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UBC Theses and Dissertations

The synthesis of some antergan analogues with unsaturated cyclohexyl and substituted aromatic rings Park, Jung Kil 1974

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T H E SYNTHESIS O F S O M E A N T E R G A N A N A L O G U E S WITH U N S A T U R A T E D C Y C L O H E X Y L AND S U B S T I T U T E D A R O M A T I C RINGS  by JUNG KIL P A R K B.Sc.  in P h a r m a c y ,  The Seoul National U n i v e r s i t y ,  A T H E S I S S U B M I T T E D IN P A R T I A L  FULFILLMENT  OF T H E REQUIREMENTS FOR T H E DEGREE OF M A S T E R O F SCIENCE(iN  PHARMACY)  in the D i v i s i o n of M e d i c i n a l C h e m i s t r y of The F a c u l t y of P h a r m a c e u t i c a l Sciences  We accept this thesis as conforming to the r e q u i r e d standard  T H E UNIVERSITY O F BRITISH C O L U M B I A January,  1974  1965  In  presenting  this  an a d v a n c e d  degree  the  shall  I  Library  f u r t h e r agree  for  scholarly  by h i s of  this  written  thesis at  the U n i v e r s i t y  make  that  it  purposes  for  may It  is  fulfilment  of  of  Columbia,  British  available  for  for extensive  be g r a n t e d  financial  by  gain  Columbia  shall  the  that  not  requirements I  agree  r e f e r e n c e and copying  t h e Head o f  understood  permission.  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada  Date  freely  permission  representatives. thesis  in p a r t i a l  of  or  that  study.  this  thesis  my D e p a r t m e n t  copying  for  or  publication  be a l l o w e d w i t h o u t  my  ABSTRACT  A n t e r g a n i s one histamines;  o f the e t h y l e n e d i a m i n e type  of anti-  i n t h i s w o r k ten a n a l o g u e s of i t w e r e p r e p a r e d .  That  c o n j u g a t i o n i s e s s e n t i a l to a n t e r g a n ' s a n t i h i s t a m i n i c a c t i v i t y already been established. and  S i x of t h e s e a n a l o g u e s ( A - l a-d,  2, i l l u s t r a t e d i n F i g . £  the s i g n i f i c a n c e of p;&  , p. 4  p^  has and  B-l  ) were synthesized in order  that  c o n j u g a t i o n i n the a n t i h i s t a m i n i c p r o p e r t i e s  of a n t e r g a n m o l e c u l e may  at s o m e f u t u r e t i m e be i n v e s t i g a t e d .  p r o b l e m i s to f i n d i n what way  a l t e r a t i o n ( i . e. , i n c r e a s e o r  The  decrease  in) e l e c t r o n i c d e n s i t y o f the p/fr  - c o n j u g a t e d m o i e t y o f the m o l e c u l e  affects antihistaminic activity.  The  analogues A - l a-d i n v o l v e d  ortho-,  m e t a - , a n d p a r a - m e t h y l , a n d p a r a - b r o m o s u b s t i t u t i o n to the a r o m a t i c r i n g w h i c h g i v e s r i s e to p ^ j  c o n j u g a t i o n i n the a n t e r g a n m o l e c u l e ;  w h i l e the r i n g w h i c h g i v e s r i s e to h o m o c o n j u g a t i o n was  r e p l a c e d by  a  c y c l o h e x y l m o i e t y to e l i m i n a t e any p o s s i b l e c o n t r i b u t i o n of h o m o c o n j u g a t i o n to a n t i h i s t a m i n i c a c t i v i t y . was  modified  g a t i o n was  so that the a r o m a t i c r i n g w h i c h g i v e s r i s e to p/£,  left u n m o d i f i e d .  r e p l a c e d by a benzyl moiety. A n o t h e r c o m p o u n d (B-2)  a r o m a t i c r i n g g i v i n g r i s e to p ^ carbon,  conju-  r e m o v e d f r o m the r e s t o f the m o l e c u l e b y a m e t h y l e n e g r o u p ,  i . e. , the p h e n y l g r o u p was r i n g was  In a n a l o g u e B - l , the a n t e r g a n s t r u c t u r e  so that p ^  conjugation  c o n j u g a t i o n was  ii  The  other  r e l o c a t e d the  to the a d j a c e n t  methylene  e l i m i n a t e d ; t h i s c o m p o u n d i s the  nitrogen analogue of diphenhydramine and  thiodiphenhydramine.  In order that the importance of homo conjugation to antergan's antihistaminic activity may ring which gives rise to p^, moiety (A-3).  Two  be established, the aromatic  conjugation was replaced by a cyclohexyl  compounds were synthesized in which the aromatic  ring giving rise to homoconjugation were replaced by 3-cyclohexyl moieties (A-2a and b); while the aromatic ring which gives r i s e to pjij, conjugation was left unaltered in one of the compounds (b) and replaced by a cyclohexyl moeity in the other (a).  In the tenth compound (A-1 e), both aromatic rings giving rise to both homo- and  pfij.  by cyclohexyl moieties.  - conjugation were removed and replaced  The resulting analogue of antergan has already  been demonstrated to have a very low antihistaminic activity compared to diphenhydramine, but it was felt that it would provide a useful comparison for the antihistaminic activities of the other antergan analogues prepared in this work.  Two  final intermediates in the synthesis of other analogues  of antergan were prepared.  In these analogues (C-2a and b) the  aromatic ring giving rise to homoconjugation would have been replaced by the 1-cyclohexenyl moiety, while the other aromatic ring which gives rise to pfo  conjugation would have been the same in one of the  analogues, and replaced by a cyclohexyl moiety in the other. iii  In intermediates of analogues D - l and 2, the ring giving rise to homoconjugation would have been r e p l a c e d by 2, 5- and cyclohexadiene r e s p e c t i v e l y , P7L  1,4-  while the aromatic r i n g giving r i s e to  conjugation was r e p l a c e d by the cyclohexyl moiety.  In intermediates D - 3 and 4,  the aromatic r i n g giving r i s e  to homoconjugation would have been r e p l a c e d by cyclohexyl, while the aromatic ring giving r i s e to p H, conjugation would have been r e p l a c e d by 2, 6-dimethylphenyl and 3-cyclohexenyl m o i e t i e s .  iv  ACKNOW L E D G E M E N T  I e x p r e s s m y most sincere thanks to Dr.  T . H . B r o w n for his understanding, and help in r e s o l v i n g  technical difficulties encountered in this w o r k .  I also wish to extend m y appreciation to Dean B . E . R i e d e l of the F a c u l t y of P h a r m a c e u t i c a l  Sciences  for his understanding, and i n s p i r a t i o n .  F i n a n c i a l support f r o m the U n i v e r s i t y of B r i t i s h C o l u m b i a is gratefully acknowledged.  v  TABLE OF  CONTENTS  Page ABSTRACT  ii  ACKNOWLEDGEMENT  v  T A B L E OF CONTENTS  vi  LIST O F F I G U R E S  xii  LIST O F T A B L E S  xiv.  I.  INTRODUCTION  1  II.  DISCUSSION O F T H E C H E M I S T R Y  3  III.  ANALYTICAL METHODS  46  IV.  EXPERIMENTAL  47  A.  SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O HEXYLMETHYL-N'-o -METHY LPHENYLETHYLENEDIAMINE 1. 2. 3. 4. 5.  B.  <k -Chloro-o-methylphenylacetamide o( - D i m e t h y l a m i n o - N - o - m e t h y l p h e n y l acetamide . N , N - d i m e thy I - N - o - m ethyIpheny 1 enediamine . N -£-methylphenyl-N-(/? - N , N-dimethylaminoethyl)- cyclohexanecarboxamide N, N-dimethyl-N'-cyclohexylmethy 1-N o-methylphenylethylenediamine  3.  47 48  1  49  /  51  1  N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L N'-m-METHYLPHENYLETHYLENEDIAMINE . . 1. 2.  47  o ( - C h l o r o - N -m-methylphenylacetamide . . . fj\ - D i m e thyl a m i n o - N - m - m e thy Ipheny 1 acetamide N, N-dimethyl-N'-m-methvlphenylethvlenediamine vi  52  54 54 55 57  T A B L E OF CONTENTS B.  (Continued)  Page  N, N - D I M E T H Y L - N ' - C Y C L O H E X E Y L M E T H Y L N - m - M E T H Y L P H E N Y L E T HY L E N E D I A M I N E (Continued) 1  4. 5.  C.  3. 4. 5.  60  61  o^-Chloro-N-p-methylphenylacetamide e< - D i m e t h y l a m i n o - N - p - m e t h y l p h e n y l acetamide N, N-dimethyl-N'-p-methylphenylethylene diamine N'-p-methylphenyl-N-(/ - N , N-dimethylaminoethyl)-cyclohexanecarboxamide N, N-dimethyl-N'-cyclohexylmethyl-N p-methylphenylethylenediamine  61 62 63 65  1  65a  .SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T HY L - N ' - p- B R O M O P H E N Y L ETHY LENEDIAMINE 1. 2. 3. 4. 5.  E.  58  1  .N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L N ' - p - M E T H Y LPHENY L E THY LENEDIAMINE 1. 2.  D.  . N ' - m - m e t h y l p h e n y l - N ' - ^ - N , N-dimethylaminoethyl)-cyclohexanecarboxamide . N, N-dimethyl-N'-cyclohexylmethyl-N m-methylphenylethylenediamine  66 66  <k-Chloro-N-p-bromophenylacetamide o(-Dimethylamino-N-p-bromophenylacetamide N, N-dimethyl-N'-p-bromophenylethylenediamine . N - p - b r o m o p h e n y l - N - (ft- N , N - d i m e t h y l aminoethyl)-cyclohexanecarboxamide N, N-dimethyl-N'-cyclohexylmethyl-N'p-bromophenylethylenediamine  67 68 70 71  -SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L - 3 , 5 - D I M E T HY L P H E N Y L ETHY LENEDIAMINE 1. 2. 3.  c / - C h l o r o - N - 3 , 5-dimethylphenylacetamide o ( - D i m e t h y l a m i n o - N - 3 , 5-dimethylphenylacetamide . N , N - d i m e t h y l - N ' - 3 , 5-dimethylphenylethylenediamine  vii  72 ..  72 74 75  T A B L E O F C O N T E N T S (Continued) Pa-ge E.  SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O HEXYLMETHYL-3, 5-DIMETHYLPHENYLE T H Y L E N E D I A M I N E (Continued) 4.  F.  N - 3 , 5 - d i m e t h y l p h e n y l - N - ( fi - N , N - d i m e t h y l amino)- eye lohexane c arboxamide  . N, N - D I M E T H Y L - N - C Y C L O H E X Y L M E T H Y L r N - CY C L O H E X Y L E T H Y L E N E D I A M I N E 1  78  1  1. 2. 3. 4. 5. 6.  G.  2.  ...  3.  N - c y c l o h e x y l - N - ( ^ - N , N-dimethylaminoethyl)-phenylcarboxamide N, N-dimethyl-N'-benzyl-N'-cyclohexylethylenediamine . . .  <A - C h l o r o - N - d i p h e n y l m e t h y l a c e t a m i d e c>i - d i m e t h y l a m i n o - N - d i p h e n y l m e t h y l acetamide N , N-dimethyl-N'-diphenylmethylethylenedi amine  N, N - D I M E T H Y L - N ' N ' - D I B E N Z Y L E T H Y L E N E DIAMINE 1. 2.  78 78 80 81 82  1  N, N - D I M E T H Y L - N - D I P H E N Y L M E T H Y L ETHY LENEDIAMINE 1. 2.  I.  Cyclohexanecarboxyl chloride d -Chloro-N-cyclohexylacetamide J. - D i m e t h y l a m i n o - N - c y c l o h e x y l a c e t a m i d e N, N-dimethyl-N'-cyclohexylethylenediamine N - c y c l o h e x y l - N - ( ^ - N , N-dimethylaminoethyl)-cyclohexanecarboxamide N, N-dimethyl-N'-cyclohexylmethyl-N cyclohexylethylenediamine  -SYNTHESIS O F N, N - D I M E T H Y L - N ' - B E N Z Y L N'-CYCLOHEXY LETHY LENEDIAMINE 1.  H.  76  N ' - b e n z y l - N ' - ^ - N , N-dimethylaminoethyl)benzenecarboxamide N , N - d i m e t h y l - N ' , N'-dibenzylethylenediamine viii  83  85  85 86  87 87 89 90  91  91 92  T A B L E O F C O N T E N T S (Continued)  J.  N, N - D I M E T H Y L - N - 1 - C Y C L O H E X E N Y L M E T HY L - N C Y C L O H E X Y L E T HY L E N E DIAMINE 1  1. 2. 3. 4. 5. 6.  K.  ...  94 95 96 97 98 98  1  4. 5. 6.  3 - C y c l o h e x e n e c a r b o x y l chloride N - cyclohexyl-3-cyclohexenecarboxamide ... . N-cyclohexyl-N-3-cyclohexenylmethylamine -Chloro-N-3-cyclohexenylmethyl-Ncyclohexylacetamide r£ - D i m e t h y l a m i n o - N - 3 - c y c l o h e x e n y l methyl-N-cyclohexylacetamide N, N-Dimethyl-N'-3-cyclohexenylmethylN'-cyclohexylethylenediamine  N , N - D I M E T H Y L - N ' - 3 - CY C L O H E X E N Y L M E T H Y L - N ' - P H E N Y L E T H Y LENEDIAMINE  1. 2. 3. 4. 5.  M.  . Cyclohexylcyanohydrin Methyl 1-hydroxy-cyclohexanecarboxylate M e t h y l 1-cyclohexenecarboxylate 1-cyclohexenecarboxylic acid 1-cyclohexenecarboxyl chloride . N-cyclohexyl-N-( ^ - N , N-dimethylaminoethyl)-1-cyclohexenecarboxamide  94  N , N - D I M E T H Y L - N - 3- C Y C L O H E X E N Y L M E T H Y L - N ' - C Y C L O H E X Y L E T HY L E N E DIAMINE 1. 2. 3.  L.  Page  Ji - C h l o r o - N - p h e n y l a c e t a m i d e -Dimethylamino-N-phenylacetamide N , N-dimethyl-N'-phenylethylenediamine . . . . N ' - p h e n y l - N ' - f ^ - N , N - d i m ethyl a m i n o ethyl)-3-cyclohexenecarboxamide .N, N-dimethyl-N'-3-cyclohexenylmethylN'-phenylethylenediamine  N-CYCLOHEXYL-2, BOXAMIDE  1.  5-CYCLOHEXADIENECAR-  2, 5-cyclohexadienecarboxylic dihydrobenzoic a c i d ix  acid  99 99 100 101 102 103 105  106  106 107 108 109 Ill  112  (1,4112  T A B L E O F C O N T E N T S (Continued)  M.  N-CYCLOHEXYL-2, BOXAMIDE (Continued) 2. 3.  N.  2.  112  2, 5-cyclohexadienecarboxyl chloride N - c y c l o h e x y l - 2 , 5-cyclohexadienecarboxamide  . .  . N - 2 , 6-dimethylphenyl-cyclohexanecarboxamide N-2, 6-dimethylphenyl-cyclohexylmethylamine  N, N-DIMETHYL-N - C Y C L O H E X Y L M E T H Y L ETHY LENEDIAMINE  113 114  115  115 116  1  1. 2.  P.  5-CYCLOHEXADIENECAR-  -N-2, 6 - D I M E T H Y L P H E N Y L - C Y C L O H E X Y L M E T H t L AMINE 1.  O.  Page  -dimethylaminoethyl-N-cyclohexanecarboxamide N , N-dimethyl-N'-cyclohexylmethylethylenediamine  SINGLE REACTIONS 1. 2. 3. 4. 5. 6. 7.  117  117 118 119  3 - c h l o r o - 4 - c y c l o h e x e n e - l , 2-dico;rboxylic a c i d anhydride C y c l o h e x y l p-toluensulfonate 1 - C h l o r o 3*cyclohexene 3-Cyclohexenylmethylamine o( - C h l o r o - N , N - d i m e t h y l a c e t a m i d e ci - C h l o r o - N - 2 , 6 - d i m e t h y l p h e n y l - N - c y c l o hexylmethylacetamide (attempted) d.-Chloro-N-diphenylacetamide (attempted)  119 120 121 122 123 124 124  V.  HISTAMINE  126  VI.  HISTAMINE " R E C E P T O R S "  159  VII.  ANTIHISTAMINE  163  x  T A B L E O F C O N T E N T S (Continued) Page VIII.  CONCLUSION  174  BIBLIOGRAPHY  178  <  xi  LIST O F F I G U R E S  Figure 1  Page Structures of Diphenhydramine (a) and Antergan (b)  1  Illustrating the V a r i o u s Analogues and Intermediates of Analogues of A n t e r g a n P r e p a r e d in this Work  4-5  3  M e c h a n i s m of A m i d e Reduction  15  4  Reduction of with L A H  16  5  M e c h a n i s m s for Reaction Between C a r b o x y l i c A c i d and C a r b o d i i m i d e  2  6  0  -Unsaturated A m i d e  29  M e c h a n i s m s of B i r c h Reduction of B e n z o i c A c i d and A n i l i n e  32  7  G e o m e t r i c a l I s o m e r s of 1-Chlorobutadiene  36  8  Hypothetical H e p a r i n - P r o t e i n - H i s t a m i n e C o m p l e x of M a s t C e l l Granules at pH7 Degranulation and Histamine R e l e a s e in M a s t C e l l s : Suggested M e c h a n i s m of A c t i o n of Compound 48/80  133  Schematic Drawing to Show the Sequential E x o c y t o s i s of H i s t a m i n e - c o n t a i n i n g Granules  133  11  The C a t a b o l i s m of Histamine  135  12  Decarboxylation of Histidine  140  13  Schematic Representation of the A p p r o a c h of H i s t a m i n e to the P a r i e t a l C e l l s of the Stomach  151  Conformations of H i s t a m i n e  160  9  10  14  xii  130  L I S T O F F I G U R E S (Continued)  Figure  Page  15  Schematic Representation of H i s t a m i n e Receptor  162  16  G e n e r a l Structural F o r m u l a of A n t i histamines  164  xiii  LIST O F T A B L E S  Table  I II  Page  o( - C h l o r o a c e t a n i l i d e D e r i v a t i v e s  8  °( - D i m e t h y l a m i n o - N - R ^ - A c e t a m i d e Derivatives  11  III  N j N - D i m e t h y l - N - R - Ethylene diamine  IV  N - R - N ' - ( ^ - N , N-Dimethylaminoethyl)Cyclohexanecarboxamide  20  V  N - R - N - ( - N , N-Dimethylaminoethyl)3-Cyclohexene  22  VI  VII  VIII IX  1  12  ?  2  2  N, N-Dimethyl-N'-Cyclohexylmethyl-N -R E'thylenediamines (Analogues of Antergan)  24  N, N-Dimethyl-N'-3-Cyclohexylmethylmethylethylenediamine (Analogues of A n t e r g a n A - 2 a and b)  26  I  2  A c t i o n of D r u g s on the A l l e r g i c Response  158  Antihistamines  166  xiy.':  m y P a r e n t s with Love  xv  1  PART I INTRODUCTION  Interactions of lone pair electrons of hetero atoms like nitrogen or oxygen are c h a r a c t e r i s t i c of a r o m a t i c amines and ethers. The lone pair electrons interact with the electrons of an adjacent double bond or a r o m a t i c s y s t e m , or with a double bond or a r o m a t i c  system  remote f r o m the hetero atom by one or m o r e methylene groups ( 1 ). p,-j^  conjugation is said to take place when adjacent systems are i n -  volved, and the t e r m homoconjugation is used when the interacting systems are separated by a methylene group.  •CH-Q-CH -CH -N-CH 2  2  Diphenhydramine has  -CH-N-CH -CH -N-CH 2  3  2  3  CH,  CH,  Diphenhydramine (a)  Antergan (b) F i g u r e 1.  only homoconjugation but antergan has both homoconjugation and p/£, conjugation ( F i g . 1 ).  It was o b s e r v e d by Nauta _et _al. that a l k y l s u b s t i -  tution of one or both phenyls in compounds like diphenhydramine s i g nificantly affects interaction between the lone pair electrons of oxygen and those of substituted phenyl, and a certain degree of coplanarity was o b s e r v e d between one phenyl group and the C - O bond ( 2 , 3  ).  They  also demonstrated that for the alkylsubstituted analogues of diphenhy-  o  2 dramine they synthesized, antihistaminic, anticholinergic and l o c a l anaesthetic activities were greatly m o d i f i e d by m e s o m e r i c , and steric effects r e s u l t i n g f r o m the alkyl substitution.  inductive  The presence  of both phenyl groups in diphenhydramine was of p r i m e importance in the maintenance of m a x i m u m antihistaminic activity, because  replace-  ment of one or both phenyl groups of diphenhydramine by cyclohexyl groups reduced antihistaminic activity ( 2 , $ ).  F i n a l l y , Nauta et a l . proposed that the charge density on the ether oxygen of diphenhydramine type compounds is important in determining their p h a r m a c o l o g i c a l a c t i v i t i e s .  A n t i h i s t a m i n i c activity  is supposed to be related to r e l a t i v e l y low electron d e n s i t y on the oxygen. C o n v e r s e l y , anticholinergic activity is associated with r e l a t i v e l y high electron density.  T h e y also suggested that coplanarity of the C - O bond  with a phenyl group r e s u l t s i n an o v e r l a p interaction and is important in the binding of the phenyl group to the binding site of the r e c e p t o r .  