *—>  NCCH S0 C1 2  of a c y c l i c substitu-  2  (CH ) 2'n  n  0  83  S  °2  84  79  ^ 2^n G H  ^S0 CH CN 2 2 o  85  o  _ _ n = 1, 2  42 t i o n products  may be a t t r i b u t e d to the s t e r i c and e l e c t r o n i c  f a c t o r s t h a t were u n f a v o r a b l e  f o r the i n t e r m o l e c u l a r  t i o n o f the z w i t t e r i o n i n t e r m e d i a t e the f o r m a t i o n  of a c y c l i c products  cycliza-  6_3 and thus a l l o w e d f o r  as an a l t e r n a t e r o u t e .  A l t h o u g h c e r t a i n t h i e t a n e s can be e f f i c i e n t l y pared by r e d u c i n g  the c o r r e s p o n d i n g  pre-  thietane 1,1-dioxides, i n  the s i t u a t i o n s where the s y n t h e s i s o f t h i e t a n e 1,1-dioxide by c y c l o a d d i t i o n i s n o t p o s s i b l e o r t h i e t a n e 1 , 1 - d i o x i d e i s decomposed by the r e d u c i n g  c o n d i t i o n s employed, d i r e c t  synthesis  o f t h i e t a n e may be an a l t e r n a t e approach. The c l a s s i c method of s y n t h e s i s o f t h i e t a n e s i n v o l v e s the g e n e r a t i o n  of a thio-  l a t e a n i o n c o n t a i n i n g a good l e a v i n g group separated carbons from the s u l f u r atom. I n t r a m o l e c u l a r t h i s t h i o l a t e anion r e s u l t s i n formation  by t h r e e  c y c l i z a t i o n of  of 2-substituted or  43 3-substituted by the  thietanes. Synthesis  t h i s method g e n e r a l l y r e s u l t s  of 2-substituted  i n low y i e l d s  probably  due to  by the  substi-  s t e r i c h i n d r a n c e o f the c y c l i z a t i o n p r o c e s s  tuents  thietanes  (122).  -C-C-C-R  se o  R = OCN , h a l o g e n , O-S-^^-GR^ etc. 0  Dubs .et a l . (123) r e p o r t e d series  a method t o prepare a  o f s u b s t i t u t e d 2 - t h i e t a n o l s J37 i n 16-84% y i e l d s  treating  R  R  U,(5-unsaturated  \  ^  2^  by  a l d e h y d e s 86 w i t h hydrogen s u l f i d e i n  Et N  R  R-  3  -OH  HS  CHO  2  -S  R  J  86  R  2 82  R = H, GH ,  CH(GH ) , Et  3  R R  1  3  2  = H, CR~ , P r , E t 3  = H o r GH  3  the presence o f t r i e t h y l a m i n e . I t was assumed t h a t the t h i o l a t e i o n was formed and underwent i n t r a m o l e c u l a r  cyclization  44 to g i v e the p r o d u c t s .  Mayer (124) developed dime t h y l t h i e t a n e  a method o f s y n t h e s i s o f 2,2-  (89). He t r e a t e d l , 3 - d i c h l o r o - 3 - m e t h y l b u t a n e  (88) w i t h hydrogen s u l f i d e  i n the presence  amount o f aluminum c h l o r i d e and i s o l a t e d  CI i  CH  2,2-dimethylthietane  CH  CI  CH.—C—CH —CH j  of a c a t a l y t i c  0  0  d  d  H S  A1C1.  CH,  2  3 88  89  (89) i n 90% y i e l d . I t was proposed via  3  t h a t the r e a c t i o n  proceeded  the f o r m a t i o n o f i n t e r m e d i a t e 90 o r 91. The aluminum c h l o -  r i d e might a c t i v a t e the double bond to f a c i l i t a t e of hydrogen  sulfide.,  AlCl.  A1C1,  (CH ) C=CHCH C1 3  2  2  CH =:CCH CH C1 2  2  CH  3  2  the a t t a c k  45 Capanovich e_t a l . d i s c o v e r e d a method of  cyclizing  the b r o m o m e t h y l t h i o e s t e r .92 to 3 , 3 - d i p h e n y l t h i e t a n - 2 - o n e The  33  carbanion  t i o n process  was  probably  the i n t e r m e d i a t e  o f the  (94)» cycliza-  (125).  92  14  93  A r e l a t i v e l y new  and v e r y u s e f u l method of  preparing  t h i e t a n e s i s the p h o t o c y c l o a d d i t i o n o f t h i o c a r b o n y l compounds w i t h o l e f i n s b e a r i n g a v a r i e t y of s u b s t i t u e n t s . T h i s method has  l e d to the  s y n t h e s i s o f many s u b s t i t u t e d t h i e t a n e s which  can not be g e n e r a t e d by  the c l a s s i c a l i n t r a m o l e c u l a r  cycliza-  t i o n o f t h i o l a t e or c y c l o a d d i t i o n of s u l f e n e s w i t h o l e f i n s . .' The  formation  of t h i e t a n e i n t e r m e d i a t e s upon i r r a d i a t i n g  m i x t u r e o f thiobenzophenone and K a i s e r and W u l f e r s sequently  ( 1 2 6 ) .  demonstrated by  The  o l e f i n s was  a  f i r s t proposed  i s o l a t i o n of t h i e t a n e s was  by  sub-  the Japanese photochemists i n 19695  Ohno e_t a l . showed t h a t i r r a d i a t i n g a m i x t u r e of thiobenzophenone . (95) and nm  certain olefins  (.96), w i t h 366  nm  l i g h t or  l i g h t , g e n e r a t e d t h i e t a n e s (97) i n good y i e l d s  The  c y c l o a d d i t i o n r e a c t i o n was  p h o t o c y c l o a d d i t i o n of c i s - and 1  R =R  2 =G1),  found to be  589  (127-129).  s t e r e o s p e c i f i c . The  trans- dichloroethylene  (96,  f o r example, gave e x c l u s i v e l y c i s - 3 , 4 - d i c h l o r o - 2 , 2 -  46  95  diphenylthietane  diphenylthietane  97  9 6  R  1  R  2  = C I , CH COO, CH OGO, CN 3  3  = H, C I , CH"  3  (97, R =R =C1) 1  2  1  2  and t r a n s - 3 . 4 - d i c h l o r o - 2 , 2 -  (97, R =R =C1) r e s p e c t i v e l y . I n a d d i t i o n to  the g e n e r a t i o n o f t h i e t a n e s (1:1 t h i o b e n z o p h e n o n e / o l e f i n a d d u c t s ) , the f o r m a t i o n o f 1,3- o r 1,4- d i t h i a n e s (2:1 t h i o b e n z o p h e n o n e / o l e f i n adducts) h a s a l s o been observed  i n some pho-  t o c y c l o a d d i t i o n o f thiobenzophenone w i t h o l e f i n s . . The photoc h e m i c a l r e a c t i o n o f thiobenzophenone w i t h s t y r e n e (98). f o r example, a f f o r d e d both 1 , 4 - d i t h i a n e _99 and t h i e t a n e 100 w i t h y i e l d s depending on the c o n c e n t r a t i o n s o f _95_ and '98 S  99  100  (127).  47 On  the b a s i s o f the r e s u l t s o b t a i n e d  o f thiobenzophenone and Ohno and  o l e f i n s bearing  from  various  reactions  substituents,  h i s coworkers (127-129) concluded t h a t o l e f i n s b e a r -  i n g e l e c t r o n - w i t h d r a w i n g groups (eg. CN,  C00CH , G l , 0C0CH 3  366  e t c . ) upon r e a c t i n g w i t h thiobenzophenone e x c i t e d by l i g h t gave t h i e t a n e s , and ing substituents  that o l e f i n s bearing  aerated  thietanes  o l e f i n s . The  nm  electron-releas-  (eg. a l k y l , a l k o x y , p h e n y l e t c . )  i n g w i t h thiobenzophenone e x c i t e d by 366  3  or 589  upon r e a c t -  nm  light,  gen-  o r d i t h i a n e s depending on the n a t u r e of  f a c t o r s t h a t governed the course o f  the  photocyclo-  a d d i t i o n r e a c t i o n s appeared to be both s t e r i c and e l e c t r o n i c . The  r e a c t i v e s p e c i e s i n the r e a c t i o n s was  light-excited  thiobenzophenone s i n c e the o l e f i n s used i n  p h o t o c h e m i c a l r e a c t i o n s were t r a n s p a r e n t g i o n s employed cause two  (127,  132).  The  (589  nm)  ( T C ) of the  thiocarbonyl  r e s u l t i n g excited state  to  (127). The  irradia-  (n) to p i - a n t i b o n d i n g  the  o r b i t a l being unpaired The  s p i n of the  has  orbital.  The  The  been  excited electron i n  w i t h t h a t of the u n e x c i t e d  elec(366  i r r a d i a t i o n a t s h o r t wavelength  i n d u c e d t r a n s i t i o n of an e l e c t r o n from p i - o r b i t a l  pi-antibonding  orbi-  group of thiobenzophenone.  than the ground s t a t e of thiobenzophenone and  t r o n i n the n o r b i t a l .  an  0**3t) possessed an energy 40-43 K c a l  suggested to be a t r i p l e t ,  nm)  proposed  produced t r a n s i t i o n of  e l e c t r o n from non-bonding o r b i t a l  the 7C  the  types o f e l e c t r o n i c t r a n s i t i o n of thiobenzophenone,  t i o n a t l o n g wavelength  higher  the  i n the wavelength r e -  i r r a d i a t i o n was  depending on the wavelength of l i g h t used  tal  suggested to be  r e s u l t i n g excited state  (Jt)  to  (*:-»JC ; ©c-  48 c u p i e d an energy l e v e l about 50 K c a l h i g h e r than the n-4jc  state  and has been suggested to be a s i n g l e t , two e l e c t r o n s i n each o r b i t a l being paired * t h a t the n-»Jt t r i p l e t  (127, 130, 131). Ohno e t a l . suggested s t a t e o f thiobenzophenone behaved l i k e a  t h i y l r a d i c a l w h i l e " t h e K^TL s i n g l e t  s t a t e behaved l i k e a t h i o -  l a t e a n i o n (RS~). Two k i n d s o f mechanism were thus p o s t u l a t e d for  the p h o t o c h e m i c a l r e a c t i o n s o f thiobenzophenone w i t h o l e -  fins of the  (127). With e l e c t r o n d e f i c i e n t o l e f i n s , 'the 7i-*Jt  species  thiobenzophenone formed a c h a r g e - t r a n s f e r complex l e a d i n g to f o r m a t i o n o f t h i e t a n e s . The energy o f n-*7t  species of t h i o -  benzophenone was c o n s i d e r e d to be too low to t r a n s f e r to the o l e f i n s . However, w i t h e l e c t r o n r i c h o l e f i n s , of  the n-*7i s p e c i e s  thiobenzophenone r e a c t e d through a d i r a d i c a l mechanism. The  s u l f u r atom o f thiobenzophenone a t t a c k e d the o l e f i n l e a d i n g to the  f o r m a t i o n o f : ' d i r a d i c a l 101 which e i t h e r  cyclized  intramolecularly  to form t h i e t a n e o r r e a c t e d w i t h a second m o l e c u l e o f  thiobenzophenone r e s u l t i n g i n g e n e r a t i o n o f 1,3- o r 1,4- d i thiane  (102, 103). The f a c t o r s t h a t determined the r e a c t i o n  49  p a t h were suggested t o be the c o n c e n t r a t i o n o f t h i o b e n z o phenone and the s t e r i c environment o f the d i r a d i c a l .  :c=c:  n -> X 589  nm n?c  I  -  G  6  H  5  •  G  6  H  5  G  6  5  H  '  6  G  H  5  101  ID  s >f ^  \  ^  S  5 G  ^  G  G  —  -  G  G  6  6  G  6  Y  6  5  H  ^  3  5  H  5  H  5  H  '  "  G  6  H  5  •  G  6  H  5  G  6  H  5  G  6  H  5  J  102  or 6  G  5  H  "  G  6  H  5 6  G  G  6  H  5  G  6  H  5  G  6  H  5  G  6  H  H  5  5  103  The e a r l y work on the p h o t o c y c l o a d d i t i o n o f t h i o -  50 benzophenone w i t h o l e f i n s has been reviewed. (130, 132).  ,;  Recent  s t u d i e s o f the p h o t o c y c l o a d d i t i o n r e a c t i o n s u s i n g  v a r i o u s s u b s t i t u t e d o l e f i n s have l e d to the g e n e r a t i o n o f many new s u b s t i t u t e d t h i e t a n e s . A summary o f these new f i n d i n g s i s p r e s e n t e d i n the remainder  of this  section.  When a m i x t u r e o f a t h i o n e (105, 107) and a pentadiene band),  (104, 109) was i r r a d i a t e d under 589 nm l i g h t (n-»rc. the c o r r e s p o n d i n g t h i e t a n e (106, 108, 110, 111) was  isolated  (133). An a c y c l i c r e a r r a n g e d adduct  so i s o l a t e d  104  (112) was a l -  i n the r e a c t i o n s o f 104 w i t h 105.  107  108  51  The with  p h o t o c y c l o a d d i t i o n of m e t h o x y a l l e n e  thiobenzophenone  t h i e t a n e 114  (95) a t 589  nm  was  (113)  r e p o r t e d to g i v e  t o g e t h e r w i t h a b e n z o t h i a n e 115»  I t was  assum-  * ed t h a t the  triplet  a l l e n e a t the c e n t r a l a b i r a d i c a l which then  thiobenzophenone a t t a c k e d methoxy-  carbon atom r e s u l t i n g i n f o r m a t i o n cyclized  z o t h i a n e . With x a n t h e n e - 9 - t h i o n e t i o n of methoxyallene  (113)  to y i e l d t h i e t a n e and (107)  the  of  ben-  photocycloaddi-  gave o n l y t h i e t a n e 1 1 6 .  No  ben-  52 z o t h i a n e was  detected  (134a).  53  G o t t h a r d t and L i s t l e (135), by i r r a d i a t i n g mixtures of thiocarbonates (118-121) w i t h n-m responding  (117, 123) and s u b s t i t u t e d o l e f i n s  band l i g h t (328 nm), i s o l a t e d  t h i e t a n e s (122, 124)» When they i r r a d i a t e d mix-  R  J  R  R  CH.  R  3  328 nm  3 R<  117  118:  R =R =R =CH 1  2  3  R  3  122  119: R - ^ R ^ C H ^ R =H 3  120: R =CH ;  R R =:C CH  1  2  ?  J  3  / C H 3  V  3  121: R = C ( C H ) : G H ; R =R =H 1  2  3  R  J  :c=c;  GH;  123  the c o r -  .R'  V  118-120  3  2  h-v 328 nm'  124  54 (125)  t u r e s o f thiophosgene  (126)  pected thietane products  (118-120), t h e ex-  and o l e f i n s  were a l s o o b t a i n e d  R  hi>  C-G . o CH^ R^  Cl-C-Cl  455  N  1  (136).  Gl  GH  Gl  nm' R R-  126  118-120  125  With o l e f i n s 119 and 120  the p h o t o c y c l o a d d i t i o n o f t h i o -  phosgene a l s o generated  a c y c l i c adducts  127 and 128 r e s -  p e c t i v e l y . The 2,2-dichlorothietanes (126  Cl CI  R  2  R  )isolated  rapid-  1  ^CH-S-C-C=CH i R-^  0  127: R =R =CH ; R =H 1  2  3  3  128: R ^ C H ^ R = R = C ( C H ) 2  3  3  2  l y underwent d e c h l o r i n a t i o n , upon chromatography on s i l i c a g e l , t o g i v e the c o r r e s p o n d i n g t h i e t a n o n e s (129-131) • I t CH  CH GH;  GH,  CH;  CH; CH  3  0  CH;  G H  3  129  CH,  0  130  3~C^ 3 131  55 was  suggested  triplet  t h a t the r e a c t i v e  thiophosgene  was  the n-*jt  species. The  thiobenzoate  p h o t o c y c l o a d d i t i o n o f O-methyl or O - e t h y l (132) w i t h s u b s t i t u t e d o l e f i n s  t u e n t s are H, b e n z y l , m e t h y l ,  (133,  substi-  e t h y l , p r o p y l ) a f f o r d e d 2-  OR  132  133  phenyl-2-alkoxythietane was  attributed  thiobenzoate  derivatives  (134)»  to the f o r m a t i o n o f n-»x  The  triplet  reaction species of  (137 )•  When a m i x t u r e nyl  134  ethyl ether  (136) was  of d i a r y l t h i o k e t o n e (135) and v i i r r a d i a t e d under 589  nm  light,  the r e a c t i o n r e s u l t e d i n the f o r m a t i o n o f t h i e t a n e or d i t h i a n e (139) ketone used  ketone,  depending on the c o n c e n t r a t i o n o f  (135 )• A b i r a d i c a l i n t e r m e d i a t e was  f o r the product  f o r m a t i o n . At a low  the b i r a d i c a l i n t e r m e d i a t e  molecular  c y c l i z a t i o n to form  t r a p p e d by a second  thio-  suggested  c o n c e n t r a t i o n of (137) underwent  the t h i e t a n e 138.  c o n c e n t r a t i o n o f t h i o k e t o n e , the b i r a d i c a l (137) was  (138)  molecule  i n g to the f o r m a t i o n o f d i t h i a n e 139.  thio-  intra-  At a h i g h  intermediate  of thioketone l e a d The  photocycloaddi-  56 2  R-C-R  +  C H OCH=CH 2  5  N  ,R,  TJR, HCG H 0'  2  2  5  136  135  5  138  137  S 11 R-C-R  - S \ R, R, C H 0 2  5  139  R  =-<^); H(^)-CH  3  ; -0-<^)-CH  3  t i o n o f t h i o k e t o n e w i t h e l e c t r o n - d e f i c i e n t o l e f i n s l e d to more i n t e r e s t i n g r e s u l t s the r e a c t i o n o f x-*x in  (135). With methyl a c r y l a t e  s p e c i e s o f thiobenzophenone  (140),  resulted  the f o r m a t i o n o f t h i e t a n e 141 and the r e a c t i o n o f n->3t  s p e c i e s o f thiobenzophenone a f f o r d e d a 2:3 m i x t u r e o f t h i e tane 141 and b e n z o t h i a n e 142. A p p a r e n t l y the f o r m a t i o n o f t h i e t a n e 141 was n o t governed by the wavelength used. I t was observed t h a t the b e n z o t h i a n e 142 was g e n e r a t e d t h e r m a l l y by h e a t i n g a m i x t u r e o f thiobenzophenone and methyl a c r y l a t e a t 40-50°. The p h o t o c y c l o a d d i t i o n o f t h i o n e 143 with a c r y l o n i t r i l e  (144) o r methyl a c r y l a t e  (140) a t 589 nm  57  (40%)  y i e l d e d t h i e t a n e 145• c i t a t i o n o f the  (60%)  showed t h a t the Jt-»3t  t h i o c a r b o n y l compounds was  f o r thietane formation  143  This again  142  not  ex-  neccessary  from e l e c t r o n d e f i c i e n t o l e f i n s , i n  1 4 4  R=0N  1 4 5  1 4 0 R=C00CH,  contrast (138).  to the r e s u l t r e p o r t e d by Ohno and h i s coworkers  The  photocycloaddition  of xanthione with  methyl  a c r y l a t e a l s o supported the argument. I r r a d i a t i n g a  mix-  58 t u r e o f xanthene-9-thione (107) and methyl a c r y l a t e (140) a t e i t h e r 589 nm  (n-»7t  e x c i t a t i o n ) o r 405-408 nm (n-iic  c i t a t i o n ) r e s u l t e d i n the f o r m a t i o n o f s p i r o t h i e t a n e  The yl  photocycloaddition  of nitrogenous  compounds w i t h o l e f i n was r e p o r t e d  (139). The expected s p i r o t h i e t a n e s  methacrylonitrile  R 0 ^ F  I  146.  thiocarbon-  by F o u r r e y e t a l .  149 and 151 were  ed when a s o l u t i o n o f 4 - t h i o u r a c i l d e r i v a t i v e s and  ex-  obtain-  (147, 150)  (148) was i r r a d i a t e d .  .CHH2C=C ^ CN  CH  hv  3^>^CHCH -F 3  0^N CH-  R = H o r CH. 148  147 S  149  CH-  CN CHo N4-OH  3  —IT  N  I  CH150  148.  15i  59  The p h o t o c y c l o a d d i t i o n o f t h i o p a r a b a n a t e (152) with various o l e f i n s ing  (153) a l s o generated  the c o r r e s p o n d -  s p i r o t h i e t a n e s 154 (140).  R I  R< 3  R  R  +  R >  G  =  ->  % 5  0  R~ •S Ll  R  J  J  0  R152  R = X  154  153  GH-  R = H, CH^ R = G00GH , 0 C H , GH^ 3  3  R = H, GH^ R = H 5  2  or  5  R R = 4  5  =C(GH ) 3  2  6 0  SYNTHETIC APPROACH  The tial  t h i e t a n e d e r i v a t i v e s i n v e s t i g a t e d as p o t e n -  a n a l g e s i c s were compounds 32-36. The s y n t h e s i s o f  these compounds was approached through the c o r r e s p o n d i n g  CH  3  CH  CH-  >CH / 3  \  9  2  N CH-  •SO,  R  CH-  •SO, NCH, 35 c i s  32 R=H  36  33 R=CH , c i s 3  trans  34 R=CH , t r a n s 3  cyanothietanes  155-159 which were p r e p a r e d a c c o r d i n g to  the p h o t o c h e m i c a l method d e s c r i b e d by Ohno and h i s coworke r s (138).  The g e n e r a l  s y n t h e t i c pathway e s t a b l i s h e d f o r  155 R=H  158 c i s  156 R=CH , c i s 3  157 R=CH,, t r a n s  159  trans  61 the s y n t h e s i s o f 32 i s o u t l i n e d i n Scheme I :  Scheme I Synthetic route  t o 2,2-diphenyl-3-dimethylaminomethylthie-  tane 1,1-dioxide  Q2).  H 155  Replacing  p r o p e n e n i t r i l e (144) w i t h c i s - and  t r a n s - 2-hutenenitrile (162,  163)  allowed  the s y n t h e s i s o f  6 2  CH  3 ^ C=C  CH  3 \ C=C  H  H  162  163  t h i e t a n e s 156-159 which were the p r e c u r s o r s o f t h i e t a n e 1,1-dioxides  33-36 r e s p e c t i v e l y .  G e n e r a l l y , the s y n t h e s i s o f the d e s i r e d p r o d u c t s (32-36) was approached through  4 steps:  1. P r e p a r a t i o n o f the c y a n o t h i e t a n e s by photocyc l o a d d i t i o n o f thiobenzophenone w i t h priate olefinic  nitrile  2. P r e p a r a t i o n o f c y a n o t h i e t a n e  1,1-dioxides  3. S y n t h e s i s o f aminomethylthietane 4.  appro-  1,1-dioxides  S y n t h e s i s o f N,N-dimethylaminomethylthietane 1,1-dioxides  During  the course  o f s y n t h e s i s o f above t h i e t a n e  p r o d u c t s , many r e l a t e d c h e m i c a l r e a c t i o n s were performed i n an attempt to s o l v e the s y n t h e t i c problems which were encountered,  and to develop  the p r e s e n t p r o j e c t . These  be d e s c r i b e d under the f o l l o w i n g a d d i t i o n a l  will  titles:  5. S y n t h e s i s o f 2,2-diphenyl-3-dimethylamino- .. methylthietane. 6. Attempted  synthesis of thietane d e r i v a t i v e s  w i t h the <<-dime thylaminome t h y l 7. Chemical  side chain  r e a c t i o n s o f 2 , 4 - d i p h e n y l t h i e t e 1,1-  d i o x i d e and attempted s y n t h e s i s o f 2,4-diphenylthietan-3-one  1,1-dioxide  63 DISCUSSION  1.  S y n t h e s i s o f c y a n o t h i e t a n e s by p h o t o c y c l o a d d i t i o n o f thiobenzophenone  with o l e f i n i c  Thiobenzophenone (95)  nitriles  i s a blue c r y s t a l l i n e  ma-  t e r i a l which i s v e r y s e n s i t i v e to atmospheric oxygen and e a s i l y undergoes was  p o l y m e r i z a t i o n a t room temperature. I t  p r e p a r e d from benzophenone  (164). i n an amount as r e -  q u i r e d , by a m o d i f i c a t i o n o f the method o f G r o f t o n and Braude (141). Benzophenone (164)  was  s u l f i d e i n the presence of hydrogen was  hydrogen  c h l o r i d e . The p r o d u c t  immediately p u r i f i e d by r e p e a t e d r e c r y s t a l l i z a t i o n  0  S  164  95  from n-pentane which was the  treated with  found to be a b e t t e r s o l v e n t  petroleum e t h e r used by G r o f t o n and Braude. With  than n-  pentane,  c r y s t a l l i z a t i o n occured i n a s h o r t e r time and  purified  thiobenzophenone  Pure  thiobenzophenone  was  the  recovered i n a better y i e l d .  obtained a f t e r r e c r y s t a l l i z a t i o n f o r  t h r e e o r f o u r times was  s t a b l e i n the f r e e z e r f o r a  months i f the m a t e r i a l was  few  kept under n i t r o g e n or carbon  d i o x i d e atmosphere. I n most o f the p h o t o c y c l o a d d i t i o n r e actions, freshly  p r e p a r e d thiobenzophenone  was used. When  64 the  s t o r e d thiobenzophenone was  recrystallized The Propenenitrile  three  or f o u r  employed, i t was  further  times.  o l e f i n i c n i t r i l e s were c o m m e r c i a l l y (144)  was  obtained  supplied.  as a c o l o r l e s s l i q u i d  a f t e r f r a c t i o n a t i o n through a V i g r e a u x column. Upon i r r a d i a t i o n w i t h u n f i l t e r e d u l t r a v i o l e t l i g h t generated from a medium p r e s s u r e  mercury a r c , p r o p e n e n i t r i l e r a p i d l y r e -  a c t e d w i t h thiobenzophenone (95)  to produce a w h i t e ,  i d e n t i f i e d polymer which was  s o l u b l e i n common  s o l v e n t s . The  2 - b u t e n e n i t r i l e was  t r a n s i s o m e r s (162,  c i s and  c r o t o n o n i t r i l e . The liquid  not  163)  obtained  un-  organic  as a m i x t u r e  known c o m m e r c i a l l y  as  a n a l y s i s o f t h i s m i x t u r e by u s i n g  gas f..  chromatography ( g l c ) i n d i c a t e d t h a t i t c o n t a i n e d  60-70% c i s - 2 - b u t e n e n i t r i l e (162) nitrile  (163)  and  30-40%  jtrans-2-butene-  depending on the commercial sources.  b o i l i n g points  (162:  108°,  163:  were so c l o s e t h a t they were not  121°)  through a 5 f t V i g r e a u x column. The fractionation  (142)  helices also f a i l e d  The  of these two  separated  of  isomers  by f r a c t i o n a t i o n  s y s t e m a t i c a l l y repeated  u s i n g a 2 f t column packed w i t h g l a s s to separate the  two  isomers. The  cal-  c u l a t i o n based on the b o i l i n g p o i n t d i f f e r e n c e showed t h a t a d i s t i l l a t i o n column of a t l e a s t 20 required  to a c h i e v e a 95%  separation  theoretical plates of two  T h i s meant t h a t a column packed w i t h 1/4 t u b i n g and  measuring a t l e a s t 6 f t was  a r a t i o n . In order  to o b t a i n the  i n x 1/4  (142).  i n glass  needed f o r 95%  separation  i n a pure form, a column o f h i g h e r  isomers  was  sep-  of each isomer  e f f i c i e n c y was  required.  A Spinning-Band-Column d i s t i l l a t i o n a p p a r a t u s ,  k i n d l y made  a v a i l a b l e by Mr. L. T. Muenster o f the Chemistry  depart-  ment, The U n i v e r s i t y o f B r i t i s h Columbia, was s e l e c t e d f o r the s e p a r a t i o n o f 1 6 2  and 1 6 3 .  The c r o t o n o n i t r i l e was r e -  p e a t e d l y d i s t i l l e d u n t i l pure c i s - 2 - b u t e n e n i t r i l e and pure t r a n s - 2 - b u t e n e n i t r i l e were o b t a i n e d . The p u r i t y o f the sepa r a t e d isomers was c o n f i r m e d by g l c . I r r a d i a t i n g a cyclohexane phenone ( 9 5 ) and p r o p e n e n i t r i l e light  s o l u t i o n of thiobenzo-  ( 1 4 4 ) with u l t r a v i o l e t  a t the wavelength o f 3 6 6 nm, generated  a crude  pro-  duct which was p u r i f i e d by column chromatography to g i v e pure 2 , 2 - d i p h e n y l - 3 - c y a n o t h i e t a n e 1 5 5  as a white  solid i n  •S  95 a yield tion  155  114  o f 41%. The i r spectrum  o f 155 d i s p l a y s the absorp-  (2235 cm""^) f o r the cyano group i n a d d i t i o n to the  s i g n a l s f o r two phenyl  s u b s t i t u e n t s . The pmr spectrum  of  155 i s i n agreement w i t h the t h i e t a n e s t r u c t u r e . The two methylene p r o t o n s  (H , H, ) a r e m a g n e t i c a l l y n o n e q u i v a l e n t  b e i n g d i s p l a y e d as two symmetrical,  p a r t l y overlapping .  q u a r t e t s c e n t e r e d a t 3.32 and 3«47 ppm r e s p e c t i v e l y . The methine p r o t o n  ( H ) appears c  as a t r i p l e t  a t 4.99 ppm due  66 to two p a r t l y superimposing  d o u b l e t s . The  v i c i n a l coupling constants (J(H -Hb), a  geminal  J(H -H ), a  and  the  J(Hh-H ))  c  c  are a l l equal to 9 Hz i n comparison w i t h the r e p o r t e d JCHa-H^) v a l u e of 10 Hz i n compound l6_5_ (139). The  Hb  CH 155  ten  3  165  a r o m a t i c p r o t o n s are d i s p l a y e d as a m u l t i p l e t a t 7.10-7.70 ppm.  The  conformation The  due  o f 155  41% y i e l d  w i l l be c o n s i d e r e d  of 155 was  later.  not the r e s u l t  of l o s s  to the p u r i f i c a t i o n p r o c e s s . A n a l y s i s by g l c and  l a y e r chromatography methods i n d i c a t e d t h a t crude c o n t a i n e d o n l y 50% o f 155 n e n t s . Pure 155  was  not  thin  product  and a t l e a s t f o u r o t h e r compo-  s o l u b l e i n n-pentane whereas about  40% o f the crude m i x t u r e was  s o l u b l e i n t h i s s o l v e n t . The  n-pentane s o l u t i o n of the s o l u b l e components g r a d u a l l y became b l u e i n c o l o u r s u g g e s t i n g the l i b e r a t i o n o f _9_5_ from some u n s t a b l e p r o d u c t s . E v a p o r a t i n g t h i s b l u e gave a g r e e n i s h gummy substance w i t h the  solution  characteristic  odour of s u l f i d e . Attempts were made to improve the of 155 light  by u s i n g a c i d - b a s e washed 144, f i l t e r , narrowing  employing  the band w i d t h o f the  a  yield  new  isolated  67 l i g h t by using an a d d i t i o n a l l i g h t f i l t e r , shortening the irradiation  time and using d i f f e r e n t proportions of 35. to  144- No s i g n i f i c a n t  improvement i n the y i e l d of 155  was  observed. When the cyclohexane was replaced by anhydrous ether as solvent, the work-up was easier, due to the v o l a t i l i t y of ether, and the crude reaction product obtained was a s o l i d instead of a gummy substance, but the y i e l d of 155 was  comparable. Ohno and h i s coworkers (138) i n 1969  that i r r a d i a t i n g  claimed  a mixture of 144 and 9^ at 366 nm f o r  four days r e s u l t e d i n a 93% y i e l d of product. They did not specify whether t h i s y i e l d r e f e r r e d to the t o t a l crude product or the pure thietane 155» The photocycloaddition °f 144 with _95_ was re-examined by de Mayo and Shizuka  (131)  i n 1973* Their data showed that the quantum y i e l d i n the formation of 155 was low and did not change with the i r r a d i a t i o n time i n the I n i t i a l  stage of reaction. The quantum  y i e l d f o r a substance under consideration i s defined as the number of molecules that react or are formed i n a photochemical process per number of photons absorbed i n a unit of time. I f every photon absorbed can i n i t i a t e a molecule to undergo a c e r t a i n chemical reaction',; the quantum y i e l d i s unity. I f other processes compete with the one under consideration, the quantum y i e l d i s much lower. The  low  quantum y i e l d i n the generation of thietane 155 implied that more than one single process occurred i n the r e a c t i o n of 35 with 144. In f a c t , i t was discovered by de Mayo and  6 8  Schizuka  (131) t h a t t h i e t a n e 1 5 5 was n o t the f i r s t - f o r m e d  p r o d u c t but was d e r i v e d an i n t e r m e d i a t e , white 95  from the thermal d e c o m p o s i t i o n o f  1 , 3 - d i t h i a n e 1 6 6 which was i s o l a t e d as a  s o l i d i n a 6 5 % y i e l d a f t e r i r r a d i a t i n g a mixture of  and 144 a t - 7 8 °  (131). The d i t h i a n e 1 6 6 was r e l a t i v e l y  S 155  15  s t a b l e a t low temperature. A t 3 7 ° one mole o f 1 6 6 l i b e r a t ed one mole o f t h i e t a n e 1 5 5 and one mole o f 35. w i t h i n a p e r i o d o f two days ported  ( 1 3 1 ) .  