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3-Amino-2-phenylthietanes as potential MAO inhibitors Kang, Gun-Il 1977

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3-AMINO-2-PHENYLTHIETANES AS POTENTIAL MAO INHIBITORS  by Gun-II Kang M.Sc.  Seoul National University, Seoul, Korea, 1972  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Division of Medicinal Chemistry of the Faculty of Pharmaceutical Sciences  We accept . this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA April, 1977  In p r e s e n t i n g t h i s  thesis  an advanced degree at  further  agree  fulfilment  of  the  requirements  the U n i v e r s i t y of B r i t i s h Columbia, I agree  the L i b r a r y s h a l l make it I  in p a r t i a l  freely  available  for  t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f  of  this  representatives. thesis for  It  financial  this  thesis  The  of  gain s h a l l not  Pharmaceutical Sciences  U n i v e r s i t y o f B r i t i s h Columbia  2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 A p r i l 14, 1411  or  i s understood that copying or p u b l i c a t i o n  written permission.  Department  that  reference and study.  f o r s c h o l a r l y purposes may be granted by the Head of my Department by h i s  for  be allowed without my  ii  ABSTRACT  3-Amino-2-phenylthietane as  a useful  MAO  by  tool  to  elucidate  tranylcypromine-type  amino-2-phenylthietanes point for  of  view  s i n c e no  this  type  of  It  was  the  derivatives. serine with 3-ol.  inhibitors.  appeared  that  with  the  alkali  s y n t h e s i s of  3  P h e n y l s e r i n o l was  ethylester  thionyl  using  chloride  Further  mechanism  of  The  worthwhile  successful  considered  for  the  were  considered inhibition  of  s y n t h e s i s of  3-  from  p r e p a r a t i o n has  the  synthetic  been  reported  compound.  3 - d i h a l ogeno a l k a n e s effect ive  derivatives  chlorination  sulfide  between would  be  suitable the  1,  most  —amino—2—phenylthietane prepared  NaBH^.  gave  reaction  by  Treatment  reducing  of  phenyl-  phenylserino1  l-phenyl-l-chloro-2-aminopropaneof  the  3-hydroxyl  group  was  not  successful . Attempts phenylthietane  were  performed  via  l-phenyl-l-thiocyanato-2-aminopropane-  3-ol  intermediate.  3-ol  was  3-ol  with  3-ol  was  obtained  synthesize  3-amino-2-  1-Phenyl-l-thiosulfuryl-2-aminopropaneby  treating  thiosulfate. not  to  obtained  l-phenyl-l-chloro-2-aminopropane-  l-Phenyl-l-thiocyahato-2-aminopropanefrom  the  reaction  thiosulfuryl-2-aminopropane-3-ol  with  of  1-phenyl-l-  sodium  amino-4-hydroxylmethyl-5-phenyl-2-thiazoline Hydrolysis gave  of  cyanide, was  but  isolated.  1-phenyl-l-thiosulfuryl-2-aminopropane-3-o1  l-phenyl-l-mercapto-2-aminopropane-3-ol.  2-  iii  The u n s u c c e s s f u l  attempt  dichloro-2-aminopropane of  the  primary  amino  to  appeared  group.  prepare due  to  1-phenyl-1,3-  the  Supporting  electronic  this  assumption,  1-phenyl-l,3-dichloro-2-benzoylaminopropane from N - b e n z o y l p h e n y l s e r i n o l .  was  When an e t h a n o l  1-phenyl-l,3-dichlorp-2-benzoylaminopropane sodium  sulfide, instead  dicating  the  ring  of  ease  formation.  was  of  the  The same r e s u l t  used.  The r e d u c t i o n  of  treated  was  was  when  synthesized of  the  in-  compared  observed  amide  to  1-phenyl-  from c i n n a m y l group  using  with  of  1-  diborane  was  successful. N ,N-Dimethylphenylserinol  of  was  elimination reaction  phenyl-1,3-dibromo-2-benzoylaminopropane not  solution  3-N-benzoylamino-2-phenylthietane,  1,3-dibromo-2-benzoylaminopropane alcohol  synthesized  2-phenyl-4-benzylidene-2-oxazoline  isolated  character  synthesizing  intermediate  prepared  for  the  purpose  3-N,N-dimethylamino-2-phenylthietane via  of  propane-3-ol.  was  the  1-pheny1-1-thiocyanato-2-N,N-dimethylaminoSynthesis  thylaminopropane-3-ol  of l - p h e n y l - l - c h l o r o - 2 - N V - N - d i m e -  was  not  successful.  3-dichloro-2-NV-N-dimethylaminopropane nitrophenylserinol  treated  prepared  w i t h sodium  a hydrochloride salt  from  p-  sulfide.  the  product  of  bis  (l-p-nitrophenyl-2-N,N-dimethylamino-3-chloropropane)  the  formation  hydrochloride.  3-Hydroxy-2-phenylthietane propenyl  indicated  Isolation  of  sulfide  as  was  1-p-Nitrophenyl-l,  benzene  was  reacted  benzylsulfonylchloride  and  prepared  from  3-chloro-  with b e n z y l s u l f o n y l c h l o r i d e  sodium a z i d e .  A l l attempts  or  using  iv  column chromatography to i s o l a t e products  r e s u l t e d i n the  i d e n t i f i c a t i o n of s t a r t i n g m a t e r i a l s , r e v e a l i n g that the s u l f o n a t e or the azide might not be formed by the r e a c t i o n probably  because of the r e s i s t a n c e of the hydroxyl  group of  3-hydroxy-2-phenylthietane to the a l k y l a t i o n . Discussions  on the determination  of the synthesized  compounds using i r , nmr , uv, and gc-mass spectrometry  are  included.  and  Recent concepts of the a c t i v e s i t e s of MAO  mechanisms of i r i h i t i b i o n of MAO . a r e . ;  Signature  of Supervisor  reviewed.  V  TABLE OF CONTENTS Page ABSTRACT.  i i  LIST OF FIGURES...................  x  INTRODUCTION...  1  1.  General d e s c r i p t i o n of the mechanism of a c t i o n of tranylcypromine-type  2.  A c o n s i d e r a t i o n of MAO  inhibitors....  1  and i t s i n h i b i t o r s . . . .  8  A.  A c t i v e s i t e s of MAO  9  B.  R e l a t i o n s h i p s of f l a v o p r o t e i n  with  p a r g y l i n e and hydrazine type i n h i b i t o r s . . C.  M u l t i p l e forms of MAO  and t h e i r  inhibitors 3.  4.  selective  ,  20  Thietane d e r i v a t i v e s as p o t e n t i a l  MAO  inhibitors  24  S y n t h e t i c routes to t h i e t a n e s  26  DISCUSSION OF THE CHEMISTRY 1.  15  34  S y n t h e t i c approach to 3-amino-2-pheny1thietane(22)via l-phenyl-l,3-dichloro-2aminopropane . . A.  Phenylser i n o l  B.  Threo-l-phenyl-l,3-dichloro-2-aminopropane  2.  35 (55/, R =R = R = H) (  2  3  (5_6 , R ^ R ^ R ^ H )  35  39  S y n t h e t i c approach to 3-amino-2-pheny1thietane mediate  (2_2) v i a a t h i o c y a n a t e i n t e r 42  vi  Page A.  2-Amino-4-hydroxy .methyl-5-phenyl2-thiazoline  B.  ( 7_4) . .  4  l-Phenyl-l-mercapto-2-aminopropane-3-ol (63)  3.  50  S y n t h e t i c approach to 3-benzoylamino-2pheny l t h i e t a n e  (2_3)  52  A. 1-Phenyl-l,3-dichloro-2-benzoylaminopropane B.  55  1-Phenyl-l,3-dibromo-2-benzoylaminopropane  4.  (16_)  (7_2)  59  C.  2-Phenyl-4-benzylidene-2-oxazoline (7_8) . .  D.  3-Benzylamino-2-phenylthietane (9_5)  S y n t h e t i c approach to 2-phenylthietane  72  3-N,N-dimethylamino-  (2_4) and 3-N,N-dime-  t h y l a m i n o - 2 - p - n i t r o p h e n y l t h i e t a n e (2_6_)  74  A.  N,N-D imethylpheny1ser ino1 (96)  76  B.  S y n t h e t i c approach to 1 - p h e n y l - l - c h l o r o 2-N,N-dimethylaminopropane-3-ol  C.  D.  (111)....  76  l-p-Nitrophenyl-l,3-dichloro-2-N,Ndimethylaminopropane  (.97)  78  Reactions of 1 - p - n i t r o p h e n y l - 1 , 3 - d i c h l o r o 2-N,N-dimethylamihopropane sodium  5.  61  (97) with  sulfide  82  S y n t h e t i c approach to thietane  (22) from  thietane  (100)  3-amino-2-phenyl-  3-hydroxy-2-phenyl9  2  4  vii  Page  ANALYTICAL METHODS  99  EXPERIMENTAL 1.  .  Synthesis of t h r e o - p h e n y l s e r i n e  ethylester  (108)  100  2.  Synthesis of thr eo-phenylser i n o l  (5_8)  3.  Synthesis of t h r e o - l - p h e n y l - l - c h l o r o - 2 aminopropane-3-ol HCl (6J))  4.  Attempted  Attempted  (5_6_,R^ = R2 R2 H) =  (62) . .  Attempted  Bunte s a l t )  the Bunte s a l t  Synthesis of propane-3-ol  (Synthesis of 2-amino-4-  HCl (6_3) ......  105  Synthesis of t h r e o - N - b e n z o y l - p h e n y l s e r i n o l 105  Synthesis of 1 - p h e n y l - l , 3 - d i c h l o r o - 2 benzoylaminopr opane ( 66 )  11.  104  l-phenyl-l-mercapto-2-amino-  (65) 10.  104  (6_2) v i a  h y d r o x y i m e t h y l - 5 - p h e n y l - 2 - t h i a z o l i n e ,_74_)  9.  103  s y n t h e s i s of 1-phenyl-l-;  thiocyanato-2-aminopropane-3-ol  8.  103  Synthesis of 1 - p h e n y l - l - t h i o s u l f u r y l - 2 aminopropane-3-?ol(^l,  7.  =  s y n t h e s i s of 1 - p h e n y l - l -  thiocyanato-2-aminopropane-3-ol 6.  102  s y n t h e s i s of 1-phenyl-l,3-  dichloro-2-aminopropane 5.  101  106  Synthesis of 1-phenyl-l,3-dibromo-2benzoylaminopropane (_72)  107  viii  Page  12. Attempted  s y n t h e s i s of  -2-phenylthietane  3-benzoylamino-  (2_3) (Synthesis of 2-  phenyl-4-benzylidene-2-oxazoline , 7_8) 13. Attempted  s y n t h e s i s of 1-pheny1-1,3-  dibromo-2-benzylaminopropane 14. Synthesis of  110  (96_)  Ill  s y n t h e s i s of l - p h e n y l - l - c h l o r o - 2 -  N ,N-dimethylaminopropane-3-ol 16. Synthesis of phenylserinol 17. Attempted  (94 )  l-phenyl-2-N,N-dimethylamino-  propane-1, 3-d i o l 15. Attempted  108  ( 111 )  .  I l l  N,N-dimethyl-p-nitro(110)  113  s y n t h e s i s of 1 - p - n i t r o p h e n y l - l -  chloro-2-N,N-dimethylaminopropane-3-ol HCl (112)  114  18. Synthesis of 1 - p - n i t r o p h e n y l - l , 3 - d i c h l o r o - 2 N ,N-dimethylaminopropane 19. Attempted  HCl (9_7)  114  s y n t h e s i s of 2-p-nitrophenyl-3-  N ,N-dimethylaminothietane (2_6 ) ( Synthesis of bis  (l-p-nitrophenyl-2-N,N-d imethy1amino-3-  chloropropane) s u l f i d e HCl (123)  ...  115  20. Synthesis of 3 - c h l o r o - l - p h e n y l p r o p y l e n e oxide-1, 2 (107) 21. Synthesis of ^ - t o l u e n e s u l f o n y l c h l o r i d e  117 117  ix  Page  22. Synthesis of 3-hydroxy-2-pheny1thietane(100).. 23. Attempted thietane 24. Attempted  118  s y n t h e s i s of 3-azido-2-phenyl(103)  118  s y n t h e s i s of 2-phenyl-3-thietanone  (104)  120  BIBLIOGRAPHY  121  r  X  TABLE OF FIGURES Figure 1.  Page Ir spectrum  of ,2-amino-4-hydroxy. methyl-5-  phenyl-2-thiazoline 2.  I r spectrum  of  propane-3-ol 3.  4.  47  1-phenyl-l-mercapto-2-amino-  (6_3)  -  .53  Molecular s t r u c t u r e of 2-phenyl-4-benzylidene2-oxazoline  (7_8)  I r spectrum  of  oxazoline 5.  (7 4)  63  2-phenyl-4-benzylidene-2-  (7_8)  Uv spectrum  64  of 2-phenyl-4-benzylidene-  2-oxazoline ( 7_8) ....... 6.  Nmr  spectrum  of 2-phenyl-4-benzylidene-  2-oxazoline (7_8) 7.  Mass spectrum  68  of N,N-dimethylphenylserinol  (£6) 8.  65  77  Ir spectrum  of 1-p-nitrophenyl-1,3- .  dichloro-2-N , N-dimethylaminopropane (9_7) 9.  Nmr of  spectrum  80  of the products from the reaction  1-p-nitrophenyl-l,3-dichloro-2-N,N-dime-  thylaminopr opane (9 7, 1 mol) with sodium sulfide 10.  Nmr  (2.25 mol)  spectrum  of b i s  g  5  (l-p-nitrophenyl-2-N,  N-dimethylamino-3-chloropropane)sulfide (122) .  89  LIST OF ABBREVIATIONS bp  -  b o i l i n g point  DCC  -  dicyclohexylcarbodiimide  Diglyme -  d i e t h y l e n e g l y c o l dimethyl  ether  DMF  -  dimethy1formamide  DMSO  -  dimethyl s u l f o x i d e  EtOH  -  ethanol  MeOH  -  methanol  FAD  -  flavin  adenine d i n u c l e o t i d e  FMN  -  flavin  mononucleotide  gc  -  gas ( l i q u i d )  HMPT  -  hexamethylphosphoric t r i a m i d e  1,-Q  -  i n h i b i t o r c o n c e n t r a t i o n f o r 5 0 % inhib i t i o n ' o f'• the enzyme a c t i v i t y  ir  -  infrared  Km  -  M i c h a e l i s constant  MAO  -  monoamine  mp  -  melting p o i n t  nmr  -  n u c l e a r magnetic resonance  SAR  -  structure-activity  THF  -  tetrahydrofurane  tic  -  thin layer  uv  -  ultraviolet  chromatography  (spectroscopy)  oxidase  (spectroscopy)  relationship  chromatography (spectroscopy)  ACKNOWLEDGEMENTS  The author i s indebted to Dr. Frank advice and encouragement throughout  S. Abbott  for his  the course of t h i s work.  The author would l i k e to thank the Dean of the F a c u l t y , Dr. B. E. R e i d e l , f o r g i v i n g him a chance to study i n Canada.  \  1  INTRODUCTION  1.  and  General d e s c r i p t i o n of the mechanism of a c t i o n of tranylcypromine-type  inhibitors.  Tranylcypromine  because of i t s r e l a t i v e l y  (1)»  simple s t r u c t u r e and  studied  unique geometry, has  and  that two  and  pargyline  It i s now  other  known that MAO  (_3) e l i c i t  t h e i r i n h i b i t o r y a c t i o n on MAO moiety of the enzyme.  before  1965.  The  tranylcypromine with a c t i v e s i t e s of MAO with the same d e t a i l as have recent pargyline  described. recent  4  (2^) by  Most of  s t u d i e s of tranylcypromine d e r i v a t i v e s as MAO  h i b i t o r s were published  and  is a flavoprotein  important i n h i b i t o r s , phenylhydrazine  i n t e r a c t i o n with the f l a v i n  SAR  extensively  as a model compound to e l u c i d a t e the mechanism of i n -  h i b i t i o n of MAO.  the  been  rigid  in-  r e l a t i o n s h i p of has  not been dealt  s t u d i e s of phenylhydrazine  Only a broad o u t l i n e of the i n t e r a c t i o n has  Therefore,  i t appears worthwhile to  concepts of the a c t i v e s i t e s  of i n h i b i t i o n emphasizing the  been  generalize  of MAO.and i t s mechanism  f l a v i n moiety of the  receptor  2  and  to e s t a b l i s h  promine-type One  the r i g h t  f o r s t u d i e s of  tranylcy-  inhibitors.  of the important  inhibitors  direction  directly  methods to estimate whether  any  combine with a c t i v e s i t e , or whether they  complex with the enzyme a t , p o s s i b l y , a l l o s t e r i c s i t e s thereby based  lead to i n h i b i t i o n  on k i n e t i c  of b i n d i n g of s u b s t r a t e s i s  s t u d i e s using Lineweaver-Burk p l o t s .  and Nimmo (1) reported a non-competitive b r a i n MAO  inhibition  Maass  of rat  by tranylcypromine with respect to s u b s t r a t e ,  serotonin.  According to B e l l e a u and Moran (2) using  mine as the s u b s t r a t e , the mechanism of MAO tranylcypromine was and  and  Sarkar  clearly  (3) observed  kynura-  inhibition  of the competitive type.  that when tyramine  and  by Zeller  tranylcy-  promine were added simultaneously to the enzyme p r e p a r a t i o n , the degree of i n h i b i t i o n was strate  concentrations.  i n h i b i t i o n was after  observed  inhibitors.  dialysis  from MAO  h i b i t i o n was  On  decreased  with i n c r e a s i n g  the other hand, no e f f e c t  when tyramine was  Tranylcypromine (4).  to remove by  shown by d i a l y s i s against s u b s t r a t e (5).  a non-competitive for an enzyme.  inhibitor  Although  tion by tranylcypromine  refuted  minutes  However, 40 per cent r e v e r s a l of i n -  long d u r a t i o n of a c t i o n of tranylcypromine  petitive  on  added 15-30  is difficult  sub-  i s due  similar  to that of  to i t s high b i n d i n g a f f i n i t y  a report was  p u b l i s h e d that i n h i b i -  can be reversed r e a d i l y  s u b s t r a t e , 4-phenylbutylamine by l a t e r work (7).  A  by the com-  (3),,this  evidence  At p r e s e n t , most of the  was  evidence  3  p o i n t s to the f a c t  that tranylcypromine i s a competitive i n -  h i b i t o r , having high a f f i n i t y b i n d i n g and thus e l i c i t s i t s a c t i o n by d i r e c t the a c t i v e  i n t e r f e r e n c e of the b i n d i n g of s u b s t r a t e at  sites.  It was p o s t u l a t e d by B e l l e a u and Moran (2) that the chemical r o l e moting  of the cyclopropane  ring  could c o n s i s t  c h a r g e - t r a n s f e r complex formation through  e l e c t r o n s with the f l a v i n c o f a c t o r .  Burger  i n pro2  its P -like S  (8) a l s o  suggested  that i t should be p o s s i b l e to draw a p i c t u r e of t i g h t binding of tranylcypromine to protein-bound l i m i t i n g amounts of v a r y i n g mixtures and  chemical  r i b o f l a v i n . When  of p a r g y l i n e , phenylhydrazine ,  tranylcypromine were incubated with the enzyme, the nature of  the i n h i b i t i o n  observed was a d d i t i v e  $5).  Benzylamine  treatment  p r o t e c t e d MAO from i n h i b i t i o n by these i n h i b i t o r s , implying that these i n h i b i t o r s le. the c a t a l y t i c  act independently, but at the same s i t e ,  s i t e of the enzyme.  The p u z z l i n g f a c t , however,  i s that p a r g y l i n e and phenylhydrazine reduce tranylcypromine does not. Although benzylamine  (9) i s an a t t r a c t i v e  the c a t a l y t i c mechanism of MAO, of  the p a r t i c i p a t i o n  nm.  f l a v i n r e d u c t i o n by  f a c t which might  of the f l a v i n moiety  i s monitored  i n the o x i d a t i o n of  The r e d u c t i o n of f l a v i n by  by the i n c r e a s e i n absorbance  The e l a b o r a t i o n of b e t t e r methods to monitor  a c t i o n s of drugs  demonstrate  evidence p r o v i d i n g c o n f i r m a t i o n  s u b s t r a t e has not been p u b l i s h e d . inhibitors  f l a v i n while  at 412  the i n t e r -  or s u b s t r a t e s with f l a v i n might r e v e a l some  forms of i n t e r e a c t i o n s between them which have not yet been detected.  4  P o s s i b l e i n t e r a c t i o n of tranylcypromine with f l a v i n was favored by the analogy  that t r i c y c l i c  psychoactive  drugs  (chlorpromazine 4-, a m i t r i p t y l i n e .5, and c h l o r p r o t h i x e n e 6) i n hibit and  MAO and those having a double bond between the r i n g  the a l i p h a t i c  of type B MAO  side chain were the most e f f e c t i v e  -R = S  R  —  CH2  R =S 1  and Yagi  inhibitors  (10). I t has been shown by Karreman et a l . (11)  R  4_  R — R  CH2  R^— ^ R2  _CH -CH—N(CH ) 2  = N—CH  3  ^— ^^  —  ^' C—CH  (12) that chlorpromazine  3  2  2  R . = Cl 4 R. = H 4 R = Cl 4  forms c h a r g e - t r a n s f e r com-  plexes with r i b o f l a v i n and FAD, r e s p e c t i v e l y .  Molecular  o r b i t a l c a l c u l a t i o n s have i n d i c a t e d  that chlorpromazine  extemely  These data suggest  it  moiety  good e l e c t r o n donor (13).  i s an that  may be e l e c t r o n donating p r o p e r t i e s of the t r i c y c l i c  moieties of these drugs which i n f l u e n c e t h e i r a b i l i t y  to i n -  hibit  f l a v o p r o t e i n s such as MAO.  Lineweaver-Burk p l o t s showed  mixed  ( a m i t r i p t y l i n e ) or competitive type ( c h l o r p r o t h i x e n e )  inhibition. Pure beef plasma MAO was i n h i b i t e d by tranylcypromine (14)  This i n h i b i t i o n plasma MAO  i s not r e l a t e d  i s a diamine  p y r i d o x a l dependent.  to the f l a v i n moiety  oxidase enzyme which i s copper-  I t has also been reported that p a r g y l i n e  showed i n h i b i t i o n of beef plasma MAO Three hypotheses  complemented each  (15).  have been p u b l i s h e d on the b i n d i n g mode  of tranylcypromine to MAO. and  s i n c e beef  These hypotheses  can  other s i n c e they emphasize  p o i n t s of s t r u c t u r e requirement  f o r MAO  ^ be  reconciled  different  inhibitors.  Z i r k l e et a l . (16) p o s t u l a t e d that three  structural  requirements, a cyclopropane  r i n g , an amino group attached  directly  r i n g , and a 2 - s u b s t i t u e n t c o n t a i n -  to the cyclopropane  ing aromatic moiety inhibitory activity. f a c t o r s that may  are necessary f o r potent i n v i v o Emphasizing  the p o s s i b l e s t e r e o c h e m i c a l  be i n v o l v e d i n the b i n d i n g process, they  gested that i n the enzyme-inhibitor complex the promine d e r i v a t i v e s do not assume a conformation  these groups l i e i n d i s t i n c t l y  d i f f e r e n t planes.  i n h i b i t i o n of the r i g i d l y b u i l t  sug-  tranylcyi n which the  phenyl and amino groups are n e a r l y coplanar but one  a c t i v i t y of MAO  MAO  i n which  The  good  1-amino-  cycloprop (a) indane (_7) .supports t h i s suggestion s i n c e i n t h i s d e r i v a t i v e the benzene r i n g can b a r e l y a t t a c h to the same enzyme s u r f a c e as the amino group.  f^Ti  T>-  n h  2  6  On the b a s i s of isotope catalyzed  oxidation  e f f e c t s observed i n the  of deuterium-labeled  kynuramine,  MAOBelleau  and  Moran (17) concluded that i n the o x i d a t i o n t r a n s i t i o n s t a t e  the  carbon atoms of the amine s u b s t r a t e  character affinity  double bond  and thereby approach the t r i g o n a l s t a t e . of tranylcypromine f o r the enzyme  to the f a c t  could  The high  thus be due  that i n ground s t a t e t h i s amine resembles,  electronically amine s u b s t r a t e  and s t e r i c a l l y , during  the t r a n s i t i o n s t a t e of the  the o x i d a t i o n process.  suggests that substrates sites.  acquire  and i n h i b i t o r s bind  This  hypothesis  to the same a c t i v e  T h e i r i d e a , however, that the N-C^-C2 atoms of the  cyclopropylamine are e s s e n t i a l l y coplanar inhibitor  i n the enzyme-  complex seems u n l i k e l y as c r i t i c i z e d  by Z i r k l e et a l .  (16), who emphasized the importance of stereochemical for the b i n d i n g  of MAO  i n h i b i t o r s to the receptor  factors  site(s).  