This  p r o p o s a l was supported by studies of a s e r i e s of thioether analogues of substituted diphenhydramine which showed extremely low antihistaminic activity and a general i n c r e a s e of anticholinergic activity due to different electronic and s t e r i c p r o p e r t i e s of sulphur atoms compared to oxygen atoms (4").  W o r k in our l a b o r a t o r y ( 6 ) showed that the replacement of a phenyl group of antergan by a cyclohexyl group, giving r i s e to h o m o conjugation, r e s u l t e d in an antihistaminic activity equivalent to that of  3 diphenhydramine.  Replacement of both phenyl groups by c y c l o h e x y l  groups r e s u l t e d i n e x t r e m e l y low antihistaminic activity.  The object of this r e s e a r c h was to synthesize analogues of antergan by r e p l a c i n g one or both of the a r o m a t i c rings (R^ and R  2  in  F i g . 2) with m e t h y l or halogen-substituted phenyl, or with c y c l o h e x y l , cyclohexenyl, or cyclohexadienyl g r o u p s . pounds are shown in F i g . 2.  The structures of the c o m -  The relationship between the antihist-  a m i n i c activities of compounds synthesized in the present work and electronic effects (orbital o v e r l a p interactions) resulting f r o m h o m o conjugation o r p / t  conjugation i n combination with m e s o m e r i c ,  inductive, and s t e r i c effects of substituents r e m a i n s to be investigated.  P A R T II DISCUSSION O F T H E C H E M I S T R Y The present work is concerned with the synthesis of ten analogues of antergan (groups A and B i n F i g . 2).  In addition, two final  intermediates (group C - l and C-2) of other analogues of antergan have been obtained.  T h e synthesis of four m o r e analogues (group D) was  attempted, but due to their instability and synthetic difficulties with the i n t e r m e d i a t e s , only the intermediates indicated in the F i g u r e were o b tained. . Nauta et a l . ( £ , 3  ) r e p o r t e d that a l k y l substitution on one  or both phenyl groups of diphenhydramine a l t e r e d the e l e c t r o n i c i n t e r action between  p  o r b i t a l electrons of the oxygen and  77J  bond  4 Figure  2  .  Illustrating the various analogues and intermediates of analogues of antergan p r e p a r e d in this work.  R CH -N-CH -CH -N-CH r  2  2  R  1  R  =  l  2  2  C H  cyclohexyl  2  R  i  =  3 - c  3  R  i  =  P  y i°  h e n  c  n e  =  xenyi  yl  R  2 R-  R  =  3  a o - m e thy Ipheny 1 b m-methylphenyl c p-methylphenyl d p-bromophenyl e cyclohexyl a  =  2  3  y y b phenyl cyclohexyl c  c l o h e x  1  -N-CH-CH -N-CH 1 | 2 2 | 3 R CH 2  3  B 1  R^  = benzyl  R^  = benzyl  2  R-^  =  R  = diphenylmethyl  H  R  1  -N-CH-CH -N-CH | 2 2 | 3 R  1  R  =  2  2  cyclohexane c a r b o n y l  C H  3  K  =  3, 5-dime thy Ipheny 1 • 1  2  R  l  =  l-cydohexenecarbonyl  R^  =  a phenyl b cyclohexyl  Figure 2 . (Continued)  Illustrating the analogues D of antergan ' the synthesis of which was attempted. Only the intermediates l * - 4 ' were p r e p a r e d . p  1  I  R -CH -N-CH,-CH,-N-CH, 1 2 2 2 3 R,  CH,  D 1  R  =  2, 5-cyclohexadienyl  R  cyclohexyl  2  R,  =  1, 4- cyclohexadienyl  R,  cyclohexyl  3  R,  cyclohexyl  R„  4  R,  cyclohexyl  R,  =  2, 6-dime thy Ipheny 1 3- cyclohexenyl  0 , /0H V  C  CH -MH 2  l  1  2' 3' 4'  2, 5 - c y c l o h e x a d i e n e - l - c a r b o x y l i c a c i d . 3- c h l o r o - 4 - c y c l o h e x e n e - 1 , 2 - d i c a r b o x y l i c a c i d anhydride. — 2.' ^ " dimethylphenyl- c y c l o h e x y l m e t h y l a m i n e . 1- c h l o r o - 3 - c y c l o h e x e n e .  6 electrons of the phenyl groups by inductive, m e s o m e r i c , effects,  or some combination of these.  or s t e r i c  The charge density on the  oxygen, which is affected to a certain extent by o v e r l a p or d e r e a l i z a tion with adjacent groups, was c l a i m e d to be a significant factor i n the p h a r m a c o l o g i c a l activity of the m o l e c u l e .  Steric considerations in  alkylated analogues and conformational aspects like coplanarity between one of the phenyl groups and the oxygen were also c o n s i d e r e d to be important factors in the p h a r m a c o l o g i c a l activity of diphenhydramine. Because of the s i m i l a r structures of antergan and diphenhydramine, it was felt that a s i m i l a r approach to that taken by Nauta et a l . would be useful i n establishing the significance of electronic and s t e r i c effects in antergan's p h a r m a c o l o g i c a l action.  F o u r analogues ( A - l , a - d in F i g . 2  ), and two intermediates  ( C - l and D - 5 ) of antergan were synthesized to a s c e r t a i n the p h a r m a 1  cological effects of o ^ m - ^ r  p - m e t h y l - , 2,6-  p - b r o m o - substitution on the phenyl group  or 3, 5 - d i m e t h y l - , and of antergan.  pTL  conjugation is present in a l l of these compounds.  Analogues ( A - 3 and B - l and 3) were synthesized p r i m a r i l y to a s c e r t a i n the p h a r m a c o l o g i c a l significance of the aromatic ring which gives r i s e to this s e r i e s ,  pTC conjugation in antergan and its analogues.  the aromatic r i n g  In  was r e p l a c e d either by cyclohexyl  (A-3), or it was r e m o v e d f r o m the nitrogen atom and attached to an adjacent carbon atom (B-3).  Replacement of R 2 by a benzyl group ( B - l )  m a y result in less o v e r l a p than that seen in the pTC  system with  phenyl.  The analogues of antergan ( A - 2  a and b), a final i n t e r -  mediate ( C - 2 ) and intermediates ( D - l and 2 ) have a cyclohexenyl or 1  cyclohexadiene group in the place of R ^ .  1  Because of conformational  differences and electronic interaction of the diene or olefinic bond in the s i x - m e m b e r e d ring with the nitrogen atom,  it is anticipated that  the p h a r m a c o l o g i c a l activity of these compounds w i l l be different in intensity f r o m that of antergan.  R E A C T I O N O F PRIMARY AMINES WITH CHLORIDE  (X-CHLOROACETYL-  The syntheses of the compounds f r o m groups A-,B and C . i l l u s t r a ted'below.startedwibh the appropriate amines R ^ - N H ^  and  oC-chloro-  acetylchloride. O R -NH 2  2  O  " +• C 1 - C - C H - C 1 2  i c e - s a l t bath ^ ,1 J . >• R - N H - C - C H - C 1 2  + (C^Hg^NvHCl  A 1  A 2  R  2  = a  c)-methylphenyl  b  m-methylphenyl  c  p-methylphenyl  d  p-bromophenyl  R^, •= a b  cyclohexyl phenyl  9  8 B'2. C 1  = R  2  diphenylmethyl  =  3, 5-dimethylphenyl  A l l reactants were in equivalent mole quantities with a s m a l l excess of dry triethylamine to neutralize the HC1 evolved during the r e a c t i o n .  Table I OC - C H L O R O A C E T A N I L I D E D E R I V A T I V E S O  II  R -HN-C-CH -Ol 2  R  2  o-methylphenyl m-methylphenyl p-methylphenyl p-bromophenyl cyclohexyl phenyl diphenylmethyl 3, 5-dimethylphenyl  2  m . p . (-' C )  Y i e l d (%)  110 92 160 182 105 135-136 128-129 140  93 89 91 90 90 95 • 92 91.5  The most important conditions for acylation i n this r e a c t i o n are p e r f e c t l y d r y reaction conditions and control of the reaction temperature.  T h e reactions were,  therefore,  c a r r i e d out in a f l a m e -  d r i e d reaction flask at a temperature below 0 ° C .  Reagent grade  OC -  c h l o r o a c e t y l c h l o r i d e and triethylamine were c o m m e r c i a l l y available, but r e d i s t i l l a t i o n was n e c e s s a r y to obtain sufficiently d r y starting materials.  D r y n o n - p o l a r solvents like ether and tetrahydrofuran could  be used for the reaction since they do not solidify below 0 ° C as benzene does.  However, d r y ether was used e x c l u s i v e l y because its low boiling  point made it easy to remove the solvent.  The  -chloroacetamide  derivative of each p r i m a r y amine was s a t i s f a c t o r i l y p u r i f i e d under reduced p r e s s u r e in a sublimation apparatus.  The compounds (Table i )  were stable at or above their melting points.  The same synthetic route was followed using two other p r i m a r y amines,  diphenylamine and 2, 6-dimethylaniline in o r d e r to  begin to prepare C3 and D3 in F i g . 2 . reaction temperature ( 0 ° not stable.  Therefore,  In both cases, the same  /-^ 1 0 ° C ) was employed but the products were  the reaction temperature was dropped by r e -  placing the i c e - s a l t bath with a dry ice-acetone bath. temperature,  the amides were slightly unstable.  E v e n at this  It was i m p o s s i b l e to  isolate the amides?;for the next reaction due to their instability.  O  II  N H +• C I - C - C H 2 - C I >  >  tarry,  dark brown product  (i) i c e - s a l t bath, or (ii ) dry ice-acetone bath  0 CH  II  3  f  C1-C-CH -C1 • 2  >  t a r r y , blueblack product  (i) i c e - s a l t bath, or (ii) dry ice-acetone bath  The synthesis of the compounds in group B I and 2 started respectively,  with the reaction of u n s y m m e t r i c a l N,,N-dimethylethylene-  10 diamine and benzoyl c h l o r i d e , and N , N-dimethylethylenediamine and cyclohexanecarboxyl  chloride: O  O  2CH,-N-CH -CH -NH + R-C-Cl | 2 2 2 CH ?  3  ?  ?  1 C  f " ^ (Et) O S  x  a l  b a t h  ^ CH - N - C H - C H -NH-C-R 2 | 2 2 CH 7  z  3  3  +  R  =  CH.-N-CH.-CH CH CH  phenyl or cyclohexyl  The amides f o r m e d were separated, p r e d r i e d in a i r ,  -NH-HC1  3  and finally d r i e d  completely in an e l e c t r i c a l oven ( 2 5 ° C / 1 0 m m . Hg).  P A R T II N U C L E O P H I L I C SUBSTITUTION WITH D I M E T H Y L AMINE  The dimethylamino group was substituted for the chlorine of the p r e p a r e d tion to give the  J^-  ^ [ - c h l o r o a c e t a m i d e s by nucleophilic substitu-  - d i m e t h y l a m i n o - N ' - R -acetamide derivatives: O  NH-C-CH -CH -C1 + 2NH-CH„. " > I | " (Et) O and 7 - 2 _ 2 3 THF ?  L  R  l c e  ?  2  S a I t  b a t h  3  C  H  +  NH-C-CH.-N-CH f R CH 3 2  ? 2  CH -NH-HC1 CH  The boiling point of dimethylamine is 7 ° C .  3  Therefore,  3  the dimethyl-  11 amine gas used was trapped i n a graduated cylinder by a d r y i c e acetone bath. reaction.  Two equivalents of dimethylamine were used i n each  One equivalent was used for nucleophilic substitution, and  the other one acted as a neutralizing agent for the hydrogen c h l o r i d e . The reactions were conducted i n an i c e - s a l t bath for 6 hours, and overnight at r o o m t e m p e r a t u r e .  A n a c e t o n e - d r y ice condenser to  prevent the escape of dimethylamine gas was not needed under the conditions u s e d .  The most common difficulty encountered with these  reactions was the low solubility of the amides i n d r y ether.  D r y tetra-  hydrofuran ( T H F ) or a mixture of T H F and dry methanol was employed as the solvent.  T h e solvent was heated when this was n e c e s s a r y .  T a b l e II - D I M E T H Y L A M I N O - N - R - A C E T A M I D E DERIVATIVES 2  O  II  R -NH--C-CH -N-CH_ 2  2  1  CH  R  3 b . p . , ° C ( m m . Hg)  m.p. (°C)  2  o-methylphenyl . m-methylphenyl p - m e thy Ipheny 1 p-bromophenyl cyclohexyl phenyl diphenylme thy 1 3, 5-dimethylphenyl  57 - 58  ..  57 - 58 61  83  REDUCTION O F AMIDES TO AMINES: A f t e r obtaining the ^  -  ••  r  109 103  (0.35) (0.10)  135  (2.0)  125-127  (0.4)  Y i e l d (%) 81 95. 5 90 82 96 85 89 91.5  lithium a l u m i n u m hydride ( L A H )  -dimethylamino-N-R^-acetamide  derivatives,  they were reduced with lithium aluminum hydride to the  corresponding  ethylenediamines:  LAH N H - C - N - C H 3 reflux ( E t ) Q 2  R  2  C H  NH-CH -CH -N-CH  >  3  2  R  2  2  C H  3  3  T a b l e III N, N - D I M E T H Y L - N - R - E T H Y L E N E D I A M I N E 2  N-CH.-CH,-N-CH, I 1 3 R CH 2  2  R  3  b. p. ° C ( m m . H g . )  2  2  o-methylphenyl m-methylphenyl p-methylphenyl p-bromophenyl cyclohexyl phenyl dime thy Ipheny 1 3, 5-dimethylphenyl  64-65 70.0 65-68 90.0 73.0 85.0 115.0 70. 0  Y i e l d (%)  (0.1) (0.025) (0.025) (0.05) (2.0) (1.0) (0.25) (0.05)  94 95. 95. 95. 96. 95 95 94  0 5 0 5  T o obtain the N , N - d i m e t h y l - N ' - c y c l o h e x y l - m e t h y l e t h y l e n e diamine, N - c y c l o h e x y l - N - ^ - N , N - d i m e t h y l a m i n o e t h y l ) - c y c l o h e x a n e 7  carboxamide in F i g .  (intermediate  on the way to antergan analogue  2 ) was reduced with L A H to the respective a m i n e :  D-4  13 N - Z / 6 - d i m e thy lphehyl ,/cyclohexylcarboxamide, compound in the synthesis of D - 3 in F i g .  2 , by reacting  carboxyl ichloride and 2, 6 - d i m e t h y l a n i l i n e . (  the f i r s t cyclohexane-  It was attempted to reduce  this compound using L A H in ether with refluxing, but this reaction was not s u c c e s s f u l even after 48 hours of r e f l u x i n g . s t e r i c hindrance by the two methyl groups.  T h i s was because of  When the solvent was  changed to T H F and the reaction time was extended to six days, amide was r e d u c e d .  the  14 LITHIUM ALUMINUM HYDRIDE Although there are s e v e r a l ways to reduce amides, a l u m i n u m hydride was employed e x c l u s i v e l y in this w o r k .  lithium  It is  n e c e s s a r y to keep in m i n d some c h a r a c t e r i s t i c s of lithium a l u m i n u m hydride ( r e f e r r e d to hereafter as L A H ) , and the unique way in which it and its derivatives reduce amides and n i t r i l e s to a m i n e s .  L A H was  d i s c o v e r e d in 1947 by F i n h a l t , Bond and Schlesinger (i5<v).  It was  p r e p a r e d as f o l l o w s :  4 LiH f A1C1  >  3  LiAlH  4  +• 3 L i C l  The reduction of compounds in ether solution is due to the transfer of a hydride ion f r o m the L A H to the substrate.  Ultimately,  a l l four hydrogen atoms are available as h y d r i d e .  .(A1H )"  H ~  4  +• A 1 H  3  H L i H +• A 1 H 6  >  Li  +-  I-  H-Al — H I  H  T h e s e anions are nucleophilic reagents that n o r m a l l y attack p o l a r i z e d multiple bonds ( e . g .  C=0,  C=N, N=0) at the positive atom; but isolated  c a r b o n - c a r b o n multiple bonds in compounds like the 3-cyclohexene derivatives are not usually r e d u c e d .  G e n e r a l l y , sodium b o r o h y d r i d e  is ineffective for the reduction of amides but it is a good reagent for the selective reduction of aldehydes, ketones and a c i d h a l i d e s .  The  15 reduction of amides with lithium a l u m i n u m hydride i n ether produces amines in v a r y i n g yields depending upon the structure of the amide (J57).  O R-C-N-CH_ I CH„ 3  excess ^ (Et) 0, reflux L  5  1  A  I  H  4  ,  b  >  ' CH  3  (a)  3  (b)  Figure  The  3  R-CH=N-CH,  I CH  2  3  R-CH-N-CH, H 3 A I © * -  R-CH -N-CH. | CH, A  3  • M e c h a n i s m of amide reduction  reduction m e c h a n i s m for conversion of substituted  amides to amines is b e l i e v e d to proceed by an i n i t i a l reduction to a general aminoalcohol derivative (a i n F i g . 3 ), followed by elimination and subsequent reduction of the i m i n i u m salt (or amine f r o m a monosubstituted amide).  If the reaction sequence could be stopped at the  amino alcohol stage, this intermediate would be h y d r o l y z e d to f o r m an aldehyde (AHJ).  T h e use of l i m i t e d amounts of l i t h i m u m a l u m i n u m  hydride and low temperatures brings about production of aldehyde, and better y i e l d of the aldehyde is obtained by use of the less active reducing agent, L i A l H  Z  (OC H ) 0  Z  c  n  b Z  or L i A l H ( O C H ) „ at 0 ° C . 0  £  c  D  3  The use of refluxing and excess (1. 5-2 equivalents) of L A H is important in the reduction of n i t r i l e s t o the corresponding amines:  1. 5 equiv. L A H / / reflux, ( E t ) Q . / ^  •C = N  CH NH 2  2  2  The reduction of 3-cyclohexenenitrile (above) was c a r r i e d out u s i n g excess L A H (1. 5 equivalents) with r e f l u x i n g .  M i c r o a n a l y s i s of the  hydrochloride of the product c o n f i r m e d its f o r m u l a to be C ^ H ^ N C l . Spectral data gathered for the h y d r o c h l o r i d e were consistent with 3-cyclohexenylmethylamine.  However, when the Fig. and  2 ^  0(, ^  -unsaturated amide (a in  ) was reduced following the same procedure, both the amide ,^  —olefin were reduced (b).  T h e r e f o r e , L A H was not a  suitable reducing agent for the amide with an  ,^  _  unsaturated  bond.  CH -CH -N-CH 2  2  CH,  3  LAH (Et) O, reflux  (a) CH -N-CH -CH -N-CH 2  2  2  CH, (b) Figure  4  Reduction of (X . — unsaturated amide with. L A H  3  17 Because of their relative stability and availability, L A H and N a B H ^ have been used as reducing agents in organic syntheses m u c h m o r e frequently than other complex metal hydrides have been. The many applications and limitations of L A H and N a B H ^ have been the subject of a number of reviewst'.J3.R,W0.) Lewis  acids like aluminum  t  chloride and boron trifluoride have been added to the complex m e t a l hydrides to enhance the v e r s a t i l i t y of the reagents. result in 'mixed hydrides ('/QfcytfM).  These mixtures  r.y^They••> have been p r e p a r e d  ,l  f r o m various ratios of L i A l H ^ and A l C l ^ but those p r e p a r e d with a hydride:  halide ratio of 3:1,  1:1,  u t i l i z e d in reduction reactions,  1:3 or 1:4 have been most frequently  as shown in the following equations:  3 LiAlH  4  f  A1C1  3  >  3 LiCl  f  4 A1H  LiAlH  4  f  A1C1  3  >  LiCl  +  LiAlH  4  f  3A1C1  >  LiCl  3  -  (1)  2 A1H4C1  -  (2)  +• 4 A 1 H C 1 2  -  (3)  3  Unfortunately, r a p i d p o l y m e r i z a t i o n of the aluminum hydride f o r m e d in reaction (1) above ensues,  and within minutes of m i x i n g the reagents,  the p o l y m e r begins to precipitate f r o m the solution:  n A1H  3  >  (  A 1 H  3^n  The most common reducing agents include, in order of decreasing activity:  lithium aluminum hydride, l i t h i u m borohydride  and sodium b o r o h y d r i d e .  Recently,  sodium bis-(2-methoxyethoxy)-  18 aluminum hydride ( N a A l H ^ ) ( O C H ^ C H ^ - O - C H ^ ) ^ was introduced into the c o m m e r c i a l market under the names of R e d - A l ( A l d r i c h C o . ) and V i t r i d e (Eastman Kodak).  