Ohno and h i s coworkers  (138) r e -  t h a t the r e a c t i o n o f _95_ and 144 d i d n o t o c c u r a t a  l o n g e r wavelength Nicholson  (130)  1,4-dithiane  (589  nm). On the c o n t r a r y ,  de Mayo and  i s o l a t e d , i n a d d i t i o n to t h i e t a n e 155%  1 6 7 ,  benzothiane  l 6 8 y  and a d i s u l f i d e  deriva-  t i v e 1 6 9 a f t e r i r r a d i a t i n g a m i x t u r e o f 9_5_ and 144 a t wavelengths  longer  photocycloaddition  than 5 0 0 nm. C o n s i d e r i n g  t h a t so many  p r o d u c t s were i s o l a t e d and t h a t the  69  95  his 95  15_5_  26%  167  rY 6V G  2  + 144  yield 65%,  8%  o f d i t h i a n e 166  i n the r e a c t i o n a t 366  the r e a s o n o f h i g h e r y i e l d  (93%)  nm was o n l y  c l a i m e d "by Ohno and  coworkers (138) f o r the p h o t o c y c l o a d d i t i o n r e a c t i o n o f w i t h 144 i s n o t c l e a r . The 41%  periment  yield  o f 155 i n our ex-  s u p p o r t s the f i n d i n g o f de Mayo e t a l . t h a t the  t h i e t a n e 155 was n o t the o n l y product o f the photochemical r e a c t i o n . The o t h e r u n i d e n t i f i e d b y - p r o d u c t s were p r o b a b l y i d e n t i c a l o r s i m i l a r to 167,  168 and 169.  I t was observed  70 that prolonged  i r r a d i a t i o n beyond the end p o i n t r e s u l t e d  i n a poor y i e l d vated  of 155•  This indicated  to undergo secondary  t h a t 155  photochemical  the 4-1% y i e l d i n the g e n e r a t i o n of 155  was  acti-  r e a c t i o n s . Thus  and  the  formation  of o t h e r s i d e - p r o d u c t s a f t e r a l o n g p e r i o d of i r r a d i a t i o n (about  f o u r days) i s not  s u r p r i s i n g . Products  may  be d e r i v e d from the decomposition  of  155. I r r a d i a t i n g a mixture  2-butenenitrile mixture and  (162)  a t 3 6 6 nm  further reaction  of _9_5_ and  excess pure c i s -  f o r 152  hours generated  of c i s - 2 , 2 - d i p h e n y l - 3 - c y a n o - 4 - m e t h y l t h i e t a n e  S  CH  + 95  •3  \  H^  169  and  cis-2,2-diphenyl-3-methyl-4-cyanothietane  ratio  such as  3 6 6  H  a  (156)  (158) i n a  nm  1 6 2  1 5 6  158  2.5  1  of 2.5:1, c a l c u l a t e d on the b a s i s o f r e l a t i v e  s i t i e s of the two methyl s i g n a l s i n the pmr  inten-  spectrum o f  71 the r e a c t i o n m i x t u r e . A n a l y z i n g the r e c o v e r e d excess but e n e n i t r i l e by g l c i n d i c a t e d  162  t h a t no i s o m e r i z a t i o n o f  to t r a n s - 2 - b u t e n e n i t r i l e  (163)  of i r r a d i a t i o n . Only 162  was r e c o v e r e d from the photochem-  o c c u r r e d d u r i n g 152 h o u r s  i c a l r e a c t i o n and no a p p r e c i a b l e amount o f t r a n s - i s o m e r (163)  was d e t e c t e d . The pmr spectrum  o f the r e a c t i o n p r o -  duct showed two s e t s o f s i g n a l s t h a t agreed w i t h the data r e p o r t e d by Ohno e_t a l . (138) f o r t h i e t a n e s 156 The  first  156  : The t h r e e methyl p r o t o n s and H  and 158.  s e t o f s i g n a l s was a t t r i b u t e d to the t h i e t a n e  two d o u b l e t s a t  1.54  and  5*00  were d i s p l a y e d as  a  ppm r e s p e c t i v e l y . The H"b  p r o t o n , c o u p l i n g w i t h i t s a d j a c e n t methyl p r o t o n s and H , a  was l o c a t e d as a m u l t i p l e t c e n t e r e d a t 3-80 s i g n a l s o f methyl p r o t o n s and H  a  ppm. Prom the  the c o u p l i n g c o n s t a n t s ,  J(H -H-b) and JtCH^-H-fc,) were measured to be 8 and 7 Hz r e s a  p e c t i v e l y i n agreement w i t h the c o r r e s p o n d i n g c o u p l i n g c o n s t a n t s e x t r a c t e d from  the Hb m u l t i p l e t . The 10  p r o t o n s appeared as a m u l t i p l e t a t  7.10-7.75 ppm.  phenyl The s e -  cond s e t o f s i g n a l s agreed w i t h the s t r u c t u r e o f 158. The d o u b l e t s which were a t t r i b u t e d to the methyl p r o t o n s and t  the Hk were l o c a t e d a t 1.07 t  and 4-25  ppm r e s p e c t i v e l y . The t  t  c o u p l i n g c o n s t a n t s , J ( H - H k ) and J ( C H - H ) , were a l s o 8 a  3  a  t  and 7 Hz r e s p e c t i v e l y . S i m i l a r l y , H  a  c o u p l i n g w i t h the ad-  j a c e n t methyl p r o t o n s and H^,, appeared as a m u l t i p l e t t e r e d a t 4.20  cen-  ppm.  When a m i x t u r e  of trans-2-butenenitrile  (163)  and  35. was i r r a d i a t e d a t 3 6 6 nm,  a mixture  of trans-2,2-  d i p h e n y l - 3 - c y a n o - 4 - m e t h y l t h i e t a n e (157) and t r a n s - 2 , 2 - d i phenyl-3-methyl-4-cyanothietane ratio  (15'9) was o b t a i n e d i n a  o f 2.8:1, c a l c u l a t e d on the b a s i s o f the r e l a t i v e  i n t e n s i t i e s o f two methyl s i g n a l s i n the pmr spectrum. No isomerization of 1 6 3  to 1 6 2 d u r i n g the r e a c t i o n was ob-  s e r v e d . The pmr spectrum o f the mixture s i g n a l s t h a t were compatible f°  r  showed two s e t s o f  w i t h the pmr data r e p o r t e d  157 and 159 by Ohno and h i s coworkers (138). The  set o f s i g n a l s was a t t r i b u t e d t h r e e methyl p r o t o n s and H  a  first  to the t h i e t a n e 157: The  were d i s p l a y e d as two  doublets  a t 1.45 and 4 - 3 6 ppm r e s p e c t i v e l y . The Hb p r o t o n , c o u p l i n g w i t h i t s a d j a c e n t methyl p r o t o n s and H , a  was l o c a t e d as a  73  multiplet  c e n t e r e d a t 3 - 8 6 ppm.  peared as a m u l t i p l e t  at  6 . 8 - 7 - 8  The 1 0 phenyl p r o t o n s apppm.  s i g n a l s agreed w i t h the s t r u c t u r e 1 5 9  The second ;  set of  The d o u b l e t s which  were a t t r i b u t e d at  to the methyl p r o t o n s and H"b were l o c a t e d i 0 . 8 3 and 3 . 6 6 ppm r e s p e c t i v e l y . The H p r o t o n c o u p l i n g a  t  w i t h the a d j a c e n t methyl p r o t o n s and Hb, appeared multiplet  as a  c e n t e r e d a t 3 - 8 6 ppm and o v e r l a p p i n g w i t h the  s i g n a l s o f H^ i n 157. The 1 0 a r o m a t i c p r o t o n s were found in  the r e g i o n o f  6 . 8 - 7 * 8  ppm.  The c o u p l i n g c o n s t a n t s o f  c o r r e s p o n d i n g p r o t o n s i n 157 were i d e n t i c a l  to those i n  15 9 . J(CH -H) and J(H-H) b e i n g 6 and 1 0 Hz r e s p e c t i v e l y . 3  The p h o t o c y c l o a d d i t i o n o f been r e p o r t e d to be s t e r e o s p e c i f i c  w i t h o l e f i n s has (138). The configura-?,  t i o n i n the o l e f i n s was r e t a i n e d i n the t h i e t a n e p r o d u c t s . Of the 2 - b u t e n e n i t r i l e s ( 1 6 2 ,  163), the c i s - and t r a n s -  i s o m e r s g e n e r a t e d e x c l u s i v e l y the c i s - and t r a n s -  thie-  tanes ( 1 5 6 - 1 5 9 ) r e s p e c t i v e l y . The mechanism o f the photoc y c l o a d d i t i o n r e a c t i o n was proposed philic jc-7t  a t t a c k o f the e l e c t r o n d e f i c i e n t  singlet  trile  to i n v o l v e the n u c l e o o l e f i n s by the  s p e c i e s o f _95_. I n the r e a c t i o n o f p r o p e n e n i -  (144), the s u l f u r atom o f S>5_ a t t a c k e d the p-end o f  the double bond, r e s u l t i n g i n f o r m a t i o n o f p - c y a n o t h i e t a n e 155 w h i l e i n the r e a c t i o n s o f c i s - and t r a n s - 2 - b u t e n e n i triles,  the s u l f u r atom a t t a c k e d both the o<- and <a- car^.  bons o f the o l e f i n s cyano-  (l62,  1 6 3 ) to produce  and p-cyano- t h i e t a n e s ( 1 5 6 - 1 5 9 ) .  a m i x t u r e o f <*The l a t t e r r e a c -  74 t i o n s were e x p l a i n e d at  on the b a s i s t h a t e l e c t r o n d e f i c i e n c y  the (3-carbons o f 162  and 163  was somewhat weakened by  the e l e c t r o n - r e l e a s i n g a b i l i t y o f the methyl group, and as a result,  the o r i e n t a t i o n o f p h o t o c y c l o a d d i t i o n  observed  i n the r e a c t i o n w i t h p r o p e n e n i t r i l e (144) no .longer i n that with  2-butenenitriles  (l6_2, 163)  held  (138).  de Mayo and S h i z u k a (131) showed t h a t the format i o n o f t h i e t a n e 155 was d e r i v e d from the thermal s i t i o n o f the f i r s t - f o r m e d p r o d u c t 1,3-dithiane 166. r e a c t i o n between the^-^Tt  singlet  decompoThe  s p e c i e s o f 35 and 144  166 was d e s c r i b e d  t o i n v o l v e the g e n e r a t i o n  170 which, upon f o r m a t i o n ,  of a zwitterion  immediately a s s o c i a t e d w i t h an  a d d i t i o n a l m o l e c u l e o f 35 r e s u l t i n g i n the f o r m a t i o n o f  75  I i i  15 1 , 3 - d i t h i a n e which  155  15  l i b e r a t e s one m o l e c u l e o f each o f t h i e  tane and thiobenzophenone  a t room temperature.  I t i s not  known whether the f o r m a t i o n o f t h i e t a n e s from 1 6 2 also involved mediates  and  the thermal d e c o m p o s i t i o n o f s i m i l a r  163  inter-  (171, 172).  Attempts  to s e p a r a t e the o<-cyanothietanes (158,  159) and the (3-cyanothietanes (156 , 157) from t h e i r  iso-  meric m i x t u r e s were c a r r i e d out by c r y s t a l l i z a t i o n and chromatography methods but w i t h o u t  sucess. The i s o m e r i c  m i x t u r e s o f o(- and p- c y a n o t h i e t a n e s were then o x i d i z e d w i t h the hope t h a t  s e p a r a t i o n o f the o<- and the (b- cyano  i s o m e r s c o u l d be a c h i e v e d a t t h e i r s u l f o n e stage. T h i e t a n e 1-oxides and t h i e t a n e 1 , 1 - d i o x i d e s a r e u s u a l l y more  stable  76 and o f h i g h e r m e l t i n g p o i n t than the p a r e n t compounds. 2.  Synthesis of cyanothietane  1,1-dioxides  When t h i e t a n e 155 was t r e a t e d w i t h m-chloroperoxybenzQic  acid  3-cyanothietane  155  (173), the expected p r o d u c t , 1,1-dioxide  (160), was o b t a i n e d . The i r  173  spectrum  of 1 6 0  and  cm~^) and n i t r i l e  1 3 2 5  2,2-diphenyl-  trum o f l 6 0 ,  160  showed the a b s o r p t i o n s o f s u l f o n e (1143 ( 2 2 6 5  cm""'"). I n the pmr spec-  the two methylene p r o t o n s and the methine  p r o t o n appeared  as a m u l t i p l e t c e n t e r e d a t 4 . 6 3 ppm, and  the t e n phenyl p r o t o n s appeared  as a m u l t i p l e t a t  7«43  ppm. The c o u p l i n g c o n s t a n t s c o u l d n o t be measured because o f the c o m p l e x i t y o f the spectrum. S i m i l a r treatment  o f a 2 . 5 : 1 mixture  o f 1 5 6 and  158 w i t h 173 gave a 6 8 . 4 % y i e l d  of cis-2,2-diphenyl-3-cyan-  0\r- 4-me t h y l t h i e tane 1 , 1 - d i o x i d e  (174)« The <<-cyano isomer,  175,  was n o t d e t e c t e d i n the r e a c t i o n m i x t u r e ,  indicating  that t h i e t a n e 158 o r s u l f o n e 175 d i d not s u r v i v e the o x i d a t i o n r e a c t i o n . The s t r u c t u r e o f 174 was a s s i g n e d a c c o r d i n g to the s p e c t r o s c o p i c d a t a and e l e m e n t a l a n a l y s i s , and  77  (156, 158)  +  173  175  was  supported by the y i e l d o f 174  t i o n . The i r spectrum (1155  and 1330  cm" ) 1  of 174  i n the o x i d a t i o n r e a c -  showed s t r e t c h i n g s o f s u l f o n e  and n i t r i l e  (2260 cm" ) :.in, a d d i t i o n  to the phenyl and carbon-hydrogen The  60 mHz  pmr  methyl p r o t o n s protons H  a  spectrum  (1.63 ppm),  v i b r a t i o n a l absorptions.  d i s p l a y e d s i g n a l s f o r three  a m u l t i p l e t f o r the r i n g methine  and H^, (4.40-4.80 ppm)  f o r 10 p h e n y l p r o t o n s was  o f 174  1  as w e l l as a b s o r p t i o n s  (7.20-7.60 ppm).  observed:, i n the m u l t i p l e t o f H  a  High-order  and Hb  due  splitting  to s m a l l d i f -  f e r e n c e . i n the c h e m i c a l s h i f t s of these two p r o t o n s  and  t h e i r c o u p l i n g w i t h the. .methyl p r o t o n s . The h i g h - o r d e r coupl i n g , e f f e c t was 1  which appeared  a l s o observed i n the methyl  absorptions  as an abnormal t r i p l e t w i t h the middle  peak  78 s h o r t e r than the o u t e r peaks by a h a l f o f t h e i r ties mal  ( F i g u r e I I ) . I n the 100 mHz pmr spectrum, t h i s abnortriplet  of H  tended to become a doublet  and the m u l t i p l e t  and H"h was composed o f more peaks than i n the 60 mHz  a  spectrum. I n o r d e r t o measure the v i c i n a l tant, J(H -Eb), a  thyl  intensi-  c o u p l i n g cons-  s p i n - d e c o u p l i n g was employed. When the me-  s i g n a l a t I . 6 3 ppm was i r r a d i a t e d ,  the m u l t i p l e t a t  4.40-4-80 ppm c o l l a p s e d to form an AB q u a r t e t c e n t e r e d a t 4.57  ppm. The v i c i n a l  chemical and  coupling constant,  J(H -H-b), and the a  s h i f t d i f f e r e n c e , &v(H -H-b) were found t o be 9 Hz a  4-6 Hz r e s p e c t i v e l y . The s m a l l A V / J r a t i o  cause o f the c o m p l e x i t y tiplet  o f the methyl s i g n a l and the mul-  o f two r i n g methine p r o t o n s .  tween the. methyl.-protons and H The  thus was the  a  V i r t u a l c o u p l i n g be-  occurred  (143)..  y i e l d o f s u l f o n e i n the o x i d a t i o n o f the  i s o m e r i c m i x t u r e o f t h i e t a n e s 156 and 158 excluded the possibility  t h a t the product  the o x i d a t i o n product the y i e l d o f product  formed was s u l f o n e 175- I f  i s o l a t e d had been the s u l f o n e 175, would have been o n l y 59% o f the quan-  t i t y o f the pure s u l f o n e 174 a c t u a l l y i s o l a t e d , to  according  the c a l c u l a t i o n o f a 100% y i e l d o f s u l f o n e 175 on the  b a s i s o f a 2.5:1 m i x t u r e o f t h i e t a n e s 156 and 158 used i n the o x i d a t i o n r e a c t i o n . The y i e l d o f the i s o l a t e d  sulfone  exceeded the p o s s i b l e maximum y i e l d o f s u l f o n e 175 i n a q u a n t i t y o f 41%. When a 2.8:1 m i x t u r e o f t r a n s i s o m e r i c  thietanes  Figure II Pmr  spectrum  of cis-2.2-diphenyl-3-cyano-4-methylthietane  . d i o x i d e (174) d i s s o l v e d i n CDCl.  1,1-  80 157 and 159 was o x i d i z e d by p e r a c i d 173, yl-3-cyano-4-methylthietane i n 58.7% y i e l d .  1,1-dioxide  The p<-cyano isomer,  methyl-4-cyanothietane  1,1-dioxide  trans-2,2-diphen(176) was  isolated  trans-2,2-diphenyl-3(177), u n f o r t u n a t e l y v.  was n o t d e t e c t e d i n the r e a c t i o n m i x t u r e , i n d i c a t i n g  that  t h i e t a n e 159 o r s u l f o n e 177 d i d not s u r v i v e the o x i d a t i o n  r e a c t i o n . The s t r u c t u r e o f s u l f o n e 176 was a s s i g n e d a c c o r d i n g to the s p e c t r o s c o p i c d a t a and the elemental a n a l y s i s , and was supported by the y i e l d o f 176 i s o l a t e d the o x i d a t i o n r e a c t i o n . The i r spectrum  from  o f s u l f o n e 176  showed a b s o r p t i o n s o f s u l f o n e (1148 and 1318 cm""") and 1  nitrile  (2260 cm~^). The pmr spectrum  o f s u l f o n e 176»  u  n  ~  81 like for  t h a t o f s u l f o n e 174, the methyl and  protons  coupling with  peared as two 5-01  protons  the r i n g methine p r o t o n s .  ppm  the methyl p r o t o n s  p a r t l y overlapping r e s p e c t i v e l y . The  were d i s p l a y e d as two  ppm  r e s p e c t i v e l y . The  Hb)  and  vicinal  J(H -Ht>), were equal  10  proton H  The  and H ,  ap-  a  doublets  and  a  at  4'83  the methyl  a t 3.78  and  coupling constants, and  phenyl  ppm.  quartets centered  to 7 Hz  a  spectrum  The  were d i s p l a y e d as a m u l t i p l e t at 7-42  p r o t o n H-5,  and  showed a f i r s t - o r d e r  1.63 JCCH^-  10 Hz r e s p e c t i v e -  lyThe  yield  of s u l f o n e i n the o x i d a t i o n of the '  i s o m e r i c m i x t u r e o f t h i e t a n e s 157 possibility  t h a t the product  the o x i d a t i o n product the y i e l d  o f product  o f a 2.8:1  159  formed was  i s o l a t e d had  excluded  yield  and  159  o f 177  quantity to  the  on the b a s i s used i n the  of the i s o l a t e d  ceeded the p o s s i b l e maximum y i e l d  177,  according  o f s u l f o n e 177,  m i x t u r e of t h i e t a n e s 157  o x i d a t i o n r e a c t i o n . The  If  been the s u l f o n e  a c t u a l l y obtained  yield  the  s u l f o n e 177•  would have been 5 0 % o f the  o f the pure s u l f o n e 176 c a l c u l a t i o n of a 100%  and  sulfone  ex-  i n a q u a n t i t y of  50%. The  o x i d a t i o n of cis-o(-cyanothietane 158  trans-o<-cyanothietane 159  d i d not produce the  expected  s u l f o n e s . As p r e v i o u s l y mentioned i n the T h i e t a n e try  s e c t i o n , the e l e c t r o n i c n a t u r e  and  and  Chemis-  the b u l k i n e s s  of  s u b s t i t u e n t s on the t h i e t a n e r i n g determine whether the  p<-  82 cyanothietane 1,1-dioxide two  can he formed. The presence  b u l k y phenyl groups and  the l a c k of a 4-methyl  tuent t h a t can compensate f o r the effect  i f i t was  substi-  electron-withdrawing  o f the s u l f o n e f u n c t i o n may  s u l f o n e 175  of  formed. One  l e a d to breakdown o f of the p o s s i b l e paths  of  d e g r a d a t i o n i s the r e v e r s e d p r o c e s s o f c y c l i z a t i o n of s u l fene and  olefin.  175  I n the o x i d a t i o n o f t h i e t a n e s 155-157 to fone s l 6 0 , 174 was  and 176,  c h l o r o f o r m or methylene c h l o r i d e  used as s o l v e n t . When anhydrous e t h e r was  vent i n the o x i d a t i o n o f a mixture and 158,  p r e c i p i t a t i o n of a white  t e r the a d d i t i o n o f p e r a c i d 173«  156  sul-  used as  sol-  of c i s t h i e t a n e s 156 solid  soon o c c u r r e d a f -  The white  178  solid  was  83 i d e n t i f i e d as cijs-2,2-diphenyl-3-cyano-4-me t h y l t h i e t a n e oxide  (178)  according  to i t s s p e c t r o s c o p i c  quent o x i d a t i o n to 174* oxide  178  was  due  Obviously,  to i t s low  data and  the f o r m a t i o n  f o r e f u r t h e r o x i d a t i o n to s u l f o n e 174 mediate p r e c i p i t a t i o n of the  was  Thereim-  s u l f o x i d e upon i t s f o r m a t i o n .  o x i d i z e d i n an i d e n t i c a l c o n d i t i o n , the  and  159  precipitation  o f the expected t r a n s t h i e t a n e 1-oxide d i d not s o l u b i l i t y of  sulf-  p r e v e n t e d by  When a m i x t u r e of t r a n s t h i e t a n e s 157 was  subse-  of  s o l u b i l i t y i n ether.  1-  occur.  The  trans-2,2-diphenyl-3-cyano-4-methylthietane  1-oxide might be h i g h e r i n e t h e r c a r r i e d on u n t i l  the  sulfone  so t h a t the  stage was  oxidation  reached. I t  was  a l s o p o s s i b l e t h a t the r a t e o f r e a c t i o n i n o x i d a t i o n o f c i s s u l f o x i d e to c i s s u l f o n e was  slower than t h a t of  the  t r a n s isomer, p r o b a b l y  because o f the s t e r i c e f f e c t o f  ring  o x i d a t i o n of t h i e t a n e s to  s u b s t i t u e n t s . The  1 , 1 - d i o x i d e s i n f a c t proceeded v e r y f a s t i n S t i r r i n g a chloroform tane m i x t u r e of 156 174  or 176  s o l u t i o n o f p e r a c i d 173  and  158  or of 157  and  159  the  thietane  chloroform. and  a  thie-  generated  i n the expected good y i e l d w i t h i n one  or'two  hours. I n the i r spectrum of 178, s u l f o x i d e and n i t r i l e a b s o r p t i o n s 2260 cm" The  pmr  1  r e s p e c t i v e l y , and no spectrum of 178  p r o t o n s (7*40 ppm),  the  characteristic  appeared at 1080  s u l f o n e band was  observed.  showed a m u l t i p l e t f o r 10  a doublet  f o r proton H  a  and  (4.71  phenyl ppm),  84 two  o v e r l a p p i n g q u a r t e t s o f a d o u b l e t f o r p r o t o n Hb (3-41  ppm),  and a d o u b l e t f o r t h r e e methyl  The v i c i n a l  protons  (1.67 ppm).  c o u p l i n g c o n s t a n t s , J ( H - H b ) and JCCH^-H-h) a  were 10 and 7 Hz r e s p e c t i v e l y . 3. S y n t h e s i s o f 3-aminomethylthietane  1,1-dioxides  I n c o n s i d e r a t i o n o f the i n h e r e n t n a t u r e o f t h i e tane d e r i v a t i v e s t o undergo r i n g opening r e a c t i o n s , o n l y l i m i t e d methods were c o n s i d e r e d s u i t a b l e t o c o n v e r t the c y a n o - t h i e t a n e 1 , 1 - d i o x i d e s 160, 174 and 1 7 6 r e s p o n d i n g aminomethyl d e r i v a t i v e s  1 6 0  R=H  174 R=GH 176  (l6l,  1 6 1  3  R=CH-3  t o the c o r -  179, 180). I t had  R=H  cis  179 R=GH  trans  180 R=CH-,  3  cis  been r e p o r t e d from our l a b o r a t o r y (84) t h a t  trans  sponge n i c k e l  c a t a l y s t under m i l d c o n d i t i o n s (room temperature,  50 p s i  H^) c a t a l y z e d the c o n v e r s i o n o f 2 , 4 - d i p h e n y l - 3 - c y a n o t h i e tane 1 , 1 - d i o x i d e  (181)  3-aminomethylthietane l60  t o the c o r r e s p o n d i n g 2 , 4 - d i p h e n y l 1 , 1 - d i o x i d e . Attempts  to hydrogenate  by t h i s method, however, r e s u l t e d i n r e c o v e r y o f un-  r e a c t e d s t a r t i n g m a t e r i a l . When the h y d r o g e n a t i o n was p e r -  85  NH CH 2  NC  2  H, Sponge N i  •SO,  -SO,  182  181  formed under r e l a t i v e l y v i g o r o u s c o n d i t i o n s by u s i n g Raney n i c k e l , c o - c a t a l y s t s (sodium a c e t a t e and a c e t i c  anhydride),  h i g h e r temperature (90°), and 50 p s i H , d e s u l f o n a t i o n o f 2  the s u l f o n e l 6 0 o c c u r r e d .  NH CH 2  H , 2  Raney N i  90°,Co-catalysts  •so,  2  160  -SO, 1 6 1  The r e d u c t i o n o f n i t r i l e s 160, 174 and 176 was a c h i e v e d by u s i n g d i b o r a n e . C o n v e r s i o n 1,1-dioxides  (183) to the c o r r e s p o n d i n g  tane 1 , 1 - d i o x i d e s  o f 3-cyanothietane 3-aminomethylthie-  (184) by u s i n g t h i s m i l d , a c i d i c ,  reduc-  i n g agent had been r e p o r t e d from our l a b o r a t o r y (84, 8 5 ) . The method i n v o l v e d the h y d r o b o r a t i o n , f o r one day, by u s i n g excess diborane  (144), and the subsequent h y d r o l y -  s i s o f the i n t e r m e d i a t e formed. The l a t t e r step was accom-  86 p l i s h e d by t r e a t i n g the r e a c t i o n m i x t u r e w i t h e t h a n o l  fol-  lowed by r e f l u x i n g the r e s u l t i n g s o l u t i o n f o r one hour. I t had been r e p o r t e d t h a t d i b o r a n e reduced a v a r i e t y of f u n c t i o n a l groups but d i d not r e a c t w i t h s u l f i d e or s u l f o n e (144)• The mechanism of d i b o r a n e r e d u c t i o n o f n i t r i l e i n -  v o l v e s the f o r m a t i o n o f a b o r a n e - n i t r o g e n bond and  the  t r a n s f e r o f h y d r i d e i o n (145). The p r e l i m i n a r y r e a c t i o n p r o d u c t i s t h e r e f o r e a borane adduct alkylborazine  RON  • +  (185)  H-B.  R-4-K  >  R-C=N-B^  I  H  ^B;  ^-4 H  H  -H  •H •H  N,N,N-tri-  (144)- The i s o l a t i o n of p r i m a r y amine  H  H  such as  , •7  R - C - N H 0 I 2  H  H  c o n s e q u e n t l y r e q u i r e s h y d r o l y s i s of the borane i n t e r m e -  87 d i a t e . Some o f the borane-nitro'gen complexes a r e q u i t e s t a b l e and must be s u b j e c t e d to s t r o n g a c i d i c  BH  HB' RON  +  3BH  hydrolysis.  3 ^  GHgR  H 185  For i n s t a n c e , b o r a n e - t r i m e t h y l a m i n e col  complex i n w a t e r - g l y -  s o l u t i o n c o n t a i n i n g 1M HC1 r e q u i r e d a p e r i o d o f s i x  hours f o r complete In  hydrolysis  an attempt  (146).  t o reduce n i t r i l e 160 by u s i n g the  above d e s c r i b e d d i b o r a n e method, l 6 0 was t r e a t e d w i t h d i borane, and  the excess h y d r i d e was d e s t r o y e d by adding e t h a n o l ,  the r e s u l t i n g e t h a n o l i c  s o l u t i o n was h y d r o l y z e d by r e -  f l u x i n g on a steam b a t h f o r one hour. Work-up o f the r e a c t i o n m i x t u r e a f f o r d e d a gummy substance spectrum  showed the l o s s o f c h a r a c t e r i s t i c a b s o r p t i o n s o f  n i t r i l e and s u l f o n e groups, was  o f which the i r  i n d i c a t i n g t h a t the CN group  s u c c e s s f u l l y reduced, but w i t h apparent  s a c r i f i c e of  the t h i e t a n e r i n g . When the d i b o r a n e r e d u c t i o n was simi^:' l a r l y r e p e a t e d but the r e f l u x i n g step o m i t t e d to p r e v e n t thermal d e s u l f o n a t i o n o f the expected p r o d u c t , the i r spectrum o f the crude r e d u c t i o n p r o d u c t c o n f i r m e d the absence of  the CN group,  and d i s p l a y e d s t r o n g a b s o r p t i o n s f o r S 0  ?  88 and  BH groups. These r e s u l t s i n d i c a t e d t h a t the borane  adduct was formed i n the r e a c t i o n , and t h a t h y d r o l y s i s was n e c e s s a r y t o g e n e r a t e the amine under c o n d i t i o n s which would n o t d e s t r o y The  product.  l i b e r a t i o n o f p r i m a r y amine from the borane  adduct w i t h o u t d e s t r u c t i o n o f t h i e t a n e r i n g was found to be  s u c c e s s f u l by h y d r o l y z i n g  hydrochloric hydroboration  the borane adduct i n aqueous  a c i d a t room temperature f o r two days. The with f r e s h l y generated diborane  generally  gave a good y i e l d o f t h e expected p r i m a r y amine a f t e r the acid-catalysed h y d r o l y s i s process.  The use o f s t o r e d  t i o n s o f diborane i n tetrahydrofuran,  solu-  however, r e s u l t e d i n  h i g h y i e l d s o f borane adduct b u t low y i e l d s o f primary amine, p r o b a b l y due t o the f o r m a t i o n  o f more s t a b l e borane  complexes which were more r e s i s t a n t to t h e m i l d  hydrolysis  p r o c e s s used. Schematically,  the c o n v e r s i o n  174  and 176 i s shown as f o l l o w s :  160  R=H  174  R=CH , c i s  176  R=CH,, t r a n s  3  o f n i t r i l e 160,  89  l 6 l  R=H  179 R=GH , c i s 3  180 R=CH,, t r a n s  The d i b o r a n e r e d u c t i o n o f l 6 0 gave the expected amine l 6 l . The i r spectrum NH  o f l 6 l showed a b s o r p t i o n s f o r  (3300 and 3360 cm" ) and S 0 1  2  T r e a t i n g l 6 l , with a c e t i c :  primary  (1135 and 1310 cm" ). 1  2  anhydride gave the c o r r e s p o n d i n g  amide, 2,2-diphenyl-3-(acetamidomethyl) t h i e t a n e (186), as n e e d l e - l i k e c r y s t a l s .  1,1-dioxide  The i r and pmr s p e c t r a  agreed w i t h the s t r u c t u r e 186. The m o n o - s u b s t i t u t e d a b s o r p t i o n appeared  amide  a t 3425 (N-H) and 1 6 7 5 (G=0) cm"  161  1  186  whereas s t r o n g s u l f o n e bands o c c u r r e d a t 1145 and 1300 cm" . 