To i n v e s t i g a t e the importance of the e l e c t r o n i c p r o p e r t i e s of a cyclopropane r i n g to the b i n d i n g enzyme and to e x p l a i n that phenylcyclobutylamine rather  than s t e r i c  synthesized  (18).  of i n h i b i t o r s to the  the poor i n h i b i t o r y a c t i o n of 2-  (^5) i s due to i t s e l e c t r o n i c p r o p e r t i e s  f a c t o r s , 3-amino-2-phenylazetidine 3-Amino-2- p h e n y l a z e t i d i n e  has a unique  s t r u c t u r e which can maintain the e l e c t r o n d e n s i t y with s i m i l a r s t e r i c p r o p e r t i e s lamine.  The f a c t  that  (9^) was  of the r i n g  to those of 2-phenylcyclobuty-  3-amino-2-phenylazetidine was 62  as a c t i v e as i p r o n i a z i d by i n v i t r o  percent  t e s t i n g could be used as  evidence which supports B e l l e a u and Moran's  theory.  7  H  8  9  Paget and Davis of p h e n y l d i a z i r i d i n e s  (19) reported  C  H  3  _  N  \,'  YV  \\  \  // \\_CH  nitrogen  synthesis  •  confirm  NR \  / CH  R = CH(CH ) ,  2  R  C H  10 t h i s evidence.  The  (1_1_) by Wells et a l (20) helps  R = H, CH,  activity  that a f r e e amino  inhibition.  NT-H  —  inhibition  (_10) , which i m p l i e s  group i s not necessary f o r MAO of p h e n y l a z i r i d i n e s  MAO  C  H  These compounds are unique i n that the amine Similar  compounds having mesoionic s t r u c t u r e s were synthesized Wiseman and Cameron (21,22).  by  They suggested that the TT  e l e c t r o n system of the anhydrothiadiazolium  binding  C H  11  i s an i n t e g r a l part of the r i n g system.  N-arylsydnones  2 2 6 5  compunds  (12)and  (3J3) mimics that of the c y c l o p r o p y l r i n g by  to a JT area  on the enzyme.  /  8  Benzooxadiazoles such as s u b s t i t u t e d furoxanobenzofuroxan showed i n v i t r o  i n h i b i t i o n of MAO  f u r t h e r support the  theory  (23).  that a high  system as w e l l as an a r y l group are MAO  inhibition  This evidence electron  (14)  may  conjugation  requirements f o r e f f e c t i v e  i n cyclopropylamines and  structurally  similar  compounds. 2.  A consideration  of MAO  and  Amine oxidases could be MAO,  diamine oxidase,  contains  flavin  and  classified  phosphate p r o t e i n s .  are probably  MAO.  diamine  only primary amines, whereas  tertiary  amines (24).  review a r t i c l e by Youdim (25)  MAO  and  require-  o x i d i z e s secondary and A recent  MAO  copper-pyridoxal  that diamine oxidase and  accept  groups,  Diamine oxidase  These d i f f e r e n c e s i n c o f a c t o r  ments e x p l a i n the f a c t MAO  MAO  i n t o three  diamine o x i d a s e - r e l a t e d  as a p r o s t h e t i c group.  diamine o x i d a s e - r e l a t e d  oxidase-related  i t s inhibitors  amines as w e l l as  as the enzyme which i s r e s p o n s i b l e  f o r the  deamination of such amines, as a d r e n a l i n e ,  MAO  primary defined  oxidative  noradrenaline,  isopropylamine , 3 , 4-dihydro;X'-yphenylethylamine , tyramine,  and  tryptamine.  MAO  (monoamine: 0^ oxidoreductase  (deaminating)  EC 1,4,3,4) i s the name given by the Enzyme Commission of I n t e r n a t i o n a l Union of A.  A c t i v e s i t e s of  (1)  Metal The  Biochemistry. MAO  Ions  presence of metal ion at a c t i v e sites i s derived from  the o b s e r v a t i o n that c h e l a t i n g agents i n h i b i t MAO  the  (26).  Galay  and  Valcourt  (27)  mitochondrial  even proposed that  the +2  amino group of tranylcypromine (tranylcypromine)2 MAO.  participates  i n an MAO-Cu  complex which leads to an i n h i b i t i o n  T h e i r p o s t u l a t i o n was  challenged  by the f a c t  that  of trans-2  p h e n y l c y c l o p r o p y l c a r b i n o l , which i s a l s o able to form a complex with  Cu  i o n , showed a 400-  MAO  inhibitory activity  and  beef, m i t o c h o n d r i a l MAO  highly p u r i f i e d  (28).  p r e p a r a t i o n s of the enzyme, metal  Youdim and  0.12  decrease  (29) p u b l i s h e d  Sourkes (30) r e p o r t e d 0.03  According  manganese, and molybdenium were found the content  of i r o n was  l i v e r mitochondrial  0.5-2  of  contents  the presence of from  bovine  % of copper  % of i r o n i n h i g h l y p u r i f i e d m i t o c h o n d r i a l MAO  p a r a t i o n s from r a t l i v e r .  in  with human  With the a v a i l a b i l i t y  % copper i n p r e p a r a t i o n s of m i t o c h o n d r i a l MAO  liver. and  1500-fold  from that of tranylcypromine  were determined. Nara et a l . 0.07  and  to Oreland  pre-  (31), copper,  i n n e g l i g i b l e amounts but  moles per mole of f l a v i n  in pig  MAO.  Treatment of the p r e p a r a t i o n s with a strong i r o n c h e l a t o r 1,10-phenanthroline did not decrease  the enzyme a c t i v i t y , which  10  implies of  that i r o n does not play a part  the enzyme.  From experiments  ship of c h e l a t i n g  agents and  and Shermetevskaya of  i n the c a t a l y t i c  designed to prove the r e l a t i o n -  t h e i r i n h i b i t i o n of MAO,  (32,33) reported  8-hydroxyquinoline i s not due  that MAO  of MAO  s i t e of m i t o c h o n d r i a l  has been p u b l i s h e d  deficiency  in rats.  deficiency  i n rats  cantly  which  does not a f f e c t  also  that  MAO  from i r o n - d e f i c i e n t  subjects i s s i m i l a r  Recent  Youdim  s t u d i e s on p l a t e l e t that  of p l a t e l e t MAO  to the Km  rats.  decrease i n the r a t e at  subjects indicate  Although the Km  deficient  signifi-  be necessary at some stage i n  b i o s y n t h e s i s of the apoenzyme.  (34).  copper  14 > 14 pentylamine to CO2•  the  be so  MAO.  functional  enzyme a c t i v i t y but  leads to a large  i r o n may  action  from s t u d i e s of i r o n  observed with i r o n  the animals metabolize C  et a l . proposed  in f u l l  Symes et a l . (34) r e p o r t e d that  lower a c t i v i t y was  Iron d e f i c i e n c y  inhibitory  to bind to a hydrophobic  However, support f o r the r o l e of i r o n activity  Severina  to i t s c h e l a t e formation  with metal ions but to i t s a b i l i t y and a p o l a r region i n the a c t i v e  function  t h i s may  from i r o n  of the enzyme from normal  indeed deficient subjects  using the s u b s t r a t e s dopamine, s e r o t o n i n , and kynuramine, maximum v e l o c i t y iron-deficient  i s s i g n i f i c a n t l y reduced.  p l a t e l e t MAO  the  Evidence that  i s much more s e n s i t i v e  to heat  14 inactivation  and binds s i g n i f i c a n t l y l e s s  C  deprenil  \  per  mg.  platelet  protein  than p l a t e l e t s  can be e x p l a i n e d  i n terms of i m p l i c a t i n g  s y n t h e s i s of MAO  protein.  article  Youdim  from normal i r o n i n the  (36) has p u b l i s h e d  on metals and r a t l i v e r m i t o c h o n d r i a l  MAO.  subjects bioa review  11  (2)  Hydrophobic The  of a  MAO  presence  i s based  minimum  for  MAO.  MAO.  on  the  chain  oxidized  by  MAO  McEwen liver  the  fact in  order  long  et  al  (56)  have  mitochondria  with  as  by  the  fact  competitive  that  site  region  inhibitor  polar  region  some h y d r o p h o b i c  analogs  occupies of  the  region  a  and  definite  enzyme  is  in  MAO  position  active  site  not oL-naphthol  the  Some  the  is  evidence  immediate  essential for  of  suggested  nucleophilic polar  electrophilic  a was  region  vicinity  binding  of  (33,35).  Sulfhydryl Early  group  assumptions  stemmed  from  the  s u l f h y d r y l groups and  of  the  fact cause  a  Erwin  hydryl  groups  on  p r o p o r t i o n a l i t y between and were  Hellerman  might  be  measured published  importance  that  (39).  findings  by  are  using  the  and  MAO  that  enzyme.  to  kidney  have  oxidized  the  binds  the  center  affinity  of  tyramine  with  not  studies  jg - n a p h t h o l , b u t  that  group  active  diamines  kinetic  proposed  (3)  are  aliphatic  substrate  binding  hydrophobic  serotonin  the  significant  diamines  performed  the  of  at  (37).  to  that  region  a l i p h a t i c rapnQarad-ties m u s t to  chain  adjacent  potent  that  aliphatic  electrophilic  shown  region  a hydrophobic  Short only  an  of  length  is  that  Polar  chain  It  human  and  alkylating  decrease  (40)  involved the  Gomes  et  al.  a sulfhydryl agents  which  enzymatic evidence  in  observed  s u l f h y d r y l group by  in  published  directly  of  activity  content. (41)  that  activity  that  catalysis  react  sulf-  based of  beef  Contrary sulfhydryl  12  groups do not play a c a t a l y t i c structural role.  r o l e but probably only a  I t i s w e l l known that p r o t e i n  groups play a r o l e i n s t a b i l i z i n g  tertiary  structure  hydrogen bonding and hydrophobic i n t e r a c t i o n . groups which alkylating  are not present i n the c a t a l y t i c  agents to a f f e c t  Even  through sulfhydryl  s i t e react with  conformational s t a b i l i t y  a decrease i n enzyme a c t i v i t y MAO  sulfhydryl  (42). Beef l i v e r  and cause  mitochondrial  c o n t a i n s seven s u l f h y d r y l groups per 100,000 grams of MAO  (41).  Seven  s u l f h y d r y l groups were a l s o reported by Erwin  and Hellerman f o r beef kidney MAO  (40). When MAO  and methyl-  mercuric c h l o r i d e are r e a c t e d , a l l seven s u l f h y d r y l groups are t i t r a t e d , whereas, when harmaline or benzylamine  are added  before the methylmercuric c h l o r i d e , only f i v e s u l f h y d r y l are t i t r a t e d . groups  groups  I t was p o s t u l a t e d t h e r e f o r e that two s u l f h y d r y l  are near the a c t i v e s i t e of MAO which i s present i n  a hydrophobic region and that the other f i v e s u l f h y d r y l are presumably  groups  on the s u r f a c e of the enzyme p l a y i n g a r o l e i n  conformational s t a b i l i t y -(43) .  The r o l e s of two s u l f h y d r y l  .groups near the a c t i v e s i t e have not been e x p l a i n e d . Treatment  of h i g h l y p u r i f i e d MAO with o x i d i z i n g  agents  not only decreased the rate of deamination of monoamines by MAO but a l s o induced the a b i l i t y histamine.  to c a t a l y z e deamination of  This treatment also caused a r e v e r s i b l e decrease  i n the content of s u l f h y d r y l groups  (38). These f a c t s may  suggest that o x i d i z i n g agents a f f e c t result  s u l f h y d r y l groups  i n the c o n f o r m a t i o n a l change r e l a t i n g  phobic region and induce new a c t i v i t y  which  to the hydro-  of deaminating diamines.  13  (4)  F l a v i n moiety Before 1965 when MAO  could not be i s o l a t e d i n a p u r i f i e d  form, an i n d i r e c t method was used to demonstrate the presence of f l a v i n .  Studies  of r i b o f l a v i n - d e f i c i e n t r a t s by Hawkins  and  Sourkes (44) showed that  MAO  activity arising  there was a decrease i n hepatic  from the d e f i c i e n c y .  A f t e r t h a t , the  presence of f l a v i n was confirmed by absorption fluorescence  data,  data and evidence from t h i n l a y e r chromatography  of the p u r i f i e d bovine kidney  enzymes i s o l a t e d from beef l i v e r (45),  (40), and p i g b r a i n  (47). T r i c h l o r o a c e t i c a c i d  treatment of the enzyme does not r e l e a s e and  spectrum  s u b s t a n t i a l amounts were r e l e a s e d  was t r e a t e d with p r o t e o l y t i c enzyme.  the f l a v i n moiety  only when the enzyme I t was  suggested,  t h e r e f o r e , that f l a v i n may be c o v a l e n t l y bound to the enzyme. In 1971 the s t r u c t u r e of the f l a v i n peptide determined  f  R  (48,49,50) and a u t h e n t i c a t e d  from MAO  was  through s y n t h e s i s (51).  l  CH-CH— S —  HC 2  C0R  15  2  R - rest of FAD  in native enzyme or rest of FMN in pure peptide  R = serylglycylglycine 1  R = tyrosine 2  It was shown that pure f l a v i n pentapeptide i s o l a t e d from hepatic  MAO  contains  1 mole each of s e r i n e and t y r o s i n e ,  14  2 moles of g l y c i n e , and a c y s t e i n e which i s c o v a l e n t l y l i n k e d to  C-8  of r i b o f l a v i n  isolated  (15),  (52)  reported  that the enzyme  from p i g b r a i n c o n t a i n s , i n c o n t r a s t , f l a v i n  non-covalent l i n k a g e . but  Tipton  confident  Salach  et a l . (53)  in a  followed h i s  c o n c l u s i o n on the n o n - c o v a l e n t l y  bound  procedures,  flavin  could not be made s i n c e a l l samples of the b r a i n enzyme contained some a c i d - e x t r a c t a b l e f l a v i n . Any  confirming  i n the c a t a l y t i c only evidence  evidence  of the p a r t i c i p a t i o n  a c t i o n of MAO  of  flavin  have not been p u b l i s h e d .  of f l a v i n p a r t i c i p a t i o n  The  i n the o x i d a t i o n of 14  monoamines was One  from the study  mole of benzaldehyde was  enzyme.  using  C  produced per mole of FAD  S p e c t r a l changes which denote r e d u c t i o n of  were observed, but no semiquinone has existence  of semiquinone was  of Massey and for  l a b e l e d benzylamine.  Palmer ( 9 ) .  i n the flavin  yet been detected.  indirectly  shown by the procedure  A p l a u s i b l e mechanistic  hypothesis  the r e d u c t i o n of the f l a v i n molecule by a s u b s t r a t e  as benzylamine was  proposed  covalent bonding formation  (54).  and  to  aldehyde and  the corresponding  however, was  formation  based on very  Mechanisms  This .hypothesis  of s u b s t r a t e with  r e d u c t i o n of f l a v i n ,  little  flavin  molecule,  of imine which i s hydrolyzed ammonia.  This  experimental  propose that o x i d a t i o n of amine occurs a schiff  f i r m evidence  that aldehyde and  amine, are products  base.  such  described  hypothesis,  data.  e x p l a i n i n g the o x i d a t i o n of amines by  step to y i e l d  The  MAO  v i a a dehydrogenation  This idea i s based on the  very  ammonia, i n the case of a primary  of the enzyme r e a c t i o n .  15  E  +  RCH ——  RCH = EH  2  NH  2  +  NH 0  +  2  —  H0 2  >  2  E  ->  EH  i>  RCHO  +  H 0 2  This does not give a s a t i s f a c t o r y  + RCH =  2  +  N'H  NH^ ,  2  d e s c r i p t i o n of the molecular  mechanism i n terms of a f l a v i n moiety or any other  catalytic  s i t e a l t h ough i t seems r e a l that f l a v i n plays a r o l e i n that function. If t e r t i a r y  amines are s u b s t r a t e s  f o r MAO, the formation  of a s c h i f f base seems u n l i k e l y s i n c e such amines do not have a hydrogen atom attached to e x p l a i n t h i s a protonated ion  to the n i t r o g e n .  attempts  anomaly seem u n s a t i s f a c t o r y , e i t h e r invoking  substate  (6) or p o s t u l a t i n g hydride  (46) from the o i - c a r b o n atom.  the presence of a l y s i n e r e s i d u e and  Previous  Williams  ion abstract-  (55) hypothesized  at the a c t i v e center  of MAO  proposed a p l a u s i b l e dehydrogenation mechanism a p p l i c a b l e  to primary, secondary, and t e r t i a r y  amines.  however, d i d not show how an oi -proton involvement with  flavin.  This  report,  i s abstracted  The presence of a, p o l a r  and any  region  whether i t i s l y s i n e or not seems r e a l . B.  (1)  and  Relationships  of f l a v o p r o t e i n with  hydrazine  type  inhibitors.  Pargyline  type  inhibitors  According  to Hemmerich  p a r g y l i n e and  (59), the overlap  between  s u b s t r a t e 7 T - o r b i t a l s w i t h i n the c a t a l y t i c a l l y  flavin  active  16  complex can h a r d l y be  the mode of the f l a v i n s u b s t r a t e  since f o r e f f i c i e n t 7T -overlap i s needed, and obviously  this requires less s t e r i c  exist.  "Sigma c h a r a c t e r was  s u b s t r a t e contact In 1972  a rather large area of  at the two  a covalent  acceptor  by i r and occurred  nmr  system was  spectroscopy.  The  ;C(4a) and N(5)>.  and  s t r u c t u r e was  a d d i t i o n of 2-propynylamine  i t was  formed and  replaced by an o l e f i n i c  of o x i d i z e d  from beef l i v e r was  found that a  that the  group which was  purified.  triple  A d d i t i o n of p a r g y l i n e  i n the absence of l i g h t nm  peak with  f a c t s were observed  closely paralleled  induced  disappearance of the  (60).  t i o n of the enzyme.  the degree of i n h i b i t i o n .  P u r i f i e d MAO  of c a t a l y s i s and  and  iproniazid.  The  change a f t e r  does not  peak when i t i s t r e a t e d with  tranylcypromine  the 460  nm  Several  O p t i c a l changes at  of t i t r a t a b l e s u l f h y d r y l --groups did not  nm  represent-  a part of an  peak which denotes r e d u c t i o n of the f l a v i n s moiety.  ing the 410  model  (60).  appearance of a 410  nm  and  elucidated  same procedure of using a flavoquinone  to t h i s p u r i f i e d MAO  important  than  flavin-  complex which shows disappearance of peaks  enamine system MAO  The  contact  of flavoquinone  prepared  a p p l i e d to p a r g y l i n e and  ing the quinonoid bond was  sites,  to the C(4a)=N(5) azomethine grouping  enzyme (58).  covalent  expected f o r  c y c l o a d d i t i o n product  an a c e t y l e n i c enzyme i n h i b i t o r was  restrictions  contact  410  number inactiva-  respond by d i s p l a y s u b s t r a t e or  with  This i m p l i e s that the mechanism  i n h i b i t i o n of MAO  by tranylcypromine  or  17  iproniazid amines.  seems to be q u i t e d i f f e r e n t  By using MAO  from  of bovine kidney,  that of a c e t y l e n i c  identical  results  were reported (61). S p e c t r o s c o p i c a l data that showed l o s s of long wavelength a b s o r p t i o n (450-500nm) and development of a new band at 410 nm was also observed thylamino-1-propyne C(4a)=N(5) posed.  by experiments  and bovine  adduct  l i v e r MAO  formation N(5) adduct  This r e s u l t  is different  using 3-dime(62). Instead of  formation,was pro-  from the o b s e r v a t i o n when  l a c t a t e 2-monooxygenase i s t r e a t e d with the a p p r o p r i a t e a c e t y l e n i c s u b s t r a t e analog.  In t h i s case, the i n a c t i v a t o r  becomes attached to both N-5 and C-4a of the f l a v i n as i s the p a t t e r n of flavoquinone and 2-propynyl The mechanism by which adduct not  amine i n t e r a c t i o n (16).  formation occurs -at N-5  (17.)  is  known.  R:  16  Adduct formation with the f l a v i n of  17  l i v e r MAO  at p o s i t i o n 5  was a l s o reported i n the case of d e p r e n i l which i s a s e l e c t i v e inhibitor  of type B MAO (63).  18  Williams and Lawson (64) observed that a compound such as N-(2,4-dichlorobenzyl)-N-methylpropargylamine (18) i s a much b e t t e r i n h i b i t o r  than i t s non-halogenated  p a r g y l i n e and that the l a t t e r  analog,  i s more e f f e c t i v e than i t s  desmethyl d e r i v a t i v e , N-benzylpropargylamine (19).  18  19  D i f f e r e n c e s i n the p a r t i t i o n  c o e f f i c i e n t s among p a r g y l i n e  d e r i v a t i v e s showed a c l o s e r e l a t i o n s h i p  to the e f f e c t i v e n e s s of  i n h i b i t i o n of m i t o c h o n d r i a l MAO as measured by I ^ Q v a l u e s . i m p l i e s that the ease of p e n e t r a t i o n through a l i p i d  This  barrier  attached to the enzyme i s an important f a c t o r determining the i n h i b i t i o n by p a r g y l i n e  derivatives.  14 Using C that i n v i t r o ,  l a b e l l e d p a r g y l i n e and c l o r g y l i n e i t was shown these substances f a i l  to bind to p r o t e i n s other  than MAO, and that, a number of other inhibitors'., such as iproniazid to  and tranylcypromine prevent p a r g y l i n e from b i n d i n g  t h i s enzyme (65). The p r e c i s e mode of i r r e v e r s i b l e i n -  h i b i t i o n of plasma MAO by p a r g y l i n e i s not known. that the enzyme mediated  - double bond m i g r a t i o n precedes the  actual i r r e v e r s i b l e i n h i b i t i o n is  first  I t i s assumed  so that the u n r e a c t i v e a c e t y l e n e  converted i n t o the h i g h l y r e a c t i v e a l l e n e  f o r e , b e f b r e a t t a c k i n g the f l a v i n moiety  (15). There-  or unknown group of  plasma MAO, e l e c t r o n m i g r a t i o n to the a l l e n e i s a p r e -  19  r e q u i s i t e f o r a c e t y l e n i c amine-induced i n h i b i t i o n . also p o s s i b l e that other  It i s  i n h i b i t o r s such as i p r o n i a z i d and  tranylcypromine may prevent the a c t i v a t i o n or p o s i t i o n i n g of the a c e t y l e n i c amines p r i o r to secondary attack This p o s i t i o n i n g s i t e may a l s o be important  of the enzyme  f o r the c a t a l y t i c  a c t i o n of MAO. (2)  Hydrazine type i n h i b i t o r s In 1972 i t was reported  that hydrazine type i n h i b i t o r s  are a l s o o x i d i z e d by MAO f o l l o w i n g the same p a t t e r n as substrates.  