The v e r s a t i l i t y ,  ease of use,  stability,  solubility, reactivity and selectivity of this reagent are c l a i m e d to be  good m$jr46 /4!7) 3  *Bithium borohydride and especially lithium a l u m i n u m hydride react r a p i d l y with hydroxyl compounds and,  consequently,  these metal hydrides must be used with p u r i f i e d , n o n - h y d r o x y l i c s o l vents.  Anhydrous ether and T H F are treated with sodium w i r e ,  or  refluxed with l i t h i u m a l u m i n u m hydride and d i s t i l l e d through a V i g r e u x column.  It is essential that the solvent be free of peroxides as w e l l .  A number of explosions have been reported with lithium a l u m i n u m hydride {/5Z ) and diethylether (/S3).  E x p l o s i o n s with T H F are  attributed  to the presence of p e r o x i d e s ; those with diethylether are b l a m e d on the presence of carbon dioxide.  L A H should be weighed in a dry box and  quickly t r a n s f e r r e d to the reaction v e s s e l with a m i n i m u m of exposure to the atmosphere because a protective coating of a l u m i n u m hydroxide f o r m s in humid air  {/S^-).  . If the amides are easily soluble in ether and T H F , solutions are added dropwise through a dropping funnel into the L A H solution. A Soxhlet extractor is used to maintain dissolution of sparingly soluble amides, which are difficult to add to the reaction flask using a dropping funnel.  E x c e s s l i t h i u m a l u m i n u m hydride r e m a i n i n g in the reaction  19 m i x t u r e is decomposed by dropwise addition of ethanol, ether,  or d i s t i l l e d water.  water-saturated  Although addition of ethyl acetate is s o m e -  times employed, this procedure is not advisable when the product is an amine since the amine i t s e l f m a y r e a c t with ethyl acetate {/&]).  It  is customary to add to the reaction m i x t u r e the calculated amounts of water or dilute aqueous sodium hydroxide r e q u i r e d to convert l i t h i u m and a l u m i n u m salts to granular lithium aluminate ( L i A l O - , ) .  D u r i n g the  decomposition of excess L A H , it is important not to add excess water since its presence w i l l convert the reaction m i x t u r e to an e m u l s i o n of the solvent, water and a l u m i n u m hydroxide which is difficult to f i l t e r or extract.  A n alternative isolation procedure employs an aqueous solution of sodium p o t a s s i u m tartrate to hydrolyse and complex the aluminum salts present in the reaction m i x t u r e .  In the present work,  excess L A H was usually h y d r o l y z e d by a s m a l l excess of d i s t i l l e d water and 40% sodium hydroxide was added for clear separation. was separated by centrifugation or decantation.  The solution  The amide was  reduced to the amine and lithium aluminate was produced as a b y product.  L i t h i u m aluminate and excess L A H were decomposed by the  addition of d i s t i l l e d water: /.2RCONH  2  +• L i A l H  >  4  2LiA10  2  +  H 0  LiAlH  4  4- 4 H 0 ( e x c e s s )  LiAlH (excess) 4  >  2  2  +  2H Q 2  2RCH NH 2  2LiOH  2  4- L i A l C >  4- A 1 0 2  3  2  4- H  2  > LiOH  4- A l ( O H )  »• L i A 1 0  2  +- 4 H  2  4- H  3  f  2  20 F O R M A T I O N O F A M I D E S : (Table IV) The secondary amines (Table III ) were reacted with cyclohexane c a r b o x y l chloride i n the presence of d r y triethylamine, The products of these reactions were the final intermediates of antergan analogues A - l a, b, c, d, e and C - l i n F i g . 2 .  O  O  II  II  i c e - salt bath C + HN-CH -CH -N-CH (Et) N I CH, Cl 2 2  2  3  C-N-CH,-CH -N-CH, 7  I  3  R  R  +  L  c  CH,  2  (Et) N-HCl 3  T a b l e IV N-R -N-(/#-N, N-DIMETHYLAMINOETHYL)CY C L O H E X A N E C A R B O X A M I D E 2  O  II  C-N-CH_-CH,-N-CH_  I  2  2  R,  R  2  o-methylphenyl m-methylphenyl p-methylphenyl p-bromophenyl cyclohexyl 3, 5-dimethylphenyl  m . p. ( ° C )  81-82  |  3  CH,  b . p. ° C ( m m . Hg) 125-125 116-118 128-130  (0.15) (0.05) (0. 125)  165 145  (5.0) (0.4)  I  Y i e l d (%) 92.4 85. 0 89 80 74 81  J  21 T o obtain the final intermediate for antergan analogue C-2,  N , N - d i m e t h y l - N ' - p h e n y l e t h y l e n e d i a m i n e was reacted with 1-  cyclohexenecarboxyl c h l o r i d e :  C  V - C - C 1 + HN-CH.- C H , - N-CH,  f  T  ^V-C-N-CH - C H - N - C H  >/  3 CH.  n  I ^  +  Similarly,  II  C  3  CH  jj  (Et)  H  N'.HCl  3 - c y c l o h e x e n e c a r b o x y l chloride was reacted with  N , N - d i m e t h y l - N ' - R ^ - e t h y l e n e d i a m i n e i n the presence of t r i e t h y l a m i n e . The products of these reactions were the final intermediates of antergan analogues A - 2 a and b .  f, (/  \  O II  O \ II  i c e - s a l t bath  V-C-Cl + N H - C H - C H - N - C H 2  R  2  2  C H  3  (Et) N 3  *\  >C-N-CH -CH -N-CH 2  3  R  +  2  2  C H  (Et) N«HCl 3  3  3  22 Table V N-R^-N- ( - N , N-DIMETHYLAMINOETHYL)3- C Y C L O H E X E N E C A R B O X A M I D E  R  Y i e l d (%)  b . p . ° C ( m m . Hg)  2  Phenyl  120  (0.3)  82  Cyclohexyl  160  (0.65-0.75)  96  N , N - d i m e t h y l - N ' - b e n z y l e t h y l e n e d i a m i n e was reacted benzoyl chloride in the presence of triethylamine to f o r m the final intermediate of the antergan analogue B - l i n F i g .  2 :  O <^~^-CH -NH-CH -CH -N-CH 2  2  2  3  CH,  i c e - s a l t bath (Et) N  CH -NH-CH -CH -N-CH 2  2  2  3  3  c=o  ••fc  CH,  (Et) N-HCl 3  N , N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l e d i a m i n e was r e a c t e d with benzoyl chloride i n the presence of triethylamine to f o r m the final intermediate of antergan analogue A - 3 .  23  P R E P A R A T I O N O F A L I C Y C L I C ACID CHLORIDES In o r d e r to make cyclohexanecarboxyl and 3 - c y c l o h e x e n e c a r boxyl amides,  c o m m e r c i a l l y available 3 - c y c l o h e x e n e c a r b o x y l i c  cyclohexanecarboxylic  a c i d and  acid were converted into their a c i d chlorides by  the procedure of Cope and Ciganek {!£&).  1 - cyclohexenecarboxylic  acid  was p r e p a r e d in this work, and also converted into the acid chloride to make other a m i d e s .  The substitution of chlorine for the hydroxy of the  above acids with" tbionyf chloride was an endothermic reaction.  Other  methods of formation of a c i d chlorides are reaction of carboxylic acids with phorphorous pentachloride or phosphorous t r i c h l o r i d e .  R-CO-OH  +  3R-CO-OH  +  R-CO-OH  +'  R-CO-C1  f  >3R-CO-Cl  4-  H3PO3  SOCl^—* R-CO-C1  +-  SO  PC1  P  C  1  5  3  —>  HCl  z  +  f  POCl  3  HCl  The choice of reagent for preparation of an acid chloride was l a r g e l y determined by the relative boiling points of the a c i d chloride and the  24 b y - p r o d u c t s for the convenience of separation of the products by fractional d i s t i l l a t i o n .  REDUCTION OF TERTIARY The N - R ~ N -  AMIDES - N , N - d i m e thylaminoethyl)- cyclohexane-  2  carboxamide were reduced by L A H with refluxing to y i e l d analogues of antergan A - 1 a, b, c,  / \  V J  C-N-CH -CH,-N-CH, ^ > / I 2 2 j 3 ( E t ) 0 , reflux \ R CH A  0  H  2  2  R  d and e:  3  as in T a b l e  )-CH -N-CH.-CH -N-CH, / 2 , 2 2 | 3 R CH 2  3  VI .  T a b l e VI N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L - N ' - R z E T HY L E N E D I A M I N E S ( A N A L O G U E S O F A N T E R G A N )  R  2  0 - m e thy Ipheny 1 m-methylphenyl p-methylphenyl p-bromophenyl cyclohexyl  b.p.°C(mm. 126-128 140 138 150 73  Hg)  (0.4) (0.5) (0.8) (0.2) (2.0)  Yield  (%)  97 96 97 37. 34 95  When the N - p - b r o m o p h e n y l - N - ( ^ - N , N - d i m e t h y l a m i n o ethyl)-car clyhexanecarboxamide with refluxing for 12 hours,  was reduced by an excess of L A H  the corresponding t e r t i a r y amine ( N , N -  d i m e t h y l - N ' - cyclohexylmethyl-N'-p-bromophenylethylenediamine) was f o r m e d .  The y i e l d was only 37.4%; this was because cleavage  of the C - N bond resulted in the formation of a secondary amine and cyclohexylmethylalcohol as b y - p r o d u c t s : O (^}-  C-N-CH -CH -N-CH 2  2  ( E ^ ^ e f l ^C H , - N - C H - C H , - N - C H „  r  3  Br  9  fl  O  C H  CH -OH 2  C H  +  3  NH-CH_-CH_-N c \  2  CH  Fig.  2  3  In order to obtain the analogues of antergan A - 2 a and b in ( , N - R - N - ( ^ - N , N-dimethylaminoethyl)-3-cyclohexenecarbox2  amides were reduced with L A H : O ^  ^-C-N-CH -CH -N-CH 2  R  2  2  3  CH LAH ^ < f ~ \ ( E t ) 0 , reflux \ / 3  2  r  H  -NH-CH,-CH -N-CH, ^ 7  2  L  C  H  3  26  Table VII N, N - D I M E T H Y L - N ' - 3 - C Y C L O H E X E N Y L M E T HY L E T HY L E N E D I A M I N E (ANALOGUES O F A N T E R G A N  R  A - 2 a A N D b) Yield  b . p . 0 ° C ( m m . Hg)  2  Phenyl  162-164  (2.0)  94  Cyclohexyl  116  (0.6)  96  (%)  In o r d e r to obtain the analogues of antergan B - l and 2 i n Fig. 2 and  ,  N-benzyl-N-(^-/^{(-dimethylaminoethyU-phenylcarboxamide  o( - N , N - d i m e t h y l a m i n o - N - d i p h e n y l m e t h y l a c e t a m i d e were  reduced with L A H :  ^~^-CH -N-CH -CH -N-CH 2  2  2  C=0  3  CH, LAH  /T""^  reflux, (Et) O \ — /  I CH  2  2  I CH  5  3  O  <*fl  C  H  CH-NH- CH - CH - N - CH,  3" reflux, r e i m x ,( \Ei \t il)^^ X > \^ — /J T i" 7  r^T  iI1  I  " 2 — 2 " 7™ 3 CH. J. J.  In o r d e r to obtain the analogue of antergan A - 3 , . N ' - c y c l o h e x y l N-'C^'-'Ni N-dimetTiylaminoethyr)-benzene.carboxamide were reduced with LAH:  o  ^ 7 - C - N - C H - C H - N - C H o ,^ )^ \ c H -N-CH -CH,-N-CH, X=J >k I.. (Et) O, r e f l u x 2 ^ 2 2 ^ 3 L  ?  ?  3  c h  A  H  r  t  r^i  z  3  P R E P A R A T I O N O F l - C Y C L O H E X E N E C A R B O X Y L I C ACID The synthesis of 1-cyclohexenecarboxylic  a c i d began with  the preparation of cyclohexyl cyanohydrin by a method s i m i l a r to that reported in ref. /6? :  Q=0  , Q(  OH  •  KCN _  +- cone. HC1  +  KCl  CN  The reaction was conducted in the fume hood, because of the p o s s i b i l i t y of hydrogen cyanide production.  Although this v e r y toxic gas s m e l l s  like almond o i l , it soon d e - s e n s i t i z e s the sense of s m e l l .  The cyclohexyl  cyanohydrin was e s t e r i f i e d at r o o m temperature ( 2 5 ° C ) with dry methanol which had been saturated with hydrogen chloride in an i c e - s a l t bath:  ,  ,  OH  ,  OH + NH C1 4  C=N  C=0 I  O-CH  The methyl 1-hydroxycyclohexancarboxylate thionyl chloride in the presence of p y r i d i n e :  3  was dehydrated with  28  The m e t h y l 1 -cyclohexene  carboxylate was h y d r o l y z e d by 10% sodium  hydroxide solution, and n e u t r a l i z e d with dilute h y d r o c h l o r i c a c i d to y i e l d free cyclohexenylcarboxylic  acid:  o / < \  o  ^ V-C-OCH, / 3  reflux f !0%NaOH  11  •  / ( \  11  V~C-ONa /  o dil. H C l / „ ^ V( 25°C \ v  r f  ^ x  H V-C-OH /  A T T E M P T T O P R E P A R E A M I D E S USING A C A R B O D I I M I D E A n adaptation of the c a r b o d i i m i d e synthesis of Sheehan {/S3 ) and Vigneau {I6H-), in which a c a r b o x y l i c a c i d reacts with an amine to produce a carboxamide  and N , N ' - d i c y c l o h e x y l u r e a , was t r i e d in an  effort to find a simple and convenient method for amide f o r m a t i o n .  In  one t r i a l , one equivalent of each of N , N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l enediamine and cyclohexanecarboxylic chloride.  a c i d were d i s s o l v e d in methylene  A solution of one equivalent of d i c y c l o h e x y l c a r b o d i i m i d e was  added dropwise into the reaction mixture over a p e r i o d of five minutes with r a p i d s t i r r i n g . became cloudy.  A t the end of the addition, the reaction  mixture  T h i s procedure was c a r r i e d out in different runs at  r o o m temperature, and at 0 ° C ; the reaction was continued for two h o u r s .  = CNH H  +  O' / c  O  B  D  NH="c"-NH-/  O  \  N=C-NH rl  O  H <*  c=o  NH-  CH*-CH*-N  or  NH* - C H z - C H - M - C H 2  1 CH  9  o  3  II  N-C-NH  I  c=o  o  NH-C-NH-^  ^  and t  O  O  < U - c - Q  Figure  5 .  M e c h a n i s m s for reaction between c a r b o x y l i c a c i d and carbodiimide  30 In a second t r i a l , the solution of carboxylic acid was added dropwise to a mixture of diimide and N , N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e .  In these r e a c t i o n s , the amide was not f o r m e d . dicyclohexanecarboxylic^anhydride hexylurea was a b y - p r o d u c t . of d i c y c l o h e x y l u r e a ( m . p .  Instead,  was the m a i n product and d i c y c l o -  The i r N - H bending band at 1625 c m *  2 2 3 ° C ) was used to identify its p r e s e n c e .  Disappearance of the stretching band c h a r a c t e r i s t i c of -N=C=N- at 2115  c m ^ was taken as a proof that the d i c y c l o h e x y l c a r b o d i i m i d e was  used up. attempted.  Separation of the anhydride f r o m the d i c y c l o h e x y l u r e a was not D i c y c l o h e x y l u r e a is sparingly soluble in the solvents used  in the r e a c t i o n s :  dioxane,  T H F , benzene,  methylene chloride,  ether  and hexane; but the u r e a was d i s s o l v e d in sufficient quantities to be a contaminant of the a c i d anhydride.  In F i g .  anions of the acids are the reaction entities,  5  , the cation in A , and and the r e l a t i v e l y weak  nucleophilic secondary amine (N, N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l e n e diamine) is probably less active than the cyclohexanecarboxylic anion during the attack on the cationic carbon atom in D . formation f r o m cyclohexanecarboxylic  The amide  a c i d and N , N - d i m e t h y l - N ' - c y c l o -  hexylethylenediamine was attempted using various solvents THF,  acid  (dioxane,  hexane, and benzene) after methylene chloride was u n s u c c e s s f u l .  A l l these reactions were c a r r i e d out at two different temperatures, and r o o m t e m p e r a t u r e ; but a l l experiments dimethylethyl-N'-cyclohexyl-N 1  0°C  failed to pro duce fi - N , N -  cyclohexanecarboxamide.  31  The reaction between c a r b o x y l i c acids and c a r b o d i i m i d e s follows the pattern in F i g . 5 to give the cation A .  .  The f i r s t step is the attack of a proton  T h i s is followed by the attachment of the acid anion,  which results in the formation of B . acylurea  C.  T h i s can r e a r r a n g e to f o r m an  A l t e r n a t i v e l y , attachment of a second proton can p r o c e e d  m o r e quickly than the oxygen-to-nitrogen m i g r a t i o n and the cation is produced; D is subsequently attacked by the a c i d anion.  D  The products  of the reaction generally depend on the nature of the c a r b o d i i m i d e , the acid,  solvent, and the temperature at which the reaction is c a r r i e d out.  PREPARATIONOOF CYCLOHEXADIENE SYSTEM In order to replace the benzyl group of antergan by c y c l o hexadiene,  preparation of the appropriate hexadienecarboxylic acid  was attempted by reduction of the a r o m a t i c r i n g of benzoic a c i d . B i r c h reduction and the D i e l s - A l d e r synthesis were employed for the preparation of 2, 5-cyclohexadiene-1 - c a r b o x y l i c a c i d , and 3 - c h l o r o - 4 cyclohexene-1, 2 - d i c a r b o x y l i c a c i d anhydride, starting m a t e r i a l s r e s p e c t i v e l y for antergan analogues N , N - d i m e t h y l - N ' - 2 , 5 - c y c l o h e x a d i e n y l m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e , and N , N - d i m e t h y l - N 1  1, 4 - c y c l o h e x a d i e n y l m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e .  P R E P A R A T I O N O F 2, 5 - C Y C L O H E X A D I E N E - 1 - C A R B O X Y L I C A C I D The most important use of m e t a l - a m m o n i a reducing agents was d i s c o v e r e d by Wooster  (139).  B i r c h made a thorough study of the  reduction of benzene derivatives and developed p r a c t i c a l applications for the reaction which now b e a r s his name.  The reduction m e c h a n i s m  was proposed by h i m (/S9):  Figure 6 .  M e c h a n i s m s of B i r c h reduction of benzoic acid and a n i l i n e .  In the metal a m m o n i a reducing solution, benzene derivatives are e q u i l i b r i u m with a low concentration of the r a d i c a l anion (a) in Fig. 6  .  A suitable a c i d (ammonia is too weak) is able to displace the  e q u i l i b r i u m towards the formation of another r a d i c a l (b).  A second  electron is added to the second r a d i c a l to give another anion (c),  which  is protonated i r r e v e r s i b l y under the reaction conditions to give cyclohexa-2, 5-diene as the m a j o r product. would be greatest at positions stituent,  The electron density  and C4 to the electron-attracting  and p r e f e r e n t i a l protonation of the r a d i c a l - a n i o n at these  positions is to be expected.  S i m i l a r l y , an e l e c t r o n - r e l e a s i n g  sub-  stituent would cause the r a d i c a l anion to be protonated in the positions.  sub-  and  In a benzene derivative like benzoic a c i d which has an  electron-withdrawing group, the benzene ring is reduced in the  and  C4 positions because of the substituent.  The reduction of benzoic acid by s o d i u m - a m m o n i a was c a r r i e d out by the following method i  H liq. OH  H  NH (_33°C) 3  Na, EtOH  O  H  OH  The product,  2, 5-cyclohexadiene-1 - carboxylic a c i d was p u r i f i e d by  distillation through a V i g r e u x column, or alternatively through a spinning column which gave m o r e efficient separation. s p e c t r u m showed that one proton at  and two at  The n m r  were coupled,  c o m p r i s i n g a multiplet with an unusually large coupling constant/#f).The product obtained i n every r u n contained traces of benzoic a c i d in the n m r spectrum.  It was thought at f i r s t that i m p e r f e c t dryness of the  34 ethanol was responsible for the p r e s e n c e of benzoic acid in the product. Therefore, ethanol.  