1  The pmr spectrum  o f 186 d i s p l a y e d a s i n g l e t f o r  90 t h r e e methyl p r o t o n s , a m u l t i p l e t r i n g p r o t o n s ( H , H-^) a  ( 2 . 7 2 - 4 . 2 8 ppm)  t o g e t h e r w i t h two methylene p r o t o n s  a d j a c e n t to the amide f u n c t i o n , a broad t r i p l e t ppm)  for 3  f o r the EH p r o t o n and a m u l t i p l e t  the t e n phenyl p r o t o n s . The  (5-70-6.10  (7-10-7-65 ppm)  c o m p l e x i t y o f the  for  spectrum  p r e c l u d e d the measurement o f the c o u p l i n g c o n s t a n t s - T r e a t i n g l 6 l w i t h p i c r i c a c i d gave a p i c r a t e s a l t o f l 6 l . The i r and pmr  s p e c t r a agreed w i t h the  structure.  The d i b o r a n e r e d u c t i o n o f n i t r i l e 174 gave the expected p r i m a r y amine 179 spectrum  o f 179  3385 cm" ) 1  as n e e d l e - l i k e c r y s t a l s . The i r  showed the a b s o r p t i o n f o r lEf^ (3325 and  and S 0  2  (1140, 1155  and 1300  cm" ) 1  groups.  The  179  pmr  spectrum  singlet  o f 179  d i s p l a y e d a broad, D2Q-exchangeable  f o r the amino p r o t o n s (0.98 ppm),  three methyl p r o t o n s (1.53 ppm)  a d o u b l e t f o r ..  and a broad  distorted  d o u b l e t f o r two N-methylene p r o t o n s (2.89 ppm). H  a  ppm)  (3-50 ppm),  H-fc (4-53 ppm)  and 10 phenyl p r o t o n s  were d i s p l a y e d as 3 s e t s o f m u l t i p l e t s .  c o n s t a n t s were: J ( H - H ) = 9 Hz; a  b  Protons  JtCH.-Hft)=7  (7-42  The c o u p l i n g  Hz and  J(CH 9  91 H )=7 Hz. a  T r e a t i n g the primary amine 179 w i t h p i c r i c generated a y e l l o w p i c r a t e salt-. The i r and pmr were i n a c c o r d w i t h the s t r u c t u r e  acid  spectra  expected.  The d i b o r a n e r e d u c t i o n o f n i t r i l e 176 generated the expected p r i m a r y amine 180. The i r spectrum showed the a b s o r p t i o n s f o r NHg SO^  o f 180  (3320 and 3380 c m )  and  -1  (1145 and 1303 cm"" ) groups. T r e a t i n g 180 w i t h a c e t i c 1  anhydride gave the c o r r e s p o n d i n g N - a c e t y l d e r i v a t i v e 187> The i r spectrum  o f 187 showed the m o n o - s u b s t i t u t e d  amide  187  a b s o r p t i o n s (1650 and 3330 cm" )  i n a d d i t i o n to the s t r o n g  1  s u l f o n e bands (1145 and 1300 c m ) . - 1  The pmr spectrum  of .  187 d i s p l a y e d a d o u b l e t f o r t h r e e r i n g methyl p r o t o n s (1.52 ppm), a s i n g l e t f o r t h r e e methyl p r o t o n s a d j a c e n t to the c a r b o n y l group (1.83 ppm), a m u l t i p l e t f o r two thylene protons together with proton H  a  N-me-  (2.93-3.37 ppm), a  m u l t i p l e t f o r p r o t o n H-^ (4*40 ppm), a broad t r i p l e t f o r HH p r o t o n (5*40 ppm) and a s t r o n g s i g n a l f o r 10 phenyl p r o t o n s (7-38 ppm). The c o u p l i n g c o n s t a n t s were: JtCH^-Hb)=7 Hz; J(Ha-H-h)=9 Hz. T r e a t i n g the primary amine 187 w i t h  picric  92 a c i d generated the c o r r e s p o n d i n g p i c r a t e s a l t w i t h pmr dat a i n agreement w i t h the expected 4.  structure.  Synthesis o f 3-dImethylaminomethylthietane I t has been r e p o r t e d t h a t  1,1-dioxides  3-aminomethylthietane  1 , 1 - d i o x i d e s (184) c o u l d be d i m e t h y l a t e d u s i n g the Eschweil e r - C l a r k procedure which i n v o l v e d h e a t i n g the amines i n a  m i x t u r e o f formaldehyde and f o r m i c a c i d  (84, 85). The  r e a c t i o n p r o b a b l y proceeds through the f o r m a t i o n o f an amine a l c o h o l o r an imine which i s subsequently reduced by f o r m i c a c i d . The f i r s t  REH  RNHCH  R R  v, )C=0 —  +  2  step can be a f f e c t e d by such  R^v^ m  A HCOOH  H  x  X  1  2 ^  " 2° / ^ * RN=C"  1  > RHH-C-OH  cata-  +  > = °  1  2^ -f-° N  R  I  R H  HCOOH  >  1  I  C*-\-  E  R  >  93 l y s t s as p y r i d i n e , ammonia, and u r e a , whereas the  second  s t e p , the r e d u c t i o n o f amine a l c o h o l or S c h i f f s base,  has  f  been found, i n some r e a c t i o n s , to be a f f e c t e d more by  heat  than by o t h e r means. M e t h y l a t i o n of ammonia to t r i m e t h y l amine, f o r example, proceeded i n a good y i e l d by the formaldehyde and acid  ammonia without  heating  a d d i t i o n of formic  (147). When 2,2-diphenyl-3-aminomethylthietane  oxide  ( l 6 l ) was  heated  formaldehyde (30%)  i n a mixture  1,1-di-  of f o r m i c a c i d  and  at 90°, d e s u l f o n a t i o n o c c u r r e d as  indi-  c a t e d by the l a c k of s u l f o n e a b s o r p t i o n s i n the i r spectrum o f the r e a c t i o n p r o d u c t . be  The h e a t i n g was  the cause of d e s u l f o n a t i o n d u r i n g the  b e l i e v e d to  dimethylation  process.  32  1 6 1  Among o t h e r m i l d methods of M - d i a l k y l a t i o n , c a t a l y t i c a l l y r e d u c t i v e a l k y l a t i o n was  found  s u i t a b l e method to s y n t h e s i z e the expected 32-34 from t h e i r c o r r e s p o n d i n g 180.  primary  to be  the most  dimethylamines  amines l 6 l ,  179  The method i n v o l v e s the c a t a l y t i c h y d r o g e n a t i o n  and  of a  94 CH NH GH 2  3\  2  GH 1. GH 0 2  •SO,  R  2. H , 10% Pd/G, HAc 2  R=H  1 6 1  R  SO,  .  32 R=H  179 R=OH , c i s  13  180 R=GH^, t r a n s  34 R=CH , t r a n s  3  R=CH , c i s 3  3  m i x t u r e o f amine and c a r b o n y l compound and has been w e l l documented f o r p r e p a r i n g secondary o r t e r t i a r y  amines  (147). The r e a c t i o n i n t e r m e d i a t e i s a l s o b e l i e v e d to be the amine a l c o h o l o r the inline which i s c a t a l y t i c a l l y hy-  R  RN=C^  C=0  RHH,  J  0  R 2^"  m  ;c=o /  +  drogenated,  V  R  Catalyst  1  R<  •>  RNHCH  H, N-C-OH  R  Catalyst  J  NCH I  r e s u l t i n g i n the f o r m a t i o n o f the secondary o r  t e r t i a r y amine. By u s i n g formaldehyde,  f o r example, the  a l k y l a t i o n o f a p r i m a r y amine may l e a d to N - m e t h y l a t i o n o r N,N-dimethylation,  depending  on the q u a n t i t y o f f o r m a l d e -  hyde used. The e f f i c i e n c y o f the a l k y l a t i o n depends on the H, RNH  2  +  H C=0 2  -} REH-C-OH  ->  RFHCH.  95  RNHCH  3  +  >  H C=0 2  -^ 3  —  CE  m  ^  m  ^ 3  ease with, which aldehyde o r ketone r e a c t s w i t h amine to form a r e d u c i b l e i n t e r m e d i a t e . The b a s i c i t y o f the amine group i s thus a f a c t o r . When two amino groups a r e p r e s e n t i n the same m o l e c u l e , undergo p r e f e r e n t i a l  the more b a s i c one i s expected  to  alkylation.  V a r i o u s d i f f e r e n t k i n d s o f c a t a l y s t have been used f o r the r e d u c t i o n . Raney n i c k e l and p a l l a d i u m a r e two of  the most common c a t a l y s t s used. I n c o n s i d e r a t i o n o f the  a b i l i t y o f the Raney n i c k e l to cause d e s u l f o n a t i o n o f s u l fone s and the c a p a c i t y o f p a l l a d i u m  to c a t a l y z e low-pre-  ssure h y d r o g e n a t i o n  a t room temperature, p a l l a d i u m on c h a r -  c o a l was c o n s i d e r e d  to be the b e s t c h o i c e f o r the d i m e t h y l -  a t i o n o f 3-aminomethylthietanes l 6 l , 179 and 180. I t i s known t h a t the amine i t s e l f may have a p o i s o n o u s e f f e c t on the c a t a l y s t . A d d i t i o n o f an e q u i v a l e n t amount o f weak a c i d such as a c e t i c to the h y d r o g e n a t i o n gested  mixture  has been sug,-  to n e u t r a l i z e the e f f e c t o f base and thus  the low p r e s s u r e r e d u c t i v e a l k y l a t i o n  (147).  The r e d u c t i v e d i m e t h y l a t i o n o f primary l6l,  facilitate  179 and 180 gave the d e s i r e d p r o d u c t s  amines  32-34. The i r  s p e c t r a showed t y p i c a l a b s o r p t i o n s f o r the s u l f o n e group i n the range o f 1135-1300 c m confirming  -1  and the l a c k o f M-H s t r e t c h i n g ,  the presence o f t e r t i a r y amino s t r u c t u r e . The  96 pmr  d a t a were i n a c c o r d w i t h  the s t r u c t u r e s o f 32-34, N-  dimethylamino group a b s o r p t i o n  appearing  i n the range o f  2.1-2.2 ppm. The p r o d u c t s were f u r t h e r c h a r a c t e r i z e d as picrate  salts. The  chloroform  hydrochloride  s a l t o f 33 was n o t s t a b l e i n  s o l u t i o n . When a sample o f 33 was d i s s o l v e d i n  chloroform,  an i n s o l u b l e m a t e r i a l r a p i d l y c r y s t a l l i z e d out  from the s o l u t i o n i n one o r two minutes. T h i s u n i d e n t i f i e d crystalline  substance, d i f f e r e n t from the o r i g i n a l  materi-  a l , was i n s o l u b l e i n common l a b o r a t o r y s o l v e n t s . I r spectrum showed the".absorptions., f o r .sulfone- and ammonium groups. The  c o n f i g u r a t i o n s of.33 and 31 were a s s i g n e d i n  terms o f those o f t h e i r n i t r i l e p r e c u r s o r s  since neither  d i b o r a n e r e d u c t i o n n o r r e d u c t i v e a l k y l a t i o n would be expected  t o produce any i s o m e r i z a t i o n o f the r i n g s u b s t i -  tuents. I t i s not p o s s i b l e to apply Karplus c o r r e l a t i o n (148,  149) t o a s s i g n c o n f o r m a t i o n s f o r .33 and 34 s i n c e  both c i s and t r a n s v i c i n a l c o u p l i n g o f r i n g p r o t o n s o f j these compounds and t h e i r p r e c u r s o r s  are not d i s c r i m i n a -  t o r y i n magnitude (Table I I ) . T h i s r;esult was n o t unexpected  c o n s i d e r i n g the r e p o r t e d v a l u e s  c o u p l i n g i n t h i e t a n e d e r i v a t i v e s (138, the v i c i n a l  coupling constants  f o r c i s and t r a n s 150).  Inspection of  l i s t e d i n Table I I I r e v e a l s  t h a t J(2ax-3eq) and J(2eq-3ax) i n the c i s and J(2ax-3ax) I n the t r a n s c o u p l i n g have s i m i l a r and l a r g e r v a l u e s  where-  as J(2eq-3eq) i n the t r a n s c o u p l i n g i s d i s c e r n i b l y s m a l l e r .  97 Table I I V i c i n a l coupling constants,  J(H -Hb), o f 2,2-diphenylthiea  tane d e r i v a t i v e s  H  CH-  a  SR  Hb  1  R  Compound  157  -  178  0  174  °2  156  176 179 188  °2 °2 °2  189  °2  187  °2  177  °2  190  °2  2  i(H -H ), a  b  8  c i s CH t r a n s CH  10  c i s CH  10  c i s CH  9 10  t r a n s CH cis  CH HH 2  c i s CH HH 2  9  2  2  picrate  t r a n s CH^HH  0  picrate  9 9  t r a n s CH^HHCCH. li 11 3 0  9  cis  CH H(CH )  2  9  cis  CH H(CH )  2  2  2  3  3  9  picrate 34  °2  t r a n s CH^H(CH.)^  10  Table I I I V i c i n a l coupling constants  (Hz) o f t h i e t a n e d e r i v a t i v e s  J(cis) J(2ax-3eq) Thietane 1 , 1 - d i o x i d e  (150)  J( t r a n s )  J(2eq-3ax)  J(2ax-3ax)  10.34  J(2eq-3eq)  6.33  T h i e t a n e 1-oxide  10.63  7.49  12.53  1.83  Trans-2,4-diphenylthietane 1-oxide  10.24  8.79  11.90  3.16  Cis-2,4-diphenylthietane 1-oxide  9.53  -  12.62  Trans-2,4-diphenylthietane 1 , 1 - d i o x i d e  9-17  -  11.12  3-Substituted 1,1-dioxides  thietane 7-5-8.3  -  -  10.84  -  -  3-2-3-9  Thietane 3-carboxylic a c i d 1-oxide Thietane 3-carboxylic acid  -  8.04  9-38  3-chlorothietane  -  7.67  9.34  3-46  99 The l a r g e J(H -Hh) v a l u e s o f 9-10 Hz ( T a b l e  II) i n trans-  a  2,2-diphenyl-4-methylthietane 187  and 189 thus suggested  d e r i v a t i v e s .34, 157, 176,  t h a t both the 3 - s u b s t i t u e n t and  the 4-methyl group possessed  an e q u a t o r i a l o r i e n t a t i o n so  that a trans 2 , 3 - d i a x i a l coupling occurred. F o r 2,2-diphenyl-3-cyanothietane  157  (155), the v a l u e o f 9 Hz found f o r  176  R=;CF  189  R= CH NH  187  R= GH NHC0H  2  o  2  2  picrate  II  3  o  0 34  R= G H N ( C H ) 2  both c i s and t r a n s v i c i n a l c o u p l i n g suggested,  3  2  on the same  b a s i s , an e q u a t o r i a l o r i e n t a t i o n o f the 3-cyano group. The o t h e r p o s s i b l e c o n f o r m a t i o n h a v i n g an a x i a l cyano group  100 o r i e n t a t i o n , can be expected to r e s u l t i n a l a r g e J ( 2 a x 3eq) but a s m a l l J(2eq-3eq) v a l u e . I n the c i s - 2 , 2 - d i p h e n y l 4 - m e t h y l t h i e t a n e . d e r i v a t i v e s (33, 156,  174,  178,  179,  188  and 190), the magnitude o f J(H -H-h) v a l u e s c o u l d not be r e a  lated  to t h e i r s t e r e o c h e m i s t r y s i n c e both J(2ax-3eq)  J(2eq-3ax)  and  can be expected to have s i m i l a r v a l u e s ( T a b l e  I I I ) . I t i s , n e v e r t h e l e s s , r e a s o n a b l e to c o n s i d e r that both 32 and 33 p o s s e s s e q u a t o r i a l o r i e n t a t i o n o f the amino tituent  s i n c e non-bonding  subs-  i n t e r a c t i o n s a r e expected to be  l e s s i n such a c o n f o r m a t i o n .  32  33  5. S y n t h e s i s o f 2 , 2 - d i p h e n y l - 3 - d i m e t h y l a m i n o m e t h y l t h i e t a n e (191) S i n c e the s y n t h e t i c r o u t e to  2,2-diphenyl-3-dime-  t h y l a m i n o m e t h y l t h i e t a n e 1 , 1 - d i o x i d e s (32-34) from t h e i r  3-  cyano p r e c u r s o r s (155-157) had been e s t a b l i s h e d , i t was considered that p r e p a r a t i o n of  2,2-diphenyl-3-dimethylami-  nome t h y l t h i e tane (191) from t h e i r 3 - c y a n o t h i e t a n e tive  (155), by  employing  deriva-  the same method might be o f i n -  101  H  CH GH S  H 3. 3  S 191  155  t e r e s t i n c o n s i d e r a t i o n t h a t the  s u l f o n e group i n the com-  pounds 32-34 might cause s t e r i c h i n d r a n c e to t h e i r to the a n a l g e s i c r e c e p t o r . A l t h o u g h the methadone (23) (14), the  found ( 1 6 )  s u l f o n e group i n the  t i v e s 32-34 was as t h a t i n 23. ffect  was  not The  the b i n d i n g  to be  s u l f o n e analogue o f  as a c t i v e as methadone  semi-rigid thietane  expected to have the restricted  binding  deriva-  same f l e x i b i l i t y  s u l f o n e group thus might  o f compounds 32-34 to the r e c e p t o r  and  c o n s e q u e n t l y r e s u l t i n the l o s s of a n a l g e s i c a c t i v i t y . removal of two  oxygen atoms from the  r e s u l t i n compounds w i t h  sulfur  the a n a l g e s i c  w i t h borane d i m e t h y l was  activity  was  reduced  s u l f i d e complex, the p r i m a r y amines  generated. C a t a l y t i c r e d u c t i v e d i m e t h y l a t i o n  9 s 155  may  compounds i s a l s o an i n t e r e s t i n g problem. When 3 - c y a n o t h i e t a n e d e r i v a t i v e s 155  193  The  s i g n i f i c a n t change i n l i p o p h i l i c i -  t y . Whether t h i s change w i l l a f f e c t of the new  sulfinyl  a-  193  of  193  102  1. CH 0  /\  2  2. H , 10% Pd/C HAc 2  191 u s i n g formaldehyde d i d n o t a f f o r d the expected  dimethyl-  amine 191» An a l t e r n a t e r o u t e to 191 was c a r r i e d out by u s i n g r e p e a t e d f o r m y l a t i o n and r e d u c t i o n (151 )• The method i n v o l v e d the p r e p a r a t i o n o f a formamide, which was subseq u e n t l y reduced primary  by u s i n g l i t h i u m aluminum h y d r i d e . When  amine 155 was f o r m y l a t e d w i t h f o r m i c - a c e t i c anhy-  d r i d e , a formamide (195) was o b t a i n e d as evidenced  by the  c h a r a c t e r i s t i c a b s o r p t i o n s o f 0=0 (1675 cm" ) and I-H (3300 1  cm" ) i n the i r spectrum o f the p r o d u c t . 1  Treating this  for-  mamide (195) w i t h l i t h i u m aluminum h y d r i d e a t 0° y i e l d e d a secondary  amine (196)  f o r which the i r spectrum  confirmed  the r e d u c t i o n o f the c a r b o n y l group and showed an absorpt i o n f o r H-H s t r e t c h i n g  (3310 cm" ). When s i m i l a r  t i o n and r e d u c t i o n p r o c e d u r e s d i m e t h y l a t e d product  1  formyla-  were performed on 196, the  191 was generated.  T r e a t i n g the t e r -  103  198  191  t i a r y amine 191 w i t h HG1 gave a crude h y d r o c h l o r i d e  salt  (197) o f 191, which d i s p l a y e d c h a r a c t e r i s t i c ammonium abs o r p t i o n s i n i t s i r spectrum. The pmr spectrum o f 197 showed a s i n g l e t f o r s i x N-methyl p r o t o n s (2.73 ppm), a m u l t i plet  (2.35-3*40 ppm) f o r two TJ-methylene p r o t o n s and two  r i n g ^-methylene p r o t o n s , a m u l t i p l e t ( 4 . 1 0 ^p.pm')'for; one-mef  t h i n e p r o t o n and a s i n g l e t f o r t e n phenyl p r o t o n s (7-33 ppm).  The ammonium p r o t o n was d i s p l a y e d as a DgO  exchange-  a b l e broad s i n g l e t a t 5-88 ppm. I t had been r e p o r t e d t h a t o l e f i n s which were subs t i t u t e d by e l e c t r o n r e l e a s i n g groups (e.g. 136, 202, 204), on i r r a d i a t i o n w i t h e i t h e r 366 nm o r 589 nm l i g h t ,  reacted  w i t h thiobenzophenone (.95) t o form e i t h e r d i t h i a n e ( e . g .  104 201) o r t h i e t a n e d e r i v a t i v e s the  (e.g. 203, 205) depending on  s t e r i c f a c t o r (138). An attempt  t o generate 191 u s i n g  G  CH =CH-0C H 2 2 5 o  o  M.  4 366 c r 589 nm  + 95 —  [  6 5 6 5  5  201  t h i s simple procedure "by i r r a d i a t i n g me t h y l a l l y l a m i n e  a mixture o f  (200) and thiobenzophenone  H C=0H-CH HH 2  2  H  2 C O  ,  A H O O  OH  >  H  2  C  =  C  H  -  200  0  H  di-  (.95) was with-  out s u c c e s s .  199  H  H  136  2  H  C  C H 0 2  6 5  2 < ^  105  H hv (366  nm)  w  GH.  95  //  -s 1 9 1  6. Attempted s y n t h e s i s  of thietane  methylaminomethyl s i d e  d e r i v a t i v e s w i t h o(-di-  chain  As mentioned p r e v i o u s l y , methadone e x i s t e d i n a preferred tertiary  c o n f o r m a t i o n i n which a c l o s e approach o f the amine group to the oxygenated f u n c t i o n was o b s e r v -  ed. I n two  studies  tent a n a l g e s i c s ,  (84, 85) o f t h i e t a n e  i t was  d e r i v a t i v e s as po-  suggested that an o<-dimethylamino-  methyl s i d e c h a i n might be r e q u i r e d  f o r the a n a l g e s i c  v i t y . A c l o s e a p p r o x i m a t i o n between amino group and f u n c t i o n might be a c h i e v e d  actisulfone  (84, 85) i n compounds 35, 36  and 206-208• The p r e c i s e l o c a t i o n o f the amino group and  206  35 36  cis trans  106  3~ CH  SO,  "NCH  r  CH  3\  SO,  NCH,  CH.  3  208  207  the  o r i e n t a t i o n o f the unbonded e l e c t r o n p a i r o f n i t r o g e n  i n narcotic  analgesics  to t h e i r a n a l g e s i c  have been r e p o r t e d  activity.  to be important  ' Compounds 35". 36 and  206-208 thus might be v a l u a b l e  i n the study o f s t r u c t u r e -  a c t i v i t y r e l a t i o n s h i p s w i t h comparisons i n p a r t i c u l a r to the  thietane  d e r i v a t i v e s h a v i n g a /3-amino s i d e c h a i n (32-  34 e t c . ). Haya (85) had attempted the s y n t h e s i s reacting  o f 206 by  s u l f o n y l c h l o r i d e 79 w i t h enamine 209 but i s o l a t -  ed an a c y c l i c  sulfone  instead  o f the d e s i r e d  cyclic  210. R K 2  0  :C=CHSCH CN 2  C=GH  +  2  NCCH S0 C1 2  Et N 3  2  79  • 209 R= morpholino  NC  -SO,  or p y r r o l i d i n o  SO,  3\ CH  NCH 3  206  210  product  107 S i n c e attempts to p r e p a r e c i s - and t r a n s - 2,2-diph eny1-3-me thyl-4-dimethylaminome t h y l t h i etane 1 , 1 - d i o x i d e (35,  36) were f r u s t r a t e d by d i f f i c u l t i e s  encountered i n the  s y n t h e s i s o f the p r e c u r s o r s , 175 and 177, the s y n t h e s i s o f compounds 207 and 208 was c o n s i d e r e d and approached according  to the f o l l o w i n g  (Et) N 3  H0CH CH SH 2  scheme:  01 , H 0  2  2  J  2  G10H 0H S0 C1 2  2  2  C H -CH=0HM(0H ) 6  3  GH  3  3  212  211  GH  5  213  CH„C1 X  y  ^GH C1 2  d  SO,  SO,  214  215  ,CH N  /  C  H  •CH.  3  ,CH isr  2  2  •CH. •SO,  -SO,  216  207  CH=CCH 0H  )  9 d  (CH ) S0 3  2  CH=CCH 0CH., * 9  d  4  217  NaOBu  N  ^GH.  2  108  CH =C=CH-0CH 2  CH 0 3 o  hv  3  v  95 GH 113  114  GH^ 208  The c y c l o a d d i t i o n sulfenes  of electron r i c h o l e f i n s with  generated from s u l f o n y l c h l o r i d e s has "been des-  c r i b e d i n the i n t r o d u c t i o n  s e c t i o n . I t was expected  the r e a c t i o n between the ( 5 - c h l o r o e t h a n e s u l f o n y l (212) and (5-dimethylaminostyrene triethylamine could  that  chloride  (213) i n the presence o f  would generate the c y c l o a d d u c t 214 which  then be c o n v e r t e d to the f i n a l product 207The  sulfonyl chloride  212 was p r e p a r e d , a c c o r d -  i n g to a method taken from a p a t e n t (152), by r e a c t i n g (5mercaptoethanol  (211) w i t h c h l o r i n e and water.  The ^ - d i -  me t h y l amino s t y r e n e (213) was p r e p a r e d a c c o r d i n g to the procedure d e s c r i b e d  by Coates  hyde and dimethylamine.  (84a) from p h e n y l a c e t a l d e -  109 When a m i x t u r e o f 213 and t r i e t h y l a m i n e i n an equimolar amount was t r e a t e d w i t h ed was not the expected c y c l i c an a c y c l i c rene (218),  compound,  212, the product  isolat-  adduct 214 hut a m i x t u r e of  vinylsulfonyl)-(b-dimethylaminosty-  and t r i e t h y l a m i n e h y d r o c h l o r i d e .  The  triethyl-  214 amine h y d r o c h l o r i d e  formed was q u a n t i t a t i v e (0.03 mole)  when the amount o f s u l f o n y l c h l o r i d e (212), and  enamine (213)  t r i e t h y l a m i n e used were 0.015, 0.015 and 0.03 moles  r e s p e c t i v e l y , i n d i c a t i n g t h a t the two c h l o r i n e atoms i n 212 were removed by two m o l e c u l e s o f t r i e t h y l a m i n e and that generation  of compound 214 c o n t a i n i n g a  chloromethyl  group (A to the s u l f o n y l f u n c t i o n was not p o s s i b l e i n t h i s r e a c t i o n . The i r spectrum o f 218 showed s t r o n g o f enamine ( 1 6 2 0  cm" ), s u l f o n e 1  absorptions  (1120, 1135 and 1300  cm" ) 1  110 and v i n y l i c C-N (1185 and 1258 c m ) f u n c t i o n a l - 1  The  pmr spectrum  o f 218 d i s p l a y e d a sharp  dimethylamino p r o t o n s  (group  singlet for s i x  a, 2.68 ppm), an ABX m u l t i -  p l e t f o r three v i n y l i c protons  (group b, 5.50-6.80 ppm)  and  two s i n g l e t s f o r f i v e phenyl p r o t o n s  one  enamine p r o t o n H  (7-33 ppm) and  (7-37 ppm). These data a r e compared  c  w e l l w i t h those r e p o r t e d f o r the analogous 222,  groups.  compounds  223 (153) and 221 (84). The same v i n y l  fone 218 was a l s o i s o l a t e d by Paquette  enamino  sul-  and Rosen i n a  y i e l d o f o n l y 6% upon t r e a t i n g t h i e t a n e 219 w i t h methanes u l f o n y l c h l o r i d e and t r i e t h y l a m i n e (153). The pmr s i g n a l s  CH  /  3\  G H  3  CH H 2  CH-  CH so2  3  CH S0 C1, 3  2  Et N  218  3  219  of 218, however, were n o t c o r r e c t l y a s s i g n e d . A v a l u e o f 5.94  ppm was r e p o r t e d by these workers f o r the c h e m i c a l  s h i f t o f the =CHW p r o t o n and was n o t c o n s i s t e n t w i t h  those  £-values r e p o r t e d f o r compounds 221-223 ( T a b l e I V ) . A s i n g l e t a t 6.00 ppm was indeed p r e s e n t i n the pmr  spectrum  of 218 but was p a r t o f the ABX m u l t i p l e t o f the t h r e e CH =CHS p r o t o n s . 2  I t has been known t h a t r e a c t i o n s o f s u l f e n e s and  Table IV Chemical s h i f t s (ppm) o f s u l f o n y l enamines (84, 153)  G  C H -CH -S0 -C=CHN(CH ) 6  5  2  2  3  (221)  2  6 5- = H  G  7-41  NCH=  1(CH )  7-22  2.60  3  2  CH =CHS 2  5.73(d) CH =CH-S0 -CH=CHN(CH ) 2  2  3  2  (222)  7.18  2.92  6.10(d) 6.68(q)  C  6 5 H  CH -CH -S0 -C=CHN(CH )  2  (223)  7-22  7-14  2.59  CH =CH-S0 -C=CHM(CH )  (218)  7-33  7-37  2.68  3  2  2  3  C  2  2  6 5 H  3  2  d: d o u b l e t , q : q u a r t e t , m: m u l t i p l e t  5.5-6.8(m)  112 enamines can g i v e e i t h e r t h i e t a n e s o r a c y c l i c p r o d u c t s depending  substitution  on the n a t u r e o f r e a c t a n t s . A  two-step  mechanism (Page 36) i s g e n e r a l l y f a v o r e d (112-117) on the b a s i s o f Woodward-Hoffman s e l e c t i o n r u l e s (154), the s t e r e o s e l e c t i v i t y i n the f o r m a t i o n o f p r o d u c t s and the nuc l e o p h i l i c n a t u r e o f o l e f i n s used n a t u r e o f the product was governed ic  (106). I t appears  t h a t the  by e l e c t r o n i c and s t e r -  f a c t o r s t h a t i n f l u e n c e the Z w i t t e r i o n j33. Any e l e c t r o -  n i c e f f e c t which s t a b i l i z e s 6j3 o r any s t e r i c  hindrance  which o b s t r u c t s the i n t r a m o l e c u l a r c y c l i z a t i o n o f 6^ w i l l facilitate  the f o r m a t i o n o f a c y c l i c p r o d u c t . The i s o l a t i o n  of a c y c l i c product 218 i n the attempted  cycloaddition r e -  a c t i o n was p r o b a b l y due to the i n t r a m o l e c u l a r dehalogenat i o n o f the Z w i t t e r i o n 224» The absence  of c y c l i c  product  i n t h i s case a t t e s t s to the f a c i l e n a t u r e o f the d e h a l o genation. t!=S0  o  +  CH =CH-S0 2  218  CH CH  224  C1CH  2  214  2  P  113 As the d e s i r e d p r o d u c t , 214, c o u l d n o t be p r e pared by t h i s r o u t e , s y n t h e s i s o f 207 was abandoned, and the  attempt  to p r e p a r e an analogous compound, 208, was  c o n s i d e r e d . I t was expected t h a t 208 c o u l d be d e r i v e d 2,2-diphenyl-3-methoxy-4-methylenethietane  CH =C=CH-0CH 2  from  (114) and d i -  3  CH 0 3  x  so, GH,  115  9  208  114  methylamine.  /0H  Paquette e t a l . (155) had shown t h a t dime-  thylamine c o u l d be added  to the double bonds o f 2-methyl-  e n e - 4 - p h e n y l - 2 H - t h i e t e 1 , 1 - d i o x i d e (225) to g i v e a dimethylamino d e r i v a t i v e 219 i n 4 6 % y i e l d . /CH  OH.  -SO, 225  OH. HN^ CH.  CH„N d  CH. so2 219  X  J  CH  3  114 The  s y n t h e s i s of 114 was  coworkers (134a).  c l a i m e d by Bos  They r e p o r t e d t h a t i r r a d i a t i n g a  of thiobenzophenone (95) and methoxyallene (113) t y minutes, under uv l i g h t generated and f i l t e r e d a mixture  through  o f 114  a potassium  and 115,  low,  g e n e r a t i n g the f i n a l p r o d u c t ,  pared,  of 15-20%. A l -  a suitable quantity f o r  208,  c o u l d be  a c c o r d i n g to the p r o c e d u r e s  p r o c e s s . The  showed a t r i p l e t  d o u b l e t and  (4.14  (3*33 ppm)  ppm)  The  ace-  f o r t h r e e methyl p r o -  f o r two methylene p r o t o n s .  the h i g h f i e l d  a colorless liquid. ( 2 . 9 3 ppm) ppm)  pre-  The  the t r i p l e t r e s u l t e d from a l o n g range c o u p l -  p r o t o n . T r e a t i n g 218 w i t h  (6.30  (157)  pmr  f o r one  the methylene p r o -  (J=2.5 Hz). An a n i s o t r o p i c s h i e l d i n g of the  bond caused  let  s u l f a t e i n the  ( 2 . 6 2 ppm)  i n g between the a c e t y l e n i c p r o t o n and tons  obtained  as a c o l o r l e s s l i q u i d .  t y l e n i c proton, a s i n g l e t tons, a d o u b l e t  pre-  alcohol.  