I t was reported  this oxidation responsible  that the immediate product of  i s the hydrazone and that t h i s hydrazone i s  f o r the i r r e v e r s i b l e i n h i b i t i o n  Phenylethylidene  hydrazine  of the enzyme.  (2_0, R= CgH,_CH )was 2  i s o l a t e d and  presented as an i n h i b i t o r (66). E  +  RCH NH NH 2  2  _  >  EH EH  EH  2  +  0  2  >  E  +  2  2  H 0 2  +  RCH== NNH" , 2_0  +  R C H N = NH  2  2  21  2  It was not shown, however, what part of the enzyme molecule is  responsible  f o r t h i s conversion.  Phenylethylidene  hydrazine  (20, R = C,H CH •••)) was a l s o found to be a time dependent i n 6 > 2 C  hibitor  of MAO (67). ,  Evidence that the f l a v i n moiety of MAO plays  a part i n  the a c t i o n of hydrazine type i n h i b i t o r s was reported (68). It was suggested that the o x i d a t i o n of the hydrazine proceeds  20  with  formation  diazene  of the corresponding  i s r e s p o n s i b l e f o r the i n h i b i t i o n  adduct with  FAD.  phenylethylidene  oxidation  hydrazine  and t h i s  of MAO by forming an  was i s o l a t e d , which may r e s u l t  from  or perhaps from a d i f f e r e n t  route.  M u l t i p l e forms of MAO and t h e i r I n i t i a l evidence  multiple  forms were obtained  phoresis  of p u r i f i e d  inhibitors.  that c h a r a c t e r i s t i c by polyacrylamide  solubilized  observed from t i s s u e s of s p e c i f i c methods of s o l u b i l i z a t i o n bands detected  selective  on the presence of m u l t i p l e forms of  MAO was derived from the f a c t  used.  (21)  However, i n the case of p h e n y l e t h y l h y d r a z i n e ,  rearrangement of the diazene  C.  diazene  enzyme. origin  gel  more s e n s i t i v e MAO-5 (70).  electro-  The same p a t t e r n was r e g a r d l e s s of the  employed although  the number of such  i s v a r i a b l e depending on the t i s s u e  I n i t i a l work done by Youdim et a l . (69)  of MAO i s o l a t e d  bands of  from r a t l i v e r .  and species  showed 5 bands  MA0-l,MA0-2, and MAO-3 were  to i n h i b i t i o n by c l o r g y l i n e  than MAO-4 and  Bands, MAO-4 and MAO-5 c o n t a i n lower  than MAO 1-3 (7.1).  However, a l l forms of r a t l i v e r  MAO have the same a b s o r p t i o n  spectra c h a r a c t e r i s t i c  f l a v i n moiety and have s i m i l a r Objection  phospholipid  molecular  weight  mitochondrial of the  (72,73).  to the concept of m u l t i p l e forms of MAO was  that bands on the g e l e l e c t r o p h o r e s i s might be a r t i f a c t s from the s o l u b i l i z a t i o n outer m i t o c h o n d r i a l  of MAO s i n c e MAO i s bound to the  l a y e r so t i g h t l y  have to be employed to s o l u b i l i z e  that d r a s t i c  and i s o l a t e  condition  the enzyme.  21  It was  shown that bands on the  the v a r y i n g was  phospholipid  gel e l e c t r o p h o r e s i s  content and  (74).  Houslay and  Tipton  the degree of i n h i b i t i o n by curve obtained phospholipid m a t e r i a l by  by  also  curve.  Two  multiple  sigmoidal  It  curve  forms of MAO.  type A MAO,  and  i s now  the p h o s p h o l i p i d  The  was  of MAO  Removal of  and  first  disappearance  the double sigmoid  type B  g e n e r a l l y admitted  i n v i t r o and  phospholipid  curve designates  the second by  content of MAO  associated  u s u a l l y employed to  explain  inhibition  MAO.  that t h i s d i f f e r e n c e i n  i s not  the process of s o l u b i l i z a t i o n but istics  the  agents r e s u l t s i n the  of s u b s t r a t e - s e l e c t i v e i n h i b i t i o n  that  the double sigmoid  c l o r g y l i n e depend s o l e l y on  chaeotropic  chaeotropic  (74) suggested  c l o r g y l i n e and  membraneous m a t e r i a l .  due  to an a r t i f a c t  c o n s t i t u t e s important  in vivo.  MAO  e x i s t s i n the  s t r o n g l y bound to d i f f e r e n t amounts of p h o s p h o l i p i d . t h i s a s s o c i a t i o n may in  substrate  formational  and  i n turn account f o r observed  inhibitor  specifities  and  Heat treatment i n f l u e n c e s the a c t i v i t i e s  A p l a u s i b l e explanation in  the s p e c i f i c  i n h i b i t i o n by  would be  that the  a l s o reported  differences  i n the  conMAO. extent  inhibitors (75).  conformation of  environment of l i p o p r o t e i n could  by heat treatment and It was  and  character-  Thus,  forms of  of MAO  in  cell  also explain  d i f f e r e n c e s between the m u l t i p l e  of o x i d a t i o n of s u b s t r a t e  to  that a homogenous band  observed a f t e r treatment of the enzyme(s) by a  agent  by  are due  be  thus show d i f f e r e n t enzymatic that t h e r m o s t a b i l i t y of MAO  MAO  affected activity.  preparations  22  was  dependent on the presence of p h o s p h o l i p i d  (76).  MAO B which c o n t a i n s high p h o s p h o l i p i d i s more " s e n s i t i v e to heat than MAO A.  The e f f i c a c y of p a r g y l i n e d e r i v a t i v e s i n  i n h i b i t i n g MAO i s to some extent r e l a t e d (64).  T h i s apparent r e l a t i o n s h i p between l i p o p h i l i c i t y and  i n h i b i t o r y potency importance  of p a r g y l i n e d e r i v a t i v e s suggest the  of the l i p i d  Yang and Neff of  to l i p o p h i l i c c h a r a c t e r  environment  of MAO.  (77) reported the e x i s t e n c e of two types  MAO i n v i v o by using s e l e c t i v e i n h i b i t o r s  pargyline.  Youdim et a l . (78) administered c l o r g y l i n e or  d e p r e n i l to two d i f f e r e n t demonstrate  c l o r g y l i n e and  groups  of r a t s i n an attempt to  the i n vivo e x i s t e n c e of type A and type B enzymes.  A n a l y s i s of u r i n e samples,  however, showed i n c o n c l u s i v e  Type A MAO s e l e c t i v e l y deaminates  results.  s e r o t o n i n and nor-  epinephrine and i s i n h i b i t e d by harmine and c l o r g y l i n e . B MAO s e l e c t i v e l y  deaminates  benzylamine  Type  and phenethylamine  and i s i n h i b i t e d by p a r g y l i n e and d e p r e n i l .  Tyramine,  dopamine, and tryptamine are common s u b s t r a t e s f o r both types and i n h i b i t o r s  such as tranylcypromine and p h e n y l e t h y l h y d r a z i n e  i n h i b i t both types to a s i m i l a r extent.  S e r o t o n i n , nor-  i  e p i n e p h r i n e , and c l o r g y l i n e which i n t e r a c t with MAO A have more p o l a r aromatic r i n g s than benzylamine, and d e p r e n i l which i n t e r a c t with type B MAO. adding a p o l a r hydroxyl group or  removing  substrate.  phenylethylamine, In g e n e r a l ,  to phenylethylamine  (tyramine)  one from s e r o t o n i n (tryptamine) produces  a common  The enzyme formed with the lower p h o s p h o l i p i d  23  content,  type A appears to be more s e n s i t i v e to  b y • c l o r g y l i n e s i n c e p e n e t r a t i o n through MAO  may  be a f a c t o r i n the s e n s i t i v i t y  lipid  inhibition  a s s o c i a t e d with  of c l o r g y l i n e  towards  the m u l t i p l e forms of the enzyme (77). Some evidence  was  bably not homogenous. t h e r e f o r e , may mitochondria  reported that mitochondria  The m u l t i p l e forms of s o l u b i l i z e d  result  MAO,  from d i f f e r e n t p r e p a r a t i o n s of  (79). However, i t was  found  that there i s no  obvious  c o r r e l a t i o n between h e t e r o g e n e i t y  MAO  the e l e c t r o p h o r e t i c a l l y  and  are pro-  of m i t o c h o n d r i a l  separable m u l t i p l e forms of  enzyme (80). Multiplicity  of MAO  i s not u n i v e r s a l .  MAO  from  sources  of p i g b r a i n , monkey small i n t e n s t i n e , and human p l a t e l e t s are homogenous.  For example, MAO  of only type B MAO.  from human p l a t e l e t s c o n s i s t s  Human p l a t e l e t MAO  be used to i n d i r e c t l y  evaluate MAO  P e r i p h e r a l sympathetic  nerves  s t u d i e s should  l e v e l s i n the b r a i n .  mainly  show type A MAO  a n t i h y p e r t e n s i v e a c t i o n i s produced by b l o c k i n g MAO p e r i p h e r a l neurons. the blockade  of MAO  and  hypertensive treatment.  Type A MAO  and  Thus i n order to design  to  accumulate i n  attempt to achieve  these  i s the  primary  antianti-  s t r u c t u r e should provide  p e n e t r a t i o n i n t o the b r a i n and One  i s related  a n t i d e p r e s s a n t therapy  the drug  as  s e r o t o n i n i n b r a i n leads to the  T h e r e f o r e , i t seems that type A MAO  c o n s i d e r a t i o n f o r both  neurons.  in  metabolism of t r a n s m i t t e r amines such  a l l e v i a t i o n of d e p r e s s i o n .  h y p e r t e n s i v e drugs,  and  I t i s a l s o g e n e r a l l y recognized that  dopamine, n o r e p i n e p h r i n e ,  substrates.  not  limited  sympathetic  t h i s s e l e c t i v e a c t i o n has  been  24  reported related  (81).  I t i s also  to the d e f i c i e n c y  specific  emphasized that  of s p e c i f i c biogenic  s i t e s of the b r a i n .  mortem s t u d i e s inhibitors  of p a t i e n t s  (82).  depression i s amines at  This was i l l u s t r a t e d  who had been t r e a t e d  with MAO  D i f f e r e n t MAO i n h i b i t o r y patterns  observed at d i f f e r e n t s i t e s of the b r a i n .  by post-  were  For example, MAO  of the p i n e a l body was the most s e n s i t i v e to i n h i b i t i o n by c l o r g y l i n e which i s a type A MAO i n h i b i t o r .  C o n c l u s i v e data  for these s t u d i e s , however, i s yet to be obtained s i n c e specimens are d i f f i c u l t 3.  such  to o b t a i n .  Thietane d e r i v a t i v e s as p o t e n t i a l MAO i n h i b i t o r s . It has been considered i n t h i s research  3-amino-2-phenylthietane d e v i v a t i v e s a useful  t o o l to e l u c i d a t e  by tranylcypromine-type  22  R= H  23  R = H I  R = H R = COC^H 2 3 65  24  R = H  R ,R = CH  25  R = N0'  _2_6  R  R  ±  2  2  1 =  N0  ' 3 R  2  2  R  =  3  ' 3 R  2  H  =  H  R ,R = CH 2  3  3  3  that  ( 2_2_ - _2_6_ ) could be  the mechanism  derivatives.  project  of i n h i b i t i o n of MAO  25  R e l a t i v e to tranylcypromine, 2-phenylcyclobutylamine i s only 1/1000  times as a c t i v e by i n v i t r o  difference in a c t i v i t y  i s presumably due  e l e c t r o n i c d e l o c a l i z a t i o n and  testing.  This  to the l o s s of  geometrical f a c t o r s .  Con-  t r i b u t i o n of g e o m e t r i c a l f a c t o r s seems to be minimally s i n c e 3-amino-2-phenylazetidine thietane  (18) and  ( 8 3 ) showed MAO-inhibitory  s u c c e s s f u l examples may  2-benzyl-3-dimethyl aminoactivity.  Although  above  give an evidence on the importance  e l e c t r o n i c property of cyclopane r i n g  of  f o r the tranylcypromine  d e r i v a t i v e s , s y n t h e s i s of 3-amino-2-phenyl t h i e t a n e d e r i v a t i v e s could provide a c o n f i r m i n g proof of B e l l e a u and Moran's hypothesis t i o n and  (17).  thus may  that attachment resulting  S u l f u r i s known to p a r t i c i p a t e i n conjugaenhance e l e c t r o n d e n s i t y of the r i n g  to the a c t i v e s i t e s of MAO  i n strong i n h i b i t o r y a c t i v i t y .  a t t e n t i o n has been drawn from s i m i l a r conformation X-ray work ( 8 4 ) .  the f a c t  that a z e t i d i n e has a unpublished  3-Amino-2-phenyl t h i e t a n e 1 , 1 - d i o x i d e to be poor  Some c o r r e l a t i o n could be drawn from  chloropromazine  strengthened,  Besides, s p e c i a l  to the t h i e t a n e s shown by  d e r i v a t i v e s s y n t h e s i z e d ( 8 5 ) proved MAO.  could be  i n h i b i t o r s of  the f a c t  that  s u l f o x i d e does not i n h i b i t MAO ( 1 0 ) .  E l e c t r o n a b s t r a c t i o n from s u l f o x i d e i s more d i f f i c u l t might lead to the lack of a c t i v i t y f a c t o r s may  so  of t h i s  and  compound, or  this  steric  come i n t o p l a y .  Mono—and  d i - s u b s t i t u t i o n of the amino group of t r a n y l c y -  promine with methyl  decreases a c t i v i t y  only  slightly.  N-Carbethoxy show a f a i r  (27) and N-Carbobenzoxy  (2 8) compounds a l s o  degree of a c t i v i t y (16).  NHCOX  27  X =0C H  28  X = 0CH„C,.H  2  5  2-Carbobenzoxy d e r i v a t i v e gave twice the i n v i v o a c t i v i t y as tranylcypromine.  I t was p o s t u l a t e d  that the a c t i v i t y  of the  a c y l d e r i v a t i v e i s due to t h e i r h y d r o l y s i s i n vivo to the parent amine.  In t h i s regard,  was  to be u s e f u l .  considered The  appeared  synthesis  of compound 2_3  of 3-amino-2-phenylthietane ; d e r i v a t i v e s  Worthwhile from the s y n t h e t i c point of view.  successful preparation (85)  synthesis  has been r e p o r t e d .  attempted to reduce  No  Wells and Abbott  3-dimethylamino-2-phenylthietane  1,1-dioxide and 3-morpholino-2-phenylthietane 1,1-dioxide with L i A l H ^ , only from r i n g cleavage.. phenylthietanol  i s o l a t i n g unidentified material r e s u l t i n g M o d i f i c a t i o n of a hydroxyl  en route  to azide  formation  group of 2-  and r e d u c t i o n to  the amino group was not s u c c e s s f u l (83). 4.  Synthetic The  routes  to t h i e t a n e s .  purpose of t h i s s e c t i o n i s not to'give a com-  prehensive d e s c r i p t i o n of s y n t h e t i c routes  to t h i e t a n e s but  to e x p l a i n why the r e a c t i o n of 1,3-dihaloalkanes with sulfides  i s the most p r o s p e c t i v e  s y n t h e t i c route  a.mino-2-phenylthietane d e r i v a t i v e s . t h e r e f o r e , are b r i e f l y mentioned.  to 3-  Major s y n t h e t i c Several  review  alkali  routes,  articles  have been published  on t h i e t a n e chemistry  (102, 103, 104,  105). Reduction of t h i e t a n e Treatment of 2_9 with  1,1-dioxide r e s u l t s i n t h i e t a n e .  L i A l H ^ gave _30 (86). The a p p l i c a b i l i t y  of t h i s method i s favored  by the f a c t  R=C1,  1  S  -s.o  2  that t h i e t a n e  1,1-dioxide  0C0CH , CH 3 3  3C2  29_  i s r e l a t i v e l y more s t a b l e than t h i e t a n e , and m o d i f i c a t i o n s of oxide  d e r i v a t i v e s are more e a s i l y  c y c l o a d d i t i o n of enamines with entry  accomplished.  s u l f e n e provides  Moreover, a convenient  to s u b s t i t u t e d t h i e t a n e 1,1-dioxides which can be r e -  duced to t h i e t a n e s having p o t e n t i a l MAO by reducing  inhibitors.  s t r u c t u r e s necessary f o r study as For example, 3_3 was  synthesized  32 prepared by r e a c t i n g an a c e t o n i t r i l e s o l u t i o n  N(CH,)..  33  28  of 31 and 0-5°  t r i e t h y l a m i n e with methane s u l f o n y l c h l o r i d e at  (83).  dioxides  L i m i t a t i o n s of the r e d u c t i o n of t h i e t a n e  to t h i e t a n e s were observed  substituted  i n the case of  derivatives . LiAlH^ reduction  but o f f e r r e d a complex mixture diethylamine was  identified N(Et-)  (87).  ,  (88).  stituted  1,1-dioxides was  a l k a l i c o r a l k a l i phenoxides Christy  S  ^-c„  2  (85)  sug-  thietane  of the 2-phenyl  sub-  demonstrated.  thietane  (90) prepared  ArO 2 C 1  ) 3  be too a c i d i c f o r hydride r e d u c t i o n of the  By r e a c t i n g c h l o r o m e t h y l t h i i r a n e  Dittmer and  N ( C H  substituted  Base c a t a l y s e d r i n g opening thietane  only  of 3_5 with  Wells and Abbott  gested that theo^ proton on 2-phenyl  sulfone.  attempted  to give 3-(N,N-  }  1,1-dioxides may  of 3h_ was  Reduction  2  thietane  2-phenyl  of products from which  L i A l H ^ however, i s r e a d i l y accomplished dimethylamino)  1,1-  (^6) with e i t h e r  (_3_7) was  formed (89).  3 - t h i e t a n o l by the  /  exposure  CH C l vj,  * **~»^ 2  ArO  36  3_7  of 3-chloropropylene oxide-1,2 hydroxide.  to hydrogen s u l f i d e and  3-Hydroxy-2-phenylthietane  (39) was  barium  prepared  by  29  treating  the oxide  (_3_8) with hydrogen s u l f i d e  to modify the hydroxyl  (83). Attempts  group to an amino group proved un-  s u c c e s s f u l (83).  -CH C1 2  38 Direct  c y c l o a d d i t i o n of thioketene with  gave t h i e t a n e s (CF ) 3  C=  2  3_9 certain olefins ^  (91). For example, b i s ( t r i f l u o r o m e t h y 1 ) C = S  40 (CF ) C3  CH 0-<V  —CK =  3  CH  OCH.  2  2  41 thioketene  42  4_0 reacted with p-methoxystyrene  t h i e t a n e 4_2.  The a p p l i c a b i l i t y  of t h i s  s y n t h e s i s of 3-amino-2-phenylthietane  to give the  r e a c t i o n to the d e r i v a t i v e s seems  limited. Thietane  44  was obtained  of the 1 , 3 - d i o l 43 with a l k a l i  C—0  \/ c  "  by h e a t i n g the c y c l i c thiocyanate  -CO  SCN  \ c=o  ^C—SCN  W  -> , C  (92). The high  c—0 2\ / i^i -> C C^=N /\ / x  c —o  Cr—0 C=.N  -  >  / G  Y  carbonate  -0CN  —  n  44  30  stereospecificity c e s s i v e S^2 prepared  supports  displacements  readily  the p o s t u l a t e d mechanism of (93).  The  1,3-dioxane-2-ones were  from the corresponding  exchange with e t h y l carbonate.  The  1,3-diols by e s t e r  advantage of t h i s method  compared to the r e a c t i o n of 1,3-dibromide with is  may  sodium  the greater convenience i n c o n v e r t i n g 1,3-diols  carbonate  suc-  e s t e r r a t h e r than 1,3-dibromides.  This  sulfide  into process  have a p p l i c a t i o n to the p r e p a r a t i o n of 2-phenyl-3-amino-  thietane d e r i v a t i v e s . 1,2-Dithiolanes (diethylamino)phosphide  undergo f a c i l e  d e s u l f u r i z a t i o n with  to give t h i e t a n e s .  By t h i s method,  the t e t r a h y d r o p y r a n y l e s t e r of c^--lipoic a c i d (after hydrolysis) thietane 2 - v a l e r i c acid  An attempted p r e p a r a t i o n of benzothiete failed.  tris  (4_5_) a f f o r d e d  (4_6/) (94).  (4_7) by t h i s method  31  47 Photocycloaddition thietanes bonyl  (4_8) a n d 1 , 4 - d i t h i a n s  excited  Ph c=s  state  reacts  hV  2  Ph  of t h i o c a r b o n y l s with  CR=CH,  with  P*h  (5 89  The  electron rich  alkenes  the  products  and t h e r a t i o  concentration  thiobenzophenone as  reacts with  dichloroethylene  R  Ph R  49  on s t e r i c  A higher  factors  energy  electron deficient  (5jO) t o g i v e  to give  48  7^s  depends  of thloketone.  thiocar-  Ph  Ph both  (n,jT*)  Ph  P,h-^ P h  gives  -> Ph  Vh  Ph  nm)  (4J9) ( 9 5 ) .  alkenes  a thietane  and on  s t a t e of  alkenes  such  (5_1) ,  s t e r e o s p e c i f i c a l l y (96).  Ph  2  +  C= S  ci  Cl P.h-  50 Thietanes actions case, is  from  both  prepared  a r e formed  thiocyanate  Ph by i n t r a m o l e c u l a r  with  sodium  c i s - and t r a n s - p r o d u c t s from  cyclization re-  hydride,  but i n this  a r e formed.  the r e a c t i o n of cyanogen  51  bromide  Thiocyanate on: t h i o l o r  32  from  nucleophilic reaction  of potassium  thiocyanate  NaH HS  NCS  Tr iglyme  OH  NaS Trost and  et a l .  (97) p r e p a r e d  cis-and  2,2,4-trimethylthietane  hydride.  Limitations  3-aminosubstituted primary sodium sible  amino hydride  group. might  Using  synthesis  may  react  reaction  Controulis  and  with.either  that  cyanogen  amino  of  of  the  bromide or  o f a t h i a z o l i n e may  the f o l l o w i n g  et a l .  sodium  f o r the synthesis  a'.r;e d u e t o t h e f a c t  to the synthesis  ONa  trans-2,4-dimethylthietane  the primary  approach,  N.CS  OCN  thiocyanate  formation  between  this  be a p p l i e d  derivatives.  of t h i s  and t h a t  by r e a c t i o n  from  thietanes  group  halogen.  NaH  Br CN  OH  on  and t h e sequences  be  pos-  thiocyanate of r e a c t i o n  3-amino-2-phenylthietane  (100) have  reported  the  of 2-nitro-l,3-propanediol (52). NO,  '/ Vs_  "»^  2  // W  — *  ^>— C H — C H — C H „ 0 H  <  OH  One is  o f t h e common  to react  (5 3)  with  alkali.  T"  z  ^//  CH-CH— CH 0H ^ >— C H — C H — C H n H ( ' SCN  methods  3-halogenated  NO,  2  V >  of p r e p a r a t i o n  of  thietanes  thiolacetate, thiol,  or  thiocyanate  33  X  SR  X  S  53  By  this  R= COCH , H, CN  method,  3-hydroxythietane  hydroxy-3-chloro-propanthiol The the  X  earliest  synthesis  dihaloalkanes  of  and  so  thietanes  with  alkali  was  from  2-  (101) .  f a r t h e most comprises sulfides  a l k a l i n e telle?a;v'ag"e o f t h e t h i o u r o n i u m  54  prepared  general  method f o r  the r e a c t i o n of or t h i o u r e a salt  (54).  1,3-  followed  by  34  DISCUSSION  It~'was considered 3-dihalogenoalkanes  that the r e a c t i o n between s u i t a b l e 1,  (56)  e f f e c t i v e f o r synthesis (_57_) V  Ring formation  possible i n s t a b i l i t y  OF THE CHEMISTRY  and a l k a l i s u l f i d e would be the most  of 3-amino-2-phenylthietane d e r i v a t i v e s at the l a s t  problem of t h i e t a n e s , which i s u s u a l l y  encountered when attempting structure.  