the following methods were used to obtain completely d r y  Diethylphthalate reacts i r r e v e r s i b l y with sodium ethoxide and  water ( / S i ):  a  COOC H 2  5  +• C - H - O N a + H 0 2  COOC H 2  5  reflux  2  > RCOONa + 2 C H O H 2  5  5  A l t e r n a t i v e l y , water can be r e m o v e d by reaction with m a g n e s i u m ethoxide:  Mg  (OC H ) 2  5  2  +- 2 H O z  >Mg ( O H )  2  +  2C H OH 2  5  Since the m a g n e s i u m hydroxide is insoluble in ethanol, the reaction proceeds to completion (162-); but even when the ethanol was d r i e d using these methods, the reduction. be r e s p o n s i b l e .  some benzoic a c i d r e m a i n e d i n the product of  It was believed that i m p r o p e r distillation methods might However, after many runs using good distillation c o n -  ditions, it was concluded that spontaneous aromatization of 2, 5 - c y c l o hexadiene-1 - c a r b o x y l i c a c i d was probably o c c u r r i n g during the distillation.  N m r  was sufficiently p u r e .  and i r  spectra showed that the product obtained  The 2, 5 c y c l o h e x a d i e n e - 1 - c a r b o x y l i c  a c i d was  35 converted to its acid c h l o r i d e , and reacted with cyclohexylamine to prepare N-cyclohexyl-2, 5 cyclohexadiene-1-carboxamide. and  i r  spectra of the amide were satisfactory,  The n m r  but the result of  m i c r o e l e m e n t a l analysis was different f r o m its calculated value.  •HCl  Subsequently, reduction of N - c y c l o h e x y l 2, 5-cyclohexadiene-1 - c a r boxamide was c a r r i e d out using L A H with r e f l u x .  The c a r b o x y l . group  was reduced, but the 2, 5-cyclohexadiene was o x i d i z e d to an aromatic ring.  T h e r e f o r e , this method was not satisfactory for the synthesis of  the antergan analogue it was designed for (N, N - d i m e t h y l - N ' - 2 , 5 - c y c l o h e x a d i e n y l m e t h y l - N - cyclohexylethylenediamine). 1  P R E P A R A T I O N O F 3 - C H L O R O - 4 - H E X E N E - 1, 2 - D I C A R B O X Y L I C  ACID  ANHYDRIDE In the f i r s t step of the synthesis of 1, 4-cyclohexadiene carboxylic acid,  1-chlorobutadiene and c i s - b u t e n d i o i c a c i d anhydride  (maleic anhydride) were r e a c t e d in the p r e s e n c e of iodine and h y d r o quinone to produce 3 - c h l o r o - 4 - c y c l o h e x e n e - 1 , 2 - d i c a r b o x y l i c a c i d anhydride.  cl  (I)  ci  (II)  c i s - 1 - chlorobutadiene (S-cis-isomer)  c i s o i d conformation  Ci  Ci  ±  (III) t r a n s - 1 - c h l o r o b u t a d i e n e (S-trans - i s o m e r )  Figure  7 .  (IV)  f  c i s o i d conformation  G e o m e t r i c a l i s o m e r s of 1-chlorobutadiene  The S - c i s - i s o m e r (I) does not convert to the c i s o i d conformation (II) because of s t e r i c h i n d r a n c e .  F o r the same r e a s o n , it does not enter  the diene synthesis ( D i e l s - A l d e r r e a c t i o n ) ( f l l  ). T h e S - c i s - i s o m e r (I)  converts easily to the S-trans - i s o m e r in the presence of iodine, which y i e l d s a c i s o i d conformation.  T h e m i x t u r e of S - c i s - and t r a n s - i s o m e r s  of 1 - chlorobutadiene can, therefore,  be u t i l i z e d to react with m a l e i c  anhydride in the presence of iodine.  Diene synthesis was found to o c c u r  r e a d i l y between the c i s o i d conformation (IV) and m a l e i c anhydride:  \  +  /  C  The synthesis of 3 - c h l o r o - 4 - c y c l o h e x e n e - 1 , was c o n f i r m e d by  i r,  n m r,  2 - d i c a r b o x y l i c a c i d anhydride  and elemental a n a l y s e s .  The preparation  of 1, 4 - c y c l o h e x a d i e n c a r b o x y l i c a c i d f r o m the anhydride was not attempted,  although this reaction is possible (170 ).  Nothing further  was done with the anhydride because it was b e l i e v e d the synthesis of N , N - d i m e t h y l - N - c y c l o h e x y l - N - 1, 4- cyclohexadienylmethylethylenediamine 1  1  would be i m p o s s i b l e , after the reduction of N - c y c l o h e x y l - 2 , 5 - c y c l o h e x a dienecarboxamide to its amine was found to be impossible (p. 3$)  38 H A L O D E C A R B O X Y L A T I O N O F A C A R B O X Y L I C ACID The halodecarboxylation of a cyclohexanecarboxylic  acid  using lead tetraacetate was c a r r i e d out, following the method of K o c h i (168):  //  V . C  /  /  0  ¥ P b ( A c O ) +• L i C l 4  ^  p  N  Z  >Cl+Pb(OAc)  -> V  Benzene \  /  ?  +• A c O H  & 4-LiOAc  + CO  The reaction was conducted by adding one equivalent of halide to a solution of a c i d and lead acetate in benzene. was refluxed with s t i r r i n g under nitrogen gas. were i n i t i a l l y heterogeneous, minutes.  The m i x t u r e  Although the reactants  the r e a c t i o n was completed within five  M o i s t u r e in the a i r inhibits the r e a c t i o n and flushing with  nitrogen was n e c e s s a r y for a good y i e l d .  SYNTHESIS O F  - CHLORO-N, N-DIMETHYLACETAMIDE  The p r e p a r a t i o n of antergan analogues using c h l o r o a c e t y l chloride gave good y i e l d s , but r e q u i r e s many further reactions to get to the analogues.  In an effort to find a s i m p l e and efficient method for  synthesis of the N-dimethylethylene part of antergan analogues, c h l o r o - N , N - d i m e t h y l a c e t a m i d e was synthesized:  ^ -  z  t  39 n 2 NH-CH3 + C 1 - C - C H - C 1 CH 2  < >2° ° e-acetone bath' C H 3 - N H - C - C H - C l CH E t  d  r  y  3  ic  2  3  CH  I  5  '•  f CH -NH-HC1 3  A s the reaction is v e r y vigorous, it was conducted c a r e f u l l y at a low temperature ( - 8 0 ° C ,  in d r y ice-acetone bath) using s t o i c h i o m e t r i c  equivalents of the reactants.  The reaction of  =K - c h l o r o - N , N - d i m e t h y l -  acetamide with b e n z y l c y c l o h e x y l a m i n e , however, which would have provided an intermediate for the formation of the N - d i m e t h y l a m i n e part of the analogues, gave a poor y i e l d .  T h i s method,  therefore,  does not appear to have any advantages over the methods using chloroacetylchloride reaction.  In o r d e r to prepare antergan anlogue C - 2 b ( F i g . £ direct condensations indicated below were attempted. found that the r e a c t i o n f o r m i n g (a),  ), the  When it was  the final intermediate in the f o r -  mation of analogue C - 2 b would not go ahead, a condensation using the p r i m a r y amine was attempted.  Compound (b), which would also have  been an intermediate in the synthesis of analogue C - 2 b , was not f o r m e d either.  E x c e s s amine (1.2 times the equivalent of the ester present)  was added dropwise to the ester solution.  E v e n after refluxing for 3  days, no new compound could be detected on a thin layer silicate plate.  40  A T T E M P T T O A L K Y L A T E A S E C O N D A R Y A M I N E WITH CYCLOHEXYL p-TOLUENESULFONATE C y c l o h e x y l tosylate was f o r m e d in good y i e l d in the following r e a c t i o n :  41 A l k y l sulfonates are generally good alkylating agents; therefore, alkylation of the secondary amines N , N - d i m e t h y l - N - c y c l o h e x y l m e t h y l 1  enediamine (a in d i a g r a m below) and N , N - d i m e t h y l - N ' - b e n z y l e t h y l e n e diamine (b in diagram) with cyclohexyl tosylate was attempted.  (a)  no product  (b)  no product  It appeared that a s m a l l amount of a quaternary salt was f o r m e d during these reactions, but it was not identified.  The low r e a c t i v i t y  of cyclohexyl tosylates has been attributed to s t e r i c hinderance by the cyclohexyl group_  A l k y l a t i o n of N , N - d i m e t h y l - N ' - b e n z y l e t h y l e n e d i a m i n e with benzyl b r o m i d e and benzyl chloride was then attempted.  These  reactions were used to tell whether the secondary or t e r t i a r y amine site of the diamine is most active; since the quaternary a m m o n i u m salt was f o r m e d exclusively, it is concluded that the t e r t i a r y amine site is m o r e active than the secondary site.  H I  CH - N - C H - - C H  CH -N  25°C  + Cl-CH  THF  CH,  rCS  Cl H I ©I -CH -N-CH -CH -N-CH 2  2  2  2  CH  3  W  In the same way, alkyl halid.es generally undergo nucleophilic substitution r e a d i l y , while a r y l halides are slow in substitutions under the same reaction conditions. chloride and 1 - c h l o r o - 3 - c y c l o h e x e n e ,  extremely Cyclohexyl  like c y c l o h e x y l - p - t o l u e n e s u l -  fonate, were not active alkylating agents for N , N - d i m e t h y l - N 1  cyclohexylethylenediamine, for the same r e a s o n :  Cl  ('  W c H  2  - N - C H  2  no product  - C H . - N - C H ,  2  |  3  C H  Cl  no product  In another t r i a l , the sodium salt of N , N - d i m e thy I - N 1  cyclohexylethylenediamine was made by reaction with sodium amide, and 1 - c h l o r o - 3 - c y c l o h e x e n e  was added into the r e a c t i o n m i x t u r e .  reaction was continued for 24 h o u r s . very poor.  The y i e l d of t e r t i a r y amine was  T h i s m a y be attributed to the low activity and steric  hindrance of 1 - c h l o r o - 3 - c y c l o h e x e n e .  The  44  NaNH , N 2  CH -NH-CH -CH -N-CH 3 I CH 2  2  Na  2  benzene(reflux)  2  3  > POOT Yield. A T T E M P T E D CONDENSATION O F PRIMARY AMINES WITH fi - D I M E T H Y L A M I N O E T H Y L C H L O R I D E H Y D R O C H L O R I D E The synthesis of N , N - d i m e thy 1 - N ' - c y c l o h e x y l e t h y l e n e diamine, an intermediate for antergan analogue A - 3 in F i g . £  , was  attempted by reacting one equivalent of cyclohexylamine with two equivalents of sodium a m i d e .  A f t e r the formation of the sodium salt  of cyclohexylamine had been c o n f i r m e d , one equivalent of thylamino ethy 1c chloride* H C l was added.  ^ - dime-  The y i e l d of the d e s i r e d  product (N, N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e ) was v e r y poor, and the product consisted almost entirely of N , N - d i m e t h y l e t h y l e n e diamine.  One r e a s o n for this is probably that the sodium salt of  cyclohexylamine neutralized the hydrochloride salt f i r s t (reaction a. in figure below); returning the amine salt to cyclohexylamine, sodium c h l o r i d e , and eliminating the p o s s i b i l i t y of reaction  producing  b. o c c u r r i n g  to any significant extent.  T h i s leaves the extra equivalent of sodium  amide free to react with  ^ - d i m e t h y l a m i n o e t h y l chloride (reaction c)  to give the N , N-dimethylethylenediamine.  E v i d e n t l y , the sodium salt  of cyclohexylamine is a v e r y strong base, perhaps even stronger than sodium amide.  Another factor decreasing the y i e l d of the d e s i r e d  45 product is undoubtedly c y c l i z a t i o n of the fl - d i m e t h y l a m i n o e t h y l chloride f o r m e d in reaction b, to give the quaternary a m m o n i u m salt (reaction d).  Separation of the two products of this reaction (N, N dimethylen'ediamine and N , N - d i m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e ) was difficult on a 9 - i n c h V i g r e u x c o l u m n . NH-  NHNa 4- 2  benzene, N  NaNH,  2  +- N a N H  reflux  2  4- N H ' 3  T  CH, NH -CH -CH -N-CH 2  2  2  3  NaNH (extra equivalent)'  CH,  2  (c)  NH  CH, 0  0  2  4-  4- N a C l  ~ (a) CH, CH, X  •N' C H / C H N  3  CH»  (b)  I  C£ -CHit- CHr N - C H " N H f N a C 1 3  3  NHNa  NH - C H  2  - CH  2  - N  -  CH,  2  CH,  h- C H ,  C1-CH -C H -  C 1 - C H - C H - N * HC1  Z  CH  3  NaNH,  46 P A R T III ANALYTICAL METHODS  A B e c k m a n I . R . - 1 0 Infrared Spectrophotometer Instruments,  Inc. ) was used to r e c o r d the i n f r a r e d s p e c t r a .  (Beckman Liquid  samples were scanned as thin f i l m s between N a C l plates and solids were i n c o r p o r a t e d into K B r d i s c s .  N u c l e a r magnetic resonance  spectra were r e c o r d e d using a V a r i a n T - 6 0 S p e c t r o m e t e r .  (nmr)  The  solutions were approximately 10% and deuterated c h l o r o f o r m ( C D C l ^ ) was u s e d as solvent. standard.  T e t r a m e t h y l s i l a n e (TMS) was u s e d as an i n t e r n a l  Peaks in the n m r spectra are r e p o r t e d a c c o r d i n g to the  following f o r m a t : sionless units  c h e m i c a l shifts f r o m T M S are e x p r e s s e d in d i m e n -  & , peak m u l t i p l i c i t y , number of protons, coupling  constant where this is applicable, position of protons in the m o l e c u l e . The following abbreviations are used for the peak m u l t i p l i c i t y : s,  singlet; d, doublet; t, triplet; m , multiplet.  Melting points were  determined, unless otherwise indicated, in open c a p i l l a r i e s in a T h o m a s Hoover U n i m e l t apparatus (Arthur H . T h o m a s C o . ) . points are reported u n c o r r e c t e d .  A l l melting  47  •PART IV EXPERIMENTAL  A,  SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L N'-o-METHY LPHENY LETHY LENEDIAMINE 1. A solution of o - m e t h y l a n i l i n e (32. l g , 0. 3 mole) and t r i m e t h y l -  amine (30. 34g,  0. 3 mole) in 500 m l . of dry ether was p l a c e d in a 1 l i t r e  three-necked f l a s k .  The flask was equipped with a m e c h a n i c a l  a side a r m for setting a thermometer  stirrer,  (range -100 to 5 0 ° C ) and a  dropping funnel (1Z5 m l . ) which c a r r i e d a drying tube.  The solution  was cooled by s t i r r i n g for 1 hour in an ice - s a l t bath (-5 to - 1 0 ° C ) . A solution of chloroacetyl chloride (34 g, 0. 3 mole) in 100 m l . of dry ether was added f r o m the dropping funnel to the reaction f l a s k . The solution was added slowly, with constant s t i r r i n g , so as to keep the temperature of the solution below 0 ° C . overnight at r o o m temperature.  The m i x t u r e was  stirred  T h e n 100 m l . of d i s t i l l e d water was  added to the flask, and the m i x t u r e was s t i r r e d for 15 m i n u t e s . white product was suction f i l t e r e d through a Buchner funnel.  The  The  ethereal layer was then separated and flash evaporated to r e m o v e the solvent.  The r e m a i n i n g s o l i d was combined with the suction f i l t e r e d  product, and p l a c e d in 500 m l . b e a k e r .  5% HC1 (100 m l . ) and c o l d  d i s t i l l e d water (100 m l . ) were added, and the product was then suction  f i l t e r e d and washed with d i s t i l l e d water until no H C l could be detected using litmus paper.  T h e product was p r e d r i e d i n the a i r  and finally d r i e d at 4 0 ° C i n an oven under reduced p r e s s u r e (20 m m Hg).  The product was p u r i f i e d by reduced p r e s s u r e sublimation.  Yield:  51. 6g (93%). m . p . : 1 1 0 ° C .  i r ( K B r ) 3260 ( N - H ) , 3040 ( C - H ) , 1600 (C=0), 760, 730 c m " (C-Cl);  n m r (CDC1 )^.7. 33 - 7. 07 (m, 4, p h e n y l - H > , 3  (CH -C1), 2  2.27 (si, 3,  to-CH ), 3  19.32.  2.  Found:  2.)  1. 53 (s, 1, N - H ) .  A n a l . C a l c d . for C g H ^ N C I O : Cl,  4. 20 (s ,  1  C , 5 8 . 9 ; H , 5.45; N , 7.64;  C , 58.83; H , 5.56; N , 7.72; C l , 1 9 . 2 .  o{ - D i m e t h y l a m i n o - N - o - m e t h y l p h e n y l a c e t a m i d e DryDether (350 m l . ) was placed in a 500 m l . three-necked  flask equipped with a dropping funnel (125 m l . ) with drying tube, a m e c h a n i c a l s t i r r e r and a side a r m for setting a thermometer (range -100 to 5 0 ° C ) .  T h e solution was cooled to between -5 and - 1 0 ° C in an  i c e - s a l t bath for 1 h o u r .  D i m e t h y l a m i n e (26.5 c c . , 0.4 mole) was  trapped in a d r y graduated cylinder (50 m l . ) f r o m a dimethylamine gas tank by an a c e t o n e - d r y ice bath ( - 8 0 ° C ) , the three-necked reaction flask. phenylacetamide  and poured a l l at once into  A solution of  o( - c h l o r o - o - m e t h y l -  (27. 55g, 0. 15 mole) in d r y tetrahydrofuran  was added slowly f r o m the dropping funnel to the v i g o r o u s l y  (80 m l . ) stirred  solution so as to keep the temperature of the r e a c t i o n mixture below  49 0°C.  A f t e r the addition was completed,  s t i r r i n g was continued.  The temperature was kept below 0 ° C for 10 hours, overnight.  and below 1 0 ° C  T h e white dimethylamine salt was suction f i l t e r e d and the  solvent was r e m o v e d using a r o t a r y evaporator. water was added to the product,  30 m l . of d i s t i l l e d  and the mixture was shaken  vigorously in the separating funnel.  T h e mixture was extracted  with two 150 m l . portions of ether, and the combined ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e solution was  suction f i l t e r e d and the solvent was r e m o v e d using a r o t a r y e v a p o r a t o r . The product was further d i s t i l l e d through an a i r - c o o l e d doublesurface condenser. ether ( 3 0 ° - 6 0 ° C ) .  . The product was r e c r y s t a l l i z e d f r o m petroleum Yield:  23g (81%).  m . p . : 57-58°C.  i r ( K B r ) 3280 ( N - H ) , 2970, 2940, 2820, 2770 ( N - ( C H ) ) , 3  1670 (C=0), 765, 720 c m " (phenyl-H); n m r ( C D C 1 ) 1  £  3  2  8.5-8.13  (broad s , 1, N - H ) , 7.33 - 6.93 (m, 4, p h e n y l - H ) , 3.07 (s', 2, ;  0=C-CH ), 2  2.37(s.,  6, N C C H ^ ) ,  2.23 (Is. 3, O - C H j ) .  A n a l . . C a l c d . for C . . H , , N 0 : C , 68. 72; H , 8. 39; 11 1o 2 o  N,  14.57.  3.  Found:  C , 6 8 . 9 2 ; H , 8. 34; N , 14.49.  N , N-dimethyl-N'-o-methylphenylethylenediamine A d r y 250 m l . three-necked flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) and reflux  The funnel and condenser both c a r r i e d drying tubes.  condenser.  150 m l . of d r y  ether and lithium aluminum hydride (7. 6g, 0. 2 mole) were added to the ether, and the m i x t u r e was gently refluxed with s t i r r i n g for 3 hours A solution of  ck - D i m e t h y 1 a m i n o - N - o -methylphenylacetamide (19. 2g,  0. 1 mole) in 50 m l . d r y ether was placed in the dropping funnel and added dropwise at a rate that maintained gentle r e f l u x . addition was complete, stirring.  