T r e a t i n g 217 w i t h d i m e t h y l sence o f base gave 218  and was  me-  taken from l i t e r a t u r e ,  from methyl p r o p a r g y l e t h e r (217) which was  spectrum o f 218  easily obtain-  a known compound (156)  by m e t h y l a t i n g p r o p a r g y l  f o r twen-  dichromate s o l u t i o n , gave  ed by r e p e a t i n g the simple photochemical (113) was  mixture  from a mercury lamp  both i n a y i e l d  though the y i e l d o f 114 was  thoxyallene  and h i s  The  triple  a b s o r p t i o n s o f the a c e t y l e n i c sodium b u t o x i d e  pmr  generated  spectrum o f 113  f o r t h r e e methyl p r o t o n s and  f o r one methine p r o t o n . A g a i n ,  113  showed a a  as  sing-  triplet  l o n g range coup-  115 l i n g o c c u r r e d between the methane and the methylene p r o tons, J=5'5 Hz. When the r e a c t i o n o f thiobenzophenone (95) w i t h methoxyallene  (113) was performed,  r e s u l t s o b t a i n e d were  not i n agreement w i t h those c l a i m e d by Bos e t a l . (134a). Bos and h i s coworkers c l a i m e d t h a t the r e a c t i o n was photoc h e m i c a l b u t the p r e s e n t f i n d i n g s proved  t h a t the r e a c t i o n  was thermal. When 113 and a benzene s o l u t i o n o f 9_5_ was mixed t h o r o u g h l y under n i t r o g e n , the b l u e c o l o r o f _95_ g r a d u a l l y f a d e d and c o m p l e t e l y d i s a p p e a r e d w i t h i n 1% hours, without used.  r e q u i r i n g t h e i r r a d i a t i o n procedure  To prove  t h a t Bos est a l .  t h a t the r e a c t i o n was n o t caused by the  laboratory fluorescent  light,  two p a r a l l e l  experiments  were c a r r i e d out s i m u l t a n e o u s l y . I n one experiment, the r e a c t i o n o f 95. and 113 was a l l o w e d w h i l e i n the second  experiment,  was exposed t o uv l i g h t t a s s i u m dichromate.  filtered  to proceed  the mixture through  o f 95 and 113  a s o l u t i o n o f po-  Both r e a c t i o n s were found  p l e t e w i t h i n 1-g- h o u r s ,  i n the dark  to be com-  the same r e a c t i o n time found  the r e a c t i o n o c c u r r i n g under l a b o r a t o r y f l u o r e s c e n t The b l u e c o l o r o f 95. remained v e r y i n t e n s e a f t e r  from lights.  twenty  minutes o f i r r a d i a t i o n , w h i l e Bos e t a l . c l a i m e d t h a t the r e a c t i o n completed  a f t e r twenty minutes o f i r r a d i a t i o n .  The r e a s o n f o r t h i s d i s c r e p a n c y i s n o t known a t the p r e s e n t time A n a l y s i s by t h i n l a y e r chromatography showed t h a t the t h r e e r e a c t i o n s performed  under d i f f e r e n t c o n d i t i o n s  1 1 6  (laboratory' fluorescent to uv l i g h t  filtered  l i g h t ; i n the dark; and exposure  through potassium dichromate  solution)  r e s u l t e d i n the f o r m a t i o n o f the same p r o d u c t s i n about the same y i e l d s . Bos e t a l . (134a) r e p o r t e d t h a t 114 and 115 were both formed uv exposure  i n 15-20% y i e l d s a f t e r twenty minutes o f  and p r o b a b l y r e f e r r e d  to the c o m p o s i t i o n o f 114  and 115 i n the crude r e a c t i o n m i x t u r e b e f o r e i s o l a t i o n . The r e a c t i o n m i x t u r e s o b t a i n e d from above t h r e e experiments performed under  three d i f f e r e n t  c o n d i t i o n s were a l l p a l e  y e l l o w i n c o l o u r . A f t e r exposing to the a i r , the c o l o u r o f the s o l u t i o n s g r a d u a l l y became r e d , i n d i c a t i n g the presence o f c e r t a i n u n s t a b l e p r o d u c t s . When the r e a c t i o n m i x t u r e s were worked up, 115 was e a s i l y i s o l a t e d as a p a l e y e l l o w s o l i d i n a y i e l d g r e a t e r than 50% ( c f . 15-20% r e p o r t e d by Bos _et a l . ) -  The pmr spectrum o f 115 showed s i g n a l s compa-  t i b l e w i t h those r e p o r t e d by Bos et a l . (134a). Attempts to i s o l a t e 114 however, encountered d i f f i c u l t i e s . When a r e a c t i o n m i x t u r e o f 114 and 115 was e l u t e d through a s i l i c a g e l o r n e u t r a l alumina columns, o n l y u n i d e n t i f i e d  degraded  substances were r e c o v e r e d as a r e d m i x t u r e . I t was r e p o r t ed t h a t ' dry column chromatography  afforted a better  effi-  c i e n c y o f s e p a r a t i o n than l i q u i d column chromatography, and a good r e s o l u t i o n comparable  with that o f t h i n l a y e r chro-  matography (158). When one gram o f a mixture o f 114 and 115 was  t r e a t e d twice by u s i n g  dry column chromatography' , 115  was  found to be c o m p l e t e l y decomposed but a s m a l l q u a n t i t y  (20 mg) o f g r o s s l y p u r i f i e d 114 was o b t a i n e d . The pmr spec-  117 trum o f t h i s sample showed s i g n a l s i n agreement w i t h p r e s e n t e d by Bos  ejfc a l . f o r 114-  tons were found a t 6.8-8.0 ppm, sence  More than t e n phenyl p r o b a b l y due  o f a compound h a v i n g a s t r u c t u r e  which was munication  a l s o i s o l a t e d by Bos  those pro-  to the p r e -  s i m i l a r to 2 2 6  a c c o r d i n g to a p r i v a t e com-  (134b).  Bos  ejb a l . r e p o r t e d t h a t 114 was  an u n s t a b l e r e d  o i l which o x i d i z e d r e a d i l y i n a i r (134b). I n s p e c t i o n o f the s t r u c t u r e o f 114,  however, i n d i c a t e d  does not c o n t a i n a h i g h l y c o n j u g a t e d have c o l o u r . The r e d c o l o u r was  t h a t the compound  system  and  p r o b a b l y due  s h o u l d not  to the c o n t a -  minants d e r i v e d from the d e c o m p o s i t i o n  o f 114  and  Spontaneous e v a p o r a t i o n o f about  o f 115  dissolved i n  1 ml least  10 mg  115•  of chloroform, r e s u l t e d i n a red o i l c o n t a i n i n g at two major components which were d i f f e r e n t from  115  as r e v e a l e d by t i c a n a l y s i s . The  instability  o f 114  and  the unexpected  c u l t y encountered  i n i t s i s o l a t i o n p r e c l u d e d the  to s y n t h e s i z e 208  through 114.  further.  The work was  not  diffi-  approach pursued  118 7. Chemical  r e a c t i o n s of 2 , 4 - d i p h e n y l t h i e t e 1,1-dioxide  attempted  s y n t h e s i s of 2,4-diphenylthietan-3-one  and  1,1-di-  oxide I n c o n n e c t i o n w i t h our i n t e r e s t s i n the and  the b i o l o g i c a l a c t i v i t y  d i p h e n y l t h i e t e 1,1-dioxide  of thietane d e r i v a t i v e s , (227) was  submitted  c h e m i c a l r e a c t i o n s w i t h the hope to produce thietan-3-one 1,1-dioxide matory agent. was  The  chemistry  (228)  2,4-  to v a r i o u s  2,4-diphenyl-  f o r study as an  antiinflam-  study o f the c h e m i c a l r e a c t i v i t y o f  c o n s i d e r e d t o be i n t e r e s t i n g w i t h r e s p e c t to the  227 sus-  c e p t i b i l i t y o f the o l e f i n i c bond of t h i e t e 1 , 1 - d i o x i d e s to nucleophilic attack ( 8 4 ,  85),  i n a d d i t i o n to c h e m i c a l r e -  arrangement r e a c t i o n s ( 1 5 9 - 1 6 1 ) o f 4-membered c y c l i c s u l f o n e s . I t has been r e c e n t l y r e p o r t e d t h a t 2 - a r y l - 3 - a m i n o thiete 1,1-dioxides  (229)  (162,  thiophen-2H-3-one 1,1-dioxide inflammatory 229  and  activity.  2 3 0 suggested  The  163)  (230)  and (164)  structural  t h a t 228 may  2-phenylbenzo-(b)possessed  anti-  s i m i l a r i t y o f 228  l i k e w i s e prove  to  interest-  ing'.as an a n t i i n f l a m m a t o r y agent. Attempts to c o n v e r t  227  119 0  R  Am  J  SO, R = Halogenated  0^  phenyl  heterocyclic  or  ^0 230  aryl  2 R = H, Am=  alkyl,  or a r y l  T e r t i a r y amino group 229  to 228 were thus c o n s i d e r e d to be worthwhile  with respect  to the p h a r m a c o l o g i c a l a c t i v i t y of the expected and  the chemical n a t u r e of the s t a r t i n g The  product  material.  s y n t h e t i c r o u t e s designed to generate  expected product  228  the  involved nucleophilic addition,  hy-  d r a t i o n , h y d r o b o r a t i o n as w e l l as h y d r o l y s i s of an enamine, 231,  as shown i n Scheme I I . The  1,1-dioxides  a d d i t i o n o f HON  to the double bond of t h i e t e  (232) has been r e p o r t e d (84, 85). I t was  g e s t e d t h a t the r e a c t i o n o c c u r r e d through  the f o r m a t i o n of  R  R  R  H-  SO,  232  233 R= H, CH , 3  <^>  sug-  -SO,  183  120 Scheme I I Attempted s y n t h e s i s o f 2 , 4 - d i p h e n v l t h i e t a n - 3 - o n e  1,1-di-  oxide (228)  o -  CH=CH-N  -CH. • CH.  213  1. < ^ ^ - C H S 0 C l , 2  2. O x i d a t i v e  Et N  2  3  deamination  NaOH,  H0  —  o  ) HO  or H S0 , 2  4  SO,  or  SO,  1. BgHg 2 . H C r 0 2  227  Et  0  IT  Et' SO,  231  -so,  228  4  121 a carbanion product  183•  (233)  which p i c k e d up  I t appeared t h a t the  a proton strong  to g i v e  the  electron-with-  drawing s u l f o n e group a c t i v a t e d the double bond toward  the;  n u c l e o p h i l i c a d d i t i o n . Other s t r o n g n u c l e o p h i l i c r e a g e n t s such as 0H~  were expected to a t t a c k the double bond i n a  s i m i l a r manner. T r e a t i n g 2 , 4 - d i p h e n y l t h i e t e (227)  w i t h aqueous sodium hydroxide  1,1-dioxide  s o l u t i o n , however, r e -  0  235  s u l t e d i n the i s o l a t i o n o f d i b e n z y l s u l f o n e c i a b l e amount o f the d e s i r e d product was  likely  t h a t 235  was  235  (.234)• Wo  was  appre-  detected. I t  formed i n the r e a c t i o n but,  under  the b a s i c r e a c t i o n c o n d i t i o n s , r a p i d l y underwent r i n g vage to g i v e 234* T h i s type has been known to occur w i t h  of r e v e r s e A l d o l 2-phenylthiete  clea-  condensation 1,1-dioxide  122  H-O  H  v  OH e  OH© H0  -SO,  H  2  235  227  H 0 H  H 0 H  -HCOO  Q-rl-f-O y  (236) and 2 - p h e n y l - 3 - h y d r o x y t h i e t a n e  H  1,1-dioxide  (237)  which, upon h e a t i n g i n an aqueous sodium h y d r o x i d e t i o n , gave the same p r o d u c t , b e n z y l methyl  236  237  solu-  s u l f o n e (238).  238  123 I t was thought that an a l t e r n a t e r o u t e to 228 c o u l d be a c h i e v e d through the e l e c t r o p h i l i c a d d i t i o n o f borane to 227• O l e f i n s a r e w e l l known to undergo e l e c t r o philic  a d d i t i o n . A l t h o u g h the s u l f o n e group i n 227 would  be expected to d e a c t i v a t e  the double bond,  the phenyl sub-  s t i t u e n t a t t a c h e d to C-2 might l e s s e n t h i s e f f e c t to a c e r t a i n e x t e n t by d i s p e r s i n g the p o s i t i v e charge o f the trans i t i o n . s t a t e . - The a d d i t i o n o f borane to alkene has been  >CH 0H 2  \ /  C=CH  +  2  BH  )  3  \ •  ,  ^CH0H -B 2  2  2  -  N  H 0r0^ 2^"4 o  '  GH-0\ ^0  known to generate a borane adduct which y i e l d s an a l c o h o l or ketone a f t e r o x i d a t i o n . Because o f the e l e c t r o n i c nat u r e o f the borane, the r e a c t i o n o c c u r s i n an anti-Markown i k o f f manner. I t was t h e r e f o r e  ^  = CH  +  2  ^B—H  expected t h a t borane might  ^ 0^-0H /  2  >  /  CHCH B 2  N  H^-H H a t t a c k 0-3 o f 227 and the d e s i r e d p r o d u c t c o u l d be o b t a i n ed a f t e r o x i d i z i n g the borane i n t e r m e d i a t e 240«  Treating  227 stepwise w i t h d i b o r a n e and chromic a c i d , however, ed to g i v e changed  fail-  228 and r e s u l t e d o n l y i n the r e c o v e r y o f un-  s t a r t i n g m a t e r i a l . The r e s i s t a n c e o f 227 to borane  124  240  228  addition implies  that d e a c t i v a t i n g  e f f e c t s o f the s u l f o n e  group on the double bond and i n d u c t i v e s t i t u e n t are s u f f i c i e n t  e f f e c t s o f the sub-  to p r e v e n t s u b s t a n t i a l  formation  of the t r a n s i t i o n s t a t e 239« That the o l e f i n i c bond o f 227 was n o t s e n s i t i v e to e l e c t r o p h i l i c a d d i t i o n r e a c t i o n s was once a g a i n demons t r a t e d by means o f t r e a t i n g 227 with, c o n c e n t r a t e d  sulfuric  a c i d . O l e f i n s have been known to r e a c t w i t h c o n c e n t r a t e d s u l f u r i c a c i d to form an a l k y l hydrogen s u l f a t e which can be  e a s i l y h y d r o l y z e d , w i t h water, to an a l c o h o l . The a d d i -  t i o n o f s u l f u r i c a c i d to the double bond i n v o l v e s  the e l e c -  125 0  0 >=C  +  N  II  HO-S-OH  2  -CH-C-OSOH  II  0  0  -CH-C-OH  trophilic  H 0  +  H S0 2  4  a t t a c k o f hydrogen, l e a d i n g  to the f o r m a t i o n o f  a carbonium i o n . The o r i e n t a t i o n o f a d d i t i o n depends on the  stability  carbonium  o f the carbonium i o n formed  >J5° carbonium  > 2° carbonium  (I.e. benzylic  > 1° carbonium  .on).  © ->  i  -CH-C-  OSO-H ^  )  | | -CH-COS0 H 3  I n s p e c t i o n o f the p o s s i b l e addition of sulfuric carbonium i o n s ,  ll  o r i e n t a t i o n o f the  a c i d to 227 i n d i c a t e s two p o s s i b l e  241 and 242. I n c o n s i d e r a t i o n  H  H  H  H w  SO,  241  H  so,  242  /  o f the de-  126  s t a b i l i z a t i o n o f the b e n z y l i c carbonium i o n 241 jacent  s u l f o n e group and  by the  s t e r i c f a c t o r s involved during  adthe  subsequent n u c l e o p h i l i c a d d i t i o n of the b i s u l f a t e i o n , i t would appear t h a t carbonium i o n 242 235  might be  obtained  as  would be p r e f e r r e d  and  product.  235  When 227  was  d i s s o l v e d i n cooled  s u l f u r i c a c i d , a brown s o l u t i o n was  concentrated Diluting  this  brown s o l u t i o n w i t h water r e s u l t e d i n i s o l a t i o n of two  iso-  meric c y c l i c  sulfinates,  penta-3-ene 2-oxide (243)  obtained.  3,c-5-diphenyl-l,r-2-oxathiacycloand  3,t-5-diphenyl-l,r-2-oxathia-  cyclopenta-3-ene 2-oxide (£44),  as a 3:2  (243:244) m i x t u r e  127 Hone o f the d e s i r e d p r o d u c t 235 was  detected.  235  Cyclic  s u l f i n a t e s ( s u l t i n e s ( l 6 l ) ) a r e r a r e com-  pounds and o n l y t e n s u l t i n e s had "been r e p o r t e d t e r a t u r e a t the time when the p r e s e n t five  i n the l i -  work was performed;  (245-249) v i a thermal i s o m e r i z a t i o n o f t h i e t a n e 1,1-  d i o x i d e s a t 300-400° (159, 160, 1 6 5 ,  l 6 l ) , one (250) by  s y n t h e s i s through c h l o r i n e o x i d a t i o n ' o f b e n z o t h i a d i a z i n e  245  £46  217  24J3  249  128  (l6l),  two  (251, 252) by the a c t i o n o f j;-butoxymagnesium  bromide on 2 , 4 - d i p h e n y l t h i e t a n e 1,1-dioxides (159, 166 ) and two u n s u b s t i t u t e d f o u r - and f i v e - membered s u l t i n e s (255 and 2 5 6 ) v i a d e s u l f u r i z a t i o n o f t h i o s u l f o n a t e s by aminophosphine  + L  (257) ( 1 6 7 ) .  P(NEt ) 2  More r e c e n t l y ,  (CH ) 2  3  (253, 254) several  un-  n  -S^O  253  n=l  254  n=2  P(NEt ) 2  3  257  :0  s t a b l e four-membered  255  n=l  256  n=2  s u l t i n e s (259) were c l a i m e d  (168) to  be the i n t e r m e d i a t e s i n the f o r m a t i o n o f o l e f i n s (260) from ^-hydroxy s u l f o x i d e  (258), an analogous r e a c t i o n o f  129 H  0  II  R-SGHR CR R 1  2  so2ci2  3  OH  0  0  1' 2 3 R-a-CHR- GR^R L  2 3 CR R  "  -RC1  S 0  2  @  R CH=CR R 1  )  3  260  R  R  R  2  3  H  H  H  3  H  H  H  H  H  CH  H  H  H G H  CH  3  H  CH  3  H  H  C  H  H  6 5 H  CH C  H  3  H  3  H  H  H  CH  6 5  3  o l e f i n s y n t h e s i s . These four-membered  were found to have o n l y l i m i t e d readily lost S0  2  thermal s t a b i l i t y .  sultines They  w i t h i n a few minutes a t room temperature  to g i v e o l e f i n s . S u l t i n e stable  2  CHR 259  the W i t t i g  3  RS——OHR II© 'CI 0  W  0=S  2  J  01 C 1  258  0  CR R  11  2  6 l was found to be r e l a t i v e l y  and was the o n l y s u l t i n e f o r which the pmr d a t a was  H  H H  W A 0  S=0  261  130 p r o v i d e d . D u r i n g the l a s t  two y e a r s , o n l y one more s u l t i n e  ( 2 6 2 ) was added to the l i t e r a t u r e  The clic  c o n v e r s i o n o f u n s a t u r a t e d four-membered c y -  s u l f o n e s to t h e i r c o r r e s p o n d i n g r - s u l t i n e s was r e p o r t -  ed o n l y from two l a b o r a t o r i e s al.  (169).  (160)  (159-161,  1&5).  D i t t m e r e_fc  r e p o r t e d the i s o l a t i o n o f s u l t i n e 248 upon p y r o -  l y s i s o f a n a p h t h o t h i e t e s u l f o n e ( 2 6 3 ) i n the presence o f  9 , 1 0 - d i h y d r o a n t h r a c e n e . The p y r o l y s i s o f 263 w i t h o u t u s i n g 9 , 1 0 - d i h y d r o a n t h r a c e n e was found to take a complete  differ-  ent r e a c t i o n course and g i v e d i f f e r e n t p r o d u c t s . The au-  131 t h o r s suggested  t h a t the p y r o l y s i s o f t h i e t e s u l f o n e  involves i n i t i a l  263  s c i s s i o n of the s u l f u r - c a r b o n bond to  g i v e a d i r a d i c a l i n t e r m e d i a t e which c y c l i z e s to y i e l d s u l finate  248 hy f o r m a t i o n of an 0-C  "bond. The r o l e of  9,10-  248  dihydroanthracene t h o r s suggested  i n the r e a c t i o n was  u n c e r t a i n . The  au-  t h a t i t i n t e r a c t e d w i t h the i n t e r m e d i a t e s  formed or w i t h s u l t i n e 248  to p r e v e n t e x t e n s i v e r e a r r a n g e -  ment . T h e r m o l y s i s o f t h i e t e 1,1-dioxide p h e n y l t h i e t e 1,1-dioxide  (265)  1,2-oxathiolene  (245. 246)  2-oxides  (264)  and  gave the c o r r e s p o n d i n g (l6l).  The  25H-  reaction  132 was  a l s o e x p l a i n e d i n terms of the f o r m a t i o n of s u l f e n e  (266)  by e l e c t r o c y c l i c  opening  of the t h i e t e  ring.  0 A  R-  264  R=  265  R=  A  R.  H 266  The  R-  245  R=  246  R=  Q H  rearrangement o f a 4-membered c y c l i c  sulfone  to s u l t i n e by u s i n g c h e m i c a l r e a g e n t s has been d e s c r i b e d from o n l y one l a b o r a t o r y (159, 165). Dodson et a l . (159) reported that t r e a t i n g 2,4-diphenylthietane (266)  w i t h jfc-butoxymagnesium bromide gave  1,2-oxathiolane  2-oxides  +  (267). The  1,1-dioxides  3,5-diphenyl-  rearrangement was  t-BuOMgBr  266  267  g e s t e d to be c a t a l y z e d by base and an i o n i c mechanism proposed  sug-  as d e s c r i b e d i n the f o l l o w i n g scheme:  was  1 3 3  H  H  The  BuOH  ^MgBr  H  c o n s t i t u t i o n o f s u l t i n e s 243 and 244 was e s -  t a b l i s h e d as f o l l o w s : E l e m e n t a l a n a l y s i s proved c u l a r f o r m u l a to be C^H-^O^S. Mass spectrum  the mole-  d i s p l a y e d an  i n t e n s e peak (m/e 208) a t t r i b u t e d to (M -S0), i n agreement +  w i t h the f i n d i n g o f D i t t m e r e t a l . ( 1 6 0 ) peak was observed i n the mass spectrum  t h a t a (M -S0) +  o f 248. The i r spec-  t r a o f 243 and 244 showed the absence o f s u l f o n e and the presence  o f a s u l f i n a t e band (160, 168, 170) a t 1125 cm" . 1  The pmr s p e c t r a o f 243 and 244 confirmed t h e i r The  chemical s h i f t s  o l e f i n i c protons  structures.  (243: 6.73 ppm; 244: 6.80 ppm) o f the  (H^) agreed w i t h the v a l u e s o f 6.70 and  6.81 ppm f o r the c o r r e s p o n d i n g o l e f i n i c p r o t o n s i n 245 and 246  (Table V ) . The pronounced d i f f e r e n c e  chemical s h i f t values of proton H  a  i n 243 (6.39 ppm) and  t h a t i n 244 (6.90 ppm) i s i n accordance tion  (159, 160, 1 6 1 ,  (0.51 ppm) i n the  w i t h the o b s e r v a -  171) t h a t the s u l f i n y l bond ( S = 0 )  6  (ppm)  Ha  caused to  243  6.39  6.73  7-48  244  6.90  6.80  7.50  a downfield s h i f t  to those p r o t o n s which were c i s  the s u l f i n y l bond. T h i s e f f e c t i s i l l u s t r a t e d by the  S - v a l u e s o f p r o t o n Hb i n compounds 245-248 ( T a b l e V ) . Larger 6 - v a l u e s f o r proton H (6.39  ral  i n s u l t i n e s 243  ppm) and 244 (6.90 ppm) as compared to the p a r e n t  s u l f o n e 227 (5.92 ppm) i n d i c a t e in  a  t h a t the b e n z y l i c  243 and 244 i s i n d e e d c o n t a i n e d i n a -S-0-CH0 c o n f i g u r a t i o n . The o t h e r p o s s i b l e p o s i t i o n a l  proton structuisomers  c o n t a i n i n g the c o n f i g u r a t i o n -0-S-CH- as i n 268 would be H 0 expected  to d i s p l a y the b e n z y l i c p r o t o n a t lower  Protons v i c i n a l if  s values.  to a s u l f o n e group a r e s h i e l d e d l e s s  than  a d j a c e n t to a s u l f i n a t e group. F o r i n s t a n c e the two me-  Table V Chemical S h i f t s of  H  sultines  H a  249  248  8 H  a  (ppm)  Hb  H  c  Hd  245  (161)  5.06  5.41  6.70  6.90  246  (161)  5.32  5.72  6.81  248  (160)  5.31  5-98  -  249  (161)  5-42  5-78  -  -  a  136  thylene protons i n s u l f i n a t e 2 6 l 8-value  (168) p o s s e s s a s m a l l e r  than the c o r r e s p o n d i n g ^-methylene p r o t o n s i n s u l -  fone 2 6 9 (171-173).  The C-3 p r o t o n i n s u l t i n e s 251 and 252  H  IL  0—s=o  H<*  -SO,  Ho<Hoc 269  2 6 1  Ho<= 3.7 ppm(m) Hp=  H*= 4.34 ppm(m)  5.3 ppm(m)  has a s m a l l e r &-value than the Ru p r o t o n i n t h i e t a n e s 270 and 271 whereas the C-5 p r o t o n i n 251 and 252 has a l a r g e r 6-value sulfinyl  than the Ho< p r o t o n i n 270 and 271 (159, 174). The oxygen i n s u l t i n e s 243 and 244 was c o n s i d e r e d to  most l i k e l y assume an e q u a t o r i a l  o r i e n t a t i o n s i n c e a 1,3-  d i a x i a l i n t e r a c t i o n would he expected t o o c c u r between an axial  sulfinyl  oxygen and the C-5 a x i a l  group.  137 H  H  H --C7H  H—^ H  G  H  r  \}  G  6 5 H  ^  6 5 H  u  °6 5 H  0  C -H 3  G  I  4-29 ppm  5.58 ppm  252  4-34 ppm  6.17 ppm  G  d  H  SO,  5 H«  (6 5 H  271  270  H«<= 5-58 ppm  251  " 6 5  H  •SO,  G G  5  The r e a c t i o n  " 6 5 HV--  252  251  H  H = 5.36 ppm 0<  of concentrated s u l f u r i c acid  with  2 , 4 - d i p h e n y l t h i e t e 1 , 1 - d i o x i d e may be r a t i o n a l i z e d i n terms of i n i t i a l  s c i s s i o n o f the s u l f u r - c a r b o n bond to generate  a benzylic  carbonium i o n which then g i v e s s u l t i n e s 243 and  244 by f o r m a t i o n o f an oxygen-carbon bond. The f o r m a t i o n  243, 244  138 o f a b e n z y l i c carbonium the f a c t  supported by  t h a t the r e a c t i o n d i d not o c c u r w i t h  t h i e t e 1,1-dioxide dioxide  i o n i n t e r m e d i a t e was  2-phenyl-  (272) and 2 - p h e n y l - 4 - m e t h y l t h i e t e  (273)» The p r i m a r y and  secondary carbonium  ions  d e r i v e d from 272 and 273 r e s p e c t i v e l y would not be ed to be as s t a b l e as the b e n z y l i c carbonium from  1,1-  expect-  i o n generated  227-  H  H  H  H H  -so,  SO,  272  273  Rosen (175) and Truce et a l . (176) r e p o r t e d that 3-aminothiete 1 , 1 - d i o x i d e s (274. 275.  277,  v e r t e d i n t o t h e i r c o r r e s p o n d i n g ketones  278) were con-  (276) or e n o l s  (279) upon r e a c t i o n w i t h h y d r o c h l o r i c a c i d or treatment w i t h an ion-exchange  r e s i n . I t was  felt  that t h i s  reaction  would be a f a c i l e r o u t e f o r p r e p a r a t i o n of 2 , 4 - d i p h e n y l -  Et. N  Et 0  Et' or  SO,  CH.  SO,  CH. 274  275  I o n exchange. resin  so,  CH. 276  Et'  GH,  'Ms  or -SO,  278  277  thietan-3-one 1,1-dioxide  279  (228) from a known enamine,  diphenyl-3-diethylaminothiete 1,1-dioxide  Et^  (231). The  2,4thiete  0  ^ •SO,  SO,  228  231  c o u l d be s y n t h e s i z e d by the r e a c t i o n o f b e n z y l s u l f o n y l . chloride  (60) and 1 , 1 - d i e t h y l p h e n y l e t h y n y l a m i n e  r i v e d from p h e n y l a c e t y l c h l o r i d e p a r a t i o n of ynamine 285 was  0 \A  PCl  (177-179)- The  CI Q C-CC1 I  CI 282  depre-  s t r a i g h t forward, a c c o r d i n g to  r  AfCHp^CCl  281  (281)  (285)  HNEt —  9  f=\  I  -Et Et  ^  CI 283  140  231  p u b l i s h e d methods (178, f i r m e d by  and  i t s s t r u c t u r e was  s p e c t r o s c o p i c data which had  r e p o r t e d . The  ( 1 . 1 6 ppm)  con-  not p r e v i o u s l y been  i r spectrum d i s p l a y e d a c h a r a c t e r i s t i c  t y l e n e peak at 2210  cm" .  The  1  pmr  f o r s i x methyl p r o t o n s ,  f o u r methylene p r o t o n s f i v e phenyl protons. with  179),  and  The  spectrum showed a a quartet  (2.82  acetriplet  ppm)  a m u l t i p l e t (6.98-7-45 ppm)  for  c y c l o a d d i t i o n r e a c t i o n of ynamines  s u l f o n y l c h l o r i d e s has been e x t e n s i v e l y reviewed  107).  for  I n the presence of t r i e t h y l a m i n e , s u l f e n e 286 a t t a c k s the ynamine through an i n i t i a l  (102-  i s ge-  nerated  and  i o n 287  which undergoes i n t r a m o l e c u l a r c y c l i z a t i o n to y i e l d  2,4-diphenyl-3-diethylaminothiete s t r u c t u r e of 231 The  was  confirmed  1,1-dioxide  by the  Zwitter-  (£31).  spectroscopic  i r spectrum showed c h a r a c t e r i s t i c a b s o r p t i o n s  The data.  of s u l -  141  CH=S0  +  2  285.  286  fone  287  (1165 and 1300 cm" ) and enamine ( 1 6 2 5 cm" ). The pmr  spectrum  displayed a t r i p l e t  (0.85 ppm) and a q u a r t e t (3.03  ppm) f o r s i x methyl and f o u r methylene p r o t o n s r e s p e c t i v e ly, a singlet tiplet  (5-73 ppm) f o r one b e n z y l i c p r o t o n and a mul-  (7.15-7.65 ppm) f o r t e n phenyl p r o t o n s . When enamine 231 was t r e a t e d w i t h ion-exchange  resins  (BIO-RAD AG50W-X8 and A m b e r l i t e 120) a c c o r d i n g t o  Rosen's method f o r c o n v e r s i o n o f 3-aminothiete (£74, 275)  1,1-dioxides  t o the c o r r e s p o n d i n g t h i e t a n - 3 - o n e 1 , 1 - d i o x i d e  (276) , unchanged s t a r t i n g m a t e r i a l  (231) was r e c o v e r e d . I n  c o n c e n t r a t e d h y d r o c h l o r i c a c i d , 231 was a l s o found  resis-  tant t o expected h y d r o l y s i s . Truce et a l . (176) r e p o r t e d that 2 - p h e n y l - 3 - d i e t h y l a m i n o - 4 - m e t h y l t h i e t e 1,1-dioxide (277) was s t a b l e i n d i l u t e aqueous HC1, but i n benzene sol u t i o n and i n /the presence o f t r a c e h y d r o c h l o r i c a c i d , was r e a d i l y transformed i n t o 1,1-dioxide  2-phenyl-3-hydroxy-4-methylthiete  (279). T r e a t i n g an acetone  s o l u t i o n o f 231 w i t h  c o n c e n t r a t e d h y d r o c h l o r i c a c i d f o r one week o r r e f l u x i n g a s o l u t i o n o f 231 i n a HGl-acetone m i x t u r e f o r t h r e e hours,  142 a l s o r e s u l t e d i n r e c o v e r y o f the unchanged s t a r t i n g material,  231. I n s p e c t i o n o f the s t r u c t u r e of 231  the molecule  c o n t a i n s a h i g h l y conjugated  system. The  nance s t a b i l i z a t i o n as d e s c r i b e d by 288 may r e s i s t a n c e o f 231  account  reso-  f o r the  to a c i d h y d r o l y s i s . F u r t h e r e f f o r t s to  h y d r o l y z e 231 were abandoned and 228 was  showed t h a t  not c o n t i n u e d a t t h i s  Et  the attempted s y n t h e s i s of-  time.  Et  143 PHARMACOLOGICAL TESTING  2,2-Diphenyl-3-dimethylaminomethylthietane dioxide  (32), c i  1,1-  s-2,2-diphenyl-3-dimethylaminomethyl-4-  methylthietane 1,1-dioxide  (3.3) and t r a n s - 2 , 2 - d i p h e n y l -  3-dimethylaminomethyl-4-methylthietane  1 , 1 - d i o x i d e (34)  were t e s t e d f o r t h e i r a n a l g e s i c a c t i v i t y . The method used was s i m i l a r to t h a t d e s c r i b e d by Cox and Weinstock  32  33  34  (56) and was based on the a b i l i t y o f n a r c o t i c a n a l g e s i c s to produce  a b l o c k o f c o n t r a c t i o n s o f the e l e c t r i c a l l y  s t i m u l a t e d i l e u m . Male g u i n e a p i g s (300-500 gm) were s t a r v e d o v e r n i g h t and k i l l e d by a blow on t h e i r heads. The i l e u m was immediately i s o l a t e d and kept i n Krebs s o l u t i o n a t 3 7 ° , oxygenated  w i t h 95% 0  2  and 5% COg.