m o d i f i c a t i o n of the t h i e t a n e  In a d d i t i o n , s i n c e the most f a v o r a b l e route i . e .  r e d u c t i o n of t h i e t a n e failed  step might overcome the  1,1-dioxides from c y c l o a d d i t i o n r e a c t i o n s  to give t h i e t a n e s  especially  i n the case of 2-phenyl  d e r i v a t i v e s , i t appeared d e s i r a b l e to adopt the most common and  classical  method f o r the s y n t h e s i s  of 3-amino-2-phenyl-  t h i e t a n e d e r i v a t i v e s (Scheme 1 ) . Scheme 1.  Proposed S y n t h e t i c phenylthietanes  routes  to 3-Amino-2-  (5_7) .  N  55  R — H > CH^ 2  56  57  35  1.  Synthetic  approach to 3-amino-2-phenylthietane (22)  A.  Phenylserinol Extensive  phenylserinol intermediate fact  .(5 5 , R = R-, = R 1  = H)  s t u d i e s have been done on the s y n t h e s i s of  (l-phenyl-2-amino-l,3-propanediol) f o r t h i s s y n t h e t i c approach.  which i s a key  This i s due to the  that p h e n y l s e r i n o l i s one of the important  for the s y n t h e s i s synthesis  of chloramphenicol.  intermediates  Three main methods of  of p h e n y l s e r i n o l have been published  g l y c i n e and benzaldehyde and  3  starting  (106,107), acetophenone  cinnamyl a l c o h o l (109).  The v a r i o u s  steps  from  (108),  are shown i n  methods, 1-3. Method 1 NH-CH.COOH NH 2 2 ,2 TS* C H — CHOHCH— COONa > C^H— CH—CH—COOH 65 | I C.H _CH=N ' OH 65 NH.HC1 NH„ l 2 I 2 ~> C,H-— CH—CH—C00C H >C,H— CH— CH— CH-OH 6 5 | 25 65 | 2 OH OH 108 58 0  C,H —CHO 6 5  r  6  5  Method 2 C-H— COCH. 65 3  > C,H— COCH.Br 65 2  —>  C,H_—COCH. (C.H. _N. )Br 65 2 6 12 4 NHC0CH„  -> C,H—C0CH„NH o 5 1 1  —> C-H — COCH.NHCOCH,, 6 5 2 3  o  NHC0CH' I  -> C,H—CH—CH o 5 j OH  i  NH„ I 2  o  ->  CH^OH 2.  3  ;> C-H=- COCH—CH„0H 65 2  > C,H— CH—CH—CH„0H 65 j I OH  36 Br -Method 3  Br >  C,H_CH— CH— CH 0H 6 5| 2 OH  >  o  \  C,H— CH 6 5 \ 0 CH  -> C,H— CH 6 5 v  Methods 2-3 show p a r t s of the route economical s y n t h e s i s of chloramphenicol.  r e p r e s e n t i n g an The hydroxyl  groups  of p h e n y l s e r i n o l are p r o t e c t e d by a c e t y l a t i o n and the t r i a c e t y l d e r i v a t i v e i s n i t r a t e d with  fuming n i t r i c  a c i d to give  1-(p-nitrophenyl)-1,3-diacetyl-2-acetylaminopropane. hydrolysis,  optical purification,  and r e a c t i o n with  l o r o a c e t a t e give chloramphenicol.  Acid methyldich-  Method 1 was followed  with  some m o d i f i c a t i o n i n the r e d u c t i o n step f o r the s y n t h e s i s of p h e n y l s e r i n o l used i n t h i s p r o j e c t . be a convenient reagents  route to p h e n y l s e r i n o l , the ease of a c q u i r i n g  and references was considered  The and  Although method 3 could  main product  i n favor  from the condensation  of method 1.  of benzaldehyde  g l y c i n e under a l k a l i n e c o n d i t i o n i s o r d i n a r i l y  phenylserine. (106).  threo-  However, some erythro-compound i s a l s o formed  Shaw and Fox (107) i s o l a t e d  from the condensation  each of the  mixture by using s e l e c t i v e  diastereomers recrystal-  l i z a t i o n or by s e l e c t i v e p r e c i p i t a t i o n of the s t a b l e a d d i t i o n compound of the erythro that the r a t i o densation  form with  dioxane.  of each diastereomer  They a l s o  reported  i s dependent on the con-  time and thus found that a 24 hours r e a c t i o n time  r e s u l t s e x c l u s i v e l y i n the threo  form.  Thus, f o l l o w i n g the  37  procedure of Shaw and Fox, t h r e o - p h e n y l s e r i n e The  was  o r i g n a l work by Shaw and Fox u t i l i z e d  reduce p h e n y l s e r i n e  ethylester.  L i A l H ^ to  In t h i s experiment, NaBH^  was used f o r the r e d u c t i o n process. a c t i v e ^ - aminoalcohols  prepared.  Synthesis  of o p t i c a l l y -  by the r e d u c t i o n of^-amino a c i d  with NaBH^ was published  by Seki et a l . (110).  the r e d u c t i o n i s accomplished  esters  They found that  i n high y i e l d with more than  four moles of NaBH, to one mole of e s t e r i n a 50 % ethanol 4  solvent a f t e r s t i r r i n g at 0-10° t h i s process salt  to p h e n y l s e r i n e  showed that continuous  f o r 2 days.  A p p l i c a t i o n of  e t h y l e s t e r or i t s h y d r o c h l o r i d e e x t r a c t i o n was necessary  a high y i e l d but i t does ensure e a s i e r handling  to o b t a i n  compared to  us ing L i A l H ^ . Since  '  t h r e o - p h e n y l s e r i n o l i s a key intermediate  in this  research p r o j e c t , s e v e r a l methods were used to confirm i t s structure.  M e l t i n g p o i n t s of t h r e o - p h e n y l s e r i n o l and i t s  o x a l i c and benzoic  a c i d s a l t s were i d e n t i c a l with  values  Suzuki  (111,112).  absorption  and Shino  the reported  (113) reported  a single  i n the region of 950-1000 cm ^ i n the threo-  compound and 900-950 cm ^ i n the erythro compound p o s s i b l y due to the C-H bond of the assymetric ir  spectrum i n the region of 850-1100 cm ^ was  with  synthesized  not obtained, and  carbon atom.  threo-phenylserinol.  but Koya and Yamada  using a c e t i c a c i d as s o l v e n t .  published  identical  An nmr spectrum was  (114) reported  4.86~ for the e r y t h r o - b e n z y l i c proton c  Their  5.16"C f o r threo-  of p h e n y l s e r i n o l  The mass spectrum of threo-  38  Scheme 2.  Proposed Fragmentation Pattern of threoPhenylserinol (58) in the Mass Spectrum  /  VCH-i-CH-^CH„OH  N  OH M"m/e 167 (2) +  r  / ~ ^  H  -  C  H  -  N  NH^CH—CH OH  H 2  OH m/e 136 (19) ^  m/e 60 (100) + U&zz C~ NH„  -OH*  m/e 118 (60)  v VCH=:  + NH— CH—CH •  H  m/e 107 (26)  m/e 43 (100)  -H«  // \X  -H«  + CH= 0"  + NH^=rC=CH  m/e 106 (57)  m/e 42 (100)  -H«  A c , :  (80)  m/e 105 C  6 5 H  +  m/e 77 (100)  ^  C  4 3  +  H  m/e 51 (58)  39  p h e n y l s e r i n o l was s t u d i e d .  The molecular i o n was observed  and  c o n s i s t e n t with the peaks observed  a fragmentation p a t t e r n  i s presented i n jcheme 2. B.  Threo-l-phenyl-1.3-dichloro-2-aminopropane (56, R. l  R, "2  According  to Ikuma (115), both the threo-(5 8) and erythro-  L  phenylserinol  R  = H)  3  (5_9) give r i s e  aminopropane-3-ol(60)  to t h r e o - l - p h e n y l - l - c h l o r o - 2 -  when t r e a t e d with t h i o n y l c h l o r i d e .  This r e a c t i o n has been studied  e x t e n s i v e l y by the f a c t  i n v e r s i o n of the erythro  compound to threo  a p p l i e d i n the s y n t h e s i s  of chloramphenicol which  a threo  form.  form could be  (115).  P a r t i c i p a t i o n of the  amino group i n the s u b s t i t u t i o n of the hydroxyl  I  H— C— NIL  requires  The f o l l o w i n g mechanism was suggested to  e x p l a i n the Walden I n v e r s i o n  'HO— C- H  that  group by  vr  c i o s o - C—H  I  H— ;C —NH  CH 0H  CH 0H  2  CH 0H  2  2  CL- C —H  58  H-C—NH^HCl CH C1 2  H— C —-(OH I  H— C— NH„ CH 0H 2  " 59  I C l ^ |* H—C — 0 I . > H—C— NH„ K—C—0S0C1  I  •s—oci H— c— i r *  2  CHlOH 2  1  | H  2  CH 0H  Xll-r C —H  H—C-NH HC1 2  CH OH 2  2  60  40  c h l o r i n e when t r e a t e d with t h i o n y l c h l o r i d e was w e l l Threo-l-phenyl-l-chloro-2-aminopropane-3-ol synthesized chloride.  by t r e a t i n g p h e n y l s e r i n o l  known.  (^0) was  hydrochloride  with  A major d i f f e r e n c e i n the i r spectrum of the  product was observed i n the range of 1200-1000 cm ^. of p h e n y l s e r i n o l ,  two strong  absorptions  secondary a l c o h o l at 1070 cm The  and primary a l c o h o l at 1040 cm  However, the f a c t that r e f e r e n c e  absorption data assigned  to primary and secondary a l c o h o l are 1075-1010 cm 1120-1100 cm  respectively  In case  were assigned to the  c h l o r i n a t i o n product showed primary a l c o h o l  at 1050 cm ^.  (116) and that  structure  and deter-  mination performed i n 1950's might be based on f r i a b l e prompted c o n f i r m a t i o n The  mass spectrum c l e a r l y  154 implied  chloro  data  of t h i s s t r u c t u r e by mass spectrometry. complied with the C - l chloro  compound as shown i n Scheme 3. m/e  thion  Fragmentation at m/e  60 and  the presence of primary a l c o h o l and C - l  substitution. Threo-phenylserinol  hydrochloride  was t r e a t e d with an  excess amount of t h i o n y l c h l o r i d e i n dry chloroform f o r the purpose of o b t a i n i n g  threo-l-phenyl—.'il- „3--dichlorb-3-amino-  propane (56_, R^ = R^ = R^ = H) . (60)  was i s o l a t e d .  under r i g o r o u s material.  Only monochloro compound  The treatment of 6_0 with t h i o n y l c h l o r i d e  conditions  l e d to i s o l a t i o n of the s t a r t i n g  A p o s s i b l e reason f o r the r e s i s t a n c e  of the primary  a l c o h o l group to c h l o r i n a t i o n by t h i o n y l c h l o r i d e i s not known but  may r e s u l t from some p a r t i c i p a t i o n of the neighbouring  amino group.  Scheme 3.  Proposed  Fragmentation  Patten of 1-Phenyl-l-chloro-  r2h.aminoprc),pane-3-ole (60)  i n the Mass Spectrum.  ~1+ • IH- CH—CH 2 0H Cl (M+2)+* m/e 187  (1)  — H0CH„ (/  y-CH-CH=NH  1 2  Cl  + 154  m/e  Cl  N H ^ CH—CH 2 0H  (2)  (100)  m/e 60 -Cl-  + = NH„ m/e 119  -OH-  (53)  -H«  N H ~ C H — CH * 2  2  m/e 43 (5) ^ ~ ^ - C H = C = NH  m/e 118  2  r-H'  (61)  + -HCN  NH=  C=CH  m/e 42 ft  M  m/e 91  (7)  2  (6)  42  2.  S y n t h e t i c approach to 3-amino-2-phenylthietane v i a a thiocyanate  intermediate.  This f a i l u r e to prepare  ,  threo-l-phenyl-1,3-dichloro-2-  aminopropane l e d to a new s y n t h e t i c scheme.using  threo-1-  pheny1-1-chloro-2-aminopropane-3-o1. Scheme 4.  Proposed s y n t h e t i c route to t h i e t a n e s v i a a thiocyanate  intermediate  22 This scheme,however, contains s e v e r a l problems. of a thiocyante  group with a neighbouring  Reaction  amino group i s  w e l l documented as shown by the s y n t h e s i s of t h i a z o l i n e or t h i a z o l e d e r i v a t i v e s (117). observed  that  R a c h l i n and Enemark  3-chloro-(3,4-dihydroxy  hydrochloride r : d ^ ;  phenyl)ethylamine  (64) r e a c t s with potassium  form the t h i a z o l i n e  (6^5) .  (118)  thiocyanate to  43 HO HO - V HO-  /  /  \ V-CH—:CH—NH  2  V—CH —  CH.  HC1  Cl 64  NH  n  65 Sodium hydride i s a u s e f u l reagent its  sodio d e r i v a t i v e .  hydroxyl group may  to convert an amine to  T h e r e f o r e , the amino, as w e l l as  react with sodium hydride under the  c o n d i t i o n s causing formation of side products. of the t h i o l  group to a t h i o c y a n a t e group  the reaction  Conversion  using cyanogen  bromide may-.: a l s o i n v o l v e r e a c t i o n of the cyanogen bromide with the amino group. OH BrCN  67  66 An  example of t h i s p o s s i b l e side r e a c t i o n i s i l l u s t r a t e d  by  the r e a c t i o n of cyanogen bromide with the 1,2-amino a l c o h o l (66) to form  the t r i c y c l i c  In s p i t e  was  67  (119).  of the above weak p o i n t s , i t was  posed that the product 4 through  product  controlling  s t r o n g l y .pro-  (2_2) could be s y n t h e s i z e d v i a Scheme the r e a c t i o n  conditions.  The  assumption  that the r e a c t i o n of.': thiocyanate with amino group may  avoided by r e a c t i n g at low  temperature..  For example, the  r e a c t i o n of cyanogen bromide with the sodium s a l t type thiamine  (68) at i c e - c o o l i n g  be  temperatures  of the  thiol-  a f f o r d e d the  44  CH,  'NH  CH;  2  .CHO  NH„ ,CHO  .SNa  L  /  CH CH OH 2  2  V  CH  CH CH OH  3  68  cyanothiamine followed A.  2  2  69  (<6_9) (98) .  D i s s o l v i n g the cyanothiamine i n H 0 2  by treatment of a l k a l i gave the t h i e t a n e  (70)  2-Amino-4-hydroxy . m e t h y l - 5 - p h e n y l - 2 - t h i a z o l i n e  (99).  (74)  Thiocyanate anion i s a strong n u c l e o p h i l e , but u s u a l l y s u b s t i t u t i o n of c h l o r i n e by potassium thiocyanate r e f l u x i n g temperatures  (120).  requires  To ensure that the r e a c t i o n would  proceed at low 'temperature, dicyclohexyl-18-crown-6 (]_3^) was used.  These p o l y e t h e r  related  complexes of sodium, potassium, and  cations by n e u t r a l molecules lead-- to s o l u b i l i z a t i o n  of the s a l t  i n a p r o t i c solvent  of the i o n p a i r s provides (121).  h i g h l y r e a c t i v e , unsolvated  The h y d r o l y s i s of s t e r i c a l l y  is greatly accelerated polyether  (122).  chloroform  for 6  hindered  anions  e s t e r s (71)  i n the presence of the appropriate  The r e a c t i o n of b e n z y l c h l o r i d e  potassium thiocyanate  yield  and i n c r e a s i n g d i s s o c i a t i o n  with  i n the presence of K r y p t o f i x  days at room temperature gives  of b e n z y l t h i o c y a n a t e  (72).  222 i n  an 80 %  45 C0 CH CH„ 2  H C  COOH ,  3  ' Dicydohexyl18 — crown - 6  C R  KOH 71 Kryptofix C H  2  222 CH SCN  KSCN  C 1  2  72  73 The potassium crown-6 was Monochlof.d  t h i o c y a n a t e complex of d i c y c l o h e x y l - 1 8 -  prepared by the method of Pederson compound (60) d i s s o l v e d  with polyether-potassium perature.  (123) .  i n methanol was  t h i o c y a n a t e complex at room tem-  However, attempts  to separate r e a c t i o n  from the p o l y e t h e r complex were not s u c c e s s f u l . polyether e f f i c i e n t l y  of 2 stereoisomers and i s  s o l u b l e i n both p r o t i c and a p r o t i c s o l v e n t s . s e p a r a t i o n i s a problem out or can be d i s t i l l e d .  of  the r e a c t i o n  While  only s o l u b l e i n p r o t i c s o l v e n t s .  (_7_3) i s a mixture  the formation of any  products  a c t i v a t e s the a n i o n i c f u n c t i o n i n  a p r o t i c s o l v e n t , 60_ was Polyether  treated  Therefore,  unless the product i s p r e c i p i t a t e d I t was  not p o s s i b l e to confirm  t h i o c y a n a t e product by i r spectroscopy  mixture.  46  Another route to s y n t h e s i z e instead using 4, the  of d i r e c t r e a c t i o n with potassium t h i o c y a n a t e i s by  organic  the  t h i o s u l f a t e (Bunte s a l t ) .  Bunte s a l t  thiocyanate  usually  (61)  (6 2) at room temperature.  absorption  at 1200  and  Presence of a strong  640  cm  ^ could  be  The 1230  cm  cm  used s p e c i f i c a l l y  f u r t h e r proved that  a strong  The  not  to d i f f e r e n t i a t e -SO2CI  Bunte s a l t  (6_1) was stirred  which appeared to be  dissolved  band at 1640  cm  example  Identifi-  cm  the b a s i s  i r spectrum has  The  an  Product p r e c i p i t a t e d of a  (Fig.l) .  In  been signed as the  absence of e x t e r n a l  formation of t h i a z o l i n e (7_4) was  by mass spectrometry.  adding  at room temperature with  ^ of the  s t r e t c h i n g v i b r a t i o n i n the The  the  i n water by  a t h i a z o l i n e on  t h i a z o l i n e , a band near 1640  (125) .  shown by  s u c c e s s f u l because of i t s  equimolar amount of sodium cyanide.  strong  absorption  point.  sodium carbonate and  out  group.  band at  benzylsulfonylchloride.  c a t i o n by mass spectrometry was high melting  strong  ^ i n d i c a t i n g the -S02~  It i s evident  a c i d and  reaction is  i r spectrum showed  from -SO2OH of i t s hydrolyzed product as of b e n z y l s u l f o n i c  The  forming  1-phenyl-l-thiosulfuryl-2-  band at 640  -SO2O- group.  shown i n Scheme  Treatment of 60^  completed i n h a l f an hour (124).  aminopropane-3-ol (6>_1) .  the  As  r e a c t s with a l k a l i cyanide  with sodium t h i o s u l f a t e gave  by  t h i o c y a n a t e compounds  conjugation  further  mass spectrum reported  C =N  for  confirmed  48  2-aminothiazoline as d e s c r i b e d below the molecular  (75) shows three f i s s i o n s across the r i n g (126).  Synthesized  (7_4) gave  i o n and a l s o fragmented by a_ and b_ f i s s i o n .  m/e 56 m/e 45  thiazoline  Scheme 5.  Proposed Fragmentation Pattern of 2-Amino-4hydr.bxy ';methyl-5-phenyl-2-thiazoi.ii.f ] (74) :  1  ^ \ j - C - C H  \//  '  C  e  0H~| ' +  2  a  NH  2  M  + . m/e 208 (3)  — HOCtL H  H  c= c —CH OH1 "* 2  Y  m/e 134  NH„  m/e  177 (100) b  H H  H  H  // W c - i  m/e 117 (11)  + m/e 135 (25)  + HC= S m /e 45 (12) ^  m/e 121  +  V>^H=C=CH . m/e 115 (12)  c= s ( 9 V * _ C  „  /  +  65 H  m/e 77 (15)  + C  +  f  + il  4 3 H  m/e 51 (11)  m/e 91 (36)  50  The  facile  formation  of t h i a z o l i n e '(74) even at room  temperature i n d i c a t e s the ease of r e a c t i o n of the group with sequently B.  the neighbouring t h i s approach  amino group i n t h i s case and  to the t h i e t a n e s proved  disappointing.  investigated in a preliminary  f o r the s y n t h e s i s and adrenergic  fashion.  This stemmed  ,  .  NH„HC1 /7~\ l 2 (' )-CH- CH—CH— OH X  \=J  k  be of i n t e r e s t  t e s t i n g of chloramphenicol  compounds.  One  derivatives  p o s s i b l e m o d i f i c a t i o n of  the  CH„C,H.S0 Cl , , NH„ (or NH-S0 C,H.CH.) 3 6 4 2 /—\ |2 2 6 4 3 ^ (/ )-CH—CH-CH— 0S0„ C,H.CH o  o  X  0  J  V=L/  2  —  2 6 4  2  H  NH (or-NH—S0 C H.CH„) | 2 2 6 4 3 o  —  (63).  the compounds i n Scheme 4  from the f a c t that 1-mercapto d e r i v a t i v e s may  and  con-  l-Phenyl-l-mercapto-2-aminopropane-3-ol h y d r o c h l o r i d e An a l t e r n a t i v e approach using  was  thiocyanate  < g > -  C  / ) c H  3  £  2  s 1-mercapto compound 6_3 to t h i e t a n e s as shown above.  The  could not be r u l e d  r e a c t i v i t y of t o s y l c h l o r i d e might  s e l e c t i v e t o s y l a t i o n of the primary hydroxyl may  be cleaved  a f t e r formation  At l e a s t , t o s y l  t h i e t a n e would be worthwhile to t e s t  cological activity  as a MAO  time used f o r t h i s r e s e a r c h ,  provide  Tosylamide  of the t h i e t a n e by a l k a l i n e  c o n d i t i o n s or by r e d u c t i v e cleavage. stituted  group.  out  inhibitor. i t was  part of the work to the s y n t h e s i s  sub-  f o r pharma-  However, c o n s i d e r i n g  determined to r e s t r i c t  of the  the  this  1-mercapto compound  51  Scheme 6.  Proposed Fragmentation Pattern of 1-Phenyl-l-mercapto2-aminopropane-3-ol a i  (/  \  !  +•  2  (M+l) * m/e 184 (04) +  +  +•  V~CHrCH=NH  \=y  b NH •  y-CH-r CH-}-CHOH SH  // \\  (63) in the Mass Spectrum.  I i  NH = CH—CH 0H 2  0  2  m/e 60 (100)  HS-  SH m/e 152 (8)  CH - CH=NH  2  - HO-  m/e 119 (18)  Or N  + NH = CH—CH^  -H<  + SH m/e 123 (4) J  m/e 43 (18)  + ^ ~ ^ _ C H — C—NH  2  -H«  - H'  m/e 118 (26)  <0^  +  ch=  N H  m/e 122 (7)  -H*  m/e 91 (43)  + C= S m/e 121 (14) '6 5 m/e 77 (22) G  H  4 3 m/e 51.(18) C  H  +  Z=  C = C H  2  5 2  itself.  Acid—catalyzed  h y d r o l y s i s of S - a l k y l and S - a r y l  t h i o s u l f a t e i s a u s e f u l method of preparing Hydrolysis  of Bunte s a l t  thiols  are known A - l processes.  h y d r o l y s i s i s u s u a l l y performed i n s i t u without  R - S - S 0  using  +  3  sulfuric  H  +  f  a  ^  s  t  +  R - S - S 0  or h y d r o c h l o r i c  band at  2 5 2 0  cm ^  (61).  S  3  ± ° ™ - > - R S H  The isolation  +  patterns  3  a c i d was used to prepare 6 _ 3  The i r spectrum showed a t y p i c a l  i n d i c a t i n g the mercapto group  (Fig.  A molecular i o n was observed i n the mass spectrum. tion  S C >  acid .  Concentrated h y d r o c h l o r i c from the Bunte s a l t  - i  (127) .  2 ) .  Fragmenta-  f o r 63 which account f o r observed peaks are shown  i n Scheme 6 . 3.  Synthetic The  approach to 3 - b e n z o y l a m i n o - 2 - p h e n y l t h i e t a n e  approach proposed f o r the s y n t h e s i s  of.3-benzoylamino-  2-phenylthietane  (2_3)  i n t h i s research  p r o j e c t i s o u t l i n e d i n Scheme 7 .  considered  (23).  as a p o t e n t i a l MAO  inhibitor  54  Scheme 7.  Proposed  s y n t h e t i c route to  3-benzoylamino-2-phenylthietane  (^_3) .  NHCOCgH -> / /  \\-CH- CH— CH_OCOC-.H 2 6 5 OCOC^H 65 c  c  64 NHCOC^H  NHCOC^H  r  r  CH-CH—CH„OH  >  //  \yCH—CH—CH C1 0  66 NHCOC^H 65 r  23  A l t h o u g h 1-pheny 1-2-aminopr opane-1 , 3 - d i o l 1-phenyl-l, 3-dichloro-2-aminopropane synethesis attempt appeared group.  o f 6_6 f r o m 6_5 a p p e a r e d  to prepare  failed  (56, R ^ R ^ R ^ H ) ,  possible.  to give the  The u n s u c c e s s f u l  1-phenyl-l,3-dichloro-2-aminopropane  due t o t h e e l e c t r o n i c c h a r a c t e r  o f t h e p r i m a r y amino  A d e c r e a s e o f e l e c t r o n d e n s i t y as i n t h e amino f u n c t i o n  of t h e amide compound primary  (5_8)  alcohol  group.  (6_5) m i g h t a l l o w c h l o r i n a t i o n o f t h e  55  A.  1-Phenyl-l,3-dichloro-2-benzoylaminopropane S e v e r a l methods f o r the s y n t h e s i s of  serinol  (^4)  have been p u b l i s h e d .  r e a c t i o n does not guarantee group.  The  (128) .  (6^-) and  shown below  Schotten-Baumann  s e l e c t i v e b e n z o y l a t i o n of the amino  to hydrolyze  Another procedure  N-benzoylphenyl-  direct  T h e r e f o r e , a p o s s i b l e route was  compound  (66).  to use  the  tribenzoyl  i t by using sodium  i s to s t a r t  from  hydroxide  cinnamyl  a l c o h o l as  (128). M-CH=CH— CH„OH  (/ V~CH—CH—CH„0H \ — /' Br Br 68  >  1  1  N  // {'  ^  X  NH / \)-CH— \ " // CH— CH^-0-C-C^H (' /  I  I  Br  Br  2  6  5  r  \  N  69  NHCOCH, \v/— \ CH —CH— t CH„ OH 6  N  /  I  '  5  2  OH  «  In t h i s r e s e a r c h p r o j e c t , N - b e n z o y l p h e n y l s e r i n o l prepared The  by s e l e c t i v e h y d r o l y s i s of the t r i b e n z o y l  t r i b e n z o y l compound was  r e a c t i o n using an excess  prepared  compound.  chloride.  spectrum of s y n t h e s i z e d N - b e n z o y l p h e n y l s e r i n o l  hydrolysis.  The i r  showed amide  implying the success  N - b e n z o y l p h e n y l s e r i n o l was  of  r e f l u x e d with  selective thionyl  c h l o r i d e and work up gave c r y s t a l s which showed a s l i g h t band and no hydroxyl bands i n the range of 1200 i n the i r spectrum. solvent  Benzene was  an e f f i c i e n t  to remove the contaminating  3-dichloro-2-benzoylaminopropane  was  by the Schotten-Baumann  amount of benzoyl  bands but no ketone band thus  (^_5)  - 1000  ketone  cm ^  recrystalization  iv.ketone compound. 1-Phenyl-l,  (66) showed a mp  of 148-150.  56  A r e p o r t has been p u b l i s h e d on the s y n t h e s i s of 6^6_ from 70 by t r e a t i n g with t h i o n y l c h l o r i d e  (129).  A mp  70 was  reported.  No  of 131-132  66  s p e c t r o s c o p i c data was  mentioned.  This  d i f f e r e n c e i n m e l t i n g point of s y n t h e s i z e d compound from reported one  prompted c o n f i r m a t i o n of the s t r u c t u r e of 6_6 by  using s p e c t r o s c o p i c data and  elemental a n a l y s i s .  bands appear i n the i r spectrum. present.  the  Two  amide  Hydroxyl bands are no  In the ...nmr spectrum, two  longer  ortho-phenyl protons to-  the carbonyl group have s i g n a l s i n the 7.50-7.73^ r e g i o n . The  remaining  eight phenyl protons appeared  at 7.60-7.37 &  at 5.32 S  as a m u l t i p l e t .  A doublet appeared  methine proton.  Methylene protons attached to c h l o r i n e were  shown at 3.50^ ,-.a;s a m u l t i p l e t . due  i s due  to the  This m u l t i p l e t nature seems  to the c o u p l i n g not only with the neighbouring methine but  also with phenyl protons.  The broad  bands centered at  6.40^  were assigned to the proton i n the amide group. Mass data was  collected  f o r 66 and  compared with  s t a r t i n g material, N-benzoylphenylserinol  (65).  The  fragmen-  t a t i o n of N - b e n z o y l p h e n y l s e r i n o l i s shown i n Scheme 8. base peak at m/e phenylserinol.  164  corresponds  A peak at m/e  to the m/e  240 was  the  The  60 fragment of  observed  with high  Scheme 8.  Proposed F r a g m e n t a t i o n P a t t e r n o f N-Benzoylphenylserinol  (65) i n t h e Mass  Spectrum  0 il  NHC C ^ I  i  r  6  r  5  CH—CH-i-CH 0H I : ' 2 OH a b o  i/e  2 7 1  q NHC  ft  A-CH  — C H — N H C  6H m/e 2  C . H -  6  4 0  I  :  1  C , H  6  + C H — C H  5  ( 4 5 )  + 7  \\_CH=0.  m/e  -OH-  C  5  2  0 H  1 6 4  ( 1 0 0 )  -HOm/e  1 0 6  ( 9 5 )  NH-Cr' 6 5 C  (I  X  +CH  >-CH— C H — NHC C,.H. o 5 m/e 2 2 3 ( 2 7 ) C  M/  m/e 147 (100)  + hHm/e  1 0 5  ( 1 0 0 )  0 ^  ^-CH=^C-NHC C,H  N  -CO  I  6  m/e  2 2 2  C  H  5  ( 4 5 )  C  m/e  6 5 H  7 7  ( 1 0 )  58  Scheme 9.  Proposed Fragmentation Pattern of 1-Phenyl-l, 3-dihalo-2-N-benzoylaminopropane i n the Mass Spectrum.  0  I  Il  NHC  C . H  | | ;  L T I / /  N  >  —  '  :  \ _ C H J -  X  6  C  5  C H - ^ C H „ X  ,  a  2  b  N  NHC C^H r  1  6  +CH—CH2X X = Cl  m/e 182, 184  X = Br  m/e 226, '.228  *> 6 5  I  I  CH- CH—CH.  5  C  0  I  X X = C1  m/e 271  +  H  C,H C — C = 0 6 5  I  CHr: C—CH. m/e 235  m/e 105  +CH —CH„ f./e 146  H N C  6H5  +  i/e 77  / T V  //  A\  \ \ - C H = C — CH m/e 130  + C  4H3 m/e 51  CH m/e 103  m/e 91  59  i n t e n s i t y by b_ f i s s i o n .  As shown i n the mass s p e c t r a f o r 66^  i n Scheme 9, m/e 271 and 235 showed the rearrangement of Nbenzoyldichloro  compound  (6 6) to the o x a z o l i n e s t r u c t u r e .  Fragmentations by ID f i s s i o n were not observed. by a. f i s s i o n  Fragmentations  showed r a t i o s of n a t u r a l i s o t o p i c abundances at  m/e  182 and 184 f o r the chlorocompound 66^ and at m/e 226  and  228 f o r the bromocompound 7 2. Elemental  B.  a n a l y s i s supported  1  these  spectroscopic  data.  1-Phenyl-l,3-dibromo-2-benzoylaminopropane (72). The  r i n g c l o s u r e r e a c t i o n to t h i e t a n e was  performed using the N - b e n z o y l - d i c h l o r o r e s e a r c h progressed,  (10 9) caused a low y i e l d . has been w e l l d e s c r i b e d  6  zu  2  Rearrangement to the e s t e r  The rearrangement of 65 to 109  S0C1  5  2  /  >  0 H  __.  / /  NH HCl 2  \ V C H - C H - C H  \— /  O H  0 C 0 C  6  H  109  Moreover, p r e p a r a t i o n of 66^ s t a r t i n g benzaldehyde was considered  from g l y c i n e and  a time consuming process.  f o r e , 1-phenyl-l, 3-dibromo-2-benzoylaminopropane  The  2  ci  65  synthesized  As  (130) .  NHCOC H \ \ - C H ^ C H - C H  (6^6).  s e v e r a l problems were encountered con-  cerning the p r e p a r a t i o n of 66^.  ['  compound  initially  There-  (_7_2) was  to s u b s t i t u t e f o r the d i c h l o r o compound. s y n t h e s i s of 72 s t a r t i n g  (67) has been reported  i n the patent  i  from cinnamyl a l c o h o l literature  (131,132).  5  60  The  a l c o h o l , mp 3 0 - 3 3 ,  cinnamyl  has been assigned  H  the trans  H  H  HCl HN  C=C—CH„ OH H  '  1 6  ?  B  r B  r  68  ^ Br  "  7 1  "  q .  I' •  .  H  II  HN  .  V - C — C——CH— CH-— O-C 0 — —C — C.H \\-C-C C.H^s(' ' Br Br N  s  x  .  6  H  ^  C  C—CH.I \ \\>— — C —C—C—CH„Br ' Br H  9  configuration.  6H5  72  Assuming that halogens,  recognized, add p r e f e r e n t i a l l y in a trans f a s h i o n ( 1 3 3 ) ,  to o l e f i n i c  the dibromide  the erythro c o n f i g u r a t i o n .  as i s g e n e r a l l y double  bonds  (6J5) may be assigned  A dry ether s o l u t i o n of 6 8  and  b e n z o n i t r i l e upon s a t u r a t i o n with dry hydrogen c h l o r i d e  and  standing i n the cold gave 7_1 which was then converted to  i t s base by treatment  with sodium carbonate.  The y i e l d was  dependent upon anhydrous c o n d i t i o n s of the r e a c t i o n mixture i n the condensation before use. initial  step.  Compound 6^9 was c a r e f u l l y  dried  R e f l u x i n g 6^9 d i s s o l v e d i n dry toluene gave an  p r e c i p i t a t e , the i r spectrum of which was i d e n t i c a l  to the hydrobromide of 6_9_ reported by Taguche et a l ( 1 3 0 ) . Further r e f l u x i n g and evaporation of the s o l v e n t under pressure r e s u l t e d compound  (_72_) •  reduced  i n p r e c i p i t a t i o n of the N-benzpyl dibromo  The i r and nmr spectra of 7_2 were i d e n t i c a l to  those of the N-benzoyl d i c h l o r o compound  (6j6) .  The mass  spectrum a l s o showed the same p a t t e r n of fragmentation of the N - b e n z o y l d i c h l o r o  compound  (Scheme 9 ) .  A high  as that intensity  5  61  peak at m/e  235  was  similarly  i n d i c a t i v e of formation  of an  oxazoline. C.  2-Phenyl-4-benzylidene-2-oxazoline  (78)  When an ethanol s o l u t i o n of 1 - p h e n y l - l , 3 - d i c h l o r o - 2 benzoylaminopropane laminopropane turned  (7_2)) was  (or 1-phenyl-l,3-dibromo-2-benzoy-  t r e a t e d with sodium s u l f i d e , the  to a yellow c o l o r .  distilling and  (66)  After refluxing  the s o l v e n t , the r e s i d u e was  e x t r a c t e d with chloroform.  at R^  0.7.  0.2,  i r spectra.  present  f o r the major component  with R^  0.2  0.5  The  main e f f o r t was  0.7.  0, 0.2,  0.5  Since components  i n very small amounts, f u r t h e r  s t r u c t u r e s were not concentrated  s t r u c t u r e of the major component at R^ bands i n t h e i r spectrum did not  and  Amide bands were not  ( F i g . 4).  were i s o l a t e d  attempts to determine t h e i r  and  successful in isolating  Components of R^s  showed amide bands i n t h e i r  and  0.5,  silica  P r e p a r a t i v e column chromato-  graphy using chloroform as eluant was each of the components.  obtained  TIC of t h i s r e s i d u e on  p l a t e s showed 4 spots with R^sO,  The major spot was  and  d i s s o l v e d i n water  A v i s c o u s r e s i d u e was  a f t e r removing the chloroform. gel  f o r 2 hours  solution  support  Extensive p u r i f i c a t i o n of the s o l i d  undertaken.  on determining 0.7.  the  Absence of amide  formation of a t h i e t a n e .  from hexane using a dry  ice-acetone bath e l e v a t e d the m e l t i n g point from 60-80° to 90-93° and The  showed no s i g n i f i c a n t  changes i n the i r p a t t e r n .  yellow c o l o r a t i o n denotes high conjugation of t h i s  compound.  62  Several  possible reactions  a high  leading  degree of conjugation  i n Scheme  to the absence of amide  were examined and  and  are i l l u s t r a t e d  10.  Scheme 10.  Proposed products from the s i d e r e a c t i o n s dibromocompound  The  first  clue to the  the r e s u l t s  (72)  with sodium  by  data was  c o n s i s t e n t with e i t h e r s t r u c t u r e s _7_5 or. 7_8.  of elemental a n a l y s i s .  major component i s r e a l l y 7 5 or 7 8, to s e l e c t i v e l y  identify  of C = N absorption  sulfide.  s o l u t i o n of t h i s problem  obtained  i r i s not  t h i s compound . 1  The  The  of  was  analytical If  the  an e f f e c t i v e  identification  i n conjugated c y c l i c systems i s rendered  tool  Fig. 3  Molecular structure of 2-Phenyl-4-benzylidene-2-oxazoline (78).  66  difficult  by the i n t e r a c t i o n with other double  S p e c i f i c assignments  of C = N frequency have not been p o s s i b l e  i n t e t r a z o l e s , b e n z t h i a z o l e s , and bands found  bonds.  thiazoles.  The a b s o r p t i o n  i n the 1650-1500 cm \ r e g i o n i n such compounds  can only be a s s o c i a t e d with the e n t i r e r i n g system The  uv a b s o r p t i o n of the major component showed three  a b s o r p t i o n maxima at 201 nm 4 344  (£ 1.6x10 ) ( F i g . 5 ) .  Absorption at 344 nm  oxazole d e r i v a t i v e s phenyloxazole  (7_9_)  diphenyloxazole  used  as a s o l v e n t .  the presence  of e x t e n s i v e con-  (134), h i g h l y conjugated  275  2,5-diphenyloxazole nm  the f a c t  than isomer  was  78.  considered to favor s t r u c t u r e  105.  2,4-  showed  81  78 i s more e x t e n s i v e l y conjugated  m/e  (8J-)  80  Mass spectrum  whereas  respectively.  Considering these oxazole examples and  (Scheme 11).  2,4,5-tri-  showed a b s o r p t i o n at 306 nm,  and  79  Ethanol was  4 (6 1.9x10 ), and  According to the a b s o r p t i o n data on  (8_0) and  a b s o r p t i o n at 280  4 (£2.4x10 ), 214  indicated  jugated double bonds.  was  (116).  that compound  15_, the uv data  data showed a and b f i s s i o n of the r i n g  Molecular ion was  observed at m/e  235.  Base peak  67  Scheme 11.  Proposed Fragmentation Pattern of 2-Phenyl-4benzylidene-2-oxazoline (78) in the Mass Spectrum.  b  m/e 51 (11) m/e 91 (23)  69 The molecular shown i n F i g . 3 was (Fig.6).  s t r u c t u r e f o r 7_8 with the c o n f i g u r a t i o n c o n s t r u c t e d to f i t the observed  The proton a i s e q u i d i s t a n t  b of the r i n g .  The peaks observed  were a doublet at 5.05<S(H. )  at 5.73^(H.„) with the long range a'  being  The  low f i e l d  data  to the e q u i v a l e n t protons  and a t r i p l e t 3 Hz.  nmr  c o u p l i n g constant  bands f o r the aromatic protons are  not as e a s i l y  explained but were given the f o l l o w i n g  interpre-  tation. After  s u b s t r a c t i n g the c o n t r i b u t i o n of s o l v e n t  (CHCl^)  from the band at 7.10-7.40^, the band centered at 7.20 ^ r e p r e s e n t s 6 protons while the band centered at 7.80 S\ r e p r e s e n t s 4 protons. The  lower  field  band at 7.8<$~was assigned to the c , d, e, and f  protons, the deshielding ; of these ortho aromatic because of the paramagnetic in  the  protons o c c u r r i n g  i n f l u e n c e of n i t r o g e n and  oxygen atoms  ring. In  a d d i t i o n to the major compound 7 8, the compound with  R^=0 was i s o l a t e d as a small amount of s o l i d . Amide bands (amide -1 ' -1 -1 I, 1650 cm , amide I I , 1540 cm ),-CH— (1420 cm ), and primary OH  (1050  cm  ture 82_ was m/e  148  were observed  222  were observed  formation and  work i s not without  C— N— <  character.  struc-  Displacement  Amides (8 3)  enter i n t o r e a c t i o n s  r e a c t i o n s , because of t h e i r  C— NH— '  (Scheme 12).  i s o l a t i o n of the o x a z o l i n e 7_8 i n t h i s  precedent.  e s p e c i a l l y displacement  84  A proposed  supported by mass s p e c t r a l data i n which such ions as  and m/e The  i n the i r spectrum.  <  8_3  n u  cleophilic  > — C=NH 85  by amide groups can occur e i t h e r  the i n t e r m e d i a t e 8_5 or under s t r o n g l y b a s i c c o n d i t i o n s , the amide anion 84- (135) . This i s i l l u s t r a t e d the f o l l o w i n g set of r e a c t i o n s .  Under  by  strongly  through  through  70 Scheme 12.  Proposed Fragmentation P a t t e r n o f l - P h e n y l - 2 benzoylamino-l-propene- o l  (82) i n the Mass Spectrum.  NHCO C.H i 6 5 C  < ^ ~ ^ - CH= C — C H 0 H 2  - C^H CO 6 5  + NH ft  M - C H = C — CH 0H 2  0 NHC C.H I 6 5 Vw-CH=C+ C  m/e 148 (10) (V  m/e 222 (3)  NM  // \\_ ''  >-CH=C  /\  -C.H CO 6 5  CHOH  N  m/e 147 (9)  +  \V CH— C - NH  + V  NH  H= C  m/e 117 (6)  CH  m/e 130 (4)  + '/  // W c H  = CH  \\_C=0 m/e 105 (99)  m/e 103 (17) C  6 5 H  +  m/e 77 (45)  C  m/e 91 (9)  4 3 H  m/e 51 (11)  71  alkaline  conditions  pyrrolidone  the T-bromobutylamine  J3_9_ v i a t h e a m i d e  anion.  (86) forms t h e  Heating  or e t h a n o l y s i s  A  86  //^N Br  0  R  8.7  0  H  NR  Br  KOH f u s i o n 88 Br  89  NX) N  of  ^6^ g i v e s  the iminovale-rolactone  x  0  hydrobromide  (8_7) v i a  intermediate  85^.  The f o r m a t i o n  substitution  from  the r e a c t i o n of N-2-bromoethylbenzamide  (90)  with  reaction  methoxide  i o n has been  i s illustrated  r  of the oxazoline  published  by t h e c o n v e r s i o n  0  -  /  0  C  90  in  approximately  A  similar  of oi-benzoylamino-p -  + CH 0H + Br 3  N-CH  chloropropionic  (137).  molecular  0-CH„  C,H C-N-CH CH„Br + 0 CH — > C,H C ^ 65 2 2 3 6 5 C  9JL b y  the  r  91  acid  (91)  to 2-phenyl-4-carboxy  50 % y i e l d  i n sodium  oxazoline  bicarbonate  solution  (93) (138)  72  H  CH  CH-COOH  I  ^  Cl  NH  >  I  CH.  CH" COOH  I  I  0  ,N  C=0  C  Rh  I  RH  92  93  /  It appears t h e r e f o r e that In t h i s work the r e a c t i o n of the 1,3-dibromobenzamido a l k a l i n e sodium s u l f i d e  compound  (_7_2) with  favors formation  of the o x a z o l i n e 7_8  v i a an i n t e r m o l e c u l a r s u b s t i t u t i o n r e a c t i o n . formation  the m i l d l y  The p r e f e r e n t i a l  of the s t r u c t u r a l isomer 78 and the i s o l a t i o n of the  unsaturated  compound 8_2 would i n d i c a t e that e l i m i n a t i o n of  the 1-bromo group occurs  prior  to r i n g formation.  not r u l e out a t h i e t a n e s t r u c t u r e as a p o s s i b l e to the o x a z o l i n e any  organic  One can intermediate  (^7J3) , but the absence of a p p r e c i a b l e  sulfur  compound i n the r e a c t i o n products  amounts of  makes  this u n l i k e l y . (4)  3-Benzylamino-2-phenylthietane ( 9 5 ) The  r e d u c t i o n of the amide carbonyl  attempted to remove the p o s s i b i l i t y to the amide group. benzylaminothietane  The end product 9_5.  group of 7_2 was  of o x a z o l i n e  formation due  would then be the  A number of methods have been published  73 NHC  NHCH C H ,  C H  CH—CH—CH^Br  v  I  2  Br 72  94  95 on the r e d u c t i o n  of the amide f u n c t i o n a l group.  sodium acyloxyborohydride are examples. causing  and any reducing  f o r the r e d u c t i o n  amide d e r i v a t i v e s to the corresponding amines  agents  of the carbon-halogen bonds, however,  could not be a p p l i e d i n t h i s procedure. successfully u t i l i z e d  using  (139) and sodium borohydride ( 1 4 0 )  Alkaline conditions  hydrogenolysis  Methods  Diborane has been of  halogen-substituted  halogen-substituted  (141,142,143,144). Diborane was generated e x t e r n a l l y by the method of  Z w e i f e l and Brown ( 1 4 5 ) .  A f t e r r e a c t i o n , excess diborane and  diborane adduct were destroyed  by adding absolute  ethanol.  Hydrogen c h l o r i d e s o l u t i o n was avoided to prevent the a d d i t i o n of any p o s s i b l e water which might cause h y d r o l y s i s or r e arrangement. felt  Dry.hydrogen c h l o r i d e gas was used since i t was  that the r e d u c t i o n  hydrochloride compound.  salt  product 9_4 should  to avoid  be i s o l a t e d  p o s s i b l e formation  Work up gave a r e s i d u e .  as the  of an a z i r i d i n i u m  The i r showed a. strong  ketone band which might have r e s u l t e d from rearrangment of the s t a r t i n g m a t e r i a l under the a c i d i c implied  conditions.  that amide 7 2 i s r e l u c t a n t to r e d u c t i o n  conditions  employed.  were not performed.  Further  The end r e s u l t under the  attempts at the r e d u c t i o n  of 7_2  74  4.  S y n t h e t i c approach to 3 N,N-dimethy1amino-2-phenylthietane  (2_4) and  phenylthietane  3-N,N dimethylamino-2-p^nit>r-o  (26).  A f u r t h e r c o n s i d e r a t i o n of Scheme 4 suggested t h i e t a n e s y n t h e s i s may  -  that  be p o s s i b l e by t h i s route i f the amino  group of p h e n y l s e r i n o l was  r e p l a c e d by a dimethylamino group.  This stemmed from the f a c t  that the formation of  which was  encountered  i n the case of primary  avoided by using a t e r t i a r y  amine group  a l k y l a t i o n with formaldehyde and Eschweiler method) has  proved  p a r a t i o n of methylated  amines.  thiazoline  amine would  (Scheme 13).  be  Reductive  formic a c i d d e r i v a t i v e s ( C l a r k e -  to be a u s e f u l method f o r the preAccording  to a r e p o r t  (147)  which d e s c r i b e d the a p p l i c a t i o n of the C l a r k e - E s c h w e i l e r method to the s y n t h e s i s of N,N-dimethylephedrine, formaldehyde, formic a c i d , and  sodium formate  (1:1:1) gave high  The marked r e d u c t i o n of carbonyl s i d e product of sodium formate was  considered  yields.  by the a d d i t i o n  to presumably occur  enhancement of the r e d u c t i o n step of the methylation (148) .  through sequence  Scheme 13.  Proposed s y n t h e t i c scheme to 3-N,Ndimethylamino-2-phenylthietane  (24) and  3-N,N-dimethylamino-2-p-nitrop h e n y l t h i e t a n e (26) NH„ 58,R=.H 117,R=N0  2  R-(^  ^-CH-CH-CH^H OH  I  N(CH32) 96,R=H  110,R=N0 R2  -CH-CH-CHOH 2  OH N(CH ) 3  2  N(CH ) 3  R-( /  M-CH-CH-CHOH 2  113 R=H  U5_,R=H 116,R=N0 R2  -CH-CH-CH OH SCN  N(CH ) 3  ,58,R=H 26,R=NQ  2  R-V  ^-CH  2  CH.  2  114, R=NO,  76  A.  N ,N-(Dimethylphenylserinol  (96) .  N,N-dimethylphenylserinol  was p r e p a r e d  Eschweiler a  high  in  method.  yield.  showed  whereas  already  was n o t r e q u i r e d  dimethyl  mentioned a t 4.863 ,  was e a s i l y  p h e n y l s e r i n o l was n o t . protons  a t 4.37 & i n d i c a t i v e  appeared  proton  formate  N,N-dimethylpheny1serino1  chloroform,  clearly  Sodium  (114),  a t 2.5 S .  of the threo  threo  a t 5.14 &.  the erythro  1-phenyl-l-propanol  while  proton  at 5.20^.  dimethylphenylserinol was  present  the  fragment  the erythro  (Fig.7),  and t h e base  a t m/e  (CH^) 2N = CH-CB.20H.  As  showed  the benzylic the value  of threo-2-aminoshowed t h e  spectrum  o f N,N-  i o n (m/e 195)  88 was a t t r i b u t e d  A second  spectrum  configuration.  the molecular  peak  soluble  proton  compound  I n t h e mass  to achieve  T h e nmr  Similarly,  to the b e n z y l i c proton  the Clarke-  The b e n z y l i c  phehy1serino1  4.67 cT was a s s i g n e d  benzylic  using  l a r g e peak  to  occurred  + at  m/e  58 ( ( C H ^ )  alcohols that  (149).  for  B.  ^ = Z Y i . , ^ )  which  Otherwise,  i s d i a g n o s t i c f o r dimethylamino  the spectrum  was v e r y  similar to  phenylserinol.  S y n t h e t i c approach  to  l-phenyl-l-chloro-2-dimethylamino-  p r o p a n e - 3 - o l (110). The chloride  hydrochloride  i n order  salt  to obtain  o f J9_6 was t r e a t e d w i t h  the C - l  monochloro  Unidentifiable  gummy  that  m a t e r i a l may b e d u e t o e x i s t i n g  t h e gummy  sulting  from  m a t e r i a l was i s o l a t e d .  o x i d a t i o n o f t h e amino  group  thionyl  compound  I t was  (112) .  