A f t e r the  the m i x t u r e was refluxed for 40 hours with  When the reduction was completed, the r e a c t i o n mixture  was cooled in an i c e - s a l t bath for 30 minutes, and 20 m l . of d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in o r d e r to decompose the excess h y d r i d e .  The s t i r r i n g was continued until the  m i x t u r e became white in c o l o u r .  T h e n sufficient 40% N a O H solution  was added to allow clear separation of the ethereal l a y e r . insoluble residue was separated by centrifugation.  T h e ether-  T h e ethereal layer  was d r i e d over anhydrous m a g n e s i u m sulfate overnight.  T h e solvent  was r e m o v e d by flash evaporation and the residue was d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x column and a heating tape on an o i l bath. lected.  T h e fraction boiling at 6 4 ° - 6 5 ° ( 0 . 1 m m . Hg) was c o l -  Yield:  16. 8g (94. 1%).  i r (neat) 3380 ( N - H ) , nmr ( C D C ^ ) ^ N-H),  2920, 2860, 2820, 2760 c m  2  3  2  (C-H);  7 . 2 7 - 6 . 4 3 (m, 4 , p h e n y l - H ) , 4. 47-40 (broad a, 1,  3 . 3 0 - 2 . 9 3 (m, 2, N H - C H - C ) ,  NC.CH ) ),  - 1  2.23 ('s, 6, - N C C H ) ) , 3  2  2 . 7 0 - 2 . 33 ( m , 2,  2.10 (s, 3, 0 - C H 3 ) .  -C-CH 2  51 D i - h y d r o c h l o r i d e derivative Into a solution of the t e r t i a r y amine (2.91g, 0.02 mole) in 100 m l . d r y ether, d r y hydrogen gas was passed f r o m a cylinder through a concentrated sulfuric a c i d . completed,  When salt formation was  the s o l i d was suction f i l t e r e d under a s t r e a m of d r y  nitrogen gas to prevent it f r o m absorbing m o i s t u r e f r o m the a i r . The salt was washed with 100 m l . d r y ether on the Buchner funnel. The h y d r o c h l o r i d e was completely d r i e d , and r e c r y s t a l l i z e d f r o m d r y ethanol and ether to give c o l o u r l e s s c r y s t a l s ; m . p . 1 9 0 ° C .  A n a l . C a l c d . for C j N , 11.15; C l , 28.22.  4.  Found:  l  H  2  Q  N  2  C 1 : C , 52. 595; H , 8.03; 2  C , 52. 50; H , 7.94; N , 11.09; C l , 28.30.  N - o - m e thy Ipheny l - N - ( - N , N-dimethylaminoethyl)cyclohexanecarboxamide A d r y 250 m l . three-necked flask was equipped with a  m e c h a n i c a l s t i r r e r , dropping funnel (125 m l . ) with drying tube, and a side a r m for setting a thermometer (range -100 to 5 0 ° C ) . . N , N d i m e t h y l - N ' - o - m e t h y l p h e n y l e t h y l e n e d i a m i n e (8. 74g, 0.06 mole) and r e d i s t i l l e d triethylamine (7.07g, 0.07 mole) in 180 m l . d r y ether were placed i n the f l a s k .  T h e flask was i m m e r s e d in an i c e - s a l t bath for 1  hour until the temperature was between -5 and - 1 0 ° C . cyclohexanecarboxyl  A solution of  chloride (8. 742g, 0.06 m l . ) in 50 m l . ether was  added v e r y slowly f r o m the dropping funnel with s t i r r i n g so as to keep the temperature of the reaction mixture below 0 ° C .  A f t e r the addition  was completed,  s t i r r i n g was continued at 0 ° C for another h o u r . T h e  solution was s t i r r e d overnight at r o o m temperature.  30 m l . d i s t i l l e d  water was then added, and the solution s t i r r e d r a p i d l y for 10 m i n u t e s . The l a y e r s were separated,  and the aqueous phase was extracted with  two 100 m l . portions of ether.  T h e extracts were combined with the  ether l a y e r , and d r i e d over 50 g of anhydrous m a g n e s i u m sulphate. The solvent was r e m o v e d using a r o t a r y evaporator and the r e s i d u a l product d i s t i l l e d under reduced p r e s s u r e u s i n g a 9 inch V i g r e u x column.  The fraction boiling point at 124-125 ° C (0. 15 m m . H g . ) was  collected.  Yield:  I6g (92.4%).  i r (neat) 2920, 2940, 2910, 2860 ( C - H ) , nmr  (CDCI3) 2  NCCH ) ), 3  2  - 1  (C=0);  % 7. 35 - 7.67 (m, 5, p h e n y l - H ) , 3.42 - 2.4 (m, 4,  N-CH -CH -N), 2  1645 c m  4.47 - 3.93 (m, 1 , C H - C = 0 ) ,  2 . 0 - 0.67 (m, 10,  C H 6  1 Q  2.20 (s, 9 , ( o - C H & 3  ).  M o n o - h y d r o chloride derivative The white salt was p r e p a r e d by the same procedure as desc r i b e d i n E x p . A - 3>: i m . p . 2 3 9 - 2 4 0 ° C .  A n a l . C a l c d . for C N,  8.62; C l , 10.92.  5.  l g  Found:  H  2 9  N C I O : C , 66. 54; H , 8.99; 2  C , 66. 57; H , 8.92; N , 8.48; C l , 10.90.  N, N-dimethyl-N'-cyclohexylmethyl-N'-o-methylphenyl ethylene diamine A 250 m l . three necked flask was equipped with a m e c h a n i c a l  53 stirrer,  dropping funnel (125 m l . ) and reflux condenser.  and condenser c a r r i e d drying tubes. L A H \ ' (3. 64g,  D r y ether (180 m l . ) and .-.  0.096 mole) were placed in the f l a s k .  gently refluxed for 3 h o u r s .  T h e funnel  The solution was  A solution of N - o - m e t h y l p h e n y l - N - ( ft -  N , N - d i m e t h y l a m i n o ) cyclohexanecarboxamide  (13.84g, 0.048 m l . ) in  dry 40 m l . ether was very slowly added so as to maintain a gentle reflux.  A f t e r the addition was completed, the mixture was s t i r r e d  and refluxed for 20 h o u r s .  A t the end of the reaction,  the heating  mantle was r e p l a c e d by an i c e - s a l t bath, and the mixture s t i r r e d for 1 hour.  30 m l . d i s t i l l e d water was added dropwise to the flask to  decompose excess h y d r i d e . . S t i r r i n g was continued for 30 minutes until the mixture turned completely white.  A sufficient amount of 40%  sodium hydroxide solution was added to separate the ethereal layer f r o m the ether-insoluble r e s i d u e .  The ethereal phase was decanted  into an E r l e n m e y e r flask, and d r i e d over anhydrous m a g n e s i u m sulfate. The  drying agent was suction filtered, and the solvent r e m o v e d using  a rotary evaporator.  The residue was d i s t i l l e d under reduced p r e s s u r e  through a 9- inch V i g r e u x column w a r m e d by a heating tape. fraction boiling at 126r?128°C (0.4 m m . Hg) was collected.  The Yield:  12. 75g (97%).  ir (neat) 3010, 1495 c m '  1  3050 ( A r y l - H ) ,  ( - C H ) ; n m r (CDC13). 3  3.30 - 2.73 (m, 4, - N - C H ^ C H ^ N ) ,  £  2820, 2850  (N-(CH )^1470, 3  7. 30 - 6.87 (m, 4, p h e n y l - H ) ,  2.3 (s, 3, 0 - C H 3 ) ,  2.17 (s, 6,  - N ( C H ) ) 2 . 5 (m, 2, C H - C H - N ) , 3  2  >  2.03 - 0.67 (m, 11,  2  C  6  H  n  ) .  D i - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as d e s c r i b e d in E x p . A - 3 .  A n a l . . C a l c d . for C N,  B.  8.06; C l , 20.44.  l  g  H  3  2  N  2  Cl : 2  C , 62. 23; H , 9.27;  F o u n d : C , 62.03; H , 9.28; N , 7.84; C l , 20.09.  N.N-DIMETHYL-N'-CYCLOHEXYLMETHYL-N'-m-METHYLP H E N Y L E T HY L E N E D I A M I N E 1.  °f - C h l o r o - N - m - m e t h y l p h e n y l a c e t a m i d e A solution of m - m e t h y l a n i l i n e (32. l g , 0. 3 mole) and r e -  d i s t i l l e d triethylamine (30. 34g, 0.3 mole) in 500 m l . d r y ether was p l a c e d i n 1 l i t r e three-necked f l a s k . mechanical stirrer,  T h e flask was equipped with a  a side a r m for setting a thermometer  to 5 0 ° C ) and a dropping funnel (125 m l . ) with a drying tube.  (range -100 The  solution was cooled by s t i r r i n g it for 1 hour in an i c e - s a l t bath (-5 to - 1 0 ° C ) .  A solution of c h l o r o a c e t y l c h l o r i d e (34g, 0.3 mole) i n  100 m l . of d r y ether was added slowly f r o m the dropping funnel into the flask, with constant s t i r r i n g , so as to keep the temperature of the solution below 0 ° C . temperature.  The mixture was s t i r r e d overnight at r o o m  Then 100 m l . of d i s t i l l e d water was added to the flask,  and the mixture was s t i r r e d for 15 m i n u t e s .  T h e resulting white  product in the mixture was suction f i l t e r e d through a Buchner funnel. The ethereal layer was then separated and flash evaporated to remove  the solvent.  T h e r e m a i n i n g solids were combined with the suction  f i l t e r e d product in a 500 m l . b e a k e r .  100 m l . each of 5% HC1 and  cold d i s t i l l e d water were added and the product was v i g o r o u s l y s t i r r e d on a magnetic s t i r r e r for 1 hour.  T h e product was then suction f i l -  tered and washed with d i s t i l l e d water until no HC1 could be detected using litmus paper.  T h e product was p r e d r i e d in the a i r and finally  d r i e d at 4 0 ° C in an oven under reduced p r e s s u r e (20 m m . Hg). T h e product was p u r i f i e d by reduced p r e s s u r e sublimation. (89%).  Yield:  49. 0g  m.p. : 92°C.  i r ( K B r ) 3300 ( 0 = C - N - H ) , (C=0), 1610 (aromatic),  3140, 3100, 2920 ( N ( C H ) ) , 3  710 c m " ( C - C l ) ; n m r ( C D C 1 ) 1  3  1660  2  % 7.47-  7 . 1 3 ( m , 4, p h e n y l - H ) , 4,15 (s, 2, C H - C 1 . ) . 2.33 (s, 3, m - C H j ) . 2  A n a l . C a l c d . for C Cl,  19.35.  2.  Found:  g  H  1  Q  NCIO:  C , 5 8 . 9 ; H . 5.45; N , 7.64;  C , 59.00; H , 5. 59; N , 7.80; C l , 19.52.  c( - D i m e t h y l a m i n o - N - m - m e t h y I p h e n y l a c e t a m i d e A 500 m l . three-necked flask was equipped with a dropping  funnel (125 m l . ) fitted with a drying tube,  a m e c h a n i c a l s t i r r e r , and  a side a r m for setting a thermometer (range -100 to 5 0 ° C ) .  300 m l .  d r y ether was placed in the flask and it was cooled to between -5 and - 1 0 ° C in an i c e - s a l t bath for 1 hour.  Dimethylamine (26.5 cc,  0.4  mole) was trapped in a d r y graduated cylinder (50 m l . ) f r o m a dimethylamine gas tank using an a c e t o n e - d r y ice bath ( - 8 0 ° C ) and poured a l l at once into the three-necked flask.  A solution of  56 c \ - c h l o r o - m -methylphenylacetamide flask (27. 6g, 0.15 mole) in 80 m l . d r y tetrahydrofuran was added v e r y slowly f r o m the dropping funnel to the r a p i d l y s t i r r e d solution at such a rate as to keep the temperature of the reaction mixture below 0 ° C for 10 h o u r s . kept overnight with s t i r r i n g below 1 0 ° C .  The mixture was  The white dimethylamine  salt was suction f i l t e r e d , and the solvent r e m o v e d by a r o t a r y evaporator.  30 m l . d i s t i l l e d water was added to the product,  shaken v i g o r o u s l y in the separating funnel.  and it was  T h e m i x t u r e was extracted  twice using 200 m l . portions of ether, and the ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e solution was suction  f i l t e r e d and the solvent r e m o v e d using a r o t a r y evaporator.  The  product was r e d i s t i l l e d on o i l bath using a 9 inch V i g r e u x column under reduced p r e s s u r e .  Yield:  27. 5g (95. 5%).  i r (neat) 3300 ( 0 = C - N H ) , (C=0),  1620,  1590 (aromatic),  b . p . : 1 09?C (0. 35 m m . H g j .  2940, 2820, 2780 ( N ( C H )_),  790 c m " (phenyl-H); n m r ( C D C l j ) 1  & 7.43 - 6. 73 (m, 4, p h e n y l - H ) , 2.97 (s, 2, 0 = C - C H ) , 2  (s,  6, ( N - C H ) ), 2  1675  2.30  2.27 (s, 3, m - C H ) . 3  M o n o - p e r c h l o r a t e derivative The aminoacetamide (3. 56g, 0.02 mole), was. d i s s o l v e d i n 15 m l . of absolute ethanol. a c i d (70%) was added. 15 m i n u t e s .  T h e n 3. 08 m l (0. 022 mole) of p e r c h l o r i c  The mixture r e a c t e d at r o o m temperature for  T h e salt was c r y s t a l l i z e d out by the addition of ether.  was r e c r y s t a l l i z e d f r o m ethanol and d r y ether,  m . p . : 105-106°C.  It  r  57 A n a l . . C a l c d . for C N , 9.6;  C l , 12.14.  3.  n  H  1  7  N  C I O : C , 45. 2; H ,  F o u n d : C , 45. 27; H , 5.95;  N , 9.44;  5.82; C l , 12.03.  N, N-dimethyl-N'-m-methylphenylethylenediamine A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  mechanical stirrer, denser.  a dropping funnel (125 m l . ) and a reflux con-  The funnel and condenser both c a r r i e d d r y i n g tubes.  20 m l .  dry ether and lithium a l u m i n u m hydride (7.2g, 0.2 mole) were added to the flask, and the mixture was gently refluxed with s t i r r i n g for 3 hours.  A solution of  o(-dimethylamino-N-m-methylphenylacetamide  (19. 2g, 0. 1 mole) in 50 m l . d r y ether was p l a c e d in the dropping funnel, and added dropwise so as to maintain gentle r e f l u x i n g . the addition was completed,  the mixture was refluxed for 40 hours  with s t i r r i n g on the e l e c t r i c a l heating mantle. complete,  After  When the reduction was  the reaction mixture was cooled by placing it in an i c e - s a l t  bath for 30 m i n u t e s .  20 m l . d i s t i l l e d water was added v e r y slowly to  the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . S t i r r i n g was continued until the mixture became white i n c o l o u r . Sufficient 40% N a O H solution was added to allow clear separation of the ethereal l a y e r .  The e t h e r - i n s o l u b l e residue was separated by  centrifugation. . The ethereal l a y e r was d r i e d overnight using anhydrous m a g n e s i u m sulfate.  T h e solvent was r e m o v e d with a r o t a r y  evaporator,  and the residue d i s t i l l e d on an o i l bath under reduced p r e s s u r e using a 9 inch V i g r e u x column wrapped with a heating tape.  The fraction  58 boiling at 7 0 ° C (0.025 m m . Hg) was collected.  Y i e l d : 16. ?g (95%).  i r (neat) 3370 ( N - H ) , 3040 (phenyl-H), 3030, 2930, 2850, 2810, 2760 ( - N ( C H ) ) , 3  nmr (CDCI3) C H ), 6  2  1600 (aromatic),  770, 695 c m "  1  (phenyl-H);  $ 7. 20 - 6.92 (m, 1, C H ) , 6.63 - 6. 30 (m, 3, &  1  4. 37 - 3.97 (weak s, 1, N - H ) , 3.30 - 2.90 (m, 2, N H - C H ~ C )  3  2  2.67 - 2. 37 (m, 2, ( N H - C - C H ) ,  2.28 (s, 3, m - C H ) , 2.23 (s, 6,  2  3  -N(CH ) ). 3  2  D i - h y d r o chloride  derivative  The salt was p r e p a r e d by the same procedure as d e s c r i b e d in E x p . A - 3 . m . p . : 1 6 3 ° C .  Anal. N,  C a l c d . for C ^ ^ Q 2  11.15; C l , 28. 22. . F o u n d :  4.  ^ 2  ^" 2* 1  C  *  5  2  -  5  9  5  ;  H  «  8  -  0  3  5  C , 52. 57; H , 8.07; N , 11.01; C l , 28.12.  N - m - m e t h y l p h e n y l - N - ( (? - N , N-dimethylaminoethyl) hexanecarboxamide  cyclo-  A d r y 250 m l . three-necked flask was equipped with a mechanical stirrer,  dropping funnel (125 m l . ) with drying tube, and  a side a r m for setting a thermometer (range -100 to 5 0 ° C ) . . N , N d i m e t h y l - N ' - m - m e t h y l p h e n y l e t h y l e n e d i a m i n e (1 2. 45g, 0.07 mole) and r e d i s t i l l e d d r y triethylamine (8.08g, 0.08 mole) in 170 m l . d r y ether were placed i n the flask.  T h e flask was i m m e r s e d i n an i c e -  salt bath for 1 hour until the temperature of the solution was between -5 and - 1 0 ° C .  50 m l . of a solution of  cyclohexanecarbonylchloride  (10. 12g, 0. 07 m l . ) in ether was added v e r y slowly f r o m the dropping  59 funnel so that the temperature of the reaction m i x t u r e r e m a i n e d below 0°C.  A f t e r the addition was completed, the m i x t u r e was s t i r r e d at  0 ° C for 1 hour.  30 m l . d i s t i l l e d water was added, and the m i x t u r e  was s t i r r e d r a p i d l y for 10 minutes at r o o m temperature. were separated,  and the aqueous phase extracted with three 120 m l .  portions of ether. layer,  The layers  T h e extracts were combined with the ethereal  and d r i e d over 50g of anhydrous m a g n e s i u m sulfate.  The  solvent was r e m o v e d with a r o t a r y evaporator and the r e s i d u a l product was d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x c o l u m n . The f r a c t i o n boiling at 1 1 6 - 1 1 8 ° C (0.005 m m . Hg) was c o l l e c t e d . Yield:  17. 15g (85%).  i r (neat) 2920, 2850, 2760 ( N ( C H ) ) , 1650 (C=0), 1600 c m " , 3  (aromatic); n m r - ( C D C l ) 3  £  1  2  7.40 - 6.83 (m, 4, C  6  H^), 3.92 - 3.58  (m, 2, 0 = C - N - C H ) , 2. 70 - 2.43 (m, 2, 0 = C - N - C - C H ) , 2.70 2  2  2.43 (m, 2, 0 = C - N - C - C H ) , 2.35 (s, 3, m - C H ^ ) , 2  2.18 (s, 6,  N(CH ) ). 3  2  M o n o - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as d e s c r i b e d in E x p . A - 3 .  Anal.  l-m.p. : 2 3 1 - 2 3 2 ° C .  C a l c d . for C  N , 8. 62; C l , 10.92.  l  g  N  2  C> C l : C , 66.54; H , 8.99; 2  F o u n d : . C , 66. 70; H , 9 . 0 9 ; N ,  8.47; C l , 10.92.  60 5.  . N, N-dimethyl-N'-cyclohexylmethyl-N'-m-methylphenyle thylenediamine A Z50 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  stirrer,  a reflux condenser and a dropping funnel (125 m l . ) .  denser and funnel both c a r r i e d d r y i n g tubes.  The c o n -  180 m l . d r y ether and  l i t h i u m a l u m i n u m hydride (4. 18g, 0. 11 mole) were placed i n the f l a s k . The solution was gently refluxed for 3 hours on the heating m a n t l e .  A  solution of jN'-m-methylphenyl-N^-C^ -N,N-dimethyiaminoethyl)cyclohexane carboxamide . .Iv (15. 8g, 0. 55 mole) i n 40 m l . d r y ether was added d r o p wise to the refluxing L i A l H ^ solution f r o m the dropping funnel i n such a manner as to m a i n t a i n gentle r e f l u x i n g . completed,  A f t e r the addition was  the mixture was refluxed with s t i r r i n g for 30 h o u r s .  the end of the reaction,  At  the heating mantle was r e p l a c e d by an i c e -  salt bath, and 30 m l . of d i s t i l l e d water was added dropwise into the flask to decompose excess h y d r i d e .  S t i r r i n g was continued for 30  minutes until the mixture turned white, and sufficient 40% N a O H solution was added to separate the ethereal layer f r o m the e t h e r insoluble r e s i d u e .  T h e ethereal layer was decanted and d r i e d over  anhydrous m a g n e s i u m sulfate overnight.  The d r y i n g agent was suction  f i l t e r e d , and the solvent r e m o v e d using a r o t a r y evaporator.  The  residue was d i s t i l l e d under reduced p r e s s u r e through a 9 inch V i g r e u x column w a r m e d by a heating tape. (0.4 m m . Hg) was c o l l e c t e d .  