- A  l e n g t h o f i l e u m (2-3 cm) was removed and s e t up i n a 15-ml  organ b a t h c o n t a i n i n g oxygenated  Krebs  solution  a t 37°. The lower end o f the gut was threaded t o a g l a s s anchor p o s i t i o n e d a t t h e bottom o f the organ b a t h . The upper  end o f the gut was t i e d  to a l e v e r which r e c o r d e d  144 the gut movements on a kymograph. were l e f t open.  The t e n s i o n (about  Both ends o f t h e i l e u m 2-3 gm) on t h e gut was  a d j u s t e d so t h a t a l e v e l b a s e l i n e was o b t a i n e d .  Two  p l a t i n u m s t i m u l a t i n g e l e c t r o d e s were used, one b e i n g i n s e r t e d i n t o t h e i n t r a l u m i n a l space and t h e o t h e r p l a c e d i n t h e bath s o l u t i o n .  being  The t i s s u e was s t i m u l a t e d by  s i n g l e square wave p u l s e s (0.5 msec) d e l i v e r e d every 7 seconds from a Grass SD9 s t i m u l a t o r .  The v o l t a g e was  a d j u s t e d i n i t i a l l y t o g i v e about 80% maximum response ( 30.-35 v o l t s ) .  The t e s t e d compounds were d i s s o l v e d i n  e t h a n o l and were added i n a volume o f 0.02 5 m l .  Methadone  h y d r o c h l o r i d e which was used as a r e f e r e n c e n a r c o t i c was d i s s o l v e d i n water and added i n a volume o f 0.1 m l .  Nal-  oxone h y d r o c h l o r i d e , a n a r c o t i c a n t a g o n i s t , was a l s o d i s s o l v e d i n water and added i n a volume o f 0.1 ml.  The drugs  were l e f t i n c o n t a c t w i t h t h e t i s s u e f o r 2-5 min. ' and a f t e r washing out . , t h e i l e u m was a l l o w e d t o r e t u r n t o i t s c o n t r o l h e i g h t b e f o r e t h e next dose o r next drug was added. E t h a n o l was used as s o l v e n t f o r t h e t e s t compounds because o f t h e s o l u b i l i t y problem.  At a volume o f  0.025 ml e t h a n o l d i d not produce any d e t e c t a b l e on t h e e l e c t r i c a l l y induced ion  gut c o n t r a c t i o n s .  depression The depress-  by methadone o f t h e gut c o n t r a c t i o n s was not a f f e c t e d  by t h e presence o f 0.025 ml o f e t h a n o l as w e l l .  A solu—8  t i o n o f methadone h y d r o c h l o r i d e i n e t h a n o l (1.1 x 10  M)  produced t h e same percentage o f d e p r e s s i o n as an aqueous  145 s o l u t i o n o f methadone h y d r o c h l o r i d e  and the" d e p r e s s -  i o n was e f f e c t i v e l y r e v e r s e d by naloxone h y d r o c h l o r i d e (2 x 1 0 "  M).  8  Methadone h y d r o c h l o r i d e was found the e l e c t r i c a l l y i n d u c e d  c o n t r a c t i o n s o f i l e u m by 44%  and 83% a t c o n c e n t r a t i o n s o f 1.1 x 10" _7 10  to depress  M and 1.1 x  M r e s p e c t i v e l y . The d e p r e s s i o n s were immediately r e -  v e r s e d by the a d d i t i o n o f naloxone h y d r o c h l o r i d e a t a concentration of 2 x 10~ The  8  M (Fig. IV).  a b i l i t y o f t h r e e t e s t e d compounds to depress  the response o f i l e u m to e l e c t r i c a l  s t i m u l a t i o n i s shown  i n F i g u r e s I I I and IV. I t i s obvious  t h a t the compounds  b l o c k the c o n t r a c t i o n s a t c o n c e n t r a t i o n s much h i g h e r those  than  o f methadone. At these h i g h c o n c e n t r a t i o n s the com-  pounds a r e b e l i e v e d to a c t by n o n s p e c i f i c mechanisms. To determine whether o r n o t the b l o c k o f cont r a c t i o n s by the t e s t e d compounds was a r e a l n a r c o t i c —8 e f f e c t ,  . naloxone h y d r o c h l o r i d e  (2 x 10"  M) was  added to the organ bath a f t e r the gut c o n t r a c t i o n s had been depressed observed  by the compounds (3*3 x 10  M). I t was  t h a t naloxone was i n c a p a b l e o f r e v e r s i n g the de-  p r e s s i v e a c t i o n o f a l l t h r e e compounds. T h i s r e s u l t t h a t the compounds i n h i b i t e d  shows  the e l e c t r i c a l c o n t r a c t i o n s  by a mechanism d i f f e r e n t from t h a t o f the blockade  induc-  ed by n a r c o t i c a n a l g e s i c s such as morphine and methadone e t c . i n d i c a t i n g t h a t the compounds are d e v o i d o f n a r c o t i c  analgesic  activity. In o r d e r t o determine whether t h e compounds  possessed n a r c o t i c a n t a g o n i s t i c a c t i v i t y , t h e i l e u m was _j  t r e a t e d w i t h methadone h y d r o c h l o r i d e  (1.1 x 10  M, 2  m i n u t e s ) , f o l l o w e d by t h e t e s t e d compound a t a concen-7  t r a t i o n o f 3 x 10  .  M.  .  The i n h i b i t o r y a c t i o n o f methadone  was found not t o be r e v e r s e d  by t h e compounds but immediat-  e l y a n t a g o n i z e d by a subsequent dose o f naloxone hydro—8 c h l o r i d e (2 x 10 .M). I n an a l t e r n a t e procedure t h e _7  i l e u m was p r e t r e a t e d  w i t h t h e t e s t e d compound.. (3 x 10  f o l l o w e d by methadone (1.1 x 10  ).  M)  None o f t h e t e s t e d  compounds p r e v e n t e d o r reduced t h e b l o c k i n g a c t i o n o f methadone on t h e i l e u m  contractions..  In a d d i t i o n t o t h e g u i n e a - p i g i l e u m t e s t , t h e abse ce o f s i g n i f i c a n t a c t i v i t y of t h r e e t e s t e d compounds was f u r t h e r supported by t h e r e s u l t o b t a i n e d  from d e t e r m i n a -  t i o n o f t h e p a i n t h r e s h o l d o f one r a b b i t t o t h e e l e c t r i c a l stimulation i n i t s tooth-pulp.  The a n i m a l and t h e set-up  were k i n d l y s u p p l i e d by Dr. John G. S i n c l a i r , F a c u l t y o f Pharmaceutical Sciences,  The U n i v e r s i t y of B.C., and t h e  t e s t was performed by Mrs. M a j o r i e  F. C h a p l i n .  compounds were d i s s o l v e d i n e t h a n o l  and i n j e c t e d i n t o t h e  l a t e r a l v e n t r i c l e (180) o f t h e r a b b i t (2.3 Kg). p u l p of t h e a n i m a l was s t i m u l a t e d  The t e s t e d  The t o o t h -  by s i n g l e p u l s e s  3 Hz) d e l i v e r e d from a Grass S8 s t i m u l a t o r .  (10 msec  The v o l t a g e a t  147 which the animal l i c k e d i t s l i p s o r chewed i t s t e e t h considered  as t h r e s h o l d v o l t a g e .  o f the t e s t e d r a b b i t g i v e n 0.05  ml o f e t h a n o l  The t h r e s h o l d  i n t r a v e n t r i c u l a r l y was 13-13-5 "V. At a  and 2A  threshold voltage  analgesic  s o l u t i o n ) , com-  d i d not s i g n i f i c a n t l y change the  which was  observed e v e r y 5 minutes f o r  30 minutes a f t e r a d m i n i s t r a t i o n t i o n was  o f the drugs. Observa-  extended to 75 minutes f o r compound 34 and no a c t i v i t y was d e t e c t e d .  double dose (600 jxg,  Compound 22  0.1 ml) a l s o produce no  a c t i v i t y . Morphine s u l f a t e a t dose o f 50 jug pain cular  voltage  e i t h e r a r t i f i c i a l C. S. F. o r  dose o f 300 jjig ( i n 0.05 ml o f e t h a n o l i c pounds _3_2, 22  was  threshold  given at analgesic r a i s e d the  to 30 V a t 15 minutes a f t e r i n t r a v e n t r i -  administration.  FIGURE I I I Inhibition  of contractions of e l e c t r i c a l l y  stimulated  guinea-pig  Ileum by methadone (•), compounds _32 (>'),  33 (O) and 34. (Y)* Each p o i n t r e p r e s e n t s the average of two d e t e r m i n a t i o n s  %  on two i l e u m  preparations.  Inhibition  100  80  L  60 L  40  L  30  0 ^8  10 ^  10  -7 1  ,-6 10 "  Molar c o n c e n t r a t i o n s o f t e s t  10 v-5 J  10  compounds  •4  149  Figure IV Effect of methadone, thietane 1,1-dioxides and naloxone (2 x 10"  M) on guinea-pig ileum contractions.  150 PARTITION STUDIES  I t i s expected t h a t n a r c o t i c drug m o l e c u l e s t r a v e l through many membrane b a r r i e r s b e f o r e t h e y t h e i r locus of a c t i o n .  reach  The r e l a t i o n s h i p s between t h e an-  a l g e s i c a c t i v i t y o f n a r c o t i c s and t h e i r p a r t i t i o n c o e f f c i e n t s (P) have been w e l l documented:  Casy and Wright (181)  have r e l a t e d t h e h i g h a n a l g e s i c potency o f  benzimidazole  d e r i v a t i v e s t o t h e i r h i g h e r p a r t i t i o n c o e f f i c i e n t s than t h a t o f morphine.  I n t h e work o f K u t t e r et. a l . (182) t h e  a n a l g e s i c potency o f morphine and r e l a t e d s y n t h e t i c a n a l g e s i c s have been shown t o depend p a r t l y on t h e i r l o g P values.  The h i g h a n a l g e s i c a c t i v i t y o f n o n p o l a r n a r c o t i c s  f o l l o w i n g intravenous  a d m i n i s t r a t i o n was e x p l a i n e d by a  good p e n e t r a t i o n o f t h e s e compounds through t h e b l o o d brain barrier.  The a n a l g e s i c potency o f e t o r p h i n e  t i m e s t h e a c t i v i t y o f dihydromorphine a f t e r  (3800  intravenous  i n j e c t i o n ) has been c o n s i d e r e d  t o a r i s e i n l a r g e p a r t from  i t s high l i p o p h i l i c i t y  I n an i n v i t r o study o f  (183).  binding of narcotic analgesics to cerebroside  s u l f a t e , the  b i n d i n g was shown t o c o r r e l a t e w i t h t h e heptane, of t h e compounds  solubility  (184).  I t was o f i n t e r e s t t o see i f t h i e t a n e compounds had  any u n u s u a l p a r t i t i o n p r o p e r t i e s t h a t may account f o r  the r e s u l t s o f t h e a n a l g e s i c t e s t s . r e s t r i c t e d conformation  Compounds w i t h  have been known t o have d i s s i m i l a r  l i p o p h i l i c i t i e s as compared.to t h e extended  analogs.  151 The p r e s e n t study was undertaken  w i t h a view to  making a p r e l i m i n a r y assessment o f the p h y s i c o - c h e m i c a l i n f l u e n c e o f the t h i e t a n e s on t h e i r a n a l g e s i c a c t i v i t y by u s i n g a simple p a r t i t i o n method. D i r e c t d e t e r m i n a t i o n o f partition coefficients tical  o f compounds 32-34 p r e s e n t e d  d i f f i c u l t i e s because l i m i t e d  prac-  q u a n t i t i e s o f the t e s t  compounds were a v a i l a b l e and the compounds were p o o r l y s o l u b l e i n e i t h e r water o r n o n p o l a r phases such as 1-octanol, ing  paraffin,  heptane and c o r n o i l . The problem o f measur-  low c o n c e n t r a t i o n s o f s o l u t e by s p e c i f i c  analytical  methods was a l s o f o r e s e e n . The  quantitative  reversed-phase  t h i n l a y e r chromatography method was thus chosen to compare  the l i p o p h i l i c i t y o f the compounds to t h a t o f metha-  done. T h i s method was based s h i p between the p a r t i t i o n deduced by M a r t i n  on the t h e o r e t i c a l coefficient  relation-  and the  value  (186):  P = K ( J= 1 ) ( e q u a t i o n 1) f Where K i s the c o n s t a n t f o r the system. Bate-Smith and R  Westall  (187) i n t r o d u c e d the term R , where R = l o g m' m ( ~ - - l ). I t i s t h e r e f o r e p o s s i b l e i n p r i n c i p l e to c o r R f  relate R  m  the l i p o p h i l i c p r o p e r t y o f substances w i t h  their  v a l u e s ( e q u a t i o n 2 ) . The v a l i d i t y o f t h i s theory has log P = R  + k  ( e q u a t i o n 2)  been e s t a b l i s h e d by a number o f workers (188-191). The partition  c e f f i c i e n t s determined  with d i f f e r e n t  systems f o r twelve n a r c o t i c a n a l g e s i c s e x t e n d i n g  solvent from  the h y d r o p h i l i c N-methylmorphine to the l i p o p h i l i c metha-  152 done has been shown p a r a l l e l  to the R  by t h i n l a y e r chromatography ( 2 6 ) . substituted acetanilides,  F  values  determined  In a series of para-  the a n a l g e s i c a c t i v i t y was  shown to c o r r e l a t e b e t t e r w i t h the chromatographic s t i t u e n t c o n s t a n t A R ^ than w i t h the Hansch's s u b s t i t u e n t c o n s t a n t n d e r i v e d from c i e n t . I t was a l s o observed AR  M  lic  sub-  hydrophobic  the p a r t i t i o n  coeffi-  that b e t t e r c o r r e l a t i o n of  and a n a l g e s i c a c t i v i t y was o b t a i n e d when the l i p o p h i phase was 1 - o c t a n o l  than when i t was l i q u i d  paraffin  (189). The procedure  used was i n g e n e r a l s i m i l a r to  t h a t d e s c r i b e d by B i a g i e t a l . (192). Chromatography was c a r r i e d out on c o m m e r c i a l l y which were impregnated  available cellulose  w i t h 1 - o c t a n o l by d i p p i n g i n t o a  s o l u t i o n o f 5% 1 - o c t a n o l i n hexane. The mobile a s o l u t i o n o f 0-20% ( v / v ) methyl The  sheets  phase was  e t h y l ketone i n water.  chromatogram was v i s u a l i z e d by s p r a y i n g w i t h Dragen-  d o r f f reagent p l u s 0.01 N s u l f u r i c a c i d i f n e c e s s a r y . The R ^ v a l u e s o f the p i n k s p o t s t h a t appeared and  transformed  were measured  i n t o R v a l u e s which were p l o t t e d a g a i n s t m  the ketone c o n c e n t r a t i o n s i n the mobile  phase. The R  M  v a l u e s a t 0% ketone (Table V I ) were c a l c u l a t e d by e x t r a p o l a t i o n from  the r e g r e s s i o n l i n e s .  The R ^ v a l u e s  charac-  t e r i z e the m i g r a t i o n o f the compounds w i t h the p o l a r phase. The  g r e a t e r the R  F  v a l u e s , the s m a l l e r the R  the more h y d r o p h i l i c  M  v a l u e s and  the compounds appear to be.  Table YI shows the c a l c u l a t e d R_ v a l u e s f o r m  Table VI Rm v a l u e s a t 0% methyl e t h y l ketone c a l c u l a t e d regression  from  lines  Rm(l-octanol)  (CH 3 ) 2 NCH 2 X Eh  (CH ) 1TCH^ 3  2  GEl  (GH3)2NGH2, HI  OH3 "  H  "jVs so„  289  1.70  34  1.43  33  1.32  , 6 5 G  H  SO,  / 6 5 G  H  ^C6H5 SO,  0.89  Methadone  (CH3)2M2> E\* H  OH,  H "V6H5 so,  290  0.70  154 compounds .33, .34, 289 and 290 as w e l l as methadone as r e f e r e n c e . Compound 290 has a s m a l l e r R v a l u e m  (less  lipo-  p h i l i c ) than methadone as expected, p r o b a b l y due to the f a c t t h a t the former  compound l a c k s a l i p o p h i l i c C-2-phenyl sub-  s t i t u e n t and has a s u l f o n y l group which i n n a t u r e i s more hydrophilic  than the c a r b o n y l f u n c t i o n (193)-  The h i g h e r  l i p o p h i l i c i t y o f compounds 3J3, 34 and 289 than methadone suggests  t h a t the two C-2-phenyl s u b s t i t u e n t s e x e r t  sig-  nificant  s t e r i c e f f e c t s on the h y d r o p h i l i c n a t u r e o f the  s u l f o n y l group. The s h i e l d i n g o f the l o n e p a i r e l e c t r o n s of two s u l f o n y l oxygen atoms i s expected nificant increases i n R ce o f a l i p o p h i l i c to the l a r g e s t R  m  m  to produce  sig-  v a l u e s (185). I n 289 the p r e s e n -  chlorine substituent also contributes value  (193)•  In Table VII are presented  the l o g P and R^  v a l u e s f o r a number o f n a r c o t i c a g o n i s t s and a n t a g o n i s t s c a l c u l a t e d from  the p a r t i t i o n c o e f f i c i e n t d a t a ( 1 - o c t a n o l -  water system, pH = 7»4, 20°) determined (183)  and the R^ v a l u e s determined  ed-phase p a r t i t i o n chromatographic  from a s i m i l a r r e v e r s method (mobile phase:  water c o n t a i n i n g 10% ammonium formate, paper impregnated e s t and P a r m i l o  by Kaufman e_t a l .  s t a t i o n a r y phase:  w i t h 20% 2 - o c t a n o l i n acetone) by Gen(194). Comparison o f the R  m  data shown i n  T a b l e V I I w i t h those of "thietane 1,1-dioxides determined i n the p r e s e n t  study  ( T a b l e V I ) suggests t h a t the l i p o -  p h i l i c i t i e s o f the t h i e t a n e 1 , 1 - d i o x i d e s  33, 3JL  a  n  d  289 l i e  155 Table V I I Log P ( 1 - o c t a n o l ) and Rm(2-octanol) v a l u e s o f n a r c o t i c a g o n i s t s and a n t a g o n i s t s c a l c u l a t e d from l i t e r a t u r e dat a (183, 194)  Compounds Oxymorphone  Log  P(l-octanol)  a  Rm(2-octanol)  -0.33 0.07  -0.60  Codeine  0.23  -0.58  Levorphanol  0.63  Naltrexone  O.64  Cyclazocine  0.89  Naloxone  1.12  Nalorphine  1.27  Meperidine  1.37  Pentazocine  1.60  Methadone  1.64  MR1256BS  0  2.13  MR1029BS  d  Morphine  <K-Acetylmethadol  2.56 2.69  -  Myrophine a  Logarithms  0.55  -  -0.18  -  +0.43  -  -  +1.28 +2.00  o f p a r t i t i o n c o e f f i c i e n t s determined by  Kaufman _et a l . (183) ( 1 - o c t a n o l - w a t e r system a t 20° pH = 7.4) b  R v a l u e s c a l c u l a t e d from R~ d a t a determined by Genm f . e s t and F a r m i l o (194) (mobile phase; : water c o n t a i n i n g J  10% ammonium formate; nated w i t h  s t a t i o n a r y phase: paper  2-octanol)  c  Pure n a r c o t i c a n t a g o n i s t (183)  d  Mixed n a r c o t i c a g o n i s t - a n t a g o n i s t  impreg-  156 between  those  narcotic of R  the  R  study  2.15  A  ,  one  -]-  derived  o  P  u  e  o  R  m  (i_  o c  3)  (solvent)  =  =  In  and  a  R  l  Q  (185)  a measure  a  P  S  (Table  l  u  e  e c  VI)  in  solvent  a  l  u a  into in  o  (l-octanol) +  +  the  the larger  r  myro-  found  in  second can  regression  2 where  excellent  l  values  R  found  m(l-octanol)  potent  s o l u b i l i t y of  the  equation  Hansch's  coefficients of  a  a  lipid  those (185)  v  a  transformation  system used  -tanol) the  and  from Hansen1s  a,  be  equa-  b and  c  are  (equation  b  3)  (equation  c  review  of  4)  partition  the  constant  a has  solvent  system's  sensitivity  to  changes  In  of  alcohol-  l i p o p h i l i c ! t y of  solvent  myrophine  f  "fclie p a r t i t i o n  f  system  m(solvent)  the  l  which i s  mathematic  r e l a t i o n s h i p between  constants.  in  a  a  (equation §  l 0  u e  gives  solvent  tion  v  i n d i c a t i n g that  linear  R  v a  and myrophine  Theoretical  (2-octanol)  m  m(l-octanol)  than  methadone  analgesic.  present  *  of  systems,  the  1.00.  A maximum  oleyl  alcohol with  solute.  constant  sensitivity constant  been  a number  a varies  i s  shown  reached  a being  1.  from at  to  be  to  0.695  1-octanol  and  Substituting  i n -  to e q u a t i o n 4 the known t e r m s : a = 0 . 6 9 5 to 1.00; R / -, , N = R / „ , -, \ = 0 . 4 3 2 f o r m e t h a d o n e found m(solvent) m(2-octanol) i n the r e v e r s e d - p h a s e p a r t i t i o n system of Genest and Parmilo done  (Table  found  ant  c i s  and  -0.458.  phine ^  in  VII) the  / n , -, >, = 0 . 8 9 m(l-octanol)  present  c a l c u l a t e d to  into  study  be  Substituting  (Table VII)  2.15.  and R  in R  m  the  (Table range  (g0-Lvent)  equation  =  VI),  for the  between 2.00  4 results R  for  methaconst-0.146 myro-  . -, % m(l-octanol)  157 phine i s h i g h e r than t h a t o f t h i e t a n e 1 , 1 - d i o x i d e s VIII),  The c a l c u l a t i o n o f l o g P ( i _  o c  (Table  t a n o l ) values of t h i e -  tane - 1 , 1 - d i o x i d e s .33, .34, 289 and 290 by u s i n g e q u a t i o n 2  also gives figures i n d i c a t i n g  t h a t the l i p o p h i l i c i t i e s o f  33,  34 and 289 ( T a b l e V I I I ) l i e  between those o f methadone  and  o(-acetylmethadol which i s a potent and l o n g a c t i n g  nar-  c o t i c a n a l g e s i c . I t f o l l o w s t h e r e f o r e t h a t the l a c k o f analgesic activity  i n compounds 32-34 does n o t appear to  r e s t w i t h the n a t u r e  of t h e i r l i p o p h i l i c i t y .  The c h o i c e o f  an j_n v i t r o g u i n e a - p i g i l e u m method to t e s t the compounds e x c l u d e s many e f f e c t s o f a b s o r p t i o n and d i s t r i b u t i o n on the r e s u l t s . I n the r a b b i t t o o t h pulp t e s t tricular  a d m i n i s t r a t i o n o f compounds a l s o  the i n t r a v e n circumvents  many p e n e t r a t i o n f a c t o r s .  k i s c a l c u l a t e d by u s i n g methadone as a s t a n d a r d : § (l-octanol) = ' (Table V I I ) .  l o  P  1  6  3  5 a  n  d  R  m(l-octanol) = ° '  4 3  158 Table VIII Comparison o f c a l c u l a t e d R m ( l - o c t a n o l )  and l o g P ( l - o c t a n -  o l ) values of thietane 1,1-dioxides with l i t e r a t u r e  data  of n a r c o t i c a g o n i s t s and a n t a g o n i s t s (183, 194)'  Rm(l-octanol)  Compounds  log  c  P(l-octanol)  290  0.70  Methadone  0.89  1.64  1.32  2.07  33 MR1256BS  .  -  a  1.45  1.34  2.18  289  1.70  2.45  b  t(-Ac e t ylme t h a d o l Myrophine  -  2.56  -  2.69  2.15  '  d  2.13  34  MR1029BS  d  d  —  d  a  Pure n a r c o t i c a n t a g o n i s t (183)  b  Mixed n a r c o t i c a g o n i s t - a n t a g o n i s t (183)  c  Experimental  d a t a determined  d  from p r e s e n t  partition  study d  C a l c u l a t e d v a l u e s . See t e x t  e  Logarithms  o f p a r t i t i o n c o e f f i c i e n t s determined  Kaufman e t a l . (183) ( 1 - o c t a n o l - w a t e r pH = 7 . 4 )  system  by  at 2 0 ° ,  ;  e  159 STRUCTURE -  In analgesic taining of  two p r e v i o u s  activity  tane  of  of  sent 32-34  containing  lacked  the  inactivity  studies Other  role.  interact  with  o r even  activity  1,1-dioxides  due t o  with  In  the anionic  site  of  the  indicates  i n t h e two phenyl  had to play  binding, the proper  pre-  that previous ring. an i m -  the  dime-  orientation receptor  attached  the stereochemically  at  sulfone  the analgesic  the C-4 and the s u b s t i t u e n t  bind-  rings  the r e s t r i c t e d bulky  may n o t assume  at  1,1-dioxides  phenyl  the equatorial  the receptor  with  ring  the e f f e c t i v e  and a x i a l  analgesic  orien-  to  i t  demanding  receptor. The  supports assume  with  phenyl  2,2-diphenylthietane  equatorial  activity  2,4-diphenylthie-  the analgesic receptor.  For instance,  group  of  con-  to improper In  stereochemical features  n o t be c o m p a t i b l e  opiate  ring.  narcotic  (27-31)  the l a c k  the equatorial  thietane  may i n t e r f e r e  surface, may  both  of  t h y l aminome t h y l to  at C-2,  phenyl  that  was n o t m a i n l y  portant group  at  significant  critical  1,1-dioxides  (84a) to i n t e r f e r e  the fact  C-2  (84a, 85a) of  was a t t r i b u t e d  (27-29),  t h e compounds  study,  studies  ring  the e q u a t o r i a l  1,1-dioxides  CONSIDERATIONS  thietane  compounds  C-4 w a s t h o u g h t ing  of  a single phenyl  the tested  tation  ACTIVITY  lack  the theory  of analgesic that  activity  methadone  a c e r t a i n pharmacophoric  i n compounds  and i t s sulfone  conformation  at  32-34  analogue  the recep-  160 tor  level.  sary  to  The  flexible  render  the  open  methadone  molecule  adopt  a conformation  so  amino  group,  remaining part  be  and  the  p l a c e d p r e c i s e l y on  Restriction  of  the  pharmacophoric thus  lead  tivity. which  The the  joined did ture  not  complete  and  the  with  of  that  ponding and  to  be  loss  nitrogen  the  in  23  part  in  thus  (22)  orientation may n o t the  result  of  close  (Page of  of of  receptor  be  the  10).  so  that  achieved  analgesic  methadone  although  may ac-  in were group struc-  proposed  cyclic  The  that  explanation propionyl  of  conformation  hindering receptor  the  its  restricted  indeed mirror  can  sites.  methadone,  the  to  the  molecule  one TT-methyl  to  neces-  freedom  molecule  (195)  pharmacophoric in  the  narcotic  atom  be  rings,  longer  (25.)  deprivation  generally  the  of  analogue  methadone  of  topographical  c a n no  to  enough  aromatic  f l e x i b i l i t y of  piperidine  C-2  the  show a n a l g e s i c a c t i v i t y  component  done  the  appears  be  the  conformation  together  structure may  to  that  chain appears  the of  binding.  corresmethaRes-  1 6 1  triction rings  of  has l e d to with  295)  the r o t a t i o n a l  freedom  of  s e v e r a l methadone  diminished  t h e two  analogues  aromatic (24_,  or i n s i g n i f i c a n t analgesic  291-  activity  XJEt  B  CH," ;N U 3 / \ CH^ CH  R N CH^ CH-^ 3  24  291  X=CH CH 2  R=CH  2  292 X=CH  R=CH  293 X=0, S  R=H  2  294 X=CH CH 2  R=H  2  295  (82).  It  was c o n c l u d e d  compounds for  binding.  In  compound  of  3J3 a n d m o s t  orientation  rings  the required  the dimethylaminomethyl  equatorial  tion  the phenyl  to maintain  receptor  as w e l l , an  failed  that  •  t h e Newman p r o j e c t i o n  of  these  conformation  likely  i n 32 a n d 34  substituent  as represented  i n  possesses  b y 296.  the staggered  Examinaconfo'rma-  162  CH CH  0  H 3  0  0  3  296  t i o n o f 296  about the C3-CH E' bond shows t h a t the Q  dimethyl-  araino group most l i k e l y adopts a s y n c l i n a l r e l a t i o n s h i p r e s p e c t to C-4  as r e p r e s e n t e d by 297• The  f o r m a t i o n of 296  staggered  about C2-C3 bond as r e p r e s e n t e d by  ,-N(CH ) 3  with  con298  2  298  297  shows t h a t the t o r s i o n angle i s l e s s than 60  and  the d i -  me thylaminome t h y l group adopts a p s e u d o - a n t i p e r i p l a n a r r e l a t i o n s h i p w i t h r e s p e c t to the s u l f o n e group. The t a t i o n o f the two  phenyl  r i n g s and  f o r m a t i o n s r e p r e s e n t e d by 297  and  orien-  the amino group i n con298  do not appear to show  163 s i m i l a r s p a c i a l arrangements to t h a t  o f the c o r r e s p o n d i n g  groups i n the pharmacophoric c o n f o r m a t i o n 299 proposed by Portoghese and h i s coworkers f o r methadone (75, 7 8 ) . I n  2 CH  3  299  299 the dimethylamino group and the C-4 group were described  to assume a s y n c l i n a l r e l a t i o n s h i p as r e p r e s e n t e d  by 300 w h i l e the dimethylaminomethyl group and one o f the two p h e n y l r i n g s assume an a n t i p e r i p l a n a r  orientation  (301).  2  0 300  301  164 A f o l d e d c o n f o r m a t i o n o f 296 as r e p r e s e n t e d by 302  and 303 i n which the dimethylamino  group  i s placed  on top o f the t h i e t a n e r i n g , a f a v o r a b l e c o n f o r m a t i o n to the i n t e r a c t i o n between the s u l f o n y l and the amino groups, seems h i g h l y u n l i k e l y because  302  o f too many nonbonded i n t e r -  303  a c t i o n s . N e v e r t h e l e s s the two phenyl r i n g s i n 302 and 303 do n o t appear  to have the same o r i e n t a t i o n as t h a t i n 300  and 301• The CH^CHSO^ component o f the t h i e t a n e r i n g i n 302 and 3 0 3 may even h i n d e r the b i n d i n g o f these conformers to the n a r c o t i c r e c e p t o r . Thus the change o f s p a c i a l t i o n o f the p h e n y l r i n g s and the amino group  disposi-  i n 296 as com-  pared to 299 may account f o r the l a c k o f a n a l g e s i c  activi-  ty i n compounds 32-34» The p r e s e n t r e s u l t and the p r e v i o u s s t u d i e s (82, 195) o f r i g i d 25 i n d e e d r e f l e c t  analogues  o f methadone such as  the e x a c t i n g requirement  f o r binding  of methadone to the n a r c o t i c r e c e p t o r . A s m a l l change i n the c o n f o r m a t i o n o f methadone thus r e s u l t s i n complete  loss  of n a r c o t i c a n a l g e s i c  activity.  