considered  i m p u r i t i e sr e -  by t h i o n y l  chloride.  77  Fig.  7  Mass Spectrum of N,N-Dimethylphenylserinol (96)  «  88 (100)  +  N ( C H ) = CH— CH 0H 3  2  2  + / \Y_C-E 0 + N(CH ) r-r CH 3  2  2  C  6 5 H  +  58(14)  CH= 0'  77.(7)  1  oJUJ ll  UJ  78  Hence, another  c h l o r i n a t i o n method was used.  such as t - b u t y l a l c o h o l e a s i l y hydrochloric acid  aqueous h y d r o c h l o r i c a c i d prepared  alcohols  react with : concentrated- -  to give c h l o r o products.  such as oL-phenylethylalcohol  Tertiary  Secondary  alcohols  give ^ - c h l o r o ethylbenzene (150).  with  R a c h l i n and Enemark (118)  1-(3,4-dihydroxyphenyl)-1-chloro  ethylamine by p a s s i n g  dry hydrogen c h l o r i d e i n t o the suspension of n o r e p i n e p h r i n e i n dry dioxane.  They found  that  t h i s method gave a r a t h e r pure  product compared to that prepared by t h i o n y l c h l o r i d e . N,N-dimethylphenylser i n o l hydrochloric acid  (9j>) was t r e a t e d with concentrated  or dry hydrogen c h l o r i d e gas i n dry dioxane  or dry e t h e r , the r e s u l t was the same gummy m a t e r i a l . attempts  Further  at p u r i f i c a t i o n of t h i s m a t e r i a l f o r i d e n t i f i c a t i o n  were u n s u c c e s s f u l .  Reactions with potassium  t h i o c y a n a t e or  sodium t h i o s u l f a t e using the gummy m a t e r i a l r e s u l t e d identifiable  C.  When  i n un-  products.  1-p-Nitr ophenyl-1, 3-dichloro-2-N ,N-dimethylaminopropane (9_7 ) . Because of the tedious and d i f f i c u l t  the dimethylamino  phenylserinol  p-nitrophenylserinol  (117)  process of p r e p a r i n g  (58) , a t t e n t i o n was turned to  as a s t a r t i n g m a t e r i a l .  p-  N i t r o p h e n y l s e r i n o l i s an i n t e r m e d i a t e i n chloramphenicol s y n t h e s i s and was obtained from a pharmaceutical f i r m . D(-)  The  threo form was assigned to the p - n i t r o p h e n y l s e r i n o l  m e l t i n g p o i n t and i r spectrum and L(+)  data.  from  M e l t i n g p o i n t s of D(-)  threo forms are 164°, whereas those of DL-threo and  79  DL-erythro  are 141.5-142.5° and  This i s a case where the racemic quite d i f f e r e n t differs  from  107-9° r e s p e c t i v e l y compound has  i n m e l t i n g point and  solubility.  (110) was  prepared  as f o r N ,N-dimethylphenylser i n o l  (j^6) .  showed c o n s i s t e n t values with theory.  two  hydroxyl protons  and t h e r e f o r e  p-Nitro-N,Nby the same method Elemental  analysis  In the spectrum  a doublet f o r the b e n z y l i c proton at 4.5 S The  a crystal structure  those of the pure enantiomers  dimethylphenylserinol  form.  (112,151).  indicated  centered at 3.1 S  Two  appeared  , while the two meta phenyl protons  at 7.47^". protons.  at  group appeared  2.5 & were assigned to N-methyl  I n t e r g r a t i o n showed p a r t i a l overlap of the methine  proton with N-dimethyl  protons.  The mass data was  ment with the r e q u i r e d s t r u c t u r e ; m/e was  the threo  phenyl protons ortho to the n i t r o  Six protons  110,  disappeared  upon adding D^O. at 8.07^  of  the base peak, m/e  58  88  i n agree-  ((CH ) N=CH-CH OH) 3  ((CH„)„N=CH„) was  2  2  next most  intensive,  + m/e  209  (N0 C .H, CH (OH)-CH = N (.CH_ ) _ ) was o  Z  D  4  J  observed  as was  m/e  /  +  1-832 (N0„C,H,,CH (OH) CH = NH„ as shown i n the case of p2 o 4 2 hitrophenylserinol. In the case of c h l o r i n a t i o n of  threo-D(-)-p-hitro-N,N-  d i m e t h y l p h e n y l s e r i n o l , p o s s i b l e e f f e c t s on the o p t i c a l by t h i o n y l c h l o r i d e was i s based  This consideration  on the f a c t that p a r t i a l r a c e m i z a t i o n would lead to  difficulty  i n s e p a r a t i o n and  A method using DMF-S0C1 published  considered.  purity  2  (152,153,154).  identification  of the compound.  to o b t a i n o p t i c a l l y pure products p-Nitro-N,N-dimethylphenylserinol  was  Scheme 13.  Proposed Fragmentation Pattern of 1-pNitrophenyl-1,3Sdichloro-2-N,N-dimethylamino propane (97) in the Mass Spectrum. N(CH ) 3  NO  ^/  2  2  y-CH-CH—CH CI 2  Cl M * m/e 275 (0.2) +  N(CH ) 3  2  CH  - C H = C = NCCH )  m/e 191 (1) i/e 159  N(CH )— 3  NO — <^~^V-  C  ~ CH—CH  m/e 108 (32) N(CH )|^CH—CH »  m/e 240  3  CH  2  m/e 71 (19) N ( C H ) p CH 3  i/e 58 (5)  m/e 115 (4)  2  m/e 106 (100) H  Cl  ft +^)—CH-^CH  CH_CH C1  2  N(CH ) — C=CH 3  m/e 70 (6)  2  82  (110) and  was t r e a t e d  heated f o r one hour.  Chlorination find  with an excess amount of DMF-SOC^ reagent  using  Work up gave a c r y s t a l l i n e product.  t h i o n y l c h l o r i d e was also performed to  out any d i f f e r e n c e s  problems encountered.  i n the products formed or the  I t was found that  separation  the i r s p e c t r a  of the  two products i s o l a t e d from each c h l o r i n a t i o n r e a c t i o n were superimposable with each other. parations  Therefore, further  pre-  of 1-p-nitropheny1-1,3-dichloro-2-N,N-dimethy1-  aminopropane were made using p u r i f i c a t i o n was required a n a l y s i s was performed. Fragmentation patterns  thionyl chloride.  Extensive  to i d e n t i f y the s t r u c t u r e .  Elemental  Mass spectrum data were c o l l e c t e d . of the molecule showed c l e a r l y the 1,  3-dichloro  structure. This i s based on the mass numbers such + as m/e 106, 108 (N(CH„)=CH-CH„Cl) and m/e 191 (N0_C H -CH= 32 2 264 c  C=N(CH ) ) as shown i n Scheme 13. 3  2  Molecular i o n was observed  at m/e 2 75. D.  Reactions of 1 - p - n i t r o p h e n y l - l , 3 - d i c h l o r o - 2 - N , N dimethylaminopropane The  sulfide.  (9_7) with sodium s u l f i d e .  1,3-dichloro compound I t was assumed that  (97) was t r e a t e d  the r e a c t i o n  compound  (_9_7) and sodium s u l f i d e would lead  reaction  sequences.  give two nucleophilic  Aziridinium attacking  r e s u l t i n g i n fW& p o s s i b l e alkaline conditions, respectively.  salt  with sodium  of 1,3-dichloro to the f o l l o w i n g  formation would  positions  at C - l and C-j>. f 11G Q  end products , 2_6_ T21 'or 9*8; '-"Under 9  9_8 and 012:1> wbuM prob'3b_£y: form _99 and 130  83 ,  +  N(CH ) HC1 3  NO—<^J^)-CH— CH —  N(CH  2  1/2  CH C1  Na S 2  —_  2  ^  N 0  2  \  )~  C  H  —  C  H  )Cl —  C  H  2  C  1  Cl 97  118 Na S 2  N(CH )  N^CH ) C1 3  '/ \V C H — C H — C H  NO  3  2  • C H — CH — C H „ C 1  or  2  2  SNa  SNa 119  120 N(CH ) 3  N(CH ) 3  2  N0„— V \)-CH—CH — C H „ 2 \ - / \ / 2  2  98 N(CH -) 3  CH — C H ,  NO, NO  / \V-CH 2 \ -  \/  CH—CH„N(CH.) 2  2  0  3 2  121  99  NOj-^_y-CH=r C H — CH N(CH ) 2  3  2  130 To of  1 mol o f 1 , 3 - d l c h l o r o  sodium  mixture cake  point  for  which  soluble from  sulfide  the was  was a d d e d .  1 hour,  a t room  recrystallization  of  t h e compound  to  obtain  were  to further  was f i l t e r e d  H 0.  A brown  2  T h e same  Attempts  with  salt.  purification  to give  colored,  compound  was  f o r 3 hours.  to p u r i f y  not successful.  was t r e a t e d  a hydrochloride  2.25 m o l ( 5 0 %  excess)  r e f l u x i n g the reaction  temperature  (60-110) .  by  resistant  with  was o b t a i n e d .  reaction broad  After  theasolution  was t r i t u r a t e d  compound  compound,  filter  chloroform obtained  Melting  the product  A CHC1  3  solution  d r y H C l gas s a t u r a t e d Dark  a  black-colored  CHC1  3  material  was p r e c i p i t a t e d o u t .  84  P u r i f i c a t i o n by forming p i c r a t e s a l t was p i c r a t e could be i s o l a t e d was  performed.  and r e c r y s t a l l i z e d ,  not c o n s i s t e n t , ranging 75-110° depending  of c o l o r a t i o n . successful.  Although  the m e l t i n g p o i n t upon  the^depth  Separation by column chloromatography  was  A l k a l i - f u s i o n t e s t s r e v e a l e d the presence  not  of  sulfur. The nmr decrease  (Fig.9) showed a m u t l i p l e t p a t t e r n and a  i n the r a t i o of dimethylamino  protons.  The  r a t i o was  around  the s t a r t i n g m a t e r i a l , 9_7 and 6 : 4.  4 : 4 while i n the case of both the t h i e t a n e , 2J>, the r a t i o i s  P o s s i b l e e l i m i n a t i o n of the dimethylamino  the r e a c t i o n was at 6.40 J". range.  group during  f u r t h e r supported by the presence  of protons  An o l e f i n i c proton i s u s u a l l y assigned at t h i s  To confirm t h i s f i n d i n g , gc-mass spectrometry  performed. times, 8.9  The major f r a c t i o n s were observed (A) and  the dimethylamino Fragment 58 was B.  protons to phenyl  11.3  minutes  (B).  The  at r e t e n t i o n  compound A contained  group as i n d i c a t e d by strong m/e  not present i n the mass spectrum  58  thietane  pattern for (Scheme 14).  frag-  2-p-nitrophenyl-3-N,N-dimethylaminoHowever, s i n c e mass data alone would  not give an absolute determination of the s t r u c t u r e , attempts  fragment.  of compound  Major fragmentation f o r A agrees with a proposed  mentation  was  further  at the s y n t h e s i s with the e l a b o r a t i o n of r e a c t i o n  c o n d i t i o n s to o b t a i n a compound i n p u r i f i e d  form s t i l l  remained.  A r a t i o n a l e x p l a n a t i o n of the fragmentation p a t t e r n of B was  not s u c c e s s f u l .  of the dimethylamino  To e l u c i d a t e whether t h i s group i s due  elimination  to simple base-cat alyzed  86 Scheme  14  Proposed  Fragmentation  Pattern  2-p-nitrophenylthietane  (26)  of  3-N,N-dimethylamino-  i n t h e Mass  Spectrum.  + N(CH.)„~1 , 3 2  CH NO  —(/  CH  V>-  \\— /  s  \ N (CH.)_3 2  Jl CH  2  NO  2  m/e  2 \  CH„  \\ /  /  / CH  84  N(CHj~1 I  J  +  2  "  CH  \  m/e 206  CH2  129  (CH ) N=CH 3  2  2  m/e 58 N(CH ) 3  ,  ['  +  .  >Y-r:CH w  2  N(CH ) 3  ^CH  2  r CH NO^r  N  m/e 160  +  f W  )-CH—CH  N 0 ~ \ ^ _ / ~ C H = C = N(CH ) 2  3  2  . m/e 205 m/e 191  +  "CH  . / ^\_CH=rC=N(CH ) . r  + \_CH—CH  3  N  m/e 145  m/e 116 N(CH. ) 3  2  CH ^+^-CH—\lH-  + N ( C H  3 2~ )  m/e 159  C  H  -  C  *  H 2  m/e 71  + +  CH—CH  m/e 115  N(CH ) 3  2  C=CH  m/e 70  2  2  87  r e a c t i o n or a sodium s u l f i d e - p a r t i c i p a t i o n r e a c t i o n , the 1,3d i c h l o r o compound was t r e a t e d with NaOH. formed except NaCl, which i m p l i e s  that  No p r e c i p i t a t e was  sodium s u l f i d e plays  a r o l e i n t h i s e l i m i n a t i o n of the dimethylamino group. Further not  experiments to e x p l a i n  performed. A filtered  and  t h i s e l i m i n a t i o n r e a c t i o n were  extracted  s o l u t i o n of the r e a c t i o n mixture was evaporated  with chloroform.  after d i s t i l l i n g  A dark residue  o f f the s o l v e n t .  showed at l e a s t 6 compounds.  Gc-mass  was obtained  spectrometry  The l a r g e s t gc peak, r e t e n t i o n  time 9.3 minutes showed s i m i l a r mass fragmentation to those of compound A. portion  This  could  be explained  of compound A i s s o l u b l e  i n the r e a c t i o n s o l v e n t .  by the f a c t that some  i n ethanol  and was  retained  Attempts to i s o l a t e each compound  were not performed. An e a r l i e r assumption made was that  the side  products  r e s u l t i n g from the e l i m i n a t i o n of the dimethylamine group may be  due to the a l k a l i n e c o n d i t i o n  of the r e a c t i o n mixture and  probably from the excess amount of sodium s u l f i d e p r e s e n t . determine the e f f e c t s of the c o n c e n t r a t i o n a r e a c t i o n was performed using of d i c h l o r o compound the  (9_7) .  To  of sodium s u l f i d e ,  1 mol of sodium s u l f i d e to 1 mol  A s o l i d was p r e c i p i t a t e d out when  r e a c t i o n mixture was at n e u t r a l pH.  T r i t u r a t i o n of the s o l i d  with water gave a CHCl^-soluble yellow compound. by r e c r y s t a l l i z a t i o n was not s u c c e s s f u l .  Purification  An a l k a l i - f u s i o n  t e s t showed that s u l f u r was p o s i t i v e , which implied  that the  88  p r e c i p i t a t e r e s u l t e d from N a ^ S - p a r t i c i p a t i o n i n the r e a c t i o n . This f a c t was f u r t h e r backed up by the o b s e r v a t i o n that the r e a c t i o n of 1 mol of d i c h l o r o compound with 2 mol of NaOH gave only a p r e c i p i t a t e of NaCl. The nmr spectrum  (Fig.10) of the yellow m a t e r i a l showed  dimethyl protons at 2.373 , 2 phenyl protons  ortho to n i t r o  group at 8.10 & , 2 phenyl protons meta to n i t r o group at 7.33 <f, and 4 protons  at 3.00-363 ^".  The yellow compound was d i s s o l v e d i n ether and dry HCl gas was i n t r o d u c e d . filtration,  A white  the f i l t e r  c r y s t a l was formed.  After  cake was thoroughly washed with ether  and  recrystallized  was  so hygroscopic that a d e f i n i t e m e l t i n g point was not  obtained.  from EtOH-ether.  The h y d r o c h l o r i d e s a l t  However, d r y i n g at 50 at 0.1 mm f o r 5 hours gave  a c r y s t a l showing a d e f i n i t e m e l t i n g p o i n t . Gc-mass spectrometry hydrochloride s a l t .  was performed  on both  The base contained at l e a s t  the base and 3 compounds.  A major peak occurred at 9.3 minutes of r e t e n t i o n time by gc and  showed the same fragmentation p a t t e r n as that proposed i n  Scheme 14.  The h y d r o c h l o r i d e s a l t was r e l a t i v e l y pure and  gave the same fragmentation p a t t e r n and gc r e t e n t i o n time as those obtained f o r the major gc peak of the f r e e base. The  elemental a n a l y s i s of the h y d r o c h l o r i d e s a l t  showed  that the r a t i o of carbon, hydrogen, n i t r o g e n , and s u l f u r i s 22  : 32 : 4 : 1.  of  a dimer.  This r a t i o s t r o n g l y suggested  the formation  A r a t i o n a l e x p l a n a t i o n f o r the formation of the  dimer was at temp t ed . (Scheme 15).  Scheme 15.  Proposed Mechanism for the Reaction of 1-pNitrophenyl-1,3-dichloro-2-N,N-dimethylaminopropane with Sodium Sulfide.  97  118  123  91  Evidence s u p p o r t i n g s t r u c t u r e 12 2 as the base and s t r u c t u r e 12 3 as the h y d r o c h l o r i d e s a l t was c o l l e c t e d . assignment  The  of the protons of the base was c o n s i s t e n t with the  nmr spectrum as shown i n F i g . 10.  The mass fragmentation  p a t t e r n of 122 and 12 3 would be the same as the one proposed i n Scheme 14 since 12 2 and 123 would give 12 9 as a i n i t i a l fragmentation product.  This r e s u l t  i m p l i e s that the compund A  from treatment of 9J_ with an excess amount of sodium  sulfide  is  of gc  the same compound as the base  r e t e n t i o n time shows. salt 106  (12 2) as a comparison  The mass spectrum of the h y d r o c h l o r i d e  obtained by d i r e c t probe  showed fragmentations at m/e  and 108 with the i n t e n s i t y r a t i o , +  which  implied  s t r u c t u r e 12 3.  3 : 1 ( C l isotope  ratio),  the presence of N(CH^)^^^ CH-CH^Cl r e s u l t i n g  from  The data from the elemental a n a l y s i s was  d i r e c t evidence s u p p o r t i n g the s t r u c t u r e 12 3. Formation of 118 from 9_7 could be e a s i l y e x p l a i n e d by the ease of n u c l e o p h i l i c a t t a c k at C - l carbon because p - n i t r o f u n c t i o n on the phenyl group.  107  S  of the  As shown i n a r e p o r t  124  100  (83), e x c l u s i v e formation of 100 i s due to the f a v o r a b l e a t t a c k of s u l f h y d r y l i o n at the  -carbon of 107.  By analogy,  s u l f h y d r y l anion would favor a t t a c k at the C r l carbon of 118 to give 119 r a t h e r than 120 o . : 121. Besides t h i s ,  the p-  92  n i t r o p h e n y l group could a l s o c o n t r i b u t e to the e x c l u s i v e formation of 119 by f a v o r i n g n u c l e o p h i l i c a t t a c k at the b e n z y l i c carbon  atom.  One can use s i m i l a r argument  t i o n of the dimer nucleophilic molecule  (122).  to support  the forma-  The formation of dimer i n d i c a t e d  that  a t t a c k of the s u l f h y d r y l anion of 119 on a second  of 118 i s h i g h l y favored over  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 r e a c t i o n to form the t h i e t a n e .  To determine any  e f f e c t of the c o n c e n t r a t i o n of 118 r e l a t i v e to sodium 97 was added to an excess  amount of sodium s u l f i d e .  sulfide, A yellow  c o l o r e d - m a t e r i a l i s o l a t e d was the same compound as obtained when sodium s u l f i d e was added dropwise to a s o l u t i o n of 9 7. These r e s u l t s suggest  that the r e a c t i o n of sodium  s u l f i d e with 1,3-dichloro compound would not be an e f f e c t i v e method f o r the s y n t h e s i s of 3-amino-2-phenylthietane d e r i v a t i v e s . The  r e a c t i o n of sodium s u l f i d e with  1,3-dichloro  compounds which do not c o n t a i n 2-amino group has been  success-  f u l l y a p p l i e d to s y n t h e s i z e the intermediates f o r l i p o i c (155, 5.  156) and the 3-chloromethyl-3-hydroxylmethylthietane S y n t h e t i c approach to 3-amino-2-phenylthietane 3-hydroxy-2-phenylthietane  acid (157).  (22) from  (100) .  M o d i f i c a t i o n of a hydroxyl group of 3-hydroxy-2p h e n y l t h i e t a n e to s y n t h e s i z e 3-amino-2-phenylthietane as shown i n Scheme 16 was published  (83). The attempts at c h l o r i n a t i o n  or o x i d a t i o n of the hydroxyl group of 100 were not s u c c e s s f u l .  93  Scheme 16.  Proposed  synthetic routes  o f 3-amino-2-  phenylthietane (22;  104 Some e v i d e n c e was g i v e n of b e n z y l s u l f o n a t e were n o t c o n f i r m e d . sulfonate  105  which suggested a s u c c e s s f u l  (10 2)- and a z i d e  (10 3) b u t t h e s e  A p l a n was made t o i s o l a t e  ( 1 0 2 ) and a z i d e  (10 3) w h i c h w o u l d g i v e  evidence of a s u c c e s s f u l s y n t h e s i s of these t i o n of a hydroxyl  structures  the benzylconfirming  compounds.  Oxida-  g r o u p o f 100 was a l s o p e r f o r m e d u s i n g a  n e w l y e s t a b l i s h e d method Thietane  synthesis  (162).  ( 1 0 0 ) was s y n t h e s i z e d  f r o m 10 7 w i t h a m o d i f i c a -  t i o n o f t h e p r e p a r a t i o n method f o r t h e e p o x i d e 10 7. of m o n o p e r p h t h a . l i c a c i d , m - c h l o r o p e r b e n z o i c r e s u l t e d .in a b e t t e r y i e l d  o f 10 7.  Instead  a c i d was u s e d  The i r and m e l t i n g  which  p o i n t of  94  100  were c o n s i s t e n t with  ments of phenyl protons,  the reported  values  methine protons,  protons were the same as those reported proton  (83) .  and methylene  (83).  A hydroxy  appeared at 2.98cT which was exchanged with Modification  tempted.  Assign-  to the c h l o r o compound  (101)  l^O* was not a t -  No newly e s t a b l i s h e d methods f o r t h i s r e a c t i o n have  been published  i n the l a s t  2 years.  I t i s c e r t a i n that  direct  amination of 101 to 2_2 would not be f a v o r a b l e because of the propensity fissions  f o r side r e a c t i o n s such as ^ - e l i m i n a t i o n and r i n g (159).  Almost a l l attempts to o x i d i z e 100 to 104 were made by Haya (83).  Oppenauer o x i d a t i o n , M o f f a t t  o x i d a t i o n , and other  methods using hydrogen a b s t r a c t o r s were i n c l u d e d tempts.  Recently,  i n his a t -  s e v e r a l r e p o r t s have been published on  the o x i d a t i o n of primary or secondary a l c o h o l s .  However,  most of them d e s c r i b e s l i g h t m o d i f i c a t i o n s  of the  oxidation.  the process  Rao and F i l l e r  (160)  a s o l u t i o n of sodium dichiromate  described  Moffatt of using  and s u l f u r i c a c i d i n DMSO  to o x i d i z e primary and secondary a l c o h o l s i n high y i e l d . was  found that i n those o x i d a t i o n s  not  as a r e a c t a n t .  trifluoroacetic alcohols.  It  DMSO acts as a s o l v e n t and  Omura et a l . (161)  proposed a DMSO-  anhydride as a new reagent f o r o x i d a t i o n of  A l b r i g h t (162)  found that cyanuric  DMSO i n hexamethylphosphoramide  at -20°  c h l o r i d e with  o x i d i z e primary and  95 /  secondary a l c o h o l s i n high y i e l d .  By a p p l y i n g M o f f a t t  with DMSO and DCC i n the presence of a s u l f u r i c with DMSO a c e t i c anhydride  oxidation  a c i d (163) or  (164), Haya only i s o l a t e d  dark  residues which do not show ketone bands i n the i r spectrum. In t h i s experiment, a p p l i c a t i o n of the method of A l b r i g h t d i d not  give a p o s i t i v e i d e n t i f i c a t i o n The  performed.  formation.  r e a c t i o n of 100 with b e n z y l s u l f o n y l c h l o r i d e was B e n z y l s u l f o n y l c h l o r i d e which was prepared  b e n z y l c h l o r i d e using a known method spectrum of the crude product and  f o r ketone  (165) was used.  obtained  from The i r  by work up showed 1185  1365 cm ^ bands as mentioned by Haya.  