T h e fraction boiling at 1 4 0 ° C  Yield:  14. 5g (96%).  i r (neat) 3050 ( C - H ) , 2920, 2860, 2770 ( p C - H ) , 2  1600, 1580  61 (aromatic ring), (m,  770 c m "  1  1, p h e n y l - o - H ) , 6.60  CH-CH -N),  3.2-  3.0 (d,  N-C-CH -N),  2.30  (2s,  2  2  C  6  C.  H  (phenyl-H): - 6.33  (m,  nmr (CDC1 ) 3  3,  C H ), 6  3.6  3  & 7. 30 - 3.27  (m,  6.93 2,  2,2=6, N C H - C - N ) , 2 . 6 - 2 . 3 3 (m, 2, 2  9, N ( C H ) ) , ( m - C H j ) , 2.0 3  2  - 0.67  (m,  11,  ll>-  N, N - D I M E T H Y L - N ' - CYC LOHEXY L M E T H Y L - N ' - p - M E T H Y L P H E N Y L E T HY L E N E D I A M I N E 1.  °j - C h l o r o - N - p - m e t h y l p h e n y l a c e t a m i d e A solution of p - m e t h y l a n i l i n e (32. l g , 0. 3 mole) and d i s t i l l e d  triethylamine (30. 34g,  0.3 mole) in 500 m l . dry ether was placed in  a 1 l i t r e three-necked flask. stirrer,  The flask was equipped with a m e c h a n i c a l  a side a r m for setting a t h e r m o m e t e r ,  (range -100  and a dropping funnel (125 m l . ) with a drying tube. cooled by s t i r r i n g it for 1 hour in an ice bath. acetylchloride  The solution was  A solution of c h l o r o -  (134g, 0.3 mole) in 100 m l . dry ether was added f r o m  the dropping funnel into the flask. stirring,  to 5 0 ° C )  The solution was added slowly with  so as to keep the temperature of the solution below 0 ° C .  m i x t u r e was s t i r r e d overnight at r o o m t e m p e r a t u r e .  The  T h e n 100 m l . of  d i s t i l l e d water was added to the flask, and the mixture s t i r r e d for 15 minutes.  The resulting white product was suction f i l t e r e d through a  Buchner funnel.  The ethereal layer was separated and flash evaporated  to remove the solvent.  The product was placed in a 500 m l . beaker and  100 m l . each of 5% HC1 and d i s t i l l e d water were added.  The m i x t u r e  was v i g o r o u s l y s t i r r e d on a magnetic s t i r r e r for one hour.  The  product was then suction f i l t e r e d and washed with d i s t i l l e d water until no HC1 could be detected using litmus paper.  T h e product was p r e -  d r i e d in the a i r and finally d r i e d at 4 0 ° C in an oven under reduced p r e s s u r e (20 m m . Hg). T h e product was p u r i f i e d by reduced sublimation.  Yield:  50.6g(91%).  pressure  m . p . : 160°C.  i r ( K B r ) 3300 ( 0 = C - N H ) 2950, 2940, 2860 ( C - H ) , 1665 (C=0) 1610 (aromatic,  730 c m '  1  ( C - C l ) ; nmr (CDC1 ) 3  p h e n y l - H ) , 4. 17 (s, 2, C H ^ - C l ) ,  A n a l . . C a l c d . for Cl,  19.32.  2.  Found:  H  S 7. 55 - 7.02 (m, 4,  2.32 (s, 3, p - C H j ) .  Q  NCIO :  C , 5 8 . 9 ; H , 5.45; N , 7.64;  C , 58.96; H , 5 . 6 2 ; . N ,  7.74; C l , 19.39.  o( - D i m e t h y l a m i n o - N - p - m e t h y l p h e n y l a c e t a m i d e A 500 m l . three-necked flask was equipped with a dropping  funnel (125 m l . ) fitted with a drying tube, a m e c h a n i c a l s t i r r e r , and a side a r m for setting a t h e r m o m e t e r (range- 1 0 0 ° C to 5 0 ° C ) .  300 m l .  of d r y ether was placed in the flask and cooled to between - 5 ° and - 1 0 ° C i n an i c e - s a l t bath for 1 hour.  D i m e t h y l a m i n e (approx.  I 6 . 5 5 c c , 0.25 mole) was trapped i n a d r y 50 m l . graduated c y l i n d e r f r o m a dimethylamine gas tank using an a c e t o n e - d r y ice bath ( - 8 0 ° C ) . It was poured a l l at once into the t h r e e - n e c k e d f l a s k .  A solution of  e| - c h l o r o - N - p - m e t h y l p h e n y l a c e t a m i d e (18.36g, 0.1 mole) in 60 m l . dry tetrahydrofuran was added slowly f r o m the dropping funnel to the  63 v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the reaction m i x t u r e below 0 ° C .  When the addition was completed, the  m i x t u r e was s t i r r e d for 10 hours at a temperature below 0 ° C for 10 hours, and finally s t i r r e d overnight at a temperature below 1 0 ° C . The white dimethylamine salt was suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y evaporator,  then 20 m l . d i s t i l l e d water was added to  the product, and the m i x t u r e was shaken v i g o r o u s l y i n the separatory funnel.  It was extracted twice with 150 m l . portions of ether,  ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  and the The  solution was suction f i l t e r e d and the solvent r e m o v e d with a r o t a r y evaporator.  T h e product was r e d i s t i l l e d on an o i l bath using a 9 inch  V i g r e u x column under reduced p r e s s u r e . b.p.:  Yield:  17. 3g (90%).  1 0 3 - 1 0 5 ° C (0. 10 m m . Hg).  i r (neat) 3280 ( 0 = C - N H ) , (C=0), 1580 c m " (aromatic); 1  phenyl-H),  nmr (CDCl^),  3.03 (s, 2, C H - N ) , 2  2930, 2830, 2770 ( N ( C H ) ) , 1660 3  £  2  7 . 5 8 - 7 . 0 (m, 4,  2.35 (s, 6, N ( C H ) 3  2 >  2.27 (s, 3,  p-CH ). 3  3.  N , N-dimethyl-N'-p-methylphenylethylenediamine A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) and reflux condenser.  The funnel and condenser both c a r r i e d drying tubes,. 120 m l . d r y ether and lithium a l u m i n u m hydride (5. 7g, 0.15 mole) were placed in the flask and gently refluxed with s t i r r i n g for 3 h o u r s .  A solution of  64 «( - d i m e t h y l a m i n o - N - p - m e t h y l p h e n y l a c e t a m i d e (14g, 0.75 mole) i n 50 m l . d r y ether was placed i n a dropping funnel and added dropwise at such a rate as to maintain gentle r e f l u x . been completed,  When the addition had  the mixture was refluxed for 40 hours with s t i r r i n g on  the e l e c t r i c a l heating m a n t l e .  A f t e r the reduction was over, the  reaction mixture was cooled in an i c e - s a l t bath for 30 minutes, and 20 m l . d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . . S t i r r i n g was continued until the mixture became white i n colour, then sufficient 40% N a O H solution was added to allow clear separation of the ethereal layer.  The e t h e r - i n s o l u b l e residue was separated by centrifugation.  The ethereal layer was d r i e d over anhydrous m a g n e s i u m sulfate o v e r night.  The solvent was r e m o v e d using a r o t a r y evaporator and the  residue was further d i s t i l l e d under reduced p r e s s u r e . boiling at 6 5 - 6 8 ° C (0.025 m m . Hg) was c o l l e c t e d .  T h e fraction  Y i e l d : 12.75g  (95.5%).  i r (neat) 3360 ( N - H ) , 2930, 2850, 2810, 2760 ( N ( C H ) ), 2  1610 c m  - 1  (aromatic); n m r ( C D C 1 ) , 5 3  7 . 1 3 - 6 . 4 (m, 4, p h e n y l - H ) ,  4. 17 - 3. 73 (broad s, 1, N - H ) , 3. 22 - 2. 87 (q, 4, J=6, 2. 60 - 2.30 (q, 4, J = 6,  -CH -N(CH ') ),  A n a l . . C a l c d . for C  N,  8.62; C l ,  2  l  3  g  N  2  2  NH-CH ), 2  2.22 (s, 6, ( N ( C H ) ) . 3  2  C I O : C , 66. 54; H , 8. 99;  10. 92. . Found: C , 66. 32; H , 8.94; N , 8.52; C l ,  10.91.  65 4.  N - p - m e t h y l p h e n y l - N - ( ^ - N N - d i m e thy lamino ethyl)cyclohexanecarboxamide t  A d r y 250 m l . three-necked flask was equipped with a m e c h a n i c a l stirrer,  dropping funnel (125 m l . ) with a drying tube, and side a r m for  setting a thermometer  (range -100 to 5 0 ° C ) .  N, N-dimethyl-N'-p_-methyl-  phenylethylenediamine (10. l g , 0.06 mole) and r e d i s t i l l e d by t r i e t h y l a m ine (10. l g , 0. 06 mole) i n 170 m l . d r y ether were placed in the f l a s k . T h e flask was cooled to between -5 and - 1 0 ° C i n an i c e - s a l t bath for one hour with vigorous s t i r r i n g .  50 m l . ethereal solution of cyclohexane  carboxyl-  chloride (8. 742g, 0.06 mole) was added slowly f r o m the dropping funnel so as to keep the temperature of the reaction mixture below 0 ° C . the addition was completed,  After  s t i r r i n g was continued at 0 ° C for another h o u r .  T h e n the m i x t u r e was s t i r r e d overnight at r o o m t e m p e r a t u r e .  30 m l .  d i s t i l l e d water was added, and the mixture was s t i r r e d r a p i d l y for 10 minutes.  The l a y e r s were separated and the aqueous phase was extracted  with three 120 m l . portions of ether. the ethereal l a y e r ,  T h e extracts were combined with  and d r i e d over 50g of anhydrous m a g n e s i u m sulfate.  The solvent was r e m o v e d using a r o t a r y evaporator under reduced p r e s sure using a 9 inch V i g r e u x c o l u m n . (0. 125 m m . Hg) was c o l l e c t e d .  T h e fraction boiling at 1 2 8 - 1 3 0 ° C  Yield:  15.4g(89%).  i r (neat) 3040, 730 ( a r y l - H O , 2920, 2840, 2810, 2760 ( N - ( C H 1650 (C=0), 1600, 1580 c m " (aromatic); n m r ( C D C 1 ) , & 1  2  3  2  2.20 (s, 6, ( N ( C H ) ) . 1.87 - 0.85 (m, 11, C H 3  2  6  2  7 . 4 - 6 . 9 3 (m,  3  4, p h e n y l - H ) , 3. 93 - 3. 60 (m, 2, 0 = C - N - C H ) , 2. 60 - 2. 22 (m, 2, - C H N(CH ) ),  ) ),  u  2  ~  ) .  M o n o - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as d e s c r i b e d in Exp. A - 3 : m . p . : 2 4 0 ° C . A n a l . - Calcd. for C  l  8  H  2  g  N  2  C I O : C , 6 6 . 5 4 ; H , 8 . 9 9 ; N , 8.62;  C l , 10.92. F o u n d : C , 66. 32; H , 8. 94; N , 8.52; C l , 10.91.  65a •5. . N , N - d i m e thy 1 - N ' - c y c l o h e x y l m e t h y l - N ' - p - m e t h y l p h e n y l ethylenediamine A Z50 m l . three-necked stirrer,  flask was equipped with a m e c h a n i c a l  reflux condenser and dropping funnel (125 m l . ) .  and condenser both c a r r i e d d r y i n g tubes. aluminum hydride (3. 8g,  The funnel  180 m l . dry ether and l i t h i u m  0. 1 mole) were p l a c e d in the f l a s k .  The  solution was gently refluxed on the heating mantle f o r 3 h o u r s . solution of N - p - m e t h y l p h e n y l - N - ( . carboxamide (14. 4g,  0.05  A  -dimethylaminoethyl) cyclohexane-  m l . ) in 40 m l . d r y ether was added f r o m  the dropping funnel so as to maintain gentle r e f l u x .  A f t e r the  addition was completed, the mixture was refluxed for 30 hours with stirring.  At the end of the reaction,  the heating mantle was r e p l a c e d  by an i c e - s a l t bath and s t i r r e d for 1 hour.  20 m l . d i s t i l l e d water was  added dropwise to the flask to decompose excess h y d r i d e . . S t i r r i n g was continued for 30 minutes until the colour of the mixture turned completely white.  A solution was added to separate the ethereal layer  f r o m the e t h e r - i n s o l u b l e r e s i d u e .  The ethereal phase was decanted  into an E r l e n m e y e r flask and d r i e d over anhydrous m a g n e s i u m sulfate. The drying agent was suction f i l t e r e d , and the solvent r e m o v e d using a r o t a r y evaporator.  The residue was d i s t i l l e d under reduced p r e s s u r e  through a 9 inch V i g r e u x column w a r m e d by a heating tape.. boiling at 1 3 8 ° C (0. 4 m m . Hg) was c o l l e c t e d .  Yield:  The f r a c t i o n  13. 3g (97%).  The  i r spectrum of unpurified product showed the absence of the C=0 band at 1650 c m  - 1  ,  indicating complete reduction of the a m i d e .  66 D.  .SYNTHESIS O F N, N - D I M E T H Y L - N ' - C Y C L O H E X Y L M E T H Y L - N ' p-BRQMOPHENY LETHY LENEDIAMINE 1.  ^-Chloro-N-p-bromophenylacetamide A 1 l i t r e t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  stirrer,  side a r m for setting a thermometer  (range - 1 0 0 ° -  and dropping funnel (1Z5 m l . ) with a drying tube. b r o m o a n i l i n e (5. I6g,  50°C),  A solution of p -  0.3 mole) and d i s t i l l e d triethylamine (30. 3g,  0. 3 mole) in 50 m l . d r y ether were added to the f l a s k .  The solution  was cooled to between -5 and - 1 0 ° C in an i c e - s a l t bath with s t i r r i n g for 1 h o u r .  A solution of c h l o r o a c e t y l chloride (34. Og, 0.3 mole) i n  100 m l . dry ether was added v e r y slowly to the v i g o r o u s l y s t i r r e d solution f r o m the dropping funnel so as to keep the temperature solution below 0 ° C .  of  A f t e r the addition was completed, the mixture  was s t i r r e d at r o o m temperature overnight, then 100 m l . d i s t i l l e d water was added, and the mixture was s t i r r e d for 15 m i n u t e s .  The  white product in the mixture was suction f i l t e r e d through a Buchner funnel, and the l a y e r s were separated.  The ethereal layer was flash  evaporated to r e m o v e the solvent and the s o l i d was combined with the suction f i l t e r e d product.  The product was poured into a 500 m l . beaker  and 100 m l . each of 5% HC1 solution and cold d i s t i l l e d water were added to i t .  The m i x t u r e was s t i r r e d virogou&ly on a magnetic  stirrer  for 1 hour.  The product was suction f i l t e r e d , and washed with 300 m l .  d i s t i l l e d water until no trace of HC1 could be detected u s i n g litmus paper.  The product was d r i e d in the a i r f i r s t , and then in the oven  under reduced p r e s s u r e (40 C , 20 m m . Hg). T h e product was p u r i f i e d by reduced p r e s s u r e sublimation on the o i l bath. m . p. :  1660 (C=0). 1600, 1540,  780 ( C - C l ) , 750 c m " ( p h e n y l - B r ) ; 1  p h e n y l - H ) , 4. 1 5 ( s ,  nmr (CDC1 ) 3  8  (aromatic),  7.43 (m, 4,  2, C H - C 1 ) , 1.50 (s, 1, N - H ) . 2  A n a l . . C a l c d . for C  Cl,  67. l g (90%).  182°C.  i r - ( K B r ) 3260 (0=C-NH),  N,  Yield:  g  5.63; C l , 14. 3; B r , 32.2.  H  ?  NBrCIO:  Found:  C , 3 8 . 6 ; H , 2.82;  C , 38.69; H , 2.93; N , 5.72;  14. 22; B r , 32. 04.  2.  o( - D i m e t h y l a m i n o - N - p - b r o m o p h e n y l a c e t a m i d e A 500 m l . three-necked flask was equipped with a dropping  funnel (250 m l . ) with a drying tube, m e c h a n i c a l s t i r r e r , and a side a r m for setting a thermometer (range - 1 0 0 ° C - 5 0 ° C ) .  150 m l . each  of d r y ether and d r y tetrahydrofuran were added to the f l a s k .  The  solution was cooled to between -5 and - 1 0 ° C in an i c e - s a l t bath for 1 hour.  Dimethylamine (26.5 cc,- 0.4 mole) was trapped in a d r y  50 m l . graduated cylinder f r o m a dimethylamine gas tank using an a c e t o n e - d r y ice bath ( - 8 0 ° C ) and poured a l l at once into the flask. A solution of  of-chloro-N-p-bromophenylacetamide  (37. 2g, 0.15 mole)  in 150 m l . dry ether was added slowly f r o m the dropping funnel to the vigorously s t i r r e d solution so as to keep the temperature of the r e a c t i o n mixture below 0°;C... T h e ' m i x t u r e was then s t i r r e d for 10  68 hours while being kept below 0 ° C , and finally s t i r r e d overnight while being kept below 1 0 ° C .  T h e white dimethylamine salt was suction  f i l t e r e d and the solvent was r e m o v e d using a r o t a r y evaporator, 30 m l . d i s t i l l e d water was added to the product, shaken v i g o r o u s l y i n the separating funnel.  then  and the mixture was  T h e m i x t u r e was extracted  twice with two 200 m l . portions of ether, and the ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e solution was suction  f i l t e r e d and the solvent r e m o v e d using r o t a r y evaporator.  The  product was r e c r y s t a l l i z e d f r o m a d r y m i x t u r e consisting of hexane and a s m a l l amount of ethylacetate.  Yield:  i r ( K B r ) 3260 ( 0 = C - N H ) , 1660 ( C = 0 ) , 750 c m " 3.0 (s, 2, 0 = C - C H ) , 2  1  (C-Br);  31. 6g (82%).  2970, 2940, 2820, 2770 ( N ( C H ) ) , 3  nmr (CDC1 ) 3  3  3  10.90; B r , 31.18.  3.  2  & 7.43 (m, 4, p h e n y l - H ) ,  2.33 (s, 6, N ( C H ) . ) . 1.57 (s, 1, N - H ) . 2  A n a l . . C a l c d . for C-^Q H ^ N B r O : N,  m . p . : 57-58°C.  Found:  2  C , 46. 75; H , 5.06;  C , 4 6 . 6 2 ; H , 5.13; N , 10.80; B r , 31.08.  . N , N-dimethyl-N'-p-bromophenylethylenediamine A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) and reflux  condenser.  The condenser and dropping funnel both c a r r i e d drying tubes.  120 m l .  d r y ether and l i t h i u m a l u m i n u m hydride (7. 6g, 0. 2 mole) were added to the flask and gently refluxed with s t i r r i n g for 3 h o u r s . of  A solution  «>< - d i m e t h y l a m i n o - N - p - b r o m o p h e n y l a c e t a m i d e (25. 7g, 0. 1 mole)  69 in 180 m l . d r y ether was placed i n a dropping funnel and added d r o p wise so as to maintain gentle r e f l u x .  A f t e r the addition was completed,  the mixture was refluxed for 40 hours with s t i r r i n g . tion was over,  When the r e d u c -  the reaction m i x t u r e was cooled i n an i c e - s a l t bath for  30 minutes, then 20 m l . d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . S t i r r i n g was continued until the mixture became white in c o l o u r . Sufficient 40% N a O H was added to allow clear separation of the ethereal layer f r o m the s o l i d s .  The e t h e r - i n s o l u b l e residue was  separated by centrifugation. . The ethereal layer was d r i e d over anhydrous m a g n e s i u m sulfate overnight. evaporated,  T h e solvent was flash  and the residue d i s t i l l e d under reduced p r e s s u r e using a  heating tape on the o i l bath and a 9 inch V i g r e u x c o l u m n . boiling 9 0 ° C (0. 05 m m . Hg) was collected.  i r (neat) 3370 ( N - H ) , (N(CH ) ), 3  2  .phenyl-H), N(CH ) ), 3  2  1600 c m  - 1  Yield:  3040 ( a r y l - H ) ,  3  2  23.08g(95%).  2930, 2850, 2805, 2760  (aromatic); n m r (CDC1 )  3.33 - 2.90 (m, 2, N H - C H ) ,  The f r a c t i o n  S  7.33 - 6. 33 (m, 4,  2. 65 - 2.30 (m, 2, C H ~ 2  2.25 (s, 6, N ( C H ) ) . 3  2  D i - h y d r o chloride derivative T h e salt was p r e p a r e d by the same procedure as d e s c r i b e d i n Exp. A - 3 . m . p . :  130°C.  A n a l . C a l c d . for C  l  Q  Hj  ?  N .Br C l : 2  C , 37. 99; H , 5.42;  70 N, Cl,  8.86; C l , 2 2 . 4 6 ; - B r , 25.27. / F o u n d :  C , 38.16; H , 5.47;. «N-, 8.84;  22. 30; B r , 2.5. 20.  4.  