166 ANALYTICAL METHODS  M e l t i n g p o i n t s were determined u s i n g a ThomasHoover C a p i l l a r y M e l t i n g P o i n t Apparatus. A l l m e l t i n g p o i n t s are reported  uncorrected.  Ultraviolet  s p e c t r a were o b t a i n e d u s i n g a  Bausch and Lomb Model 505 r e c o r d i n g A Beckman IR-10 i n f r a r e d used to r e c o r d the i n f r a r e d The  spectrophotometer. spectrophotometer was  spectra.  pmr s p e c t r o s c o p y  was performed by the De-  partment o f C h e m i s t r y , U. B. C. , u s i n g a "Varian A-60, T60 o r XL-100 spectrometer.  The c o n c e n t r a t i o n o f s o l u t i o n s  was .ca. 10% and t e t r a m e t h y l s i l a n e served standard.  S o l v e n t s a r e s p e c i f i e d . Peak m u l t i p l i c i t i e s are  abbreviated plet),  as the i n t e r n a l  as f o l l o w s : s ( s i n g l e t ) , d ( d o u b l e t ) , t  q (quartet) and m  (tri-  (multiplet).  Mass s p e c t r a and gc/mass s p e c t r a l data were obt a i n e d u s i n g a V a r i a n MAT-111 mass spectrophotometer. G a s - l i q u i d chromatography ( g l c ) was c a r r i e d out u s i n g a MicroTek gas chromatograph Model MT-200 equipped w i t h a flame i o n i z a t i o n d e t e c t o r and a D i s c  Integrator  Model 222. The c a r r i e r gas was n i t r o g e n . A l l o t h e r  con-  d i t i o n s and column types a r e s p e c i f i e d . Microanalyses  were performed by A l f r e d  Bern-  h a r d t , M i k r o a n a l y t i s c h e s L a b o r a t o r i urn, 5251 E l b a c h iiber Engelskirchen,  P r i t z - P r e g l - S t r a s s e 14-16, West Germany.  16? EXPERIMENTAL  1.  S y n t h e s i s o f thiobenzophenone Thiobenzophenone was  (95).  p r e p a r e d a c c o r d i n g to a  method taken from the l i t e r a t u r e  (141) w i t h m o d i f i c a t i o n s .  I n t o a s t i r r e d and c o o l e d ( i c e - s a l t bath) s o l u t i o n of benzophenone (25 gm, drogen  0.14  mole) i n 125 ml o f 95% e t h a n o l , hy-  s u l f i d e and hydrogen  c h l o r i d e were s i m u l t a n e o u s l y  passed. A f t e r 3 hours the hydrogen ed. The b l u e s o l u t i o n was  c h l o r i d e was d i s c o n n e c t -  s t i r r e d i n the i c e - s a l t b a t h f o r  a f u r t h e r 24 hours under a stream of hydrogen b l u e p r o d u c t was rounded  filtered  sulfide.  The  through a Buchner f u n n e l s u r -  w i t h dry i c e , washed twice w i t h 30 ml of c o o l e d  95% e t h a n o l and immediately r e c r y s t a l l i z e d from n-pentane i n a g l o v e box under n i t r o g e n . Thiobenzophenone was ed as b l u e n e e d l e - l i k e c r y s t a l s (141) 53-54°,  2.  (19 gm,  73%), mp  2,2-Diphenyl-3-cyanothietane p h o t o c y c l o a d d i t i o n of thiobenzophenone (144) a t 3 6 6  nm  9J5 (21.2  distilled  3.01  (160 gm,  Was  prepared  (.95) to  gm,  0.106  by  propenebox  mole) and r e -  mole) were d i s s o l v e d i n a  s u f f i c i e n t amount o f r e d i s t i l l e d of one l i t e r .  (lit.  (155)•  (138). I n a n i t r o g e n g l o v e  freshly recrystallized 144  54°  66-77%).  Synthesis of 2,2-diphenyl-3-cyanothietane  nitrile  obtain-  cyclohexane  The b r i g h t b l u e s o l u t i o n was  to a volume  divided  and  t r a n s f e r r e d i n t o 50-ml pyrex tubes. F i v e tubes were used  168 at  one  time and mounted d i r e c t l y i n f r o n t o f a  window ( C o r n i n g CS7-60 g l a s s f i l t e r , The of  x 165  4-5  filter x 165  mm).  s o l u t i o n s and the window were a i r - c o o l e d w i t h two compressed  air.  About  jets  two i n c h e s behind the f i l t e r  a medium-pressure mercury a r c (Hanovia 679A36, 450  was  W)  p l a c e d i n a w a t e r - c o o l e d q u a r t z v e s s e l . The apparatus  was  e n t i r e l y e n c l o s e d i n a dark hood and exposed o n l y to the light the  through the window. I r r a d i a t i o n was  performed  until  b l u e c o l o r o f the s o l u t i o n c o m p l e t e l y d i s a p p e a r e d  (about 4 days) and a p a l e y e l l o w s o l u t i o n was o b t a i n e d . A f t e r i r r a d i a t i o n the content o f each tube f i l t e r e d and evaporated to a v i s c o u s l i q u i d  (1.34  P u r i f i c a t i o n o f t h i s crude m a t e r i a l by column graphy  (silica  gave a white s o l i d  (155) ( 0 . 6 l gm,  and e t h e r y i e l d e d a c o l o r l e s s c r y s t a l l i n e  tance (155)  (0.4 gm,  31%), mp  i r (KBr) 708,  752,  2234 ( n i t r i l e ) cm" ;  pmr  1  (t,  chromato-  R e c r y s t a l l i z a t i o n o f t h i s s o l i d from a m i x t u r e o f n-  pentane  93%);  gm).  g e l , 48 ml i n 50-ml b u r e t ; benzene/petro-  leum e t h e r 30-60°, 5:3) 41%).  was  775,  84-85.5° 1400,  ( l i t . (138) 8 4 ° ,  1478  (phenyl) and  (CDC1 )S3.40 (m, 3  2, S C H ) ,  1, CNCH, s p l i t t i n g = 9 Hz) and 7.10-7-70 (m,  phenyl)  subs-  2  4-99  10,  ppm. Attempts  to improve  the y i e l d  o f the p r o d u c t  were u n s u c c e s s f u l . R e p e a t i n g the experiment by u s i n g fied propenenitrile  , r e p l a c i n g cyclohexane w i t h  e t h e r o r employing combined  filters  puri-  anhydrous  ( C o r n i n g CS7-60 and  169 CS52) d i d n o t s i g n i f i c a n t l y improve the y i e l d . I t was observed t h a t u s i n g aged s o l u t i o n s radiation usually  3.  o f 95 o r p r o l o n g e d i r -  r e s u l t e d i n a poor y i e l d .  Synthesis of 2,2-diphenyl-3-cyanothietane 1,1-dioxide (160). To  a s t i r r e d and c o o l e d s o l u t i o n o f 2,2-diphen-  yl-3-cyanothietane  (155) (3-0 gm, 0.012 mole) i n c h l o r o -  form (50 ml) was added a s o l u t i o n o f m - c h l o r o p e r o x y b e n z o i c acid  (85%, 5.0 gm,  such a speed t h a t  0.024 mole) i n 100 ml o f c h l o r o f o r m a t the temperature o f the t h i e t a n e  was m a i n t a i n e d a t 15-20°. A f t e r  the a d d i t i o n  solution  o f the p e r -  a c i d , 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 room temperature  f o r 1 day. One hundred m i l l i l i t e r s  was added to d i s s o l v e the  o f anhydrous e t h e r  the p r e c i p i t a t e t h a t  s e p a r a t e d and  s t i r r i n g was c o n t i n u e d f o r 4 more days. C a u t i o u s con-  centration  o f the s o l u t i o n a t room temperature to about 80  ml r e s u l t e d i n the f o r m a t i o n o f a white p r e c i p i t a t e which was c o l l e c t e d by f i l t r a t i o n and was t r e a t e d work-up o f the f i l t r a t e .  The f i l t r a t e was washed  s i v e l y w i t h 20% sodium s u l f i t e carbonate and s a t u r a t e d  Propenenitrile  a f t e r the  solution,  sodium c h l o r i d e  succes-  saturated solutions,  was washed s u c c e s s i v e l y  sodium dried  w i t h 10% s u l -  f u r i c a c i d , 10% sodium carbonate s o l u t i o n and a rated  s o l u t i o n o f sodium s u l f a t e . A f t e r d r y i n g  satuover  c a l c i u m c h l o r i d e i t was d i s t i l l e d a t atmospheric preS' sure and f i n a l l y d i s t i l l e d cuo.  a t room temperature i n v a -  170 (anhydrous sodium crude l 6 0  s u l f a t e ) and evaporated to g i v e the  as a white powder ( 2 . 6 2 gm),  mp  129-143°.  The p r e c i p i t a t e p r e v i o u s l y o b t a i n e d was in  50 ml o f s a t u r a t e d sodium carbonate s o l u t i o n .  milliliters  o f c h l o r o f o r m was  added  stirred Fifty  to d i s s o l v e the i n -  s o l u b l e substance. The c h l o r o f o r m s o l u t i o n was s e p a r a t ed, washed, d r i e d and evaporated as above to g i v e more white s o l i d p r o d u c t ( 0 . 3 gm) p r o d u c t was  combined  mp  (2.92 gm,  155-160°. The 86%)  and  isolated  recrystallized  once from a m i x t u r e o f c h l o r o f o r m and e t h e r to y i e l d lorless crystalline 160° 1450, and  substance ( l 6 0 ) ( 2 . 3 gm,  3040, 3065 ( p h e n y l ) , 1143,  2265' ( n i t r i l e ) cm" ; 1  and SCH^)  and 7-43  pmr  1172,  (CDCl^) S 4 - 6 3  (m, 10, p h e n y l )  156.5-  70%) mp  ( l i t . (138) 157-158.5°); i r (KBr) 540, 710, 1498,  a co-  1325  788, (S0 (172)) 2  (m, 3, CNCH  ppm.  Using p e r a c e t i c a c i d i n place of m-chloroperoxybenzoic a c i d i n a s i m i l a r experiment r e s u l t e d i n a lower  4.  yield  (67%)  o f crude  160.  Synthesis of 2,2-diphenyl-3-aminomethylthietane dioxide  1,1-  (l6l).  The r e a c t i o n was necked f l a s k which was  performed i n a 250-ml t h r e e -  equipped w i t h a magnetic  stirrer  and a s i n t e r e d g l a s s d i s p e r s i o n tube connected to a d i borane g e n e r a t i o n a p p a r a t u s . The o u t l e t o f the t h r e e necked f l a s k was  connected to an i n a c t i v a t i o n t r a p .  The  171 i n a c t i v a t i o n t r a p was a mercury b u b b l e r i n which some mercury was l a i d  a t the bottom. Above the mercury was a  l a y e r o f acetone which served to d e s t r o y the diborane e s c a p i n g from the r e a c t i o n f l a s k . The d i b o r a n e g e n e r a t o r was a d r y 500-ml t h r e e necked netic  stirrer,  f l a s k equipped w i t h a mag-  a p r e s s u r e - e q u a l i z i n g a d d i t i o n f u n n e l and  a d i b o r a n e o u t l e t which was connected  to a d r y t r a p  (ser-  v i n g as a r e s e r v o i r i n case o f back f l o w o f the s o l u t i o n from the r e a c t i o n f l a s k to the g e n e r a t o r ) and then to the gas d i s p e r s i o n tube dipped i n the r e a c t i o n f l a s k . The top of  the a d d i t i o n f u n n e l served as an i n l e t  f o r the d r i e d  nitrogen. Under a stream o f d r i e d n i t r o g e n , the generat i o n r e a c t i o n u n i t was t h o r o u g h l y d r i e d w i t h an open flame. The system was then a l l o w e d to c o o l to room temp e r a t u r e w i t h the d r i e d n i t r o g e n b e i n g passed s l o w l y through the system. The r e a c t i o n f l a s k was f i l l e d w i t h 100 ml o f dried  tetrahydrofuran  to c o v e r the s i n t e r e d g l a s s o f the  d i s p e r s i o n tube. 2,2-Diphenyl-3-cyanothietane (160)  (2.3 gm, 0.008 mole) was added 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 In  *  1,1-dioxide  and c o o l e d i n an i c e bath.  the g e n e r a t o r were p l a c e d 20 ml o f diglyme  T e t r a h y d r o f u r a n was f r e s h l y d i s t i l l e d  over l i t h i u m  aluminum h y d r i d e . **  Diglyme was p u r i f i e d by d r y i n g over c a l c i u m h y d r i d e and  then d i s t i l l e d  over l i t h i u m aluminum h y d r i d e .  172 and 23 ml of p u r i f i e d boron t r i f l u o r i d e gm,  0.18  etherate  mole, 50% e x c e s s ) . The a d d i t i o n f u n n e l was  ed w i t h a s o l u t i o n o f sodium b o r o h y d r i d e mole, 20% e x c e s s ) i n p u r i f i e d diglyme borane  (25-5  (0.0375 mole) was  (3*4 gm,  0.09  (about 300 m l ) . D i -  generated by slow a d d i t i o n o f  the sodium b o r o h y d r i d e s o l u t i o n to the boron e t h e r a t e and was  fill-  f o r c e d to pass i n t o  trifluoride  the s o l u t i o n of l 6 0  by a s l i g h t f l o w o f d r i e d n i t r o g e n . A f t e r the a d d i t i o n o f sodium b o r o h y d r i d e s o l u t i o n , the g e n e r a t o r was f o r 1 hour a t 70-80° to ensure the complete the d i b o r a n e to the n i t r i l e t i o n was  s o l u t i o n . The r e a c t i n g  The i n l e t and  were d i s c o n n e c t e d , the f l a s k was s o l u t i o n was  excess d i b o r a n e was  d r o l y z e d by s t i r r i n g  t i g h t l y stoppered and  s o l u t i o n was  The borane  days.  adduct was  hy-  the c o l o r l e s s s o l u t i o n w i t h 20 ml of f o r t h r e e days.  b a s i f i e d w i t h a c o o l e d s o l u t i o n of 3 gm  o f sodium h y d r o x i d e i n 30 ml of water. evaporated a t room temperature  Boron  f o r two  the  d e s t r o y e d i n an i c e bath by c a r e -  10% h y d r o c h l o r i c a c i d a t room temperature  *  solu-  the o u t l e t  then s t i r r e d a t room temperature  f u l a d d i t i o n of 10 ml of water.  The  t r a n s f e r of  then r a i s e d above the i c e b a t h and a l l o w e d to  r e t u r n to room temperature.  The  heated  The m i x t u r e  was  i n a r o t a r y e v a p o r a t o r to  t r i f l u o r i d e d i e t h y l e t h e r a t e , 100 ml, was  f i e d by adding 2 ml of anhydrous e t h e r and i n g under reduced p r e s s u r e from 2 gm cium h y d r i d e .  puri-  distill-  of granular c a l -  173 remove p o s t of the t e t r a h y d r o f u r a n . The r e s i d u a l aqueous m i x t u r e was  e x t r a c t e d w i t h c h l o r o f o r m . The  r o f o r m s o l u t i o n was  d r i e d and  t u r e to a v i s c o u s l i q u i d ir  (neat) 705,  1310  760,  ( s u l f o n e ) , 1598,  gm  1495,  3020, 3050 ( p h e n y l ) ,  d e r i v a t i v e was  p o s i t was te and  1135, cm" . 1  prepared by  dis-  (0.007 mole) o f the crude l 6 l i n 2.5 ml  a c e t i c a n h y d r i d e . When the exothermic s o l u t i o n was  quantitatively);  3300 and 3360 (primary amine)  The acetamide s o l v i n g 0.2  chlo-  evaporated a t room tempera-  ( l 6 l ) (2.40 gm,  1448,  combined  r e a c t i o n ceased,  d i l u t e d w i t h 15 ml of i c e water. The  s e p a r a t e d by d e c a n t a t i o n of the aqueous  amidomethylthietane  oily  1,1-dioxide  2,2-diphenyl-3-acet-  (186) was  collected  ( 7 4 % ) . R e c r y s t a l l i z a t i o n o f the product from s u b s e q u e n t l y from a m i x t u r e  gave n e e d l e - l i k e c r y s t a l s mp 1450, 1675 pmr  de-  superna-  by  f i l t r a t i o n and washed w i t h d i s t i l l e d water, weighing  and  the  s o l i d i f i e d by t r i t u r a t i o n i n d i s t i l l e d water w i t h  a g l a s s r o d . The white p r e c i p i t a t e ,  gm  of  1498,  toluene  of benzene and n-hexane  160-170°;  3020, 3065 ( p h e n y l ) , 1145,  i r (KBr) 710, 1300  3  ( s , 3 , GH^),  2.72-4-28 (m,  CHCH N), 5.70-6.10 ( t , broad, 1, MH) 2  phenyl)  cm" ; 1  5, SCH  and 7-10-7.65  2  and  (m,  10,  ppm. Attempts  mixture  770,  (sulfone),  (amide c a r b o n y l ) and 3425 (secondary amide) (CDC1 ) 81.85  0.17  to r e c r y s t a l l i z e  the product from a  o f e t h a n o l and water r e s u l t e d i n d e s u l f o n a t i o n . The p i c r a t e  s a l t was  prepared by d i s s o l v i n g  the  174 crude l 6 l (0.2 gm, 95% methanol  0.0007 mole) i n a minimum amount o f  (about 1 m l ) . A f t e r f i l t r a t i o n , 2 ml o f  s a t u r a t e d s o l u t i o n o f p i c r i c a c i d i n 9 5 % ethanol was added. The y e l l o w s o l u t i o n was evaporated to a y e l l o w l i q u i d which was r e d i s s o l v e d i n 5 ml o f a b s o l u t e methanol.  The r e -  s u l t i n g y e l l o w s o l u t i o n was f i l t e r e d and the f i l t r a t e was c o o l e d i n the f r e e z e r f o r a l o n g p e r i o d u n t i l line picrate  s a l t appeared.  The y e l l o w s o l i d  the c r y s t a l (lOOmg, 24%)  was c a r e f u l l y f i l t e r e d and washed t h o r o u g h l y w i t h 9 5 % met h a n o l ; mp 160.5-164.5°, ( p h e n y l ) , 1142, 1260-1365  i r (KBr) 705, 753, 778, 799, 1615 ( s u l f o n e and n i t r o ) and 2050-  3300 (ammonium and carbon-rhydrogen (DMS0-d ) 5 2.73-4-20 6  p u r i t y peaks, t i n g =7.5  1  ( d , broad, 2, SCHg, s p l i t -  ( s , broad, 10, p h e n y l ) , 7-97  ad, 3, NH-j) and 8 . 6 5 ( s , 2, t r i n i t r o p h e n y l ) Attempts  pmr  (m, o v e r l a p p i n g w i t h s o l v e n t im-  3, C H C i y O , 4-50  H z ) , 7.42  s t r e t c h i n g ) cm" ;  to r e c r y s t a l l i z e  (m, b r o -  ppm.  the p i c r a t e  resulted  i n degradation.  5.  Synthesis of 2,2-diphenyl-3-dimethylaminomethylthietane 1 , 1 - d i o x i d e ( 3 2 ) . Crude 2,2-diphenyl-3-aminomethylthietane  dioxide  (161)  formaldehyde ml).  1,1-  (1.9 gm, 0.0063 mole) and 3 ml o f 3 6 . 4 % s o l u t i o n were d i s s o l v e d i n 95% e t h a n o l (100  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 room  tempera-  t u r e f o r 9 h o u r s and then f i l t e r e d . The f i l t r a t e was  175 t r a n s f e r r e d i n t o a 400-ml P a r r b o t t l e . Seven hundred grams o f 10% p a l l a d i u m on c h a r c o a l was was  added. The  milli-  bottle  then p l a c e d on a P a r r h y d r o g e n a t i o n apparatus.  The  former and the tank were evacuated and f i l l e d w i t h hydrogen f o r 10 times and f i n a l l y f i l l e d w i t h hydrogen The  shaker was  s t a r t e d and the m e t h y l a t i o n was  to 50 p s i .  a l l o w e d to  proceed f o r 12 hours. A f t e r v e n t i n g the hydrogen bottle aid  s a f e l y , the e t h a n o l s o l u t i o n was  o f " C e l i t e " and the c a t a l y s t was  e t h a n o l . The f i l t r a t e was  the  f i l t e r e d w i t h the  washed c a r e f u l l y w i t h  evaporated a t room  i n a r o t a r y e v a p o r a t o r . The  from  temperature  o i l y r e s i d u e was mixed w i t h  50 ml o f water, b a s i f i e d w i t h a c o o l e d sodium h y d r o x i d e s o l u t i o n and  e x t r a c t e d w i t h c h l o r o f o r m . The combined  r o f o r m s o l u t i o n was  washed w i t h a s a t u r a t e d s o l u t i o n of  sodium c h l o r i d e , d r i e d over anhydrous evaporated to g i v e a v i s c o u s l i q u i d m a t e r i a l was eal  and d r y i c e . The e t h e r was  sodium s u l f a t e  (1.86  gm).  the e t h e r -  c o o l e d i n a f r e e z i n g m i x t u r e o f acetone solid  p r o d u c t which p r e c i p i t a t e d from -  c o l l e c t e d by f i l t r a t i o n . Repeated c o n c e n t r a t i o n  and c o o l i n g o f the f i l t r a t e gave a t o t a l of 0.81 of  crude 32, mp  141-152°;  i r (KBr) 705,  3020, 3050 ( p h e n y l ) , 1140, NH  s t r e t c h i n g ; pmr  (d, 4.35  (CDC1 ) 3  1300 2.18  760,  gm  1445,  ( s , 6, N ( C H ) ) , 3  1495,  2, CH S) and 7-05-7.60 (m, 10, p h e n y l )  of  2.17  2  2  2  (41%)  ( s u l f o n e ) and absence  2, 0H N, J = 8 Hz), 3-20-3.83 (m, 1, CHOHgS), (m,  and  This o i l y  r e d i s s o l v e d i n anhydrous e t h e r and  s o l u t i o n was  chlo-  3-93-  ppm.  176 Attempts to f u r t h e r p u r i f y the product by lumn chromatography ( n e u t r a l  alumina/benzene-chloroform-  methanol) r e s u l t e d i n u n i d e n t i f i e d degraded The p i c r a t e s a l t was (0.1 gm)  prepared by d i s s o l v i n g  32  b i d i t y had  so-  f i l t e r e d . A s u f f i c i e n t amount o f e t h a n o l i c  t i o n of p i c r i c  a c i d was  added u n t i l  ceased. Upon s t a n d i n g w i t h o u t  c a r e f u l l y withdrawn and  t h o r o u g h l y washed s e v e r a l  solu-  the f o r m a t i o n o f t u r -  solution yielded yellow needle-like  Finally  substances.  i n a minimum amount o f a b s o l u t e methanol. The  l u t i o n was  was  co-  d i s t u r b a n c e , the  c r y s t a l s . The  solvent  the c r y s t a l l i n e substance  was  times w i t h 60% aqueous methanol.  the b r i g h t y e l l o w p i c r a t e  salt  (0.1 gm)  was  col-  l e c t e d by f i l t r a t i o n and d r i e d , mp > 1 8 4 . 5 ° (decomp.); i r (KBr) 709,  750,  1460,  1490,  1525,  1544,  3070, 3090 (phenyl and n i t r o ) , 1135, and n i t r o ) and 2.85  1565,  1310,  2050-2850 (ammonium) cm" ; 1  ( s , 6, F ( C H ) ) , 3  2  3.03-3.35 (m,  (m, 1, CH CH), 4.35-4-87 (m, p  3010,  1360 pmr  3040,  (sulfone  (DMSO-dg)S  2, E C H ) , 3-50-4.20 2  2, S C H ) , 7-38 ?  (m,  10,  phen-  + yl),  8.57  ( s , 2, t r i n i t r o p h e n y l ) and  9-47  (broad, 1,  EH)  ppm. A n a l - C a l c d . f o r C ^ H ^ N ^ S : C, 52.89; H, Found: C,  52.82; H, The  4-43;  E, 10.37-  E, 10.18.  f r e e base 32 was  r e g e n e r a t e d as white  by a l k a l i z a t i o n o f the p i c r a t e and l i b e r a t e d amine by  4-44;  solid  e x t r a c t i o n o f the  chloroform.  Attempted d i m e t h y l a t i o n o f l 6 l by u s i n g  Eschwei-  177 l e r - C l a r k procedure of  (196) was u n s u c c e s s f u l : A  crude l 6 l (0,177 gm,  formic a c i d lution  (0.06 mole) and 0 . 1 m l  (0.0013 mole) was  hours. The  s o l u t i o n was  b a s i f i e d w i t h sodium form. The to  0.00062 mole), 3-2  gm  solution of  90.7%  o f 37% formaldehyde  s t i r r e d and heated a t 68° f o r 24 evaporated to a r e s i d u e which  was  carbonate and e x t r a c t e d w i t h c h l o r o -  c h l o r o f o r m s o l u t i o n was  s e p a r a t e d and  evaporated  remove the s o l v e n t . The r e m a i n i n g m a t e r i a l was  ed i n 10% h y d r o c h l o r i c a c i d . A f t e r f i l t r a t i o n , f i l t r a t e was  so-  basified  dissolv-  the a c i d  (sodium c a r b o n a t e ) and e x t r a c t e d w i t h  c h l o r o f o r m . E v a p o r a t i o n o f the d r i e d c h l o r o f o r m s o l u t i o n gave a s o l i d , i r (KBr) 710, 2960, 3020 and 3060 cm" . 1  the  6.  l o s s of a sulfone  760,  925,  1450,  group.  ( 1 6 2 ) and  trans-  (163).  The commercial  2-butenenitrile  (crotononitrile)  c o n t a i n e d a m i x t u r e o f c i s - (60-70%) and t r a n s i s o m e r s . The  two  distillation  through a Spinning-Band-Column  a p p a r a t u s (motor  1490,  The i r d a t a o b v i o u s l y i n d i c a t e s  Separation of c i s - 2 - b u t e n e n i t r i l e 2-butenenitrile  1025,  (30-40%)  components were s e p a r a t e d by r e p e a t e d  speed  76OO  RPM).  distillation  The p u r i t y o f the se-  p a r a t e d i s o m e r s (bp: c i s , 108°; trans,' 121°) were d e t e r mined by g l c (1/8 i n x 6 f t s t a i n l e s s s t e e l column packed w i t h 3-2 ABS,  gm  o f 15% GE SE-30 on 90 to 100 mesh Anakrom  column temperature 6 0 ° ) .  178 7.  Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthietane  (156 ) and c i s - 2 , 2 - d i p h e n y l - 3 - m e t h y l - 4 - c y a n o -  thietane  (158).  Freshly r e c r y s t a l l i z e d  thiobenzophenone  (2.4 gm,  0.0121 mole), pure c i s - 2 - b u t e n e n i t r i l e  (7.0 gm,  0.105  mole) and r e d i s t i l l e d  (95) (162)  cyclohexane  (10  ml)  were mixed under a carbon d i o x i d e atmosphere. The  solu-  t i o n was  a pro-  tightly  s e a l e d and i r r a d i a t e d at 366 nm,  cedure d e s c r i b e d i n the s y n t h e s i s o f 155  (experiment 2 ) .  A f t e r 152 hours o f i r r a d i a t i o n the y e l l o w s o l u t i o n ed was  filtered  and d i s t i l l e d  cuo to g i v e a v i s c o u s l i q u i d  obtain-  a t room temperature in. va (3.6 gm).  The d i s t i l l a t e  con-  t a i n i n g a m i x t u r e o f cyclohexane and excess 2-butenenit r i l e was  trapped i n a f l a s k c o o l e d i n a dry i c e - a c e t o n e  m i x t u r e . A n a l y s i s by g l c showed that the r e c o v e r e d t e n e n i t r i l e was  entirely cis-isomer  that no i s o m e r i z a t i o n o f 1 6 2  ( 1 6 2 ) .  2-bu-  This revealed  o c c u r r e d d u r i n g the photo-  chemical process. A n a l y s i s o f the pmr cous l i q u i d 2.5  (CDCl^) o f the v i s -  o b t a i n e d above i n d i c a t e d the presence o f a  : 1 m i x t u r e o f 156  (d, 3, CKy,  spectrum  and 158;  J = 7 Hz), 3.80  pmr  ( C C l ^ ) 156  (m, 1, SCH),  5-00  J = 8 Hz) and 7.10-7-75 (m, 10, phenyl) ppm; (d, 3, 0H , 3  SCH,  J = 7 Hz), 4-20  (d, 1, CHCT, 158: S l - 0 7  (m, 1, CH^CH), 4-25  J = 8 Hz) and 7-10-7-75 (m, 10, p h e n y l ) Attempts  : £1.54  (d, 1,  ppm.  to s e p a r a t e these two isomers by c r y -  179 s t a l l i z a t i o n and chromatography  methods were u n s u c c e s s -  ful.  8.  Synthesis of c i s - 2 , 2 - d i p h e n y l - 3 - c y a n o - 4 - m e t h y l t h i e tane 1 , 1 - d i o x i d e  (174). (3.6  The v i s c o u s m i x t u r e 3-cyano-4-methylthietane  (156)  d i s s o l v e d i n methylene  s o l u t i o n was  (162)  chloride  ml o f methylene  r i n g a t room temperature  was  (2.4  (50ml).  gm,  0.012  0.105  mole)  The  acid  (85%,  4-58  chloride. After  ml. The m - c h l o r o b e n z o i c a c i d that  stir-  sodium  precipitated  The f i l t r a t e was washed s u c c e s -  sulfite  solution,  saturated  carbonate s o l u t i o n and water. A f t e r d r y i n g over sulfate,  the s o l u t i o n was  ml. Anhydrous e t h e r (10  sidue and the mixture was line  gm,  c a r e f u l l y c o n c e n t r a t e d under reduced p r e s s u r e to  s i v e l y w i t h 10%  about 10  resulting  f o r 5 days the o x i d a t i o n mix-  removed by f i l t r a t i o n .  sodium  pho-  s t i r r e d i n a c o l d water b a t h and t r e a t e d w i t h  0 . 0 2 6 mole) i n 150  about 100  (.95)  ( 7 . 0 gm,  a s o l u t i o n o f m-chloroperoxybenzoic  t u r e was  cis-2,2-dl-  (158) p r e p a r e d by the  t o c y c l o a d d i t i o n o f thiobenzophenone  was  of c i s - 2 , 2 - d i p h e n y l -  and i t s isomer,  phenyl-3-methyl-4-cyanothietane  mole) to c i s - 2 - b u t e n e n i t r i l e  gm)  anhydrous  c o n c e n t r a t e d a g a i n to ml) was  shaken. The  added to the r e -  colorless  crystal-  c o l l e c t e d by  filtration  and washed w i t h a minimum amount o f anhydrous  e t h e r . The  pmr  substance t h a t appeared was  sodium  spectrum o f t h i s p r o d u c t showed t h a t i t was  pure  174.  180 The y i e l d was 1.75 gm  (68.4%).  The m a t e r i a l was f u r t h e r p u r i f i e d by r e c r y s t a l lization  a t room temperature  from a mixture  of chloroform  and n-pentane o r from a mixture  o f methylene c h l o r i d e and  e t h e r to g i v e c o l o r l e s s l e a f l e t  c r y s t a l s , mp 1 8 4 - 1 8 6 . 5 ° ;  ir  (KBr) 705,760, 1450, 1496, 1600, 3025, 3060 ( p h e n y l ) ,  1155,  1330 ( s u l f o n e ) , 2260 ( n i t r i l e ) cm" ; pmr (CDCl^) 8 1  1.63  (m, 3, 0 H ) , 4.40-4-80  7.60  (m, 10, p h e n y l ) ppm.  3  Anal. Oalcd. f o r C  1 7  H  1 5  (m, 2, CHCN and SCH) and 7-20-  N S 0 : C, 68.66; H, 5-08; ET, 4-71. 2  Pound: C, 68.69; H, 5-09; N, 4-76. The  e t h e r e a l mother l i q u i d  i s o l a t e d , was evaporated this oily of  to an o i l . The pmr spectrum o f  substance i n d i c a t e d t h a t no a p p r e c i a b l e amount  cis-2,2-diphenyl-3-methyl-4-cyanothietane  (175)  9.  from which 174 was  1,1-dioxide  existed.  Synthesis of cis-2,2-diphenyl-3-cyano-4-methylthietane 1-oxide  (178).  A crude l i q u i d cyano-4-methylthietane  (7.3 gm) o f c i s - 2 , 2 - d i p h e n y l - 3 -  (156) p r e p a r e d by the p h o t o c y c l o -  a d d i t i o n r e a c t i o n i n experiment  7 was d i s s o l v e d i n a m i n i -  mum amount o f anhydrous e t h e r and a s o l u t i o n o f m-chloroperoxybenzoic  acid  (9-7 gm) i n 20 ml o f anhydrous e t h e r was  added w i t h s t i r r i n g . A f t e r the a d d i t i o n o f p e r a c i d p r e c i p i t a t i o n o c c u r r e d . The r e s u l t i n g m i x t u r e was p l a c e d a s i d e  181 o v e r n i g h t and f i l t e r e d  to g i v e a white powder (178) (3-03  gm), mp 135-136°; i r (KBr) 708, 762, 1450, 1500, 1600, 3040, 3070 ( p h e n y l ) , 1080 (S=0 (172)), and 2260 cm" ; 1  pmr  ( C D C 1 ) 6 1.67 3  (d, 3 ,  CH , 3  (cyano)  J = 7 H z ) , 3-41 (two  o v e r l a p p i n g d o u b l e t s c e n t e r e d a t 199.5 and 210.1 Hz r e s p e c t i v e l y , 1, SOH, J(CH-CH) = 10 Hz, J(CH -CH) = 7 H z ) , 3  4-71  ( d , 1, CNCH, J = 10 Hz) and 7-40  (m, 10, p h e n y l )  ppm.  