Contrary  to h i s  f i n d i n g s that the residue was not s o l u b l e i n common s o l v e n t s , the residue was found to be s o l u b l e i n chloroform.  Since  the i r  spectrum d i d not appear to give c o n f i r m a t i o n of formation of a s u l f o n a t e e s t e r i n the r e a c t i o n mixture,  p u r i f i c a t i o n of the  residue using column chromatography was performed. was  r a i s e d as to the s t a b i l i t y  product  (102)  while  graphic  techniques  of the p o s s i b l e s u l f o n a t e e s t e r  on the column.  However, column chromato-  f o r the p u r i f i c a t i o n of s u l f o n a t e s  for use as l e a v i n g groups have been widely The  Some question  r e a c t i o n mixture product  used  synthesized  (166,167,168).  d i d not appear to be u n s t a b l e .  T i c showed 4 spots at R S A (0), B (0.1), C (0.25), and f  D (0.8). and water.  The r e a c t i o n mixture was p a r t i t i o n e d between The chloroform  added to a column of s i l i c a  l a y e r a f t e r reducing  chloroform  i n volume was  g e l and e l u t e d using the same  96  s o l v e n t s as used f o r t i c . The major component was D while B and C were i s o l a t e d unreacted  as gummy m a t e r i a l s .  3-hydroxy-2-phenylthietane  determination  by i r and  of C was u n s u c c e s s f u l .  a m e l t i n g p o i n t over  B was s i m i l a r to values but  A was a p r e c i p i t a t e  having'  200° and was assumed to be a s a l t .  Absence of a band at 1370 cm ^ i n the i r spectrum r u l e d out the possibility unreacted  of a s u l f o n a t e .  D was p o s i t i v e l y  i d e n t i f i e d as  b e n z y l s u l f o n y l c h l o r i d e by t i c , i r , and m e l t i n g p o i n t .  This r e s u l t  s t r o n g l y suggests  that the r e a c t i o n d i d not proceed  under the c o n d i t i o n s used to form the s u l f o n a t e (10 2) although  some p r e c i p i t a t e of 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 was  formed. To confirm t h i s  f i n d i n g , the r e s i d u e from the r e a c t i o n  of 3-hydroxyphenylthietane directly  t r e a t e d with  and b e n z y l s u l f o n y l c h l o r i d e was  sodium azide i n hexamethylphosphoramide.  Work up gave a r e s i d u e , which showed three spots by t i c . The  r e s i d u e gave a strong azide band at 2110 cm  spectrum.  This band, however, would not n e c e s s a r i l y be an  i n d i c a t i o n of the formation  of 3-azido-2-phenylthietane  since even small contamination  with an azide impurity  cause a strong band i n the i r spectrum. unstable and p o t e n t i a l l y hazardous products  i n the i r  has been d e s c r i b e d .  components having  could  azides are  (169), the i s o l a t i o n of azide  Reckendork (170) i s o l a t e d  azide  an amino sugar s t r u c t u r e by column chromato-  graphy using alumina. c h o l e s t e r y l azide  Although  (10 3)  Alumina was a l s o used to i s o l a t e  (171) and s i l i c a  g e l chromatography was a p p l i e d  97  to  i s o l a t e an azide compound  (172).  The r e a c t i o n mixture  of a c e p h a l o s p o r i n  intermediate  from the r e a c t i o n of c h o l e s t e r y l  3.(?-p-toluenesulf onate with azide i o n was separated chromatographic techniques it  using f l o r i s i l  appeared worthy to i s o l a t e  evidence  of the r e a c t i o n .  amount of chloroform n-hexane.  (173).  the azide (to obtain  by  Therefore, positive  The r e s i d u e was d i s s o l v e d i n a small  and f r a c t i o n a t e d on a f l o r i s i l  column using  One major compound A with R^ 0.8 by t i c was  isolated.  E l u t i o n of the column with sether gave two f r a c t i o n s , B of R^ 0.4-0.7 ( t a i l i n g ) and C showing a b a s e l i n e spot by t i c . E l u t i o n with methanol gave D which showed a b a s e l i n e spot by tic. of  Initially  an azide band was observed  A, which disappeared  benzylsulfonylchloride.  after r e c r y s t a l l i z a t i o n . B and C were i s o l a t e d  small amounts of dark r e s i d u e s . bands at 650 cm but  i n the i r spectrum A was  as u n i d e n t i f i e d  The:"±r spectrum of D showed  and 3390 cm ^ i n d i c a t i v e of a s u l f o n i c  acid  c o n f i r m i n g i d e n t i f i c a t i o n was not s u c c e s s f u l . Haya reported that the hydroxyl  resistant  group of 100 was  to a l k y l a t i o n using methods such as t r i e t h y l o x o n i u m  t e t r a f l u o r o b o r a t e , Na-EtBr, and p - t o l u e n e s u l f o n y l c h l o r i d e . Two experimental sulfonate  r e s u l t s performed a l s o revealed that the  (102) might not be formed by the r e a c t i o n of 3-  hydroxy-2-phenylthietane  with b e n z y l s u l f o n y l c h l o r i d e . A sug-  g e s t i o n could be made that the use of a p p r o p r i a t e leaving  selective  groups and r e a c t i o n c o n d i t i o n s would be necessary to  confirm these f i n d i n g s .  98  Since u n s u c c e s s f u l azide  (103)  formation  of s u l f o n a t e  (102)  appeared clerao:,, f u r t h e r r e d u c t i o n of the r e -  a c t i o n mixture was  not performed.  It i s w e l l known that  can be reduced to amines by r e d u c t i v e methods such.as hydrogenation It would be  or  (174),  L i A l H ^ (169),  of i n t e r e s t  to use  and  azides  catalytic  sodium borohydride  ammonium s u l f i d e f o r the  (175). reduction  of azido compounds of the t h i e t a n e r i n g s i n c e t h i s reagent widely  used i n recent  cephalosporin  (172)  semisythetic p e n i c i l l i n chemistry.  (176)  and  is  99  ANALYTICAL METHODS  M e l t i n g p o i n t s were determined using Thomas-Hoover C a p i l l a r y M e l t i n g Point Apparatus.  A l l m e l t i n g p o i n t s and  b o i l i n g p o i n t s are u n c o r r e c t e d . A Beekman  IR-10 I n f r a r e d Spectrophotometer was used to  record a l l i n f r a r e d  spectra.  60 MHz nmr s p e c t r a were determined at the Department of Chemistry,  U.B.C., using a V a r i a n T-60 NMR  Spectrometer.  100 MHz nmr s p e c t r a were determined at the F i s h e r i e s Research Laboratory,  Vancouver, Canada, using V a r i a n HA-100 NMR  Spectrometer. s ( singlet  Peak m u l t i p l i c i t i e s  ), d ( doublet  are abbreviated  ), t ( t r i p l e t  as f o l l o w s :  ), b ( broad  ), and  m ( multiplet ) . Ultraviolet  s p e c t r a were obtained  using Beekman Model  25 Spectrophotometer. Mass s p e c t r a and gc/mass s p e c t r a l data were using a V a r i a n MAT-111 mass spectrometer. was 80 ev unless  obtained  The i o n i z i n g  voltage  specified.  Microanalyses  were performed by A l f r e d  M i k r o a n a l y t i s c h e s Laboratorium, F i r t z - P r e g l e - S t r a s s e 14-16, West  Be nhardt r  :J  5251 Elbach Uber E n g e l s k i r c h e n , Germany.  100  EXPERIMENTAL  1.  Synthesis of t h r e o - p h e n y l s e r i n e e t h y l e s t e r The methods reported by Shaw and Fox  adopted 0.4  with minor m o d i f i c a t i o n .  mol)  chilled  and NaOH (24.0 to 15°.  g. 0.6  (106*107) were  A s o l u t i o n of g l y c i n e  mol)  i n 100 ml of H 0  With c o o l i n g maintained  added a l l at once.  to paste but minutes,  The  emulsified  further s t i r r i n g  at 15° on a water  gave d i s s o l u t i o n .  the r e a c t i o n mixture became a l i g h t  After  cake was was  (84.9  24 hours  fragmented  added dropwise  bath at 15°. after addition  concentrated HCl  After  mol) changed  30  syrup which turned  complete  at room temperature,  and  g, 0.8  r e a c t i o n mixture  i n t o a p r e c i p i t a t e , followed by r a p i d and tion.  (30 g,  was  2  bath, and with r a p i d s t i r r i n g , benzaldehyde was  (108)  the  solidifica-  condensation  (50.0 ml, ca. 0.6  mol)  during 30 minutes with c o o l i n g on a water  Mechanical of a c i d .  s t i r r i n g was The  filter  continued f o r one  cakes  hour  obtained a f t e r  a c i d i f i c a t i o n were thoroughly mixed with b o i l i n g EtOH (3x200 ml) and  the r e s u l t i n g s l u r r y was  washed product was  filtered  r e c r y s t a l l i z e d from H 0 2  t h r e o - p h e n y l s e r i n e monohydrate (44.6 (lit.  (158),  each  time.  Alcohol  and d r i e d  g, 56 % ) . mp  to give  192-193°  193-194°).  A vigorous stream of dry HCl gas was  passed  through a  suspension of t h r e o - p h e n y l s e r i n e monohydrate (40 g, 0.2 i n absolute EtOH (250 ml). evolution  of s u f f i c i e n t  The  s o l u t i o n was  mol)  accompanied by  heat to promote gentle r e f l u x i n g .  101  The  s o l u t i o n was  (300 ml.)  and  phenylserine 140°  ether  ammonia was  filtered  (39.5  ether  g, 80 % ) .  passed through a suspension  f o r 15 minutes.  gave t h r e o - p h e n y l s e r i n e  (sec. OH),  2.  The  (35 g, 0.14  mp  137-  1580  threo-  mol)  Evaporation  e t h y l e s t e r (27.8  82-83°)  of  in  granular ammonium c h l o r i d e  and washed with warm ether.  79-80° ( l i t . (106),  1040  A d d i t i o n of  i n the c o l d gave threo-  ethylester hydrochloride  (500 ml)  filtrate  i r (KBr)  1740  of  the  g, 95 % ) .  cm"  (carbonyl),  1  (NH ). 2  Synthesis of t h r e o - p h e n y l s e r i n o l (58) . To an i c e - c o l d  EtOH (200 ml) ethylester mixture  EtOH).  was  R^s  g, 1 mol)  g, 0.17  mol)  i n 70 %  phenylserine  i n 70 % EtOH (100 ml).  with i c e c o o l i n g f o r 3 days.  The  The  extent  of  monitored by t i c ( s i l i c a g e l , i o d i n e chamber, of e s t e r and The  p h e n y l s e r i n o l were on 0.8  r e a c t i o n mixture  to a volume of 20 ml.  filtered  (300 ml)  s o l u t i o n of NaBH^ (37.8  added dropwise a s o l u t i o n of  stirred  respectively. centrated  was  (35.5  r e a c t i o n was  was  storage  ml.  ethylester hydrochloride  phenylserine  mp  overnight  to 100  ( l i t . (106) , 140°) . Dry  was  concentrated  o f f and  utilizing  The  the f i l t r a t e was a continuous 2  (20.4  g, 71.8'%). mp  from ether-cyclohexane  filtered  and  con-  p r e c i p i t a t e that e x t r a c t e d with  0.3  deposited ether  e x t r a c t i o n apparatus.  the ether on anhydrous Na S0^ and gave c r y s t a l s  was  and  Drying  s t r i p p i n g o f f the s o l v e n t 86-89  on  ( l i t . (106), 86-87 ).  recrystallization ir  (KBr)  102  1070 cm ^, 1040 (—OH), 1580 (primary  amine), no c a r b o n y l ;  mass spectrum M-t'm/e 167(2), m/e 42 (100), m/e 60 (100), m/e 77 (100), m/e 105 (80), m/e 118 (19), m/e 136 (60). Treatment of a s o l u t i o n of p h e n y l s e r i n o l (560 mg) MeOH (5 ml) with o x a l i c a c i d  in  (215 mg) i n MeOH (5 ml) gave,  a f t e r washing with water (1 ml), the oxalate  (450 mg), mp 222-  223 ( l i t . ( I l l ) 215°). ' P h e n y l s e r i n o l (370 mg) i n absolute EtOH (1 ml) was t r e a t e d with benzoic i n absolute EtOH (1 m l ) . collected. 3.  (270 mg) d i s s o l v e d  P h e n y l s e r i n o l benzoate  mp 159-161° ( l i t .  Synthesis  acid  (112),  (300 mg) was  162-163°).  of threo-l-phenyl-l-ctiloro-2-aminopropane -  3-ol h y d r o c h l o r i d e (60). Dry  HC1 was passed through the s o l u t i o n of threo-  phenylserinol (15 ml).  (3 g, 0.018 mol) d i s s o l v e d i n absolute EtOH  After d i s t i l l i n g  the EtOH o f f , the v i s c o u s  residue  was suspended i n dry CHCl^ (30 ml), followed by adding distilled  SOC^ (2.5 g, 0.02 mol).  overnight  at room temperature.  The mixture  The s o l i d was  i n absolute MeOH and to t h i s s o l u t i o n dry ether was  added to give a s o l i d (1.95  was s t i r r e d  The s o l u t i o n was evaporated  in vacuo at room temperature to give a s o l i d . dissolved  freshly  (mp 174-176°).  g, 49 %) was obtained  MeOH-ether.  mp 193-194  Purified  product  on second r e c r y s t a l l i z a t i o n  ( l i t . (115),  -1 1050 cm (-0H); mass spectrum  (20 ev)  192-193°);  ir  from  (KBr)  +* ' ' (M+2) m/e 187(1),  m/e 60 (100), m/e 118 (61), m/e 119 (53).  103  4.  Attempted  synthesis  HG1  1  To 0.001  and  (.56, R = R = R = H) 2  3  l-phenyl-l-chloro-2-aminopropane-3-ol  mol) i n dry CHC1  S0C1  2  of 1-phenyl-l,3-dichloro-2-aminopropane.  (10 ml) was added f r e s h l y d i s t i l l e d  3  (2 g. 0.017 mol),  Refluxing  d i s t i l l a t i o n of the solvent  dissolved  i n MeOH.  on a water bath f o r 2 hours  gave a s o l i d .  A d d i t i o n of ether  m a t e r i a l with  i n MeOH.  material i d e n t i f i e d 5.  gave a s o l i d .  C r y s t a l s obtained  Mp  starting material.  added SOCI,, (10 g) was  r e f l u x e d on a water bath f o r 2 hours. under reduced pressure  The s o l i d was  gave c r y s t a l s .  (193-195°) and the i r spectrum showed unreacted This unreacted  (0.22 g,  D i s t i l l a t i o n of S0C1  2  The s o l i d was r e d i s s o l v e d  by adding ether  showed  starting  by i t s i r and mp.  Attempted s y n t h e s i s aminopropane-3-ol  of l - p h e n y l - l - t h i o c y a n a t o - 2 -  (62).  A s o l u t i o n of KSCN (393 mg, 0.00405 mol) and d i c y c l o h e x y l 18-crown-6 (1.49  g, C00004 mol)  i n MeOH (30 ml) was mixed  with  l-phenyl-l-chloro-2-aminopropane-3-ol  hydrochloride  0.002 mol) i n MeOH (10 ml).  at room temperature f o r  Stirring  4 hours and d i s t i l l a t i o n of the solvent The  gave a v i s c o u s  r e s i d u e was d i s s o l v e d i n H 0 (10 ml) and e x t r a c t e d 2  CHC1 Tic  (444 mg,  3  (2 x 100 ml) and t h e r e a f t e r with  (silica  from CHC1  3  ethylacetate  liquid. with  (2 x 100 ml).  g e l , i o d i n e chamber, e t h y l a c e t a t e ) of the r e s i d u e s and e t h y l a c e t a t e showed the same p a t t e r n having  than 3 spots.  more  The i r spectrum of e t h y l a c e t a t e and CHC1, ex-  104  t r a c t i o n s showed strong p o l y e t h e r (2090 cm ^) a b s o r p t i o n s . for  (1100  cm  ) and  thiocyanate  Attempts to f i n d a developing  solvent  t i c which would give c l e a r s e p a r a t i o n of the spots were  performed using e t h y l a c e t a t e , CHC1 and EtOH-hexane only to r e s u l t  EtOH, CHCl ~EtOH, hexane,  3>  3  i n severe  t a i l i n g or  incomplete  separat i o n . 6.  Synthesis of (61,  3-ol  1-phenyl-1-thiosulfuryl-2-aminopropane-  Bunte  Na S 0 .5H 0 2  2  (15 ml) was (1.68 for  3  (1.935 g, 0.078 mol)  2  g, 0.075 mol)  i n EtOH (45 ml).  5 hours on a water bath.  1200  7.  cm" ,  (900 mg.  1230,  1  640  H0 2  compound  The mixture  was  refluxed  45.7  %).  s o l i d was  mp  filtered  246-249°;  ir  ( S0 H ). 3  Attempted s y n t h e s i s of l - p h e n y l - l - t h i o c y a n a t o - 2 aminopropane-3-ol  (6_2) v i a the Bunte s a l t  (Synthesis of  2-amino-4-hydroxy.." m e t h y l - 5 - p h e n y l - 2 - t h i a z o l i n e Bunte s a l t Na C0 2  3  solution  of NaCN (49 mg, temperature. one hour. was  (60)  A f t e r reducing the volume to  pressure, p r e c i p i t a t e d  give a Bunte s a l t  (KBr)  dissolved in  added to the s o l u t i o n of 1-chloro  3 ml under reduced to  salt)  61  (263 mg,  (53 mg, 0.001  0.001  mol)  0.0005 mol)  mol)  in H 0 2  A p r e c i p i t a t e was  After s t i r r i n g  in H 0 2  dissolved in  (10 ml).  (2 ml) was  observed  f o r one  was  7 4).  A solution  added at room  after s t i r r i n g for  a d d i t i o n a l hour, white  obtained by s u c t i o n f i l t r a t i o n .  Recrystallization  solid  from  105  H 0 gave a t h i a z o l i n e 74 (100 mg, 48.0 %) mp 152-153.5°; 2  ir  (KBr)  -1 1640 cm  +' (C = N); mass spectrum M m/e 208  m/e 177i (100), m/e 91 (36), m/e 135 (25), m/e 45  (3),  (12),  m/e 115 (12) . 8.  Synthesis  of 1-pheny1-1-mercapto-2-aminopropane-3-ol  h y d r o c h l o r i d e (63). Bunte s a l t HC1  61 (300 mg, 0.0014 mol) with  (5 ml) was s t i r r e d  at 50-60° f o r 1.5 hours.  changed to a c l e a r s o l u t i o n .  Stirring  temperature gave a white p r e c i p i t a t e . crystallized 180-182°;  from MeOH-ether. Y i e l d  i r (KBr)  concentrated  overnight  120 mg (48.1 % ) . mp  2520 cm (-SH); mass spectrum (M+l) * _1  +  m/e 118 (26), m/e 77 (22), m/e 51 Synthesis  'phenylserinol  (65).  (1.67 g, 0.01 mol) d i s s o l v e d i n  10 % NaOH (30 ml) was added benzoyl at once.  (43),  (18).  of threo-N-benzoyl  To t h r e o - p h e n y l s e r i n o l  all  at room  The s o l i d was r e -  m/e 184 (0.4), m/e 60 (100), m/e 42 (78), m/e 91  9.  The mixture  c h l o r i d e (5.62 g, 0.04 mol)  The mixture was shaken v i g o r o u s l y f o r 30 min.  to give a s o l i d .  The s o l i d was f i l t e r e d  and r e e r y s t a l l i z e d  from MeOH to give t r i b e n z o y l p h e n y l s e r i n o l (4.17 g, 87 % ) . mp 193° ( l i t .  (128),  194-195°).  i r (KBr)  (amide),. 3360 ( NH) , 1720 ( c a r b o n y l ) . benzoylphenylserinol 0.01  1640 cm" , 1530 1  A s o l u t i o n of t r i -  (2.4 g, 0.005 mol) and NaOH (0.4 g,  mol) i n MeOH (200 ml) was r e f l u x e d f o r an hour.  A clear  106  solution  observed.  V7as  A s o l i d was  t i o n of the r e a c t i o n mixture  i n vacuo.  washed with, s a t u r a t e d NaHC0_, and 153-156°). needles. ir  Recrystallization Yield  (KBr) 1630  1.0  m/e  105  (100), m/e  m/e  240  (45), m/e  10.  1530  1  mp  then H 0, o  162°  (45), m/e  164  filtered,  and  ( mp  dried  ( lit.  (128),  223  (100), m/e  163-164°); spectrum  106  (95),  (27).  Synthesis of 1-phenyl-l,3-dichloro-2-benzoylaminopropane(6^) Threo-N-benzo.yl-phenylserinol  freshly d i s t i l l e d  S0C1 (59.5 g, 0.5 2  water bath f o r 1.5  hours.  (2.71 mol)  ether to o b t a i n a s o l i d  g) .  150°; i r (KBr) (CDC1  3330 cm"  (m,  ( d, 1, C H  146  1, C,H 0  182  m/e  (30), m/e  105  235  C a l c d . f o r C, -H., N C 1 „ 0 : C, 62.33 ; H, 16 15 I mol. wt.', 308.05. Found: C, 62.21; H, 4.89; C l , 23.20. C  % ) . mp  obtained 148-  group),  (b, 1,-NH-C0-),  —  (32), m/e  under r e -  2, protons ortho to carbonyl  2, -CH^Cl ); mass spectrum  (100), m/e Anal.  J  the  1640,1530 (amide), no c a r b o n y l ;  -CHC1- ), 4.43-5.00 ( m,  C  (m,  (NH),  with  t r e a t e d with dry  g, 56.8  8, phenyl p r o t o n s ) , 6.40  D  3.50  1  2  on  P u r i f i e d product was  from benzene (1.75  )• 7.50-7.73 ^" (m,  7.60-7.37 5.32  (2.89  mol)  heated  A f t e r e v a p o r a t i n g S0C1 residue was  on r e c r y s t a l l i z a t i o n  g, 0.01  was  duced p r e s s u r e , the r e s u l t i n g  nmr  s o l i d was  (amide), no c a r b o n y l ; mass  147. (100), m/e 222  The  concentra-  from e t h y l a c e t a t e gave c o l o r l e s s  g (74 % ) .  cm ,  obtained a f t e r  -CH-CH- ), J  (100), m/e  130  (31). 4.91;  C l , 23.02 ;  .  107  11.  Synthesis of 1-phenyl-l,3-d ib romo-2-benzoylaminopropane(72) . A general procedure  literature alcohol  (130,131,132).  f o r t h i s s y n t h e s i s was taken from the To a s o l u t i o n  (10 g, 0.075 mol) i n CC1  4  of trans-cinnamyl  (100 m l ) , bromine  0.082 mol) i n C C l ^ (10 ml) was added with s t i r r i n g  (13.1 g, at -5° f o r  35 minutes.  The CC1. s o l u t i o n was washed with 10 % NaHS0„ 4 3 (15 m l ) , s a t u r a t e d NaHC0 (30 and 30 ml) and f i n a l l y with R^O 3  (50 m l ) . The CC1 ' s o l u t i o n was d r i e d 4 and  concentrated i n vacuo u n t i l  -5° f o r 24 hours petroleum  over anhydrous  a solid  appeared.  Na„S0. 2 4  Standing at  gave c r y s t a l s , which were r e c r y s t a l l i z e d  from  ether (30 to 60) to give c o l o r l e s s needles of  erythro-3-phenyl-2 , 3-dibromopropameI—ll-ol (15 g, 68.2 % ) . mp 72-73° ( l i t . (130), A solution benzonitrile  73-74°).  of dibromopropano1 (10 g, 0.034 mol) and  (3.5 g, 0.034 mol) i n dry ether (10 ml) was  s a t u r a t e d with dry HCl gas at 0°. standing i n the cold  f o r 7 days.  A solid  precipitated  after  The s o l i d was c o l l e c t e d and  washed with dry ether to give ery thro-3"-rphenyl-2 ,3dibromopropyl 150°  benzimino  ether HCl (5.2 g, 35.3 % ) . mp 147-  ( l i t . (130), 148-150°);  i r (KBr) 3450 cm" , 1640 1  \  (—NH.HC1). Benzimino ether HCl (5 g, 0.0115 mol) was ground 10 % Na^CO^ s o l u t i o n  (25 ml) i n a mortar  f o r 20 minutes and the  s o l i d was c o l l e c t e d , washed with water and d r i e d . lization  from acetone  gave c o l o r l e s s  with  Recrystal-  erythro-3-phenyl-2,3-  108  dibromopropyl (  l i t . (130), A  (  benzimino  133.5-135°).  solution  35 m l , d r i e d  bath. into  A solid  lized mp  from  ortho 6.50 5.0  was  to carbonyl  group),  ( b , 1, -NH-CO-  m/e  235  ( 1 5 ) , m/e  12.  Attempted (23)  To EtOH  ) , 5.38  82  (Synthesis of  was  refluxed was  pressure  a t room  gave  146  went  the s o l u t i o n  was  was  recrystal-  ( 40 % , l i t . ( 1 3 0 ) ,  13  % ) ,  i r ( K B r ) 1650 c m " , 1530 1  7.6 - 7 . 8 6 < f ( m, ( m,8,  ( m,  2,  protons  phenylprotons), 4.63-  2, - C H „ C 1 ) ; —2  ( 2 0 ) , m/e  103  mass  spectrum  (20),  3-benzoylamino-2-phenylthietane  compound 2  ( 7 2 ) ( 3 9 7 mg,  ( 3 6 0 mg , 0 . 0 0 1 5  temperature  over  0.001 m o l ) i n  mol) i n EtOH  30 m i n u t e s .  