N-p-bromophenyl-N-( - N , N-dimethylaminoethyl)cyclohexanecarboxamide A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  m e c h a n i c a l s t i r r e r , a dropping funnel (125 m l . ) with a drying tube, and side a r m for setting a thermometer (range - 1 0 0 ° C - 5 0 ° C ) . N , N - d i m e t h y l - N ' - p - b r o m o p h e n y l e t h y l e n e d i a m i n e (19.44g, 0.08 mole) and r e d i s t i l l e d d r y triethylamine (9.1g, 0.09 mole) in 170 m l . dry ether were added to the f l a s k .  The flask was cooled to between - 5 °  and - 1 0 ° C in an i c e - s a l t bath for 1 hour. cyclohexanecarboxyl  50 m l . ethereal solution of  chloride (11.68g, 0.08 mole) was added v e r y  slowly f r o m the dropping funnel to the r a p i d l y s t i r r e d contents of the flask,  so as to keep the temperature of the r e a c t i o n mixture below 0 ° C .  After the addition was completed,  s t i r r i n g was continued at 0 ° C for 1  hour, and then overnight at r o o m temperature.  30 m l . of d i s t i l l e d  water was added, and the mixture was s t i r r e d r a p i d l y for 10 m i n u t e s . T h e l a y e r s were separated, and the aqueous phase was extracted with three 120 m l . portions of ether. . The extracts were combined with the ether l a y e r ,  and d r i e d over 50g of anhydrous m a g n e s i u m  sulfate.  The solvent was r e m o v e d using a r o t a r y evaporator and the r e s i d u a l product was r e c r y s t a l l i z e d using petroleum ether ( 3 0 ° C - 6 0 ° C ) . Yield:  22. 5g (80%).  m.p.: 8l-82°C.  "71  i r (neat) 3040 (phenyl-H), 2920, 2850, 2760 ( N ( C H ) ) • 3  1640 (C=0),  750 c m " ( C - B r ) ; n m r 1  2  (CDCI3) 5 7. 65 - 6.97 (m, 4,  p h e n y l - H ) , 3.90 - 3.60 (m, 2, 0 = C - N - C H ) , 2.53 - 2 . 2 0 (m, 2, - C H ^ 2  N(CH ) ), 3  2  2 . l 6 ( s , 6, N ( C H ) ) .  Anal. N,  3  C a l c d . for C  7.95; B r , 22.68.  5.  Found:  1  2  ?  H  2  5  N  2  O B r : C , 57.93; H , 7.09;  C , 57.61; H , 7. 08; N , 8. 00; B r . 2 2 . 4 3 .  N, N-dimethyl-N'-cyclohexylmethyl-N'-p-bromophenylethylene diamine A 500 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel (125 m l . ) and reflux condenser.  and condenser both c a r r i e d d r y i n g tubes.  The funnel  30 m l . d r y ether and lithium  a l u m i n u m hydride (3. 8g, 0. 1 mole) were placed in the f l a s k . The solution was gently refluxed for 3 hours on the heating mantle.  A  solution of N , p - b r o m o p h e n y l - N - (ft- N , N - d i m e t h y l a m i n o e t h y l ) cyclohexanecarboxamide  (24. 6g, 0.07 mole) i n 50 m l . d r y ether was added v e r y  slowly to the flask so as to maintain gentle r e f l u x . was completed,  A f t e r the addition  the mixture was refluxed for 12 hours with s t i r r i n g .  The heating mantle was then r e p l a c e d by an i c e - s a l t bath and the mixture was s t i r r e d for 1 hour.  30 m l . of d i s t i l l e d water was added dropwise to  the cooled reaction m i x t u r e , excess h y d r i d e .  with vigorous s t i r r i n g , to decompose  S t i r r i n g was continued for half an hour.  Next,  cient 40% N a O H solution was added to separate the ethereal  suffi-  layer,  which was decanted into an E r l e n m e y e r flask and d r i e d over anhydrous  m a g n e s i u m sulfate.  The drying agent was suction f i l t e r e d , and the  solvent r e m o v e d using a r o t a r y evaporator.  The residue was d i s t i l l e d  under reduced p r e s s u r e through a 9 inch V i g r e u x column w a r m e d by an e l e c t r i c a l heating tape.  The fraction boiling at 1 5 0 ° C (0.2 m m . Hg)  was collected to y i e l d t e r t i a r y amine (14.88g, 62.85%), and 6.35 g of the secondary amine decomposition product of the amide,  corres-  ponding to 8. 78g (37. 34%) of t e r t i a r y amine product.  i r (neat) 3040 (phenyl-H), 2920, 2850, 2820, 2780 ( N ( C H ) ) 3  1590 (aromatic), H at C  3  &C  5  2  750 c m " ( C - B r ) ; n m r ( C D C 1 ) S 7. 30 - 7.10 (m, 2, 1  3  of phenyl), 6. 60 - 6. 37 (m, 2, H at C  3.55 - 2.92 (m, 4, C H - N - C H ) , 2  2  2.58 - 2. 28 (m, 2,  2.23 (s, 6, N ( C H ) ) , 2. 0 - 0.67 (m, 11, C 3  2  2  f e  H  &C  6  of phenyl),  CH -N(CH ) ), 2  3  2  ).  D i - h y d r o chloride derivative T h e salt was p r e p a r e d b y the same p r o c e d u r e as d e s c r i b e d in Experiment A - 3 .  '  m . p . : 183°C.  A n a l . C a l c d . for C ^ H  N, 6.79; C l , 17.22; B r , 19.28.  N' Br C l 2  Found:  2  : C , 49. 52; H , 7. 086;  C , 49.58; H , 7. 1 9 ; N ,  6.94;  Cl,  17. 05; B r , 19. 55.  E.  S Y N T H E S I S O F N , N - D I M E T H Y L - N - C Y C L O H E X Y L M E T H Y L - 3, 5DIMETHY LPHENY L E T H Y LENEDIAMINE 1  1.  °( - C h l o r o - N - 3 , 5-dimethylphenylacetamide A one l i t r e t h r e e - n e c k e d f l a s k was equipped with a m e c h a n i c a l  stirrer,  side a r m for setting a thermometer  (range -100 \C - 5 0 ° C ) , Q  73 and dropping funnel (125 m l . ) with a drying tube.  A solution of 3. 5  dimethylaniline (24g, 0.2 mole) and triethylamine (20.24g, 0.2 mole) in 400 m l . d r y ether was p l a c e d i n the f l a s k .  The solution was cooled  to between -5 and - 1 0 ° C in an i c e - s a l t bath with s t i r r i n g for 1 hour. A solution of chloroacetyl chloride (22. 6g, 0. 2 mole) in 70 m l . dry ether was added v e r y slowly to the v i g o r o u s l y s t i r r e d solution f r o m the dropping funnel so as to keep the temperature of the solution below 0°C.  A f t e r the addition was completed, the mixture was s t i r r e d at  r o o m temperature overnight.  100 m l . d i s t i l l e d water was added to  the flask and the mixture was s t i r r e d for 15 m i n u t e s .  The white  product in the mixture was suction f i l t e r e d through a Buchner funnel and the l a y e r s were separated. . The ethereal layer was flash evaporated to remove the solvent and the solid was combined with the suction f i l t e r e d product.  The product was poured into a 500 m l . beaker and  100 m l . each of 5% H C l and cold d i s t i l l e d water were added to i t . T h e product was s t i r r e d v i g o r o u s l y on a magnetic s t i r r e r for one hour. The product was suction f i l t e r e d , and washed with 300 m l . d i s t i l l e d water until no trace of H C l could be detected with litmus p a p e r .  The  product was d r i e d in the a i r , and then i n the oven under reduced p r e s sure ( 4 0 ° C ,  20 m m . . Hg).  limation on an o i l bath.  It was p u r i f i e d by reduced p r e s s u r e sub-  Yield:  36g(91.5%).  i r ( K B r ) 3300 ( 0 = C - N H ) , (CH , 2  C H ) , 1660 (C=0), 3  (CDC1 ) 3  §  m . p . : 140°C.  3220, 3160, 3120, 2960, 2980, 2860  1615 (aromatic), 645 c m " ( C - C l ) ; n m r  7.30 - 7.06 (m, 2, p h e n y l - H at  1  & C  6  ), 6.80 (m, 1,  74 p h e n y l - H at C ) , 4.13 (s, 2, C H - C l ) . 2.27 (s, 6, 3. 5-dimethyl). 4  A n a l . C a l c d . for C N,  1  0  H  1  2  N O Cl:  C , 60. 7; H , 6.07;  7.08;. C l , 17.98. . F o u n d : C , 60. 74; H , 6. 12; N , 7.27; C l . 18.09.  2.  °( - D i m e t h y l a m i n o - N - 3 , 5-dimethylphenylacetamide A 500 m l . three-necked flask was equipped with a dropping  funnel (125 m l . ) with d r y i n g tube, a m e c h a n i c a l s t i r r e r , a r m for setting a thermometer  and a side  (range f r o m - 1 0 0 ° C - 5 0 ° C ) .  150 m l .  each of d r y ether and d r y tetrahydrofuran were p l a c e d i n the f l a s k . The solution was cooled to between -5 and - 1 0 ° C i n an i c e - s a l t bath for 1 hour.  D i m e t h y l a m i n e (approx.  8. Occ, 0.3 mole) was trapped i n  a d r y graduated cylinder f r o m a dimethylamine gas tank using an acetone-dry i c e bath ( - 8 0 ° C ) , necked reaction f l a s k .  and poured a l l at once into the three-  A solution of ^ - c h l o r o - N - 5 , 6 - d i m e t h y l p h e n y l -  acetamide (23. 8g, 0. 13 mole) i n 80 m l . d r y tetrahydrofuran was added v e r y slowly f r o m the dropping funnel-to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the reaction mixture below 0 ° C .  After  the addition had been completed, the mixture was kept below 0 ° C for 10 hours arid s t i r r e d overnight.  The.white dimethylamine salt was  suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y 30 m l . d i s t i l l e d water was added to the product, v i g o r o u s l y in the separating funnel.  evaporator.  and it was shaken  T h e mixture was extracted twice  with 150 m l . portions of ether, and the ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e solution was suction f i l t e r e d and the  75 solvent was r e m o v e d by flash evaporation.  i r (neat) 3290 ( C O N H ) , (aromatic); n m r ( C D C l ^ ) (s,  S  2930, 2820, 2770 ( N ( C H ) ) , 3  7.20 (s, 2, p h e n y l - H at C  1, p h e n y l - H at C ) , 3.00 (s, 2, C - C H ) , 4  2  2  2  1600 c m "  1  and C ^ ) , 6.70  2. 33 (s, 6, N ( C H ) ) . 3  2  . M o n o - p e r c h l o r a t e derivative The salt was p r e p a r e d by the same procedure as d e s c r i b e d in Exp. B - 2 .  m . p . : 188°C.  Anal. Calcd. f o r C ^ H Cl,  11.58.  3.  N ^ . O : C , 4 7 . 0 ; H , 6. 20; N , 9.14;  F o u n d : C , 4 7 . 1 3 ; H , 6.31; N , 9.25; C l , 11.52.  . N , N - d i m e t h y l - N | - 3 , 5-dimethylphenylethylenediamine A d r y 250 m l . three-necked flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) and reflux condenser.  Both the funnel and the condenser c a r r i e d drying tubes.  150 m l . d r y  ether and lithium a l u m i n u m hydride (6. 45g, 0. 17 mole) were placed in the flask and gently refluxed with s t i r r i n g for 3 h o u r s .  A solution of  °1 - d i m e t h y l a m i n o - N - 3 , 5-dimethylphenylacetamide (17g, 0. 085 mole) in 50 m l . d r y ether was placed in a dropping funnel and added dropwise at such a rate as to maintain a gentle reflux. completed,  When the addition was  the mixture was refluxed for 40 hours with s t i r r i n g on the  e l e c t r i c a l heating mantle.  A f t e r the reduction had been completed, the  reaction mixture was cooled i n an i c e - s a l t bath for 30 minutes and 20 m l . of d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d m i x t u r e in the flask to decompose excess h y d r i d e .  S t i r r i n g was continued until the  76 mixture became white i n colour and then sufficient 10% N a O H solution was added to facilitate separation of the ethereal l a y e r .  The ether-  insoluble residue was separated by centrifugation and the ethereal layer was d r i e d over anhydrous m a g n e s i u m sulfate overnight. solvent was r e m o v e d with a r o t a r y evaporator,  The  and the residue was  d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x column and a heating tape on the o i l bath.  The fraction boiling a t ' 7 0 ° C (0.05 m m .  Hg) was c o l l e c t e d .  i r (neat) 3370 ( N - H ) ,  2930, 2850, 2810, 2760 ( N ( C H ) . ) , 3  1600 c m " (aromatic); n m r ( C D C 1 ) 5 6.40 - 6.20 (d, 3, 1  3  p h e n y l - H ) , 4 . 3 0 - 3.90 (broad's,  (s,  3  J=4,  1, N - H ) , 3.50 - 2.87 (m, 2,  2.63 - 2.30 (m, 2, C H - N ( C H ) ) . 2  2  2  2.23 (s, 6, 3, 5-dimethyl),  NH-CH ), 2  2.17  6, N ( C H ) ) . 3  2  D i - h y d r o chloride derivative T h e salt was p r e p a r e d by the same procedure as d e s c r i b e d in Exp. A - 3 . . m . p . :  188°C.  - A n a l . C a l c d . for C j H 2  Cl,  26.76. . F o u n d :  4.  2  2  N  2  Cl .  54. 39;• H , 8 . 2 3 ; N ,  C , 54. 33; H , 8. 35; N , 10.56;  10.45; C l , 2 6 . 8 3 .  . lNf-3, 5 - d i m e t h y l p h e n y l - N - (ft- N , N - d i m e t h y l a m i n o ) - c y c l o h e x a n e carboxamide A d r y 250 m l . three-necked flask was equipped with a  mechanical stirrer,  a dropping funnel (125 m l . ) with d r y i n g tube, and  a side a r m for setting a thermometer  (range -100  to 5 0 ° C ) . . N , N -  d i m e t h y l - N ' - 3 , 5-dimethylphenylethylenediamine (1.5g, 0.02  mole),  r e d i s t i l l e d dry triethylamine (7. l g , 0. 7 mole) and 170 m l . dry ether were added to the f l a s k .  The flask was cooled to between -5 and - 1 0 ° C  in an i c e - s a l t bath for one hour.  50 m l . of a solution of cyclohexane-  c a r b o x y l chloride (8. 742g, 0. 06 mole) in ether was v e r y slowly added to the r a p i d l y s t i r r e d m i x t u r e f r o m the dropping funnel so as to keep the temperature of the mixture below 0 ° C . completed,  When the addition had been  s t i r r i n g was continued at the same temperature for another  hour, and then overnight at r o o m temperature.  20 m l . of d i s t i l l e d  water was added and the mixture was s t i r r e d r a p i d l y for 10 m i n u t e s . The l a y e r s were separated,  and the aqueous phase was extracted with  three 120 m l . portions of ether. . The extracts were combined with the ether l a y e r ,  and d r i e d over anhydrous m a g n e s i u m sulfate.  was r e m o v e d with a r o t a r y evaporator.  The product was d i s t i l l e d under  reduced p r e s s u r e using a 9 inch V i g r e u x c o l u m n . at 1 4 5 ° C (0.4 m m . Hg) was c o l l e c t e d . . Y i e l d :  i r (neat) 2920, 2840, 2760 ( N f C H ^ ) , (CDC1 ) S  7. 03 - 6. 73 (d, 3, J= 10.  3  0=C-N-CH ), 2  (s,  6,  2.57  - 2.30  3. 5-dimethyl) 2.22  (m, 8, (s,  The solvent  The fraction boiling  14. 6g (81%).  1645 c m "  1  (C=0); n m r  p h e n y l - H ) , 3. 93 - 3. 60 (m,  2,  3,5-dimethyl & C H ( N C H ^ ) ,  2.33  2  6, N ( C H ) > , 3  2  2.0  - 0.40  (m,  11,  C  6  H  u  ).  M o n o - p e r c h l o r a t e derivative The salt was p r e p a r e d by the same procedure as in E x p . A - 3 .  m.P.:  193-194°C.  described  F.  -N, N - D I M E T H Y L - N - C Y C L O H E X Y L M E T H Y L - N ' - C Y C L O H E X Y L E T HY L E N E D I A M I N E 1  1.  . Cyclohexanecarboxyl chloride A one l i t r e t h r e e - n e c k e d flask was equipped with a reflux  condenser and a dropping funnel. . Both the funnel and condenser c a r r i e d d r y i n g tubes.  C y c l o h e x a n e c a r b o x y l i c a c i d (128g, 1 mole) was  placed in the flask and thionyl chloride (179g, 1. 5 mole) was added over a p e r i o d of 5 minutes with s t i r r i n g .  The flask was placed in an  o i l bath and heated at a bath temperature of 1 5 0 ° C for 1 hour.  The  reflux condenser was then r e p l a c e d by a distillation head. 200 m l . dry benzene was added and the m i x t u r e was d i s t i l l e d until the t e m p e r a ture of the vapour reached 9 5 ° C .  The m i x t u r e was then cooled and  another 200 m l . of anhydrous benzene was added.  The distillation was  continued until the temperature of the vapour again reached 9 5 ° C .  The  r e s i d u a l a c i d chloride was r e d i s t i l l e d under reduced p r e s s u r e on the o i l bath to give a c o l o u r l e s s l i q u i d .  Yield:  120g (82%).  b.p. :  46°C  (2. 75 m m . H g ) . ( L i t . ) b . p . : 67-67. 5 ° C (14 m m . Hg).  i r (neat) 2920, 2850 ( C - H ) , 1770 (C=0), 790 c m 2  2.  - 1  (C-Cl).  °{ - C h l o r o - N - c y c l o h e x y l a c e t a m i d e A 2 l i t r e three-necked flask was equipped with a m e c h a n i c a l  stirrer,  side a r m for setting a thermometer  250 m l . dropping funnel with a d r y i n g tube.  (range -100 - 5 0 ° C ) and A solution of c y c l o h e x y l -  amine (198. 1 8g, 2 mole) i n 1. 5 1. d r y ether was p l a c e d i n the f l a s k .  79 T h e solution was s t i r r e d over a d r y ice-acetone bath for 30 minutes until it reached - 3 0 ° C .  A solution of chloroacetyl chloride (112. 95g,  1 mole) was added dropwise to the v i g o r o u s l y s t i r r e d solution f r o m the dropping funnel so as to keep the temperature below - 3 0 ° C .  A f t e r the  addition was completed, the s t i r r i n g was continued in the i c e - s a l t bath for 3 hours, and overnight at r o o m temperature.  200 m l . 5% HC1  solution was added to the reaction m i x t u r e , which was then s t i r r e d for 5 minutes.  T h e white product which precipitated was suction f i l t e r e d  and the ethereal layer was separated f r o m the a c i d i c aqueous phase with a separatory funnel.  T h e f i l t e r e d product was washed with  d i s t i l l e d water until no trace of a c i d could be detected on.litmus p a p e r . The ethereal layer was washed twice with 200 m l . portions of d i s t i l l e d water, and d r i e d over anhydrous m a g n e s i u m sulfate overnight.  The  solvent was r e m o v e d with a r o t a r y evaporator to r e c o v e r m o r e a m i d e . The product was p r e d r i e d in the a i r and then sublimed under reduced pressure.  Yield:  158g(90%).  m . p . : 105°C.  ir ( K B r ) 3220 ( 0 = C - N H ) , 790 c m " ( C - C l ) ; n m r ( C D C 1 ) § 1  (s,  3  2, C H - C 1 ) , 2  3023, 2875, 2800  20.2.  3.43 (m, 1, C H - N ) ,  Found:  2  1630 (C=0),  ) ,  6. 92 - 6. 00 ( s , 1, N H ) , 2.40 - 0.50 (m, 10,  A n a l . C a l c d . for C„ H , . N C l O : ——— o 14 Cl,  ( C H  C  4. 03 6  H  1  Q  ) .  C , 54.65; H , 7.97; N , 7.97;  C , 54. 56; H , 8.15; N , 7.84; C l , 20.21.  80 3.  o( - D i m e t h y l a m i n o - N - cyclohexylacet amide A 2 l i t r e three-necked flask was equipped with a dropping  funnel (500 m l . ) with drying tube, m e c h a n i c a l s t i r r e r , for setting a thermometer  (range - 1 0 0 ° C - 5 0 ° C ) .  and side a r m  500 m l . d r y ether  and 200 m l . d r y tetrahydrofuran were placed in the f l a s k . . The solution was cooled to below 0 ° C i n an i c e - s a l t bath for 1 h o u r . (approx.  Dimethylamine  122. 5cc, 1.7 mole) was trapped in a d r y graduated cylinder  f r o m a dimethylamine gas tank using an acetone-dry ice bath ( - 8 0 ° C ) and poured into the flask a l l at once. cyclohexylacetamide  A solution of o| - c h l o r o - N -  (149g, 0.85 mole) in 400 m l . d r y T H F was added  slowly f r o m the dropping funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature below 0 ° C .  A f t e r the addition was completed,  the solution was kept below 0 ° C and s t i r r e d for 10 hours, and then kept below - 1 0 ° C and s t i r r e d overnight. . T h e white dimethylamine salt was suction f i l t e r e d off and the solvent r e m o v e d by flash evaporation. 