O x i d a t i o n o f the s u l f o x i d e 178 i n c h l o r o f o r m w i t h excess m - c h l o r o p e r o x y b e n z o i c a c i d gave c o r r e s p o n d i n g s u l f o n e 174-  10.  S y n t h e s i s o f cis-2,2-diphenyl-3-aminomethyl-4-methylt h i e t a n e 1 , 1 - d i o x i d e (179). The procedure d e s c r i b e d i n the experiment 4 was  used. A stream o f d i b o r a n e (0.0375 mole) g e n e r a t e d by add i t i o n o f sodium b o r o h y d r i d e (3.4 gm, 0.09 mole) to boron trifluoride  e t h e r a t e (25.5 gm,  0.18 mole) was s l o w l y p a s s -  ed i n t o a s t i r r e d and c o o l e d s o l u t i o n o f 174 (3.3 gm, mole) i n 200 ml o f d r i e d  0.01  t e t r a h y d r o f u r a n . The c o l o r l e s s  s o l u t i o n was s t i r r e d a t room temperature f o r 48 hours. The excess d i b o r a n e was d e s t r o y e d w i t h 10 ml o f water, 27 ml o f 20% aqueous h y d r o c h l o r i c a c i d was added 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 40 hours. A f t e r  alkalization  to pH 12 w i t h sodium h y d r o x i d e s o l u t i o n , the aqueous mixt u r e was evaporated a t room temperature  to remove the t e -  t r a h y d r o f u r a n . The r e m a i n i n g aqueous m i x t u r e was  extract-  182 ed w i t h c h l o r o f o r m . The c h l o r o f o r m e x t r a c t was washed with saturated  sodium c h l o r i d e  s o l u t i o n and d r i e d  over  anhydrous sodium s u l f a t e . The crude 179 (2.84 gm, 86%) was o b t a i n e d as a gummy substance a f t e r e v a p o r a t i o n o f the  solvent  material ture  and d r y i n g  was g r o s s l y  i n vacuo. A sample o f t h i s gummy  p u r i f i e d by d i s s o l v i n g i n a mix-  o f methanol and n-pentane and a l l o w i n g  the s o l u t i o n  to be c o n c e n t r a t e d spontaneously a t room temperature to give c o l o r l e s s needle-like ir  (KBr) 710, 7 6 3 ,  1140,  c r y s t a l s (179), mp 136-143°;  780, 1450, 1495, 3030, 3060  1155, 1300, 1320 ( s u l f o n e ) ,  (phenyl),  3325 and 3385  (primary  amine) c m ; pmr (0001^)8 0.98 ( s , broad, 2, NH , exchang-1  2  ed by D 0 ) , 1.53 ( d , 3, CE J 2  y  = 7 H z ) , 2.89 ( d , broad, 2,  CH^T, J = 7 H z ) , 3.50 (m, 1, NCH CH, J(CH -CH) = 7 Hz, 2  2  J(CH-CH) = 9 H z ) , 4-53 (m, 1, SCH, J(CH -CH) = 7 Hz, J(CH3  OH) = 9 Hz) and 7-42 (m, 10, p h e n y l ) ppm. The  picrate  crude 179 i n a minimum an  ethanolic  s a l t was p r e p a r e d by d i s s o l v i n g the amount o f 95% e t h a n o l . A d d i t i o n o f  solution of p i c r i c  a c i d gave the y e l l o w  s t a l l i n e p i c r a t e which was r e c r y s t a l l i z e d s e v e r a l  cry-  times  from a m i x t u r e o f 95% e t h a n o l and 10% a c e t i c a c i d , mp 198201°;  i r (KBr) 715, 755 ( p h e n y l ) ,  1495, 1530, 1555, l 6 l 0 ,  1630 (phenyl and n i t r o ) , 1210-1400 ( s u l f o n e  and n i t r o ) and  2150-3420 (ammonium) cm" ; pmr (DMSO-dg)S 1.51 ( d , 3, CH , 1  3  J = 7 H z ) , 2.95 ( d , broad, 2, OE^, (m, 1, NCH CH), 4.40-5.15 2  J = 7 H z ) , 3.82-4-35  (m, 1, SCH), 7-43 ( s , 10, phenyl  183  + ), 7-87 ( s , broad, 3, NH^) and 8.72 ( s , 2, t r i n i t r o p h e n y l ) ppm. Anal. Calcd.for C  2 3  H  2 2  N S O : C, 52.07; H, 4-18; N, 10.56. 4  g  Found: C, 52.29; H, 4-21; N, 1 0 . 6 9 . 11.  Synthesis of cis-2,2-diphenyl-3-dimethylaminomethyl4 - m e t h y l t h i e t a n e 1 , 1 - d i o x i d e (33)• A m i x t u r e o f crude  2,2-diphenyl-3-aminomethyl-  4 - m e t h y l t h i e t a n e 1 , 1 - d i o x i d e (179) formaldehyde  solution  (2.5 gm, 0.0083 mole),  (3: ml o f 3 6 . 4 % ) and 95% e t h a n o l (  100 ml) was s t i r r e d a t room temperature then f i l t e r e d .  f o r 9 hours and  To the f i l t r a t e were added 0.49 ml o f g l a -  c i a l a c e t i c a c i d and 0.7 gm o f 10% p a l l a d i u m on c h a r c o a l . The r e s u l t i n g m i x t u r e was immediately shaken a t 50 p s i of hydrogen,  a procedure d e s c r i b e d i n experiment  5- A f t e r  11 hours o f m e t h y l a t i o n the dark m i x t u r e was f i l t e r e d w i t h the a i d o f " C e l i t e " . The s o l v e n t and the excess  form-  aldehyde were removed a t room temperature by vacuum evap o r a t i o n . The r e s i d u e was b a s i f i e d w i t h sodium  hydroxide  s o l u t i o n and e x t r a c t e d w i t h e t h e r . The p o o l e d e t h e r ext r a c t was washed w i t h s a t u r a t e d sodium filtered liquid  chloride  solution,  and d r i e d . Crude J33_ was o b t a i n e d as a v i s c o u s  (3-0 gm) a f t e r e v a p o r a t i o n o f the e t h e r i n a r o -  t a r y e v a p o r a t o r . The i r spectrum o f t h i s crude p r o d u c t showed the absence  o f N-H s t r e t c h i n g o f the primary amino  group. White h y d r o c h l o r i d e p r e c i p i t a t e  (mp 120-150°) was  184 o b t a i n e d when a sample ed i n e t h e r was  o f the crude t e r t i a r y amine d i s s o l v -  t r e a t e d w i t h an e t h e r e a l s o l u t i o n of hydro-  gen c h l o r i d e . T h i s h y d r o c h l o r i d e i n chloroform. very  A sample  o f 0.02  salt deteriorated rapidly gm o f the h y d r o c h l o r i d e  s o l u b l e i n about 0.4 ml o f CDCl^ but an i n s o l u b l e  t e r i a l r a p i d l y c r y s t a l l i z e d out from the c h l o r o f o r m  ma-  solu-  t i o n i n one or two minutes. T h i s c r y s t a l l i n e m a t e r i a l , f e r e n t from the o r i g i n a l m a t e r i a l , was  was  dif-  i n s o l u b l e i n most  common l a b o r a t o r y s o l v e n t s . The i r spectrum showed t h a t . ;  t h i s m a t e r i a l was  a hydrochloride  f e r e n t from the o r i g i n a l  and s u l f o n e but was  dif-  hydrochloride.  The crude 33 (0.50 gm) was  p u r i f i e d by u s i n g co-  lumn chromatography  ( n e u t r a l alumina/benzene). The  ed pure p r o d u c t was  s o l i d i f i e d upon a d d i t i o n o f n-pentane.  A white s o l i d  (33) was  715, 752, 1 4 4 5 , and 1300  1495, 1  (s, 6,  1596,  132-135°; i r ( K B r ) 702,  3020, 3050 ( p h e n y l ) ,  p m r ( C D C l ) Si.53 ( d , 3 ,  ( s u l f o n e ) cm" ;  7 Hz), 2.20 3-92  1456,  o b t a i n e d , mp  3  2  CH) = 9  quartets  a t 2 6 5 . 0 and 274-5 Hz r e s p e c t i v e l y , 1, SCH, Hz) and 7-38  (m, 10, p h e n y l p r o t o n s )  The p i c r a t e s a l t was  3.18-  2  2  1135 J =  3  1.83-2.77 (m, 2, NCH ),  (m, 1, FCH CH), 4-20-4.83 (two o v e r l a p p i n g  centered  0H ,  3  N(GH ) ),  isolat-  J(CH-  ppm.  p r e p a r e d by d i s s o l v i n g 33_ i n  a. minimum amount o f methanol. A d d i t i o n o f e t h a n o l i c s o l u t i o n o f p i c r i c a c i d y i e l d e d a y e l l o w p r e c i p i t a t e which c o l l e c t e d and r e c r y s t a l l i z e d from a m i x t u r e o f methanol acetone to g i v e f i n e , n e e d l e - l i k e c r y s t a l s , mp  was and  212-214°; i r  185 (KBr) 705,  752  t r o ) , 1490,  ( p h e n y l ) , 1150,  1560,  (ammonium) cm" ; 1  2.90  1615 pmr  ( s , broad, 6,  1210-1385 ( s u l f o n e and n i -  ( n i t r o and p h e n y l ) , and  (DMSO-dg) 51.52 tfCCH^),  2100-3100  (d, 3, CH^,  J = 7 Hz),  3.00-3-30 (broad band, 2,  NCH ), 3-80-4-40 (m, 1, TTCHpCH), 4-50-5-10 (m, 1,  SOH),  2  7-45  (m,  10, phenyl p r o t o n s ) , 8 . 6 3  p r o t o n s ) , and 9.37  ( s , 2,  (broad band, KH)  ppm.  A n a l . C a l c d . f o r C^H^CT^SOg: C, 53-76; H, Pound: C, 53-79; H,  4-82;  H,  trinitrophenyl  4-69;  N, 10.03-  10.23-  12. S y n t h e s i s of t r a n s - 2 , 2 - d i p h e n y l - 3 - c y a n o - 4 - m e t h y l t h i e tane (157) and tane  trans-2,2-diphenyl-3-methyl-4-cyanothie-  (159). Freshly r e c r y s t a l l i z e d  gm,  thiobenzophenone  ('95)  O.OO56 mole), g l c - p u r e t r a n s - 2 - b u t e n e n i t r i l e  (163)  (3«l6 gm,  0.0471 mole), and r e d i s t i l l e d  cyclohexane  (4-5  ml) were mixed under a carbon d i o x i d e atmosphere. The t i o n was  tightly  stoppered and i r r a d i a t e d a t 366 nm,  cedure d e s c r i b e d i n the s y n t h e s i s o f thietane  (155) - The r e s u l t i n g y e l l o w s o l u t i o n was  s o l v e n t and  o n l y 163  was  a pro-  filtered (1.7  gm).  the excess 2 - b u t e n e n i t r i l e were r e c o v e r e d  i n a c o l d t r a p . A n a l y s i s by g l c i n d i c a t e d z a t i o n o f 163  solu-  2,2-diphenyl-3-cyano-  and evaporated i n vacuo to g i v e a v i s c o u s l i q u i d The  (1.1  that no  isomeri-  o c c u r r e d i n the photochemical p r o c e s s and recovered.  A n a l y s i s o f the pmr  spectrum  of the v i s c o u s  li-  186 quid i n d i c a t e d the e x i s t e n c e o f an i s o m e r i c mixture o f trans-2,2-diphenyl-3-cyano-4-methylthietane  (157) and  trans-2,2-diphenyl-3-methyl-4-cyanothietane  (159) i n a r a -  t i o o f 2.8:1; pmr ( C C l ^ ) 157: S 3.86  i.45  ( d , 3 , GH^, J = 6 H z ) ,  (m, 1, CH^CH), 4 - 3 6 ( d , 1, CNCH, J = 10 H z ) , and  6.80-7.80 (m, 10, phenyl p r o t o n s ) ppm; 159: SO.83 ( d , 3 , CH , 3  J = 6 H z ) , 3.66 ( d , 1, CNCH, J = 10 H z ) , 3-86 (m, 1,  CH^CH) and 6.80-7-80 (m, 10, phenyl p r o t o n s ) ppm. Attempts to separate the two isomers by chromatography o r by c r y s t a l l i z a t i o n were u n s u c c e s s f u l .  13-  Synthesis of trans-2,2-diphenyl-3-cyano-4-methylthietane 1 , 1 - d i o x i d e The  (176) •  crude m i x t u r e  3-cyano-4-methylthietane methyl-4-cyanothietane  (1.7 gm) o f t r a n s - 2 , 2 - d i p h e n y l -  (157) and t r a n s - 2 , 2 - d i p h e n y l - 3 (159) p r e p a r e d by the p h o t o c y c l o -  a d d i t i o n o f thiobenzophenone (.95) (1.1 gm, 0.0056 mole) to trans-2-butenenitrile  ( 1 6 3 ) ( 3 - l 6 gm, 0.0471 mole) was d i s -  s o l v e d i n methylene c h l o r i d e  (50 m l ) . The s o l u t i o n was  s t i r r e d i n a c o l d water bath and t r e a t e d with m-chloroperoxybenzoic thylene c h l o r i d e  acid  a solution of  (2.13 gm, 0.0123 mole) i n me-  (150 m l ) . The r e a c t i o n mixture was s t i r r e d  f o r 5 days. The excess m-chloroperoxybenzoic product m-chlorobenzoic  a c i d and i t s  a c i d were removed by washing  c e s s i v e l y w i t h 10% sodium s u l f i t e ,  suc-  s a t u r a t e d sodium carbo-  n a t e , and s a t u r a t e d sodium c h l o r i d e s o l u t i o n s . The o r g a n i c  187 s o l u t i o n was then d r i e d over anhydrous sodium s u l f a t e and evaporated under reduced p r e s s u r e . The r e s i d u e o b t a i n e d was chromatographed on s i l i c a g e l (benzene) to g i v e t r a n s 2,2-diphenyl-3-cyano-4-methylthietane a white  solid  (176) as  (0.88 gm, 52'i-.8%). No a p p r e c i a b l e amount o f  o t h e r isomer, 1,1-dioxide  1,1-dioxide  trans-2,2-diphenyl-3-methyl-4-cyanothietane  (177) was d e t e c t e d .  The i s o l a t e d product was r e c r y s t a l l i z e d  three  times from a m i x t u r e o f c h l o r o f o r m and n-pentane to g i v e a colorless crystalline (KBr) 710, 7 3 5 ,  755,  substance  (176), mp 167-2-171°; i r  774, 1450, 1498, 1600, 3030, 3060  ( p h e n y l ) , 1148, 1318 ( s u l f o n e ) , and 2260 ( n i t r i l e ) pmr (CDC1 ) 3  Si.63  (d, 3 ,  cm" ; 1  CH" , J = 6.6 H z ) , 3-78 ( d , 1, 3  CNCH, J = 10 H z ) , 4-92 (two o v e r l a p p i n g q u a r t e t s c e n t e r e d at 290.0 and 300.8 Hz r e s p e c t i v e l y , 1, SCH, J(CHCH) = 10 Hz,  J(CH CH) = 7 Hz) and 7-42 3  (m, 10, phenyl p r o t o n s ) ppm.  A n a l . C a l c d . f o r C-^H^NSO^ C, 68.66 ; H, 5-08; N, 4-71. Pound: C, 6 8 - 5 7 ;  14-  Synthesis of  H, 5-20; N, 4-84-  trans-2,2-diphenyl-3-aminomethyl-4-methyl-  thietane 1,1-dioxide  (180).  A stream o f diborane a d d i t i o n o f sodium b o r o h y d r i d e trifluoride  (0.0375 mole) generated by (3-4 gm, 0.09 mole) to boron  e t h e r a t e (25-5 gm, 0.18 mole) was s l o w l y passed  i n t o a s t i r r e d and i c e - c o o l e d  s o l u t i o n of trans-2,2-diphen-  yl-3-cyano-4-methylthietane 1,1-dioxide  (176 ) (1.37 gm,  188 0.004& mole) i n 100ml o f d r i e d  t e t r a h y d r o f u r a n . The  i n g m i x t u r e was  s t i r r e d a t room temperature  ml o f water was  added to i n a c t i v a t e  f o r 2 days,  s o l u t i o n o f 3 gm  i n 30 ml o f water was was  borane  of sodium h y d r o x i d e  added. The r e s u l t i n g b a s i c  evaporated a t room temperature  t e t r a h y d r o f u r a n . The product was  mixture  to remove most of the  e x t r a c t e d from the  i n g aqueous m i x t u r e w i t h c h l o r o f o r m . The t i o n was  the r e s u l t i n g  s t i r r e d f o r 3 days to h y d r o l y z e the  adduct. Then a c o l d  10  the excess di"borane,  20 ml of 10% h y d r o c h l o r i c a c i d f o l l o w e d and m i x t u r e was  react-  remain-  chloroform solu-  washed w i t h s a t u r a t e d sodium c h l o r i d e  solution  and  d r i e d . Removal o f the s o l v e n t from the c h l o r o f o r m e x t r a c t gave t r a n s - 2 , 2 - d i p h e n y l - 3 - a m i n o m e t h y l - 4 - m e t h y l t h i e t a n e dioxide 710,  (180) as a gummy substance  738,  760,  1450,  1500,  ( 1 . 6 9 gm);  ethanolic o f 180  i r (neat)  3030, 3060 ( p h e n y l ) , 1145,  ( s u l f o n e ) , 3320 and 3380 ( p r i m a r y amine) The p i c r a t e  s a l t was  1303  cm" . 1  p r e p a r e d by a d d i t i o n o f an  s o l u t i o n of p i c r i c a c i d to a m e t h a n o l i c  (0.1 gm).  1,1-  Upon s t a n d i n g the r e s u l t i n g  solution  solution for  one hour w i t h o u t d i s t u r b a n c e , the y e l l o w c r y s t a l l i n e p i c r a t e t h a t appeared  was  c o l l e c t e d by f i l t r a t i o n and washed  t h o r o u g h l y w i t h 50% aqueous methanol. picrate  salt  s i s , mp  168.5-170.5°;  1150,  (0.1 gm)  was  733,  V  752 ( p h e n y l ) ,  s u l f o n e ) , 1400-1650 ( n i t r o  p h e n y l ) and 2100-3300 (ammonium and C-H) 81.50 (d, 3,, C H  the  pure enough f o r e l e m e n t a l a n a l y -  i r (KBr) 710,  1200-1400 ( n i t r o and  A f t e r drying,  cm" ; 1  pmr  (DMS0-dg)  J = 7 H z ) , 2.70-4.0 (m, HCH , OH CH ?  and  and  189 4 . 8 5 (qd, 1 ,  solvent i m p u r i t i e s ) ,  (CHCH) = 9 H z ) , 7 . 0 - 7 - 7 2,  SCH, J(CH CH) = 7 Hz, J 3  (m, 1 0 , phenyl p r o t o n s ) , 8 . 6 0 ( s ,  t r i n i t r o p h e n y l p r o t o n s ) ppm.  Anal. Calcd. f o r C  2 3  H  2 ?  N4S0g;  C, 5 2 . 0 7 ;  H, 4-18;  N, 1 0 . 5 6 .  Pound: C, 52.18; H, 4 - 4 2 ; I , 1 0 . 6 l . R e c r y s t a l l i z a t i o n o f the p i c r a t e from a m i x t u r e of acetone and methanol  r e s u l t e d i n a depressed m e l t i n g  p o i n t and the appearance  o f c a r b o n y l a b s o r p t i o n i n the i r  spectrum. The 1 - a c e t y l d e r i v a t i v e was p r e p a r e d by r e a c t i n g 180  ( 0 . 1 5 gm) w i t h a c e t i c anhydride ( 0 . 5 ml) f o r 15 minutes.  The gummy substance t h a t appeared upon d i l u t i n g  the anhy-  d r i d e s o l u t i o n w i t h 10 ml o f c o o l e d water, was s e p a r a t e d by d e c a n t a t i o n o f the aqueous s o l u t i o n and then p u r i f i e d by u s i n g a s i l i c a g e l column ( 3 0 gm, e l u t e d  successively  w i t h c h l o r o f o r m and methanol). The acetamide which was i s o l a t e d as a c o l o r l e s s s o l i d was then r e c r y s t a l l i z e d  several  times from benzene to g i v e the c o l o r l e s s c r y s t a l l i n e 2,2-diphenyl-3-acetamidomethyl-4-methylthietane mp 182-185°; i r (KBr) 7 1 0 ,  7 3 8 , 7 5 8 , 1448,  ( p h e n y l ) , 1 1 4 5 , 1 3 0 0 ( s u l f o n e ) , 1 6 5 0 (amide  trans-  1,1-dioxide,  1 5 0 0 , 1 5 4 0 , 3060 c a r b o n y l ) and  3 3 3 0 (secondary amide) cm" ; pmr (CDCl^) S i . 5 2 (d, 3 , CHCH , 1  3  J = 7 Hz), 1 . 8 3 ( s , 3 , C 0 C H 3 ) , 4-10-4-60 10,  (m, 1 ,  SCH),  2.93-3-37  (m, 3 , CHCH H), 2  5 - 4 0 ( t , broad, EH), and 7 - 3 8 ( s ,  phenyl p r o t o n s ) ppm.  190 15-  S y n t h e s i s of  trans-2,2-diphenyl-3-dimethylaminomethyl-  4 - m e t h y l t h i e t a n e 1 , 1 - d i o x i d e (34)• The  crude  trans-2,2-diphenyl-3-aminomethyl-4-me-  t h y l t h i e t a n e 1,1-dioxide  (180)  (1.49 gm,  p r e p a r e d i n the p r e v i o u s experiment ml of 36.4/0 formaldehyde The r e s u l t i n g filtered.  s u l t i n g m i x t u r e was  t e r e d . The  ml of g l a c i a l  shaken i n a P a r r h y d r o g e n a t i o n f o r 11 hours, and  f i l t r a t e was  the r e s i d u e was  r o f o r m s o l u t i o n was  basified,  bottle  the s o l v e n t was  fil-  evaporat-  e x t r a c t e d w i t h c h l o r o f o r m . The  chlo-  washed w i t h s a t u r a t e d sodium c h l o r i d e  ed a t room temperature  to an o i l to which was  amount of anhydrous e t h e r to p r e c i p i t a t e A f t e r f i l t r a t i o n , J34 was 6 5 % ) which was  ace-  then c a r e f u l l y  s o l u t i o n , d r i e d over anhydrous sodium s u l f a t e and  gm,  then  of 10% p a l l a d i u m on c h a r c o a l . The r e -  50 p s i o f hydrogen  ed and  s t i r r e d f o r 10 hours and  To the f i l t r a t e were added 0.4 gm  d i s s o l v e d i n 2.5  s o l u t i o n and 80 ml of 95% e t h a n o l .  s o l u t i o n was  t i c a c i d and 0.5  at  was  0.00428 mole)  evaporat-  added a s m a l l  the crude p r o d u c t .  o b t a i n e d as a white  solid  (0.92  r a p i d l y chromatographed on n e u t r a l  mina ( c h l o r o f o r m ) to g i v e a gummy substance which was  alusoli-  d i f i e d by t r i t u r a t i o n i n a s m a l l amount of methanol and r e c r y s t a l l i z e d a t room temperature (34) was  as f o l l o w s : The  material  d i s s o l v e d i n methylene c h l o r i d e , the s o l u t i o n  was  c a r e f u l l y c o n c e n t r a t e d to a v e r y s m a l l volume i n a r o t a r y e v a p o r a t o r , a s m a l l amount o f methanol was s o l u t i o n was  set a s i d e f o r s e v e r a l hours. A  added, and  the  crystalline  191 substance which appeared  d u r i n g t h i s p e r i o d was  and t r e a t e d by r e p e a t i n g the above procedure. 34 was  712,  760,  1447, 1500,  ( p h e n y l ) , 1143,  1153  and 1293  S i . 5 8 (d, 3, CH , WCH ), 2.14 2  1600,  ( s , 6, N ( C H ) ) , 3  2  3030, 3050, 3065  ( s u l f o n e ) cm ; -1  J = 7 Hz), 2.06  3  pmr  (CDCl^)  (obscured d o u b l e t , 2,  2.74-3-33 (m,  1, MCH CH), 2  (two o v e r l a p p i n g q u a r t e t s c e n t e r e d at 257-50 and  268.25 Hz r e s p e c t i v e l y , 1, SCH, = 7 Hz) and 7-37  i g  H  2 3  2  IT,  The p i c r a t e s a l t was l u t i o n o f 34 (0.1 gm)  J(CHCH ) 3  ppm.  N S 0 : C, 69-27; H, 7-04;  Pound: C, 68.97; H, 6.77;  p i c r i c acid  J(CHCH) = 10 Hz,  (m, 10, phenyl p r o t o n s )  Anal. Calcd. f o r C  IT, 4-25-  4-10. prepared by r e a c t i n g a so-  i n a minimum amount of methanol  (0.3 ml of s a t u r a t e d e t h a n o l i c  c r y s t a l l i n e p i c r a t e was mp  Consequently  o b t a i n e d as c o l o r l e s s c r y s t a l s , rap 125•5-130,5°; i r  (KBr) 702,  4-38  collected  solution).  c o l l e c t e d and washed w i t h  with The  methanol,  184-188°.  16. S y n t h e s i s of 2 , 2 - d i p h e n y l - 3 - d i m e t h y l a m i n o m e t h y l t h i e tane (191). To a s t i r r e d thietane  (l_5_5) (2.0 gm,  t r a h y d r o f u r a n was  s o l u t i o n of  2,2-diphenyl-3-cyano-  0.008 mole) i n 60 ml o f d r i e d t e -  added 0.025 mole of b o r a n e - m e t h y l - s u l -  f i d e complex (2'ml, neat l i q u i d ,  c o n t a i n i n g about 5% methyl  s u l f i d e ) . The r e a c t i n g mixture was  s t i r r e d f o r 24 hours  and then h y d r o l y z e d f o r 20 hours by s t i r r i n g  the  solution  192 i n a m i x t u r e o f 10 ml  each of water and  d r o c h l o r i c a c i d . A f t e r evaporating f u r a n , the remaining chloroform. was  The  converted  i n t o f r e e amine by  and  760,  775,  The  1450,  ficient  1493,  solution  was  ir  (neat) 3300  amine) cm"'". -  f i l t e r e d . To  d i s s o l v e d i n anhydrous e t h e r . the f i l t r a t e was  added a s u f -  amount of e t h e r e a l s o l u t i o n of hydrogen c h l o r i d e  c o l l e c t e d and  d r i e d , weighing 0.9  ir  755,  (KBr)  710,  780,  3300 (ammonium) cm" ; + 1  and 8.15  1448,  pmr  (0.8  gm)  was  (phenyl  2100-  protons)  ppm.  palladium  o f the  hydrochlo-  on c h a r c o a l  and  unsuccessful. m e t h y l a t e d by  r e d u c t i o n method (151). d i s s o l v e d i n 2 ml  minimum amount o f e t h e r . The a cooled  then  >149° (decomp.);  ( p h e n y l ) , 1 6 0 0 and  crude h y d r o c h l o r i d e was  ed f o r m y l a t i o n and  mp  methylation  r i d e by u s i n g formaldehyde, 10%  The  gm,  1495  (NHrj, exchanged by D^0)  50 p s i of hydrogen was  s a l t , which was  (CDCl^) $7-15  Attempted c a t a l y t i c  bath,  s o l u t i o n with  (2.3 gm),  to p r e c i p i t a t e the crude h y d r o c h l o r i d e  ride  solution  3025, 3060 ( p h e n y l ) , 1600,  crude amine was  s o l u t i o n was  with  s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d ,  3360 (primary The  the  chloroform  evaporated to a p a l e y e l l o w l i q u i d  710,  extracted  shaking  hy-  tetrahydro-  i n the c h l o r o f o r m  sodium carbonate s o l u t i o n . The  and  most o f the  aqueous m i x t u r e was  hydrochloride  then washed w i t h  concentrated  The  repeat-  hydrochlo-  of f o r m i c a c i d and  s o l u t i o n was  a  c o o l e d i n an i c e  s o l u t i o n of f o r m i c - a c e t i c anhydride  prepared  193 from d r i e d f o r m i c a c i d  (5-1 ml) and a c e t i c anhydride (10  gm) (197) was added and the r e s u l t i n g mixture room temperature  s t i r r e d at  o v e r n i g h t . A f t e r e v a p o r a t i n g the e t h e r ,  the anhydride s o l u t i o n was added dropwise  i n t o an i c e -  water m i x t u r e . A gummy d e p o s i t which appeared was e x t r a c t ed w i t h c h l o r o f o r m . The c h l o r o f o r m s o l u t i o n was washed w i t h water,  d r i e d and then evaporated to a v i s c o u s l i q u i d  (0.65 gm); i r (neat) 710, 7 6 5 , 1450, 1498, 3010, 3060 ( p h e n y l ) , 1675 (amide c a r b o n y l ) , 1600 and 3300 (secondary amide) cm"'". The i r data i n d i c a t e d t h a t the p r o d u c t was a -  secondary amide. An i c e - c O o l e d s o l u t i o n o f t h i s amide (O.65  gm) i n t e t r a h y d r o f u r a n was reduced by a d d i t i o n o f  l i t h i u m aluminum h y d r i d e (0.4 gm). The m i x t u r e was s t i r r e d a t i c e temperature  f o r 6 hours. The s o l v e n t was evaporated,  the l i t h i u m aluminum h y d r i d e was i n a c t i v a t e d by sodium  sul-  f a t e s o l u t i o n and the r e s u l t i n g m i x t u r e was then e x t r a c t e d w i t h c h l o r o f o r m . Subsequent washing, d r y i n g , and evaporat i o n o f the c h l o r o f o r m s o l u t i o n r e s u l t e d i n a p a l e y e l l o w liquid  (0.5 gm); i r ( n e a t ) 710, 7 6 0 , 1450, 1495, 3025,  3060 ( p h e n y l ) , 1600, and 3310 (secondary amine) cm"" . The 1  ir  data i n d i c a t e d  t h a t the secondary amide was reduced to  a secondary ¥-methyl amine. T h i s secondary amine was f o r mylated by u s i n g the same method to g i v e a t e r t i a r y  forma-  mide (0.4 gm); i r (neat) 710, 760, 1450, 1495, 3020, 3060 ( p h e n y l ) and 1670 (amide c a r b o n y l ) cm" . Subsequent r e d u c 1  t i o n o f the t e r t i a r y amide w i t h l i t h i u m aluminum h y d r i d e  194 by employing  the above method gave a crude  amine as a p a l e y e l l o w l i q u i d 760,  1450,  1498,  The absence  1600,  (0.3 gm);  i r (neat) 710,  3030, 3060 and 3090 (phenyl)  o f the c a r b o n y l a b s o r p t i o n i n d i c a t e d  formamide was  c h l o r o f o r m ) . The i s o l a t e d l i q u i d d i s s o l v e d i n d r i e d e t h e r and s o l u t i o n o f hydrogen t a t e formed was  (neutral  substance  1  t h a t the  2  (0.2 gm)  was  ethereal  c h l o r i d e . The h y d r o c h l o r i d e p r e c i p i -  i r (KBr) 740,  760,  3060 ( p h e n y l ) , and 2200-2800 (NH) 6, N ( C H ) ) ,  alumina/  treated with a dried  c o l l e c t e d , weighing 0.1  vacuo; m p > 7 0 ° ;  3  cm" .  reduced. The crude t e r t i a r y amine was g r o s s -  l y p u r i f i e d by column chromatography  (s,  N,N-dimethyl-  2.35-3-40 (m,  gm  1498,  cm" ; 1  4 , HCH  2  a f t e r drying i n 1505,  pmr  1600,  3040,  (CDC1 )S2.73 3  and SCH" ), 4.10 2  (m,  + 1, SCH CH), 5-88 2  7-33  ( s , broad, 1, KH,  exchanged w i t h D 0)  ( s , broad, 10, phenyl).ppm. The  2  spectroscopic data  i n d i c a t e d t h a t the i s o l a t e d h y d r o c h l o r i d e s a l t was  a crude  m a t e r i a l of 2,2-diphenyl-3-dimethylaminomethylthietane drochloride  (191) • Attempts  and  hy-  to f u r t h e r p u r i f y t h i s mater-  i a l by c r y s t a l l i z a t i o n were u n s u c c e s s f u l . 17. S y n t h e s i s o f N , N - d i m e t h y l a l l y l a m i n e (200). A s t i r r e d mixture of a l l y l a m i n e mole), 90% f o r m i c a c i d aldehyde  solution  (66.8 gm,  (86 ml, 1.2  24 h o u r s . T h i r t y m i l l i l i t e r s a c i d was  (25.2 gm,  1 . 2 6 mole) and 37%  mole) was  0.30 form-  heated a t 90° f o r  of concentrated hydrochloric  added. The m i x t u r e was  c o n c e n t r a t e d under  reduced  195 p r e s s u r e to 150 ml,  then b a s i f i e d w i t h sodium  and e x t r a c t e d w i t h c h l o r o f o r m . The  carbonate,  chloroform s o l u t i o n  was  d r i e d over anhydrous sodium s u l f a t e , bubbled w i t h hydrogen c h l o r i d e to c o n v e r t the f r e e amine i n t o i t s s a l t and ly  s t r i p p e d o f f the c h l o r o f o r m by e v a p o r a t i o n . The  liquid  (31.2  gm)  s o l u t i o n o f 12 gm  was  c o o l e d (-9°)  vacuo and  residual  and b a s i f i e d w i t h a c o o l  of sodium h y d r o x i d e i n 12 ml of water.  t e r t i a r y amine ( 1 6 . 6  The  final-  gm)  was  then g r o s s l y d i s t i l l e d i n  trapped i n a f l a s k c o o l e d i n a dry  Ice-acetone  m i x t u r e . A f t e r r e p e a t e d r e d i s t i l l a t i o n a t atmospheric sure, N , N - d i m e t h y l a l l y l a m i n e less liquid mm));  pmr  (13.5  (200) was  40%), bp 6 5 - 6 6 °  gm,  (neat) £ 2 . 2 0  (s, 6,  pres-  o b t a i n e d as a c o l o r (lit.  (198) 6 4 °  (743  N ( C H ) ) , 2.80-3-08 (m, 3  2  2,  NCH ), 4-95-5-40 (m,  2, =CH ) and 5 - 5 6 - 6 . 3 0 (m, 1,  ppm.  o f t h i s amine d i d not show a b s o r p t i o n  2  The uv  a t 366  nm,  2  spectrum  the wavelength  employed to prepare  =CH)  the t h i e t a n e  d e r i v a t i v e s by p h o t o c y c l o a d d i t i o n of thiobenzophenone to olefins.  18. Attempted  p h o t o c y c l o a d d i t i o n of thiobenzophenone  to N . N - d i m e t h v l a l l y l a m i n e A mixture gm, (95) was  0.077 mole), (4-80 gm,  (200).  