on a w a t e r  bath.  The  CHCl^  SO. a n d d i s t i l l a t i o n  After  adding  H 0 2  (3 x 100 m l ) . o f CHC1  gave  (10 m l ) mixture  Precipitated  and d i s t i l l i n g o f f t h e s o l v e n t  a residue.  extracted with  then  2-phenyl-4-benzylidene-2-oxazoline,'78),  f o r 1.5 h o u r s  filtered  which  o i l  (14) .  (10 m l ) , N a S . 9 H 0 added  3.5  (=NH).  on an  C  synthesis of  2  refluxed  which  g  1640  ( d , 1, C , H - C H - C 1 - ) ,  ( 2 9 ) , m/e  the dibromo  was  NaBr  77  1.4  133-135°  mol) i n t o l u e n e  f o r 1.5 h o u r s ,  7.13-7.57  (m, 1, C^H -CH-CH-) 6 5 — ( 7 6 ) , m/e  1  30 m i n u t e s  132-134°); (CDCip  mp  cm" ,  was  a solid  Yield  ( NH) ; nmr  105  Na  to give  ( l i t . (130),  m/e  was  after  refluxing  i n vacuo  3320  i r ( K B r ) 3340  and d i s t i l l e d )  2  formed  After  (3.85 g, 8 4 . 1 % ) .  ( 3 . 5 g, 0 . 0 0 8 8  ethylacetate.  132-134°  (amide),  of base  on C a H  solution.  concentrated  ether  at  reduced  (10 m l ) , t h e m i x t u r e  Drying  a yellow  over  anhydrous  viscous  material.  109  Tic  ( s i l i c a g e l , i o d i n e chamber, CHCl^: cyclohexane  showed four spots at R s b a s e l i n e (A), 0.2  (B) , 0.5  1:1) (C), and  0.7(D). Above v i s c o u s m a t e r i a l was  dissolved  i n ether  A small amount of e t h e r - i n s o l u b l e c r y s t a l s was identified mp  (amide),  m/e  77  m/e  235  collected  as l-phenyl-2-benzoylamino-l-propene-3-ol  162-167°; t i c R  1650  (20 ml).  0;  f  1420  (45), m/e  i r (KBr) 1050  cm"  (-CH=); mass spectrum  103  (17), m/e  51  (82) .  (primary OH),  1  m/e  (11), m/e  105  148  and  1540,  (99),  (10),  (2) . A f t e r f i l t e r i n g l-phenyl-2-benzoylamin -l-propene  -  0  3-ol,  the ether s o l u t i o n  was  concentrated to 2 ml and  ated on a column using s i l i c a g e l and  CHCl^ f o r e l u t i o n .  F r a c t i o n s showing R^  0.7  column was  by i t s yellow band.  monitored  was  isolated.  P a r t i t i o n on  (£ 19 ,000),  344  mp  92-94°;  ( £, 1, C H C H = ) , 5.05 6  m/e  235  m/e  91  (25), m/e  50.6 % ) .  105  ( m,  (EtOH) 210  (£ 24,000),  (CDC1 ) 7.67-8.10<f (m, 3  6, 6 p h e n y l p r o t o n s ) ,  ( d, 2, -CH_ -0) ; mass spectrum  5  2  (100), m/e  77  (37), m/e  103  (31),  (23).  Anal..  C a l c d . f o r C^H „N0 16 13 mol. wt., 235.11. Found:  uv max  (B 16,000); nmr  4, 4 p h e n y l p r o t o n s ) , 7.10-7.40 5.73  of  from hexane on dry ice-acetone gave needle-  l i k e yellow c r y s t a l s . 241  the  Distillation  CHCl^ gave a yellow c r y s t a l of o x a z o l i n e (120 mg, Recrystallization  fraction-  C, 81.56; H, 5.65;  :  N,  C, 81.67; H, 5.57;  5.81.  N,  5.80;  M" +  110  B and C were obtained as v i s c o u s l i q u i d s having amide bands at 1540  and 1650  was  obtained from 1 - p h e n y l - l , 3 - d i c h l o r o - 2 - b e n z o y l -  similarly  aminopropane .-. . impos&ble 13.  cm  i n the i r spectrum.  1  mp . 90-93°.  Oxazoline 7j8  The i r of the product was  with that from the 1,3-dibromo compound  Attempted  s y n t h e s i s of  super-  reaction.  1-phenyl-l,3-dibromo-2-  (9h).  benzylaminopropane  Diborane prepared by the method of Z w e i f e l and Brown (145) from NaBH^ (284 mg, etherate  (1.42  during 1.5  g, 0.01  mol) was  the r e a c t i o n mixture was (10 ml). gas was  Evolving passed  (10 ml) was of s o l i d was  i n dry THF  (20 ml,  f o r 2 hours,  mixed c a u t i o u s l y with absolute EtOH w  a  s  observed.  A stream of dry HCl  I t was  then evaporated  showed a c a r b o n y l band at 1720  cm . 1  ^0  added to the v i s c o u s r e s i d u e and a s m a l l amount p r e c i p i t a t e d out. (1640  The i r spectrum  cm , 1  of the s t a r t i n g m a t e r i a l .  e x t r a c t e d with CHCl^. gave a . s o l i d which spectrum  1,3-  reduced pressure to give a v i s c o u s r e s i d u e .  showed an amide band to that  a s  mol)  After refluxing  through the s o l u t i o n .  to dryness under The i r spectrum  S  borontrifluoride  s o l u t i o n of the  (72.) (397 mg , 0.001  from L i A l H ^ ) at 0°.  and  passed i n a stream of n i t r o g e n  hours through a s t i r r e d  dibromo compound distilled  0.0075 mol)  and 1520) The  of t h i s  and was  solid  identical  apeous layer  was  A f t e r p o o l i n g the CHCl^, a d d i t i o n of ether  soon changed to a gummy m a t e r i a l .  showed a carbonyl band at 1730  cm  1  .  The i r  Ill  14.  Synthesis  of  l-phenyl-2-N,N-dimethylaminopropane-l,  3-diol(9j6) . Freshly d i s t i l l e d and formaldehyde serinol  formic  acid  ( 85 %, 2.5  g, 0.046 mol)  (37 %, 5 g, 0.062 mol) were added  ( 2 g, 0.012  bath f o r 20 hours.  mol).  The mixture was  to phenyl-  r e f l u x e d on a water  The r e a c t i o n mixture was  made a l k a l i n e  to litmus using 50 % NaOH and e x t r a c t e d with ether ml).  A f t e r drying on anhydrous  Na^SO^, d i s t i l l a t i o n  solvent gave d i m e t h y l p h e n y l s e r i n o l crystallization  ( 3 x 100  ( 1.85  of the  g, 79 % ) .  from hexane gave n e e d l e l i k e  Re-  crystals.  64-66; i r (KBr) disappearance of NH^  (1580 cm" ); nmr  7.3  ( d, 1, C_H  S ( s , 5, phenyl protons) , . 4.37  ( t , 2, ( m, m/e  -CH 0H), 2 . 97-3.33 3  88  Anal.  (100), m/e  Found: 15.  -CH ); mass spectrum M ' m/e 2  58 (21), m/e  105  (7), m/e  3.43  195  (0.2),  77(12).  Calcd. f o r C-^H^NO^ C, 67.64 ; H, 8.78;  mol wt.,  CHOH ),  C  +  2  (CDCl^)  ( b, 2 , hfy^pxy^. .) > 2.50-2.85  2  7, -CH(NCH )  1  mp  N,  7118;  195 .15 C, 67.69; H, 8.85;  Attempted  N,  7.01.  sy.hthesis of  - l - p h e n y l - l - c h l o r o - 2 - N ,N-  dimethylaminopropane-3-ol Dimethylphenylserinol  (111) .  (1.95 g, 0.01  i n CHCl^ (50 ml) and dry HCl gas was minutes.  Distillation  which was  recrystallized  mol) was  dissolved  passed through f o r 5  of the solvent gave a p r e c i p i t a t e , from EtOH-ether  dimethylphenylserinol hydrochloride  to give pure  (2.0 g, 86.6  %) mp  154-  112  156°. mol)  To d i m e t h y l p h e n y l s e r i n o l h y d r o c h l o r i d e i n CHC1  0.0075 mol)  (20 ml),  3  freshly d i s t i l l e d  i n CHCl^ (10 ml)  was  (1.16  S0C1  2  f o r 24 hours at room temperature.  under vacuum r e s u l t i n g i n a brown viscous of ether gave a s o l i d which was hydrochloride The refluxed  same procedure  EtOH (30 ml) was  The  was  Stripping ml) was The  2  2  3  2  i r (1230, 640  cm" )  unreacted  was  at room temperature  g, 0.005 mol) While  distilled  in H 0  (5  2  distilling  Na S 0 . 2  Absolute  identified  to give a r e s i d u e ; i r  -1  2  EtOH  (neat)  P o s i t i v e i d e n t i f i c a t i o n of a Bunte s a l t  was  not s u c c e s s f u l . Dimethylphenylserinol ether  (100  of i s o l a t e d The  ml).  gas was  g) was  d i s s o l v e d i n dry  passed i n t o the  dimethylphenylserinol hydrochloride  mixture was  isolated  Dry HC1  (2.0  filtered.  from the f i l t r a t e  showed the same mp  and  The  filter  cake and  a f t e r evaporating  i r spectrum as that f o r  suspension f o r 5 hours.  a solid  the  3  (10  as NaCl.  ' .  ml)  p r e c i p i t a t e d out.  residue.  added to i s o l a t e a s o l i d , which was  cm  Addition  i n d i c a t e d unreacted  1  the solvent gave a v i s c o u s  640  removed  r e s u l t i n g v i s c o u s residue d i s s o l v e d i n  EtOH s o l u t i o n was  1230,  was  followed except the mixture  with N a S 0 . 5 H 0 (1.24  and  mixture  residue.  r e f l u x e d on a water bath f o r 5 hours.  ( 280)  cooling  Solvent was  the solvent o f f , a small amount of s o l i d was Mp  g,  the i r spectrum.  f o r 2 hours i n s t e a d of s t i r r i n g  f o r 24 hours.  The  i d e n t i c a l with  as i d e n t i f i e d by  (0.89  added dropwise with  i n an i c e bath during a p e r i o d of 20 minutes. stirred  g, 0.0053  solvent  dimethyl-  113  p h e n y l s e r i n o l h y d r o c h l o r i d e . D i m e t h y l p h e n y l s e r i n o l (700 mg) was  dissolved  i n dry dioxane  (15 ml, d r i e d  on CaH^ and d i s t i l l e d ) .  Dry HC1 gas was passed through the c l e a r s o l u t i o n f o r 2 hours. Distillation  of dioxane under  brown r e s i d u e .  reduced pressure gave a v i s c o u s  Positive identification  of 111 was not  successful. 16.  Synthesis of N , N - d i m e t h y l - p - n i t r o p h e n y l s e r i n o l (110). D(-)-threo-p-nitrophenylserinol  37 % formaldehyde  (6.36 g, 0.03 mol) with  (12.5 g, 0.154 mol) and 85 % formic a c i d  (7.5 g, 0.139 mol) was s t i r r e d  at 80-100°for 13 hours.  After  making a l k a l i n e to litmus using 50 % NaOH, the mixture was e x t r a c t e d with ether (3 x 150 ml). Na^SO^ and d i s t i l l a t i o n Recrystallization (5.24  of the solvent  from ether-hexane  gave a brown  gave a white  solid.  crystal  g, 72.18 % ) . mp 90-92°; i r (KBr) 1530 cm" , 1360 1  ( - N 0 ) , disappearance of NH 2  ortho to n i t r o 4.50  Drying on anhydrous  group), 7.47  2  (1580); nmr (CDC1 ) 8Q07<$~( d, 2, 3  (d, 2, meta to n i t r o  group),  ( d, 1, N0„C,H CHOH-), 3.52 ( d, 2, -CH-OH), 3.10 ( b, 2 o 5 — —  2, hydroxyl OH, disappeared on a d d i t i o n of D O ) , 2.33-2.66 ( m, 7, -CHN(CH ) ); mass spectrum 3  m/e 209 (6), m/e Anal.  2  m/e 88 (100), m/e 58  (64),  163(6).  C a l c d . f o r C H , N 0 . : C, 54.96 ; H, 6:.72; N, 11.67; 11 l o I 4 mo1. wt., 2 4 0.15. Found: C, 55.09; H, 6.71; N, 11.54. 11  1  o  114  17.  Attempted s y n t h e s i s of l - p - n i t r o p h e n y l - l - c h l o r o - 2 N,N-dimethylaminopropane-3-ol h y d r o c h l o r i d e To p - n i t r o - N , N - d i m e t h y l p h e n y l s e r i n o l  ether to  (100  ml), HCl gas-saturated  obtain a s o l i d .  a white HCl s a l t . and  Filtration This s a l t  ether  (2.4  2  (262 mg,  HCl s a l t was  0.0022 mol)  (553 mg,  r e f l u x e d f o r 2 hours.  brox/n s o l i d .  was  added  and washing with ether gave  ( mp  116-123°) was  i n dry CHC1  0,002 mol)  g) i n dry  (200 ml)  changed to a yellow c o l o r on s t a n d i n g .  S0C1  (112) .  3  hygroscopic  Freshly  (10 ml) was  i n dry CHC1  3  distilled added to  (20 ml).  The  mixture  D i s t i l l a t i o n of the solvent gave a  Recrystallization  from EtOH-ether showed p-  nitro-N,N-dimethylphenylserinol.HCl  which was  identified  by  superimposable i r spectrum. 18.  Synthesis of 1-p-nit ropheny 1-1 , 3.-d i c h l o r o-2-N , Ndimethylaminopropane h y d r o c h l o r i d e  (.97.) .  N,N-dimethy1-p-nitropheny1serino1 HCl with  freshly d i s t i l l e d  (5.43  g, 0.02  t h i o n y l c h l o r i d e (50 ml) was  heated  mol) at  o 70-80  f o r 1.5  under reduced ing  hours. pressure  D i s t i l l a t i o n of the t h i o n y l c h l o r i d e gave a v i s c o u s r e s i d u e .  the r e s i d e by adding  EtOH (20 ml), ether  added to obtain a p r e c i p i t a t e . ether gave a d i c h l o r o compound ir  (KBr)  3420 cm"  1  (tertiary  After dissolv-  (150 ml)  Recrystallization (4.73  g, 75.4  from EtOH-  % ) . mp  amine),'1530, 1350  strong a b s o r p t i o n at 1200-1000; mass spectrum m/e  was  161-163°;  (-N0 ), no 2  106  (100) ,  115  m/e  (32), m/e  i m  Anal.  Calcd. for  33.93; mol. wt. Found: 19.  71 (19), m/e c  H 1 1  i  N 5  2  °2  C 1  70 ( 6 ) , m/e  3  :  C  '  4 2  -  1 0  ;  58 (5).  H  »  4.82; C l ,  313.52.  C, 42.10; H, 4.84; Attempted  C l , 33.81.  s y n t h e s i s of  thylaminothietane  2-p-nitrophenyl-3-N,N-dime-  (2 6)  (Synthesis of b i s (1-p-  nitrophenyl-2-N,N-d imethy1amino-3-chloropropane) s u l f i d e HC1, 1)  123).  Reaction using excess amount of Na S.9H 0. 2  Na S.9 H 0 2  (4.032 g, 0.0168 mol)  2  (50 ml) was  added  2  dissolved  i n EtOH  dropwise to the s o l u t i o n of 1-p-nitropheny1-1,  3-dichloro-2-N ,N-dimethylaminopropane  H-C;l (2.34 g, 0.0075 mol)  i n EtOH (30 ml) during 10 minutes at room temperature. r i n g was  continued f o r 2 hours a f t e r a d d i t i o n of  s u l f i d e at room temperature. filtering  The f i l t e r  the r e a c t i o n mixture was  d i s s o l v e p r e c i p i t a t e d NaCl. were obtained.  mp  gc-mass spectrum  (3 % 0V-17  column temperature  m/e  206  (37), m/e  162  (14), m/e  2  cm" ,  1350  1  /  70 (100), m/e 115  227  (13), m/e  (26).  116  77 (11-).  2  170°  Compound A ;  58 (55),  Compound B ;  (74), m/e  g)  (-N0 );  temperature  80-300°, programming 20° min.)  84 (30), m/e  to  crystals(1.22  column, i n j e c t o r  r e t e n t i o n time 11.3 minutes, m/e m/e  cake obtained a f t e r  Brown-colored  r e t e n t i o n time 8.9 minutes, m/e  sodium  t r i t u r a t e d with H 0  60-110°; i r (KBr) 1520  Stir-  115 (22),  116  2)  Reaction using equimolar c o n c e n t r a t i o n of Na^S.^H^O (Synthesis of b i s ( 1 - p - n i t r o p h e n y l - 2 N, N-dimethylamino-3-chloropropane) HC1.H  0  sulfide  123) .  Na S.9H 0 (1.441 g, 0.00 6' raol) d i s s o l v e d 2  was  added  to the s o l u t i o n  N,N-dimethylaminopropane (50 ml).  Yield  sulfur, positive;  :nmr  2  group), 2.37 /  o  —  —  J  column, i n j e c t o r  660 mg.  were f i l t e r e d mp.  and  tri-  115-135; a l k a l i - f u s i o n  test  gc-mass spectrum  0  —Z  (m, (3 %  OV-17  Z  temperature 170° column temperature 80-2 75°,  58 (44), m/e free  CH„C1) S;  o  Z  programming 20°/min.)  The  f o r 3 hours at room temperature.  (s, 6, dimethyl p r o t o n s ) , 3.00-3.63  c  J  stirred  i n EtOH  (d, 2, phenyl protons meta to n i t r o  (N0^C .H CHCHN(CH ) O  (1.881 g, 0.006' mol)  (CDCl^) 8.10 & (d, 2, phenyl protons ortho  to n i t r o group), 7.33  m/e  HCl  yellow c r y s t a l s  turated with H 0.  Z  of 1 - p - n i t r o p h e n y l - l , 3 - d i c h l o r o - 2 -  The mixture was  The p r e c i p i t a t e d  4,  i n EtOH (30 ml)  2  retention  115  (19), m/e  base  (600 mg)  A white c r y s t a l was ether s o l u t i o n .  time 9.3 minutes, m/e 84 (14), m/e  was  70 (61),  206 (12).  dissolved  i n ether (200 ml).  obtained by passing HCl gas through the  Yield  560 mg  ( o v e r a l l y i e l d .15.4  (dec.) ( r e c r y s t a l l i z a t i o n from EtOH-ether  %);mp  148  and drying at  o 50/0.1 mm  for 5 hours); a l k a l i - f u s i o n  gc-mass spectrum  (3 % OV-17  column temperature 80-275°, time 9.3 minutes, m/e m/e  206  Anal. 9.24;  (18), m/e Calcd. f o r  S, 5.29;  test  sulfur,  column, i n j e c t o r  temperature  programming 20°/min.)  70 (77), m/e  positive;  58 (55), m/e  retention 84 (21),  115 (18). C  2 32 4°5 H  2  mol. wt.  N  S C 1  4  606.20.  :  C  '  4  3  -  5  5  5  H  >  170°  5.32;  N,  117  Found: C, 43.89 ; H, 5.24; N, 9.06; S, 4.98. 20.  Synthesis of 3 - c h l o r o - l - p h e n y l p r o p y l e n e oxide-1,2(107) . Freshly d i s t i l l e d  mm,  3-chloropropenylbenzene  (68-69°/0.1  15.2 g, 0.1 mol) was added to 300 ml of a chloroform  s o l u t i o n of 85 % m-chloroperbenzoic The  acid  (25.8 g, 0.12 mol).  s o l u t i o n was kept at 0° f o r 24 hours with frequent  A precipitate time.  (m-chlorobenzoic  acid) was formed during  To the r e a c t i o n mixture,  shaking, this  10 % Na^SO^ was added to  destroy excess  peracid u n t i l  a t e s t with s t a r c h - i o d i n e paper  was n e g a t i v e .  The r e a c t i o n mixture v/as f i l t e r e d  i n t o a 1000  ml separatory funnel and washed with s a t u r a t e d NaHCO^ (150 ml) until  the washing s o l u t i o n remained b a s i c .  The .CHCl^ l a y e r  a f t e r washing with H„0 was d r i e d over anhydrous Na.SO, i n the 2 2 4 cold f o r 24 hours. evaporator.  The r e s u l t i n g yellow o i l (15.4 g) was d i s t i l l e d  under reduced 14.1  The s o l v e n t was removed using a f l a s h  pressure u t i l i z i n g  g (84 %) of a c o l o r l e s s l i q u i d .  ( l i t . (83) 67/0.3 mm); 21.  a vigreaux condenser to give bp 74-75°/0.03 mm  i r (neat) 890, 940 cm"  (epoxide r i n g )  Synthesis of o Z - t o l u e n e s u l f o n y l c h l o r i d e The  p r e p a r a t i o n of o i - r t o l u e n e s u l f o n y l c h l o r i d e was  c a r r i e d out according to a known procedure (0.6 mol) of b e n z y l c h l o r i d e was used of  1  J. -toluenesulfonylchloride'...  88-91°).  (165). 75.6 g  to o b t a i n 103 g (90.3 %)  mp 89-91° ( l i t . (165),  118  22.  Synthesis of 3-hydroxy-2-phenylthietane  (100) .  The method d e s c r i b e d by Haya (83) was used. 14.89 g (68 %) of 3-hydroxy-2-phenylthietane was obtained from 22.3 g (0.132 mol) of 3 - c h l o r o - l - p h e n y l p r o p y l e n e oxide-1,2. mp 5455°  ( l i t . (83), 5 65-5 7.5) ; i r (KBr) 1065 , 3220 , 3310  (-0H) ; nmr of  1  (CDC1 ) 2.95 <^(s, 1, OH, disappeared on a d d i t i o n 3  D 0 ) , 3.10 2  cm"  ( d, 2, SCH ), 4.60  (m, 2, ArCHCHOH),  2  7.33  ( m, 5, phenyl protons) 23.  Attempted  s y n t h e s i s of 3-azido-2-phenylthietane (10 3) .  This experiment (83). to  was performed  3-Hydroxy-2-phenylthietane  f o l l o w i n g known procedures  (4.6 g, 0.027 mol) was used  prepare 3 - b e n z y l s u l f o n o x y l - 2 - p h e n y l t h i e t a n e .  distilled  over L i A l H . . 4  Et„N was d i s t i l l e d 3  THF was  and d r i e d over K0H.  Half of the r e s i d u e was used f o r d e t e r m i n a t i o n of 3berizylsulfonoxyl-2-phenylthietane.  The attempted  s y n t h e s i s of  3-azido-2-phenylthietane was c a r r i e d out using another  half  residue. Half of the r e s i d u e was d i s s o l v e d  i n CHCl^ and f r a c t i o n a t e d  on column of s i l i c a g e l (60-200 mesh, Davison Chemical). CHCl^ was used as eluent. (silica of  As shown by p r e l i m i n a r y t i c  g e l , i o d i n e chamber, pet. e t h e r i C H C l ^ 1:1)  4 compounds was achieved.  separation  values of the compounds were:  A b a s e l i n e spot, B 0.1, C 0.25, D 0.8.  B and C were i s o l a t e d  as gummy m a t e r i a l s . B showed the same R^ values as 3hydroxy-2-phenylthietane.  D. showed a high m e l t i n g point  119  (over 200°) and strong a b s o r p t i o n at 3400 cm spectrum.  1  i n the i n f r a r e d  D; mp 84-86° (89° on r e c r y s t a l l i z a t i o n  ether-benzene), i r (KBr) 1175, 1370 cm"  1  from pet.  ( S 0 ) ; nmr 2  (CDCl^  4.83cT( , 2, ArCH_ ) , 7.43 (m, 5, Ar).' s  2  Half of the residue was d i s s o l v e d i n f r e s h l y  distilled  j  HMPT (25 ml, 83°/0.9 mm). and  the suspension  NaN  was s t i r r e d  atmosphere f o r 15 hours. H 0 and e x t r a c t e d with  on a c o l d water bath under N  ( 3 x 50 m l ) . . A f t e r d r y i n g  with anhydrous Na S0^, the ether  e x t r a c t was concentrated  2  vacuum. in  The r e s i d u e showed a strong azide  the i n f r a r e d  2  The s o l u t i o n was added to 50 ml of  ether  2  (1.5 g, 0.023 mol) was added  spectrum.  under  ( 2110 cm ^) band  The r e s i d u e was d i s s o l v e d i n a  small amount of CHCl^ and f r a c t i o n a t e d on a column of F l o r i s i l (60-100 mesh, F i s h e r S c i e n t i f i c  Company).  hexane gave F r a c t i o n A (R^ 0.8, s i l i c a hexane  : CHCl^ 3:1).  E l u t i o n with  ( B; R^0.4-0.7, t a i l i n g  E l u t i o n with n-  g e l , i o d i n e chamber,  ether gave two f r a c t i o n s  C; b a s e l i n e s p o t ) ,  E l u t i o n with  MeOH gave f r a c t i o n D which showed a l s o b a s e l i n e spot. A; mp 87-88.5° (on r e c r y s t a l l i z a t i o n azide band  from e t h e r ) , i r (KBr) no  (azide band was observed before  1175, 1370 cm  1  (S0 ). 2  of dark r e s i d u e s having  recrystallization),  B and C were i s o l a t e d  as small amount  strong band at 2110 cm . 1  T i c of the  f r a c t i o n D showed a mixture of the s e v e r a l m a t e r i a l s . dissolving  i n MeOH,  cipitation  of a c r y s t a l , which showed strong band at 650 and  3390 cm  1  e  t h e r was added r e s u l t i n g  After  as w e l l as at 2210 cm ^.  i n pre-  ~  120  24.  Attempted  s y n t h e s i s of 2-phenyl-3-thietanone (104) .  A s o l u t i o n of 3-hydroxy-2-phenylthietane (1.32 g, 0.008 mol) i n f r e s h l y d i s t i l l e d was cooled  to -20° and cyanuric c h l o r i d e  was added.  After  (2.95 g, 0.016 mol)  5 hours at -20°, t r i e t h y l a m i n e  0.032 mol) was added at  HMPT (15 ml) and DMSO (6 ml)  (3.23 g,  and the mixture was allowed to stand  room temperature f o r 10 minutes.  The mixture was poured  i n t o ice-water (30 ml) and e x t r a c t e d with CHCl^  (3 x 150 m l ) .  A f t e r d r y i n g over anhydrous Na^SO^, CHCl^ was d i s t i l l e d . T i c (silica  g e l , i o d i n e chamber, methanol)  0.8 and b a s e l i n e .  showed 2 spots at  The r e s i d u e was d i s s o l v e d  amount of CHCl^ and f r a c t i o n a t e d  i n a small  on a s i l i c a g e l column.  E l u t i o n with CHCl^ gave a yellow o i l which showed a spot at 0.8 by t i c .  That yellow o i l changed  to dark brown c o l o r .  E l u t i o n with methanol  gave a v i s c o u s r e s i d u e which showed the  b a s e l i n e spot by t i c .  I r of the m a t e r i a l showed a b s o r p t i o n  at  1650 cm . 1  121  BIBLIOGRAPHY 1.  Maass, A. R., and Nimmo, M. 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