of N , N - d i m e t h y l a l l y l a m i n e  freshly recrystallized  0.024 mole) and  i r r a d i a t e d a t 366  nm  (200)  (8.6  thiobenzophenone  250 ml of anhydrous e t h e r  f o r 211 hours, a procedure  d e s c r i b e d i n the s y n t h e s i s of  (.9^)  being  2,2-diphenyl-3-cyanothietane  196 (155) • A sample o f the d e c o l o r i z e d  s o l u t i o n ( 5 0 ml) was  evaporated to an o i l (1.48 gm). A n a l y s i s chromatography  by t h i n l a y e r  ( n e u t r a l alumina, c h l o r o f o r m ) i n d i c a t e d the  presence o f a t l e a s t seven components. Attempts  to prepare  a p i c r a t e d e r i v a t i v e o r to s e p a r a t e the d i f f e r e n t components by u s i n g column chromatography  method were unsuc-  c e s s f u l . A white s o l i d was o b t a i n e d when H G l - e t h e r was added to an e t h e r e a l >91°  s o l u t i o n o f the above crude o i l , mp  (decomp.). The pmr spectrum  showed t h a t  the m a t e r i a l  was n o t the expected p r o d u c t . O x i d a t i o n o f the crude phot o a d d i t i o n products with m-chloroperoxybenzoic  a c i d gave a  crude m i x t u r e e x h i b i t i n g c a r b o n y l and s u l f o n y l a b s o r p t i o n In the i r spectrum.  19•  S y n t h e s i s o f ft-chloroethane s u l f o n y l c h l o r i d e  (212).  The method used was taken from a p a t e n t (152). T h i r t y - o n e m i l l i l i t e r s (47 gm) o f c h l o r i n e was c o l l e c t e d i n a graduated c y l i n d e r c o o l e d a t -80°. The y e l l o w c h l o r i n e l i q u i d was s l o w l y b o i l e d a t about - 3 0 ° , and the c h l o r i n e vapor was passed i n t o a s t i r r e d t i o n o f |3-mercaptoethanol dichloroethane  solu-  gm, 0.213 mole) i n 1,2-  (30 gm). A f t e r 13 ml o f c h l o r i n e had been  passed i n t o the t h i o l dropwise  (16.6  and i c e - c o o l e d  s o l u t i o n , 4 ml o f water was added  to the r e a c t i n g m i x t u r e s i m u l t a n e o u s l y . When the  t r a n s f e r o f the r e m a i n i n g c h l o r i n e was completed,  the ex-  c e s s i v e h a l o g e n i n the r e a c t i n g mixture was e x p e l l e d  with  197 a stream of n i t r o g e n . A small amount of l i q u i d that separated  from the mother l i q u i d was  t h e r s o l u t i o n was filtered  and  (212). bp  gm  The  (84%)  (21 gm)  (chloro), II65 4.40  (m,  bp  and  (lit.  20. R e a c t i o n  mole) and  distill-  (29 gm)  (1-2 mm);  94%).  gave a c o l o r l e s s  mm),  i r (neat) 670, 1  pmr  (neat) 8 3-75-  and  (213)-  of /a-dime t h y l amino s t y r e n e  mole), p u r i f i e d  t r i e t h y l a m i n e (3.02  (213) gm,  of d r i e d e t h e r v;as s t i r r e d and  a dry i c e - a c e t o n e  (2.21  0.03  cooled i n  bath at -80°, a s o l u t i o n o f 2-45  gm  (0,015 mole) of / 8 - c h l o r o e t h a n e s u l f o n y l c h l o r i d e (212) 20 ml was  o f d r i e d e t h e r was  allowed  to proceed  added dropwise and  r e s u l t i n g mixture  r e t u r n to room temperature and s o l i d m a t e r i a l which was  e a l s o l u t i o n was  the r e a c t i o n  filtered  was  allowed  to  to g i v e a white  i d e n t i f i e d as t r i e t h y l a m i n e hy-  f i l t r a t e was  y e l l o w mass, 10 ml  in  f o r l i hours d u r i n g which a white  p r e c i p i t a t e appeared. The  d r o c h l o r i d e . The  li710  o f / 3 - c h l o r o e t h a n e s u l f o n y l c h l o r i d e (212)  20 ml  .  ppm.  2  . A mixture 0.015  80°  ( s u l f o n y l ) cm" ;  @-dimethylaminostyrene  gm,  (152)  40.5° (0.01  1370  CH CH S) 2  mo-  of /5-chloroethane s u l f o n y l c h l o r i d e  52-54° (0.2 mm)  (212)  removed. The  r e s u l t i n g r e s i d u e was  R e d i s t i l l a t i o n o f the product quid  ml)  d r i e d over anhydrous sodium s u l f a t e ,  evaporated.  ed to g i v e 29.2  (ca. 2  evaporated  o f d r i e d e t h e r was  c h i l l e d y i e l d i n g 1.1  to a brownish  added and gm  the  of s o l i d .  etherThe  198 pmr spectrum showed t h a t i t c o n t a i n e d f o n y l )-$-dimethylamino styrene  semi-solid  c a l c u l a t e d y i e l d o f the t o t a l  r i d e obtained ed  was q u a n t i t a t i v e  amount  The f i l t r a t e was e v a p o r a t (1.44 gm). I n f r a r e d an-  a l y s i s i n d i c a t e d that t h i s m a t e r i a l The  7  (218) and a l i t t l e  of t r i e t h y l a m i n e hydrochloride. ed to a "brownish y e l l o w  m a i n l y o /-(vinyl s u l -  contained  m a i n l y 218.  triethylamine  hydrochlo-  (0.03 mole). T h i s i n d i c a t -  t h a t one mole o f (5-chloro ethane s u l f o n y l c h l o r i d e was  dechlorinated  "by two moles o f t r i e t h y l a m i n e  and the e x p e c t -  ed c y c l i c p r o d u c t was n o t produced. The eal  crude 218  was d i s s o l v e d i n e t h e r ,  the e t h e r -  s o l u t i o n was washed s u c c e s s i v e l y w i t h sodium carbonate  s o l u t i o n and water. The s o l v e n t was evaporated and the r e sidue was r e c r y s t a l l i z e d f o u r times from anhydrous to g i v e  the pure 218  as c o l o r l e s s l e a f l e t  c r y s t a l s , mp  102-105°; i r (KBr) 722, 740, 1448, 1500 ( p h e n y l ) , 1258 ( v i n y l GE"), 855, 958, 970, 990, 1 6 2 0 ,  ether  1185,  3035, 3065 (dou-  b l e bond), 1120, 1135.and 1300 ( s u l f o n e ) cm" ; 1  pmr  (CDCl^)  S 2 . 6 8 ( s , 6, E ( G H ) ) , 5.50-6.80 (m, 3, CHCHg), 7-33 ( s , 3  2  5, p h e n y l ) and 7-37 ( s , 1, ECH) Anal.  Calcd.  ppm.  f o r Cj- -H N0 S: C, 60.73; H, 6.37; E, 5-90. 2  15  2  Found: C, 60.73; H, 6.29; E, 5-86. The r i n e was  sodium f u s i o n t e s t f o r the presence o f c h l o -  negative. R e p e a t i n g the experiment by u s i n g an equimolar  amount o f t r i e t h y l a m i n e  a t temperature o f -80, 0, o r 25°  199 a l s o r e s u l t e d i n the i s o l a t i o n o f 218. No a p p r e c i a b l e amount o f c y c l i z a t i o n product mixture  Addition of a  o f t r i e t h y l a m i n e and 213 t o the s o l u t i o n o f 212,  a r e v e r s e d a d d i t i o n procedure,  21.  was observed.  a l s o gave same r e s u l t s .  S y n t h e s i s o f methyl p r o p a r g y l e t h e r  (217)•  Methyl p r o p a r g y l e t h e r was s y n t h e s i z e d to  a method taken from l i t e r a t u r e  according  (157). A mixture  of r e -  d i s t i l l e d p r o p a r g y l a l c o h o l (89 gm, 1.59 mole), 71 ml o f water and 176 gm o f 50% (w/v) aqueous sodium hydroxide sol u t i o n was heated gm o f d i m e t h y l  a t 40°. The s o l u t i o n was s t i r r e d and 120  sulfate  (120 gm, 0.95 mole) was added i n  s l o w l y so t h a t the temperature o f the s o l u t i o n was maint a i n e d below 60°. hours, 57-9  The mixture  was heated  a t 50-60° f o r 2  and then d i s t i l l e d a t atmospheric p r e s s u r e  gm  ( 6 1 % )  o f methyl p r o p a r g y l e t h e r  (217). bp  to g i v e 60-61.5°;  pmr ( n e a t ) 8 2 . 6 2 ( t , 1, CH, J = 2.5 H z ) , 3-33 ( s , 3, C H ) , 3  and  22.  4.14 (d, 2, CH , J = 2.5 Hz) ppm. 2  S y n t h e s i s . o f methoxyallene  (113).  M e t h o x y a l l e n e (113) was prepared  a c c o r d i n g to  the method d e s c r i b e d by H o f f et a l . (156). A mixture o f methyl p r o p a r g y l e t h e r sium t - b u t o x i d e  (217) (52 gm, 0.866 mole) and p o t a s -  (7-15 gm, prepared  c o h o l and potassium i n vacuo) was heated  and e v a p o r a t i n g  by r e f l u x i n g  t-butyl a l -  the e x c e s s i v e a l c o h o l  a t 70° f o r two hours.  The mixture  was  200 distilled  a t atmospheric p r e s s u r e to g i v e 32.5  methoxyallene (113), hp 50.8-51.5°; pmr 3, C H ) , 3  5-00  J = 5.5 Hz)  23.  (d, 2, CH , 2  gm  (63%) o f  (neat) £2.93 ( s ,  J = 5.5 Hz), and 6.30  ( t , 1,  GH,  ppm.  Synthesis of  2,2-diphenyl-3-methoxy-4-methylenethie-  tane (114)• A v e r y b r i e f note taken from l i t e r a t u r e  (134a)  was used as a r e f e r e n c e . F r e s h l y r e c r y s t a l l i z e d t h i o b e n z o phenone (95) (5 gm, (113) (7.2 gm,  0.025 mole) and p u r i f i e d methoxyallene  0.1 mole) were d i s s o l v e d I n 280 ml o f anhy-  drous e t h e r r e a g e n t . The b l u e c o l o r o f  thiobenzophenone  c o m p l e t e l y d i s a p p e a r e d w i t h i n 3^- hours a t room temperature. The s o l v e n t was removed by e v a p o r a t i o n . To the o i l y due was  added about 100 ml o f ether-n-pentane s o l u t i o n (2:  3) and the r e s u l t i n g p r e c i p i t a t e s was  filtered  methoxymethylene-6-phenyl-benzo(d)thiane yellow s o l i d  (>3-5  gm, ^>50%) ( l i t .  (CDC1 ) S3-42 ( s , 2, C H ) , 3  CHS), ppm.  resi-  2  6.15  ( s , 1, CH0)  The pmr  3.60  to g i v e  2-  (115 ) as a p a l e  (134a) 15-20%):  ( s , 3, 0 C H ) , 5-31 3  pmr ( s , 1,  and 7-1-7.6 (m, 9, phenyl p r o t o n s )  d a t a was i d e n t i c a l  to t h a t r e p o r t e d i n the  literature. The f i l t r a t e was  evaporated to a s e m i - s o l i d . Ana-  l y s i s by u s i n g t h i n l a y e r chromatography  method  (neutral  alumina; GCl^) i n d i c a t e d the presence of two major components and some i m p u r i t i e s . One major component was  benzo-  201 t h i a n e 115, thietane  another was  2,2-diphenyl-3-methoxy-4-methylene-  (114)• The prar spectrum  (CDCl^) o f t h i s mixture  showed that i n a d d i t i o n to the s i g n a l s accounted f o r "by 115 and o t h e r i m p u r i t i e s ,  s i g n a l s a t 8 3*33 ( s ) , 4«98 ( t , s p l i t -  t i n g = 2.5)  (m) ppm  t u r e pmr  and 5 • 38  d a t a of 114  J = 2.3 Hz), 5-24  (lit.  were comparable  (134)  ( C C l ^ ) 3-21  ( t , J = 2.3 Hz), and 5-35  to the  litera-  ( s ) , 4-91 ( t , ( t , J = 2.2  Hz)  ppm). An experiment was r e a c t i o n o f 113  and 95 was  c a r r i e d out to prove t h a t  the  a thermal r e a c t i o n : A 50-ml so-  l u t i o n o f 95. (0.1 M) i n d r i e d and t h i o p h e n e - f r e e benzene was  tightly  num  foil  s e a l e d w i t h a rubber septum, wrapped i n a l u m i -  and p l a c e d i n a dark p l a c e to p r o t e c t  from l i g h t . M e t h o x y a l l e n e sured i n a s y r i n g e was then shaked  (113)  (1.44 gm,  0.02  the  solution  mole) mea-  i n j e c t e d i n t o the s o l u t i o n which  was  t h o r o u g h l y . The b l u e c o l o r d i s a p p e a r e d w i t h i n  1-g- hours and the s o l u t i o n became y e l l o w . T i c a n a l y s i s  Indi-  c a t e d t h a t the p r o d u c t s were the same as o b t a i n e d above. I n another experiment,  two pyrex f l a s k s each  con-  t a i n i n g 100-ml o f a s o l u t i o n o f 95. (0.1 M) i n t h i o p h e n e f r e e benzene were s e a l e d w i t h r u b b e r septa and p l a c e d i n a dark hood. A f t e r a d d i t i o n of 113  (2.88 gm,  0.01  mole),  s o l u t i o n s were immediately i r r a d i a t e d w i t h uv l i g h t r a t e d from a medium p r e s s u r e mercury through a 3% potassium dichromate  a r c (450 W)  the  gene-  filtered  s o l u t i o n . The b l u e c o l o r  o f the r e a c t i n g mixture remained v e r y i n t e n s e a f t e r 20 mi-  202 n u t e s of i r r a d i a t i o n , but hours. T h i s was a c t i o n was  completely  incompatible  disappeared  by 1-g-  wi-th the r e p o r t t h a t the r e -  complete d u r i n g 20 minutes of i r r a d i a t i o n  A n a l y s i s by u s i n g presence of the  t h i n l a y e r chromatography i n d i c a t e d the  same p r o d u c t s  y i e l d s o f b e n z o t h i a n e 115 The  and  and work up thietane  i s o l a t e d benzothiane 115  gave comparable  114. was  not  stable at  room temperature. T i c a n a l y s i s i n d i c a t e d t h a t 115 p l e t e l y decomposed upon e v a p o r a t i n g (about  10 mg)  i n chloroform  (1 ml)  h o u r s . Attempts to p u r i f y 115 phy  was  a s o l u t i o n of  d u r i n g a p e r i o d of  phy was  (114)  isola-  appreciable  recovered.  Attempts to i s o l a t e thylenethietane  24  by u s i n g column chromatogra-  t i o n o f s e v e r a l u n i d e n t i f e d m a t e r i a l s . Wo c o u l d be  com-  115  ( n e u t r a l alumina or s i l i c a g e l ) r e s u l t e d i n the  amount o f 115  (134a).  2,2-diphenyl-3-methoxy-4-me-  by u s i n g l i q u i d  column chromatogra-  a l s o u n s u c c e s s f u l . Repeated chromatography of 1  of m i x t u r e c o n t a i n i n g 114 tography method (158)  by employing Dry  gm  Column Chroma-  ( n e u t r a l alumina c o n t a i n i n g 4-5%  wa-  t e r ; benzene or C C l ^ used as s o l v e n t ) r e s u l t e d i n i s o l a t i o n of o n l y a s m a l l amount of crude 114 s t a b i l i t y o f both 114 i s o l a t i o n of the  24-  and  115  (about  20 mg).  The i n -  caused the d i f f i c u l t y i n the  former.  Attempted h y d r o x y l a t i o n o f 2 , 4 - d i p h e n y l t h i e t e dioxide  (227)  with  sodium h y d r o x i d e .  Isolation  1,1of  203 dibenzylsulfone  (234)•  To a s t i r r e d m i x t u r e o f 2 , 4 - d i p h e n y l t h i e t e 1,1dioxide 10 ml  ( 0 . 5 gm,  (227)  0.002 mole) (84), 3 ml o f ¥/ater and  o f d i m e t h y l s u l f o x i d e , was  added a s o l u t i o n o f 1  gm  o f sodium h y d r o x i d e i n 20 ml o f 50% aqueous d i m e t h y l s u l f oxide s o l u t i o n . The r e s u l t i n g g r e e n i s h s o l u t i o n was f o r 5 hours and  r e d a t room temperature  r e f r i g e r a t o r f o r 3 days i n an attempt  stir-  then c o o l e d i n the  to i n d u c e  crystalli-  z a t i o n o f the d e s i r e d 2 , 4 - d i p h e n y l - 3 - h y d r o x y t h i e t a n e dioxide  (£35).  When s o l i d  then d i l u t e d w i t h 75  was  ether  (150 m l ) . The  failed ml  to s e p a r a t e , the  of water  ethereal  ( 0 . 4 gm).  s o l u t i o n was  separated, d r i e d evaporated to  R e c r y s t a l l i z a t i o n from a .  m i x t u r e o f e t h e r and n-pentane gave c o l o r l e s s c r y s t a l s , mp 1498,  1604,  cm" ;  pmr  1  y l ) ppm.  148-152°;  3  The  i r and mp  r a t u r e d a t a (198, 199) was  i r (KBr) 706,  3028, 3058 ( p h e n y l ) , 1135  ( C D C 1 ) 5 4-10  716,  needle-like  738,  and 1308  ( s , 4, C H ) a n d 7 - 4  770,  1458,  (sulfone)  ( s , 10,  phen-  d a t a were i n a c c o r d w i t h the  lite-  2  :  of d i b e n z y l s u l f o n e  (£31).  The  yield  81%. Repeating  the experiment  a t room temperature  16 h o u r s w i t h o u t r e f r i g e r a t i o n r e s u l t e d i n the o f the same p r o d u c t .  25.  solution  and e x t r a c t e d w i t h  over anhydrous sodium s u l f a t e and f i n a l l y give a yellow s o l i d  1,1-  R e a c t i o n o f 2 , 4 - d i p h e n y l t h i e t e , 1,1-di-r-  for  isolation  204 oxide  (227) w i t h " s u l f u r i c  acid.  of  Isolation  diphenyl-1,2-rOxathiacyclopenta-3-ene  2-oxide  3,5(.243,  244). 2,4-Diphenylthiete 1 , 1 - d i o x i d e 0.0039 m o l e )  w a s d i s s o l v e d i n 15 m l o f  (-5°) c o n c e n t r a t e d lution  was added  sulfuric acid.  dropwise  into  tation. and  d i l u t i o n of  The d e c a n t e d  the e t h e r e a l  More e t h e r ly.  was a d d e d  The e t h e r e a l  sodium  sulfate  to d i s s o l v e  material  data  indicated that  the b e n z y l i c  ponents lica  were  2-oxide  ether  to t h e p r e c i p i t a t e .  dried  over  complete-  anhydrous  reduced pressure  to  The i r , p m r a n d t i c of  t w o ••  3,t-5-diphenyl-l,r-2-  the s i g n a l s  i n t h e pmr s p e c t r a .  separated by u s i n g  attributed  These t w o  column chromatography  and r e c r y s t a l l i z e d from  oxide  ( 2 4 3 ) : mp 129-131°;  1495,  1600  i r  com( s i -  anhydrous  3,cs-5-diphenyl-l,r-2-oxathiacyclopenta-3-ene  (sulfinate)  decan-  (244) ( 4 0 . 4 % ) . The p e r c e n -  on the b a s i s of  protons  (phenyl),  that  3,£-5-diphenyl-l,r-2-oxathiacyclopen-  g e l , chloroform)  ether:  under  (243) (59-6%) a n d  was determined  stir-  with  the p r e c i p i t a t e  (1 g m , 100%).  oxathiacyclopenta-3-ene  to  was e x t r a c t e d  t h i s m a t e r i a l was a m i x t u r e  isomeric s u l f i n a t e s , 2-oxide  while  was s e p a r a t e d by  was r e t u r n e d  and evaporated  a solid  tage  the a c i d  s o l u t i o n was then  give  ta-3-ene  The r e s u l t i n g "brown s o -  The white p r e c i p i t a t e  supernatant  extract  s t i r r e d and cooled  150 m l o f w a t e r  r e d a n d c o o l e d i n an i c e h a t h . appeared upon  (£27) (1.0 g m ,  2-  (KBr) 710, 748, 768, 1450,  1630, 3035, 3060, 3070  c m " 1 ; p m r (CDC1.J 5 6.39  (C=C) a n d 1125  ( d , 1, S-0-CH, J = 2  205 Hz),  6.73  mass  (d, 1 ,  spect.  Anal.  m/e  Calcd.  Pound:  C,  =CH;  J  208  for  ^  70.12;  H,  1  =2  Hz),  7-48  (m,  10,  phenyl)  ppm;  +  (M-SO). ^ ?  2  0  S  4-64;  C,  :  70.28;  H,  4-72;  S,  12.50,  12-51-  S,  3 ,_t-5.-Diphenyl-l ,r-2-oxathiacyclopenta-3-ene oxide  (244):  1450,  1495,  mp 1 3 0 - 1 3 2 ° ; 1600  (phenyl'),  (sulfinate)  cm"1;  6.90  S-O-CH,  (s,  1,  i r  pmr J  (KBr)  1630,  705,  3030,  735, 3060  (CDCl^)S6,80  (d,  1,  =  (m,  10,  2 Hz),  7-50  745,  2770,  (C=C), =CH,  J  1125 = 2  phenyl)  Hz),  ppm;  + mass  spect,  Anal.  m/e  Calcd.  Pound:  C,  "both  C  70.17;  H,  In  similar  two  In  solved -7°C  in  and  slightly bonate.  A  mixture  the one  1 2  diluted brown The  0.2  the  was  reduced spectra  same  4-72;  0°  227  and  at  gm  room  S,  12.50.  acid  ml)  absolute  filtered,  pressure showed  and  that  was u s e d of 227  was  with the  the  this  with  obtained.  dis-  yellow residue  to  The  sodium  residue  as  cooled  ethanol.  was n e u t r a l i z e d then  were  mole)  (2  reacted  temperature.  ethanol  (0.00078  of  was  sulfinates  absolute  ml  bicar-  filtrate dried was  in  a  sulfinates.  concentration  r e a c t i o n was  at  sulfuric 15  H,  experiments,  isomeric  of  with  70,28; 12.51-  experiment,  mixture under  C,  S,  acid  solution  Infrared of  02S:  4-78;  same  solution  The the  H  concentrated  evaporated vacuo.  1 5  sulfuric  cases  diluent.  (M-SO).  for  concentrated In  208  of  investigated.  sulfuric  acid required  2,4-Diphenylthiete  for  1,1-di-  206 oxide  (£27) was s o l u b l e i n the c o n c e n t r a t e d but n o t the  dilute  s u l f u r i c a c i d . T h e r e f o r e a s u s p e n s i o n was used.  S t i r r i n g a suspension o f (227) i n 70% (w/w) s u l f u r i c f o r 22 hours o r h e a t i n g the mixture  acid  a t 50° f o r one hour  r e s u l t e d i n the r e c o v e r y o f the s t a r t i n g m a t e r i a l . A g a i n no r e a c t i o n was observed when 227 was d i s s o l v e d i n a mixt u r e c o n t a i n i n g o r g a n i c s o l v e n t (acetone o r benzene) and 60% o r 70% aqueous s u l f u r i c  acid.  No r e a c t i o n was observed when 2 - p h e n y l t h i e t e 1,1-dioxide dioxide  (272) (85) o r 2 - p h e n y l - 4 - m e t h y l t h i e t e  (273) (85) was t r e a t e d w i t h c o n c e n t r a t e d  a c i d . H e a t i n g a mixture 272  at  50-60°  of concentrated  1,1sulfuric  s u l f u r i c a c i d and  f o r ^ hour a l s o r e s u l t e d i n r e c o v e r y o f un-  changed s t a r t i n g m a t e r i a l .  26.  Attempted h y d r o b o r a t i o n o f 2 , 4 - d i p h e n y l t h i e t e 1,1dioxide  (227).  A s o l u t i o n o f 222 (0.5 gm, 0.002 mole) i n 25 ml of d r i e d  t e t r a h y d r o f u r a n was c o o l e d i n an i c e b a t h ,  swept  w i t h d r i e d n i t r o g e n and t r e a t e d w i t h 0.012 mole o f d i borane i n 20 ml o f d r i e d t e t r a h y d r o f u r a n . The r e s u l t i n g mixture was swept w i t h d r i e d n i t r o g e n , stoppered and then s t i r r e d o v e r n i g h t . The excess diborane was c a r e f u l l y t r o y e d by adding 5 ml o f water and 3 ml o f chromic  des-  acid  ( p r e p a r e d by d i s s o l v i n g 5-5 gm o f sodium dichromate. i n a mixture  o f 4-2 ml c o n c e n t r a t e d  s u l f u r i c a c i d and 24 ml o f  207 water) was  added i n . The r e a c t i o n m i x t u r e was  a steam b a t h f o r ^ hour and the s o l v e n t was p o r a t i o n . The r e s i d u e was c h l o r o f o r m s o l u t i o n was  (0.15  gm,  73%)  The i r spectrum  t h a t appeared indicated  e t h e r e a l f i l t r a t e was  was  added and  evaporated  27-  solid  unchanged 227•  a crude m i x t u r e and o t h e r  substances.  detected.  2 , 2 - D i c h l o r o p h e n y l a c e t y l c h l o r i d e was a c c o r d i n g to a method adopted  and p h e n y l a c e t y l c h l o r i d e  (209 gm,  I.36  gm,  140° f o r 3.6 hours. The r e s u l t i n g m i x t u r e was  at  73-76°  a c t i o n by-product. i n vacuo to y i e l d  gm  gm  2.72  (85%) o f 282,  mole)  refluxed  distilled  of phosphorous t r i c h l o r i d e ,  The r e s i d u a l l i q u i d was 262  (117).  mole) was  at  (282).  prepared  from the l i t e r a t u r e  o f phosphorous p e n t a c h l o r i d e (567  to g i v e 311  The  of s e v e r a l  S y n t h e s i s of 2 , 2 - d i c h l o r o p h e n y l a c e t y l c h l o r i d e  A mixture  of  to an o i l y l i q u i d . T i c  components, c o n t a i n i n g u n r e a c t e d 227 d e s i r e d p r o d u c t was  the  gm  an-  c o l l e c t e d by f i l t r a t i o n .  that I t was  and i r d a t a showed t h a t i t was  ¥0  to g i v e 0.4  eva-  The  washed w i t h water, d r i e d over  A s m a l l amount of e t h e r was  on  removed by  extracted with chloroform.  hydrous sodium s u l f a t e and evaporated liquid.  refluxed  a re-  then d i s t i l l e d  bp 110-115° ( 8  mm)  (lit.  (117) 102-105° (6.5-7 mm);  28.  S y n t h e s i s of E , N - d i e t h y l - 2 , 2 - d i c h l o r o p h e n y l a c e t a m i d e  90%).  (283). N,N-diethyl-2,2-dichlorophenylacetamide  (283)  208 was  s y n t h e s i z e d a c c o r d i n g to a known method (117). To  a  s t i r r e d and i c e - c o o l e d s o l u t i o n of 2 , 2 - d i c h l o r o p h e n y l acetyl chloride  (254 gm,  benzene, d i e t h y l a m i n e  1.14  mole) i n one l i t e r  (170 gm,  2.36  mole) was  of d r i e d  introduced  dropwise from a p r e s s u r e - e q u a l i z i n g a d d i t i o n f u n n e l . A f t e r s t i r r i n g a t i c e temperature filtered  and  evaporated  o v e r n i g h t , the s o l u t i o n  to g i v e a y e l l o w l i q u i d which  d i s t i l l e d i n vacuo t o y i e l d 2 5 1 gm (0.05 1665  mm)  29.  (85%) o f 283,  ( l i t . (117) 142-144° (1-3 mm);  (carbonyl)  was  bp  was  120°  50%); i r (neat)  cm . -1  S y n t h e s i s of N,E-die t h y l -  fi-dichloro-fi-styrylamine  (284). The method was A mixture (52 gm, mole),  adopted  mole) and  under a stream  t r i - n - b u t y l p h o s p h i n e ( 4 1 gm, o f d r i e d n i t r o g e n , was  a steam b a t h f o r one hour. The  0.04  mm)  the l i t e r a t u r e  (117).  of N,N-diethyl-2,2-dichlorophenylacetamide  0.2  distilled  from  i n vacuo. The was  (283) 0.2  heated  s l i g h t l y brown l i q u i d  .  on was  f r a c t i o n b o i l i n g a t 103-106° (  c o l l e c t e d . R e d i s t i l l a t i o n of t h i s crude  pro-  duct gave a c o l o r l e s s p r o d u c t  (284) bp 81-83° (0.03  (lit.  i r (neat) absence of c a r -  (117)  90-92° (0.1 mm));  mm)  bonyl absorption.  30.  S y n t h e s i s of N,E"-diethylphenylethynylamine The p r e p a r a t i o n o f the t i t l e  compound  c a r r i e d out a c c o r d i n g to a known procedure  (285). was  (179). B u t y l  209 lithium  (0.14 mole) I n 82 ml of d r i e d benzene was  stirred  under a stream of d r i e d n i t r o g e n and c o o l e d to - 1 0 ° . A  so-  l u t i o n of E,N-diethyl-o(,P-dichloro-/i-styrylamine  (30  gm,  0.125  mole) i n 18 ml  of d r i e d benzene was  (284)  added  drop-  wise from a stoppered p r e s s u r e - e q u a l i z i n g d r o p p i n g f u n n e l , the temperature at -10".  of the r e a c t i n g m i x t u r e b e i n g m a i n t a i n e d  A f t e r the a d d i t i o n had been completed,  i n g m i x t u r e was  p l a c e d a t room temperature  one more hour. The brown t u r b i d mixture was the supernatant was and  the s o l u t i o n was  and  the r e a c t stirred for  centrifuged,  s e p a r a t e d w i t h the a i d o f more benzene evaporated under reduced p r e s s u r e to  a brown l i q u i d . P u r i f i c a t i o n by vacuum d i s t i l l a t i o n ed 13-3 75°  gm  (72%) of pure 285,  (0.2 mm),  85%); i r (neat) 698,  ( p h e n y l ) and 2210 6, CH , 3  7-45  31.  (m,  bp 78° (0.03 mm)  1  (q, 4, CH ,  5, phenyl p r o t o n s )  2  (lit.  (179)  7 6 5 , 1 4 4 0 , 1 5 8 0 , 3050  ( a c e t y l e n e ) cm"""; pmr  J = 7 H z ) , 2.82  yield-  (neat) 8 1 . 1 6 ( t ,  J = 7 Hz) and  6.98-  ppm.  S y n t h e s i s o f 2 , 4 - d i p h e n y l - 3 - d i e t h y l a m i n o t h i e t e 1,1dioxide  (231).  T h i s compound was  p r e p a r e d a c c o r d i n g to a p r o c e -  dure taken from the l i t e r a t u r e sulfonyl chloride a c e t o n i t r i l e was  (0.57 gm,  0.003 mole) i n 10 ml of d r i e d  added dropwise  ed m i x t u r e of t r i e t h y l a m i n e  (200). A s o l u t i o n o f b e n z y l -  to a s t i r r e d and  (0.39 gm,  e t h y l p h e n y l e t h y n y l amine (0.51 gm,  ice-cool-  0.003 mole),  l,N-di-  0.003 mole) and 30 ml  of  210 d r i e d a c e t o n i t r i l e . The r e s u l t i n g s o l u t i o n was the i c e bath f o r 18 hours, r e s i d u e which was  evaporated  duct which was 0.4  gm  (KBr) 720,  ( 2 3 1 ) , mp 780,  790,  gm  142-144° ( l i t . 1470,  1505,  (56%) o f s o l i d  (q, 4, 0H , 2  and 7-15-7.65 (m,  32.  Attempted h y d r o l y s i s of t h i e t e 1,1-dioxide  pro-  (185) 143-144°); i r  (CDCl^)8 0.85  J = 7 Hz), 5-73  10, p h e n y l )  of s u l f o n i c a c i d r e s i n The  ( t , 6, ( s , 1,  2,4-diphenyl-3-diethylamino-  (231).  d i e t h y l a m i n o t h i e t e 1,1-dioxide  r e d f o r 3 hours.  1130  ppm.  A suspension o f w a t e r - i n s o l u b l e  gm  fil-  3070 ( p h e n y l ) , 1165, pmr  1  SCH),  2.5  The  2,4-diphenyl-3-diethylaminothiete  (enamine) cm" ;  J = 7 Hz), 3.03  3  to a  r e c r y s t a l l i z e d from e t h y l a c e t a t e to y i e l d  ( s u l f o n e ) , 1625 CH ,  removed by f i l t r a t i o n .  to g i v e 0.55  of c r y s t a l l i n e  1,1-dioxide  evaporated  r e d i s s o l v e d i n t e t r a h y d r o f u r a n . The i n -  s o l u b l e h y d r o c h l o r i d e was t r a t e was  f i l t e r e d and  stirred i n  2,4-diphenyl-3-  (.231.), 5 ml  o f water and  (BI0-RAD AG50W-X8) was  r e s u l t i n g aqueous m i x t u r e was  stir-  ex-  t r a c t e d w i t h c h l o r o f o r m . E v a p o r a t i o n of the c h l o r o f o r m  so-  l u t i o n r e s u l t e d i n q u a n t i t a t i v e r e c o v e r y o f the unchanged 231. Repeating  the experiment  by u s i n g A m b e r l i t e  120  r e s i n gave the same r e s u l t . I n one of acetone  and  experiment  231 was  d i s s o l v e d i n a mixture  5% h y d r o c h l o r i c a c i d . The  s o l u t i o n was  re-  211 f l u x e d on a steam b a t h f o r three hours and a s i d e a t room temperature  f o r three weeks. ¥/ork-up a l s o  r e s u l t e d i n the r e c o v e r y o f unchanged  231.  2,4-Diphenyl-3-diethylaminothiete (231) was  then p l a c e d  1,1-dioxide  a l s o r e c o v e r e d unchanged from a c o n c e n t r a t e d  h y d r o c h l o r i c a c i d suspension a f t e r s t i r r i n g  at room tem-  p e r a t u r e f o r one week, or from a s o l u t i o n made of concent r a t e d h y d r o c h l o r i c a c i d and a minimum amount of  acetone.  212 BIBLIOGRAPHY  1.  G.P. Blane and A.L. Boura, Br. J . Pharmacol., 26, 307 (1966).  2.  G.P. Blane, A.L. Boura, A.E. F i t z g e r a l d and R.E. L i s t e r , B r . J . Pharmacol., 30, 11 (1967).  3-  G.F. Blane and D.S. Robbie, Br. J . Pharmacol., 39. 252P (1970).  4-  A. 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