30 m l . d i s t i l l e d water was added to the product and it was shaken v i g o r o u s l y in the separatory funnel.  The mixture was extracted twice  with 200 m l . portions of ether, and the ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e solution was suction f i l t e r e d and the  solvent r e m o v e d by flash evaporation.  T h e crude product was r e c r y s -  t a l l i z e d f r o m a mixture of ether, petroleum ether and hexane. 176. 8g (96%).  m.p. :  Yield:  6l°C.  i r ( K B r ) 3260 (0=C-NH),  2960 - 2760 ( N ( C H ) J , 1630 c m " 3  1  81 (C=0); n m r ( C D C 1 ) 5 3  CH -N),  4. 0 - 3. 57 (broad s, 1, N - H ) , 2. 90 (s, 2,  2.27 (s, 6, N ( C H ) ) , 2.10 - 0.80 (m, 11, C H  2  3  2  A n a l . . C a l c d . for C N,  15.21.  4.  Found:  1  6  Q  H  2  Q  N  2  O:  n  ) .  C , 65.2;. H , 10.87;  C , 64.99; H , 10. 74;. N , 15.33.  . N , N - d i m e t h y l - N ' - eye lohexylethylenediamine A 2 l i t r e three-necked flask was equipped with a 500 m l .  dropping funnel, reflux condenser,  and m e c h a n i c a l s t i r r e r .  and condenser both c a r r i e d d r y i n g tubes.  The funnel  One 1. d r y ether was p l a c e d  in the flask and lithium a l u m i n u m hydride (51. 4g, 1. 35 mole) was added.  The m i x t u r e was gently refluxed with s t i r r i n g for 3 h o u r s .  A  solution of o| - d i m e t h y l a m i n o - N - c y c l o h e x y l a c t a m i d e (165. 5g, 0.9 m l . ) in 250 m l . d r y ether was added to the flask so as to maintain gentle reflux.  A f t e r the addition was completed,  40 hours with s t i r r i n g .  the mixture was refluxed for  When the reduction was over,  cooled in an i c e - s a l t bath.  the flask was  E x c e s s l i t h i u m a l u m i n u m hydride was  decomposed by dropwise addition of d i s t i l l e d water until the m i x t u r e turned white. - Sufficient 40% N a O H was added to give clear of the ethereal phase f r o m the e t h e r - i n s o l u b l e r e s i d u e .  separation  The ethereal  solution was d r i e d over anhydrous m a g n e s i u m sulfate overnight.  The  ether was r e m o v e d by flash evaporation and the product was d i s t i l l e d under reduced p r e s s u r e .  Yield:  I45g (95%).  b . p . : 7 3 ° C ( 2 . 0 m m . Hg).  i r (neat) 3300 (NH), 2920, 2860, 2840, 2780 c m " . ( N ( C H ) J ; 1  3  2  82 nmr (CDC1 ) 3  N{CH ) ), 3  2  8  3. 00 - 2.30 (m, 4, N - C H - C H - N ) , 2  2.05 - 0.7 (m, 12, C D i - h y d r o chloride  6  H  n  2  2.20 (s, 6,  ,NH).  derivative  The salt was p r e p a r e d by the same procedure as d e s c r i b e d in Exp. A - 3 . m . p . : 2 3 1 - 2 3 2 ° C .  A n a l . C a l c d . for C j C1-, 2 9 . 2 . . F o u n d :  5.  0  H  2  4  N  2  Cl : 2  C, 49.3; H , 9 . 8 ; N ,  11.5;  C , 4 9 . 2 9 ; H , 9.77;. N , 11.54; C l , 29.39.  N-cyclohexyl-N-( P - N , N-dimethylaminoethyl)-cyclohexanecarboxamide A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  and a dropping funnel (125 m l . ) with a drying tube.  N, N -  d i m e t h y l - N ' - c y c l o h e x y l e t h y l e n e d i a m i n e (5.1g, 0.03 mole) and d r y triethylamine (4. 04g, 0.4 mole) in 120 m l . d r y ether were placed in the flask.  The solution was cooled to between -5 and - 1 0 ° C i n an i c e - s a l t  bath for one hour with s t i r r i n g .  A solution of  cyclohexanecarboxyl  chloride (4. 35g, 0.03 mole) in d r y ether (40 m l . ) was added v e r y slowly f r o m the dropping funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C .  After the addition was c o m -  pleted, the s t i r r i n g was continued at r o o m temperature overnight, 20 m l . of d i s t i l l e d water was added and the mixture was s t i r r e d for 10 minutes.  T h e ether layer was separated f r o m the aqueous layer using  a separatory funnel. . The aqueous phase was extracted twice with 80 m l . portions of ether.  The extracts were combined with the ether  83 layer and d r i e d over anhydrous m a g n e s i u m sulfate.  T h e drying agent  was suction f i l t e r e d and most of the solvent was r e m o v e d using a r o t a r y evaporator.  The crude product was d i s t i l l e d under  reduced  p r e s s u r e through a 9 inch V i g r e u x column, w a r m e d by a heating tape. The fraction boiling at 1 3 5 ° C (0.1 m m . Hg) was collected. product s o l i d i f i e d at r o o m t e m p e r a t u r e .  Yield:  7. 04g (84%).  i r ( K B r ) 2940, 2860, 2840, 2785 ( - N ( C H ) . ) , 3  nmr (CDC1 ) S 3  (s,  1644 c m "  2  3.60 - 2.20 (m, 11, C H - N - C H - C H - N ( C H ) ) , 2  6, N ( C H ) ) , 2.20 - 0.87 (m, 21, C 3  T h e liquid  2  . M o n o - h y d r o chloride  &  H  n  , C  2  &  H  3  1 Q  2  1  (C=0); 2.32  ).  derivative  The salt was p r e p a r e d by the same procedure as d e s c r i b e d i n Exp.A-3.  m . p . : 197°C.  A n a l . C a l c d . for C Cl,  11.2.  6.  Found:  1  ?  H  N ' O C l : C , 6 4 . 4 ; H , 10.4; N , 8 . 8 ; 2  C , 64. 27; H , 1 0 . 3 1 ; N ,  8.91; C l , 11.43.  . N, N-dimethyl-N'-cyclohexylmethyl-N'-cyclohexylethylenedi amine A d r y 250 m l . three-necked flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) and refluxing  Both the funnel and condenser  c a r r i e d drying tubes.  condenser.  120 m l . d r y ether  was placed in the flask and l i t h i u m aluminum hydride (0. 76g, 0. 04 mole) was added to it. hours.  The solution was gently refluxed with s t i r r i n g for 3  A solution of N - c y c l o h e x y l - N - ( ^ - N , N - d i m e t h y l a m i n o e t h y l ) - N -  84 cyclohexanecarboxamide  (5.715g, 0.0219 mole) in 30 m l . d r y ether  was added dropwise f r o m the funnel to the L i A l H ^ solution, so as to maintain gentle r e f l u x .  A f t e r the addition was completed,  was refluxed with s t i r r i n g for 30 h o u r s .  the m i x t u r e  The heating mantle was then  r e p l a c e d by an i c e - s a l t bath, and the solution was cooled below 0 ° C . 10 m l . of d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . tinued for 20 m i n u t e s .  S t i r r i n g was c o n -  Sufficient 40% N a O H solution was added to b r i n g  about clear separation of the ethereal l a y e r .  The m i x t u r e was c e n t r i -  fuged and the ethereal layer was d r i e d over anhydrous m a g n e s i u m sulfate overnight.  T h e drying agent was suction f i l t e r e d and the solvent  r e m o v e d using a r o t a r y evaporator.  The crude product was d i s t i l l e d  under reduced p r e s s u r e through a 9 inch V i g r e u x c o l u m n . boiling at 1 6 0 ° (2 m m . Hg) was c o l l e c t e d . . Y i e l d :  The fraction  5. 6g (96%).  i r (neat) 2920, 2850, 2760 ( N ( C H ) ) ; n m r ( C D C l j ) S 3  2.08 (m, 11, C H - N - C H - C H - N ( C H ) ) , 2  0.42 (m, 23, C  &  H  n  2  CH , C 2  3  H  6  1 Q  2  2  2.27 (s, 6, N ( C H ) ) , 3  2  2.70 2.10-  ).  D i - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as d e s c r i b e d in Exp. A - 3 . m . p . : 2 1 9 - 2 2 0 ° C .  •Anal. Calcd. f o r C Cl,  20.9.  1  ?  H  3  6  N  2  Cl  2  : C , 6 0 . 1 ; H , 10.6; N , 8 . 2 ;  F o u n d : C , 59.91; H , 10.68;. N , 8.09; C l , 20.74.  85 G.  SYNTHESIS O F N . N - D I M E T H Y L - N ' - B E N Z Y L - N ' - C Y C L O H E X Y L E T HY L E N E D I A M I N E 1.  . N - c y c l o h e x y l - N - ( ft - N , N - d i m e t h y l a m i n o e t h y l ) - p h e n y l carboxamide A 250 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  s t i r r e r , dropping funnel with drying tube, and a side a r m for setting a thermometer (range - 1 0 0 ° C - 5 0 ° C ) . cyclohexylethylenediamine  (6. 8g,  0.04  A solution of N , N - d i m e t h y l - N ' mole) and d r y triethylamine  (V. 5g, 0. 05 mole) i n 150 m l . d r y ether was p l a c e d i n the flask.  The  flask was i m m e r s e d i n an i c e - s a l t bath for 1 hour until the temperature of the solution was below 0 ° C .  A solution of benzoyl chloride (5.6g,  0. 04 mole) in 50 m l . d r y ether was added dropwise to the flask f r o m the dropping funnel with s t i r r i n g , r e a c t i o n mixture below 0 ° C .  so as to keep the temperature of the  A f t e r the addition was completed,  stirring  was continued at 0 ° C for another hour, and at r o o m temperature o v e r night.  50 m l . of d i s t i l l e d water was added, the l a y e r s were separated  and the aqueous phase was extracted with two 100 m l . portions of ether. The extracts were combined with the ether l a y e r ,  washed with saturated  sodium chloride solution and d r i e d over 50g anhydrous sulfate.  magnesium  The solvent was r e m o v e d by flash evaporation and the r e s i d u a l  liquid d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x c o l u m n . The fraction boiling at 1 5 5 ° C - 1 6 0 ° C (0,5 m m . Hg) was collected, the product was r e c r y s t a l l i z e d f r o m a pentane-hexane m i x t u r e . 8.98g (82%).  m.p. :  56°C.  and Yield:  86 i r (neat) 2930, 2860, 2820, 2770 ( N ( C H ) ) , 3  nmr (CDC1 ) 3  CH ), 2  S  A n a l . C a l c d . for C  2.  1630 c m  7.33 (m, 5, p h e n y l - H ) , 3.63 - 3.23 (m, 2,  2. 68 - 0.50 (m, 19, C  Found:  2  1  &  7  C , 74.29; H , 9 . 3 4 ; N',  Hj  H  (C=0);  0=C-N-  & CH -N(CH ) ).  1  2  - 1  2  &  3  2  N ' 0 : . C , 74. 5; H , 9. 5; N , 10.2. 2  10.05.  N, N-dimethyl-N'-benzyl-N'-cyclohexylethylenediamine A 250 m l . three-necked flask was: equipped with a dropping  funnel (125 m l . ) , reflux condenser,  and m e c h a n i c a l s t i r r e r .  denser and funnel both c a r r i e d drying tubes.  The c o n -  175 m l . d r y ether and  lithium a l u m i n u m hydride (1.248g, 0. 032 mole) were added to the flask, and gently refluxed with s t i r r i n g for 3 hours on the e l e c t r i c heating mantle.  A solution of N - c y c l o h e x y l - N ' - ( ^ - N , N - d i m e t h y l a m i n o e t h y l ) -  benzenecarboxamide  (4. 38g, 0.016 mole) in 25 m l . d r y ether was  placed in the dropping funnel, and added v e r y slowly so as to maintain gentle r e f l u x .  When the addition was completed,  s t i r r e d and refluxed for 40 h o u r s .  the mixture was  A f t e r the reduction was over, the  reaction flask was cooled in an i c e - s a l t bath.  Excess lithium aluminum  hydride was decomposed by the slow addition of d i s t i l l e d water with vigorous s t i r r i n g so as to avoid violent r e a c t i o n .  A sufficient amount  of 40% N a O H solution was added to give good separation of the ethereal layer f r o m the ether-insoluble residue,  and the ethereal solution was  d r i e d over anhydrous m a g n e s i u m sulfate overnight.  T h e ether was  r e m o v e d by flash evaporation and the residue was d i s t i l l e d under  87 reduced p r e s s u r e .  Yield:  4. 25g (97%).  i r (neat) 3040 (phenyl-H), 2920, 2850, 2820, 2760. ( N ( C H ) ) , 3  1600 c m "  1  (aromatic); n m r ( C D C 1 ) 8 3  7. 42 - 7.02 (m, 5, p h e n y l - H ) ,  3.60 (s, 2, p h e n y l - C H ) , 2.77 - 2.17 (m, 4, N - C H - C H - N ) . 2  6, N - ( C H ) ) , 3  2  2  2.00 - 0.70 (m, 11, C  Di-perchlorate  &  2  H  2  2.12 (s,  ).  derivative  The salt was p r e p a r e d by the same procedure as that d e s c r i b e d in E x p . B - 2 , except that two equivalents of p e r c h l o r i c a c i d was used, m.p.:  94°C.  Anal.. Calcd. for C N,  H.  6.09; C l , 15.08.  1  Found:  ?  H  3  Q  N 'Og. C l : C , 44. 40; H , 6. 50; 2  C , 4 4 . 1 3 ; H , 6.47; N , 5.97; C l , 15.23.  N , N - D I M E T H Y L - N - D I P H E N Y L M E T H Y L E T HY L E N E D I A M I N E 1.  ^ - Chip r o - N - d i p h e n y l m e thy lac etamide A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer, 50°C),  a side a r m for setting a thermometer (range f r o m - 1 0 0 ° C and a dropping funnel (125 m l . ) with drying tube.  methylamine (54. 9g, 0.3 mole),  Diphenyl-  r e d i s t i l l e d d r y triethylamine (40.48g,  0.4 mole) and 150 m l . d r y ether were placed in the f l a s k .  T h e solution  was s t i r r e d in an i c e - s a l t bath until the temperature of the solution r e a c h e d -5 to - 1 0 ° C .  A solution of chloroacetyl chloride (33. 9g,  0. 3 mole) in 40 m l . dry ether was added v e r y slowly to the r a p i d l y s t i r r e d solution in the flask f r o m a dropping funnel so as to keep the  88 temperature of the reaction mixture below 0 ° C . been completed,  When the addition had  the s t i r r i n g was continued for 3 hours below 0 ° C and  overnight at r o o m temperature.  50 m l . of d i s t i l l e d water was added and  the mixture was s t i r r e d for 15 m i n u t e s . . T h e white product in the m i x t u r e was suction f i l t e r e d through a Buchner funnel, and the l a y e r s were separated.  The ethereal layer was flash evaporated to remove  the solvent, and the solids were combined with the suction f i l t e r e d product.  The product was poured into a 500 m l . beaker and 100 m l .  each of 5% HC1 solution a c i d and cold d i s t i l l e d water was added to it. The mixture was s t i r r e d vigorously on a magnetic s t i r r e r for 1 hour, then suction f i l t e r e d and the product was washed with 400 m l . d i s t i l l e d water until no trace of HC1 could be detected with litmus paper.  The  product was d r i e d in the a i r and then in an oven under reduced p r e s s u r e (40°C,  20 m m . Hg). The amide was r e c r y s t a l l i z e d f r o m a mixture of  d r y petroleum ether ( 3 0 ° - 6 0 ° C ) and ethyl acetate. m.p.:  Yield:  128-129°C.  i r ( K B r ) 3200 ( N - H ) ,  3040 (phenyl-H) 1650 c m " (C=0); 1  n m r ( C D C l ) i 7 . 28 (sharp m , 10, d i - p h e n y l - H ) 408, s , 2 , 3  1. 50 (s,  71. 5g (92%).  1, C H - N ) .  (0=C-CH ), 2  >  • A n a l . C a l c d . for C , , H , N O C 1 : C , 6 9 . 4 ; H , 5.4; N , 5 . 4 ; 1 3 14 Cl,  13. 70. . F o u n d : C , 69.29; H , 5.44; N , 5.53; C l , 13.54.  89 2.  ck - d i m e t h y l a m i n o - N - d i p h e n y l m e t h y l a c e t a m i d e A d r y 500 m l . t h r e e - n e c k e d flask was equipped with a  mechanical stirrer,  a side a r m for setting a thermometer  5 0 ° C ) and a dropping funnel (250 m l . ) with a drying tube.  (-100°C 100 m l .  each of d r y ether and tetrahydrofuran were placed i n the f l a s k . T h e solution was cooled to between -5 and - 1 0 ° C i n an i c e - s a l t bath for 1 hour.  Dimethylamine (39.72 m l . , approx.  0.6 mole) was trapped i n a  d r y graduated cylinder f r o m a dimethylamine gas tank using an acetonedry ice bath ( - 8 0 ° C ) and was poured into the reaction f l a s k . of  A solution  o| - c h l o r o - N - d i p h e n y l m e t h y l a c e t a m i d e (74. 1 g, 0.285 mole) i n 150 m l .  tetrahydrofuran was added v e r y slowly f r o m the dropping funnel to the r a p i d l y s t i r r e d reaction mixture so as to keep the temperature below 0°C.  A f t e r the addition was completed,  the m i x t u r e was s t i r r e d for 10  hours below 0 ° C and then overnight below 1 0 ° C .  T h e white d i m e t h y l -  amine salt was suction f i l t e r e d and the solvent was r e m o v e d using a r o t a r y evaporator.  40 m l . d i s t i l l e d water was added to the product and  it was shaken v i g o r o u s l y i n the separating funnel.  T h e mixture was  extracted with three 150 m l . portions of ether, and the ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate.  The solution was suction  f i l t e r e d and the solvent was r e m o v e d with a r o t a r y evaporator.  The  product was r e c r y s t a l l i z e d f r o m a mixture of hexane and s m a l l amount of ethyl acetate.  Yield:  68g (89%).  i r ( K B r ) 3330 ( 0 = C - N - H ) ,  m . p . : 83°C.  2780 - 3060 ( N ( C H ) ) 1670 c m " 2  1  90 (C=C,  C=0); n m r ( C D C 1 ) §  7.4-  3  6.37 - 6.17 (d, 1, J = 9 H z C H - N ) , (s,  7.18 (m, 10, d i - p h e n y l - H ) , 2.97 (s, 2, 0 = C - C H - N ) , 2  2.20  7, N ( C H ) ) . 3  2  A n a l . C a l c d . for C Found:  3.  1  ?  H  2  Q  N ^ O : C , 7 6 . 1 ; H , 7.46; N , 10.45.  C , 76.10; H , 7. 57; N , 10.29.  . N , N-dimethyl-N'-diphenylmethylethylenediamine A one l i t r e t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  s t i r r e r and a Soxhelt apparatus connected to a r e f l u x condenser with a drying tube.  600 m l . d r y ether and lithium a l u m i n u m hydride (19. 0g,  0. 5 mole) were placed in the f l a s k . for 3 hours with s t i r r i n g .  T h e solution was gently refluxed  -dimethylamino-N-diphenylmethylaceta-  mide (55g, 0. 242 mole) was packed in the round-bottomed filter paper column of the Soxhelt e x t r a c t o r .  A glass r o d was i n s e r t e d in the packed  powder in o r d e r to give the solvent easy a c c e s s to the powder.  The  reaction mixture was refluxed for 48 hours with gentle s t i r r i n g on the o i l bath.  A t the end of the reaction, the o i l bath was r e p l a c e d by an  i c e - s a l t bath and the reaction m i x t u r e was cooled for 1 h o u r .  20 m l .  d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . . S t i r r i n g was continued until the m i x t u r e turned white.  Sufficient 40% sodium hydroxide solution was  added to allow clear separation of the ethereal l a y e r . insoluble l a y e r was separated by decantation.  T h e ether-  T h e ethereal l a y e r was  d r i e d over anhydrous m a g n e s i u m sulfate overnight with s t i r r i n g . T h e  m a g n e s i u m sulfate was suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y evaporator.  T h e residue was d i s t i l l e d under vacuum on the  o i l bath using a 9 inch V i g r e u x column wrapped with a heating tape. The fraction boiling at 1 3 5 ° C (0.4 m m . Hg) was collected.  Yield:  58. 5g (95%).  D i - p e r c h l o r a t e derivative The salt was p r e p a r e d by the same procedure as that d e s c r i b e in E x p . B - 2 , except that two equivalents of p e r c h l o r i c a c i d was used, m.p.:  184-185°C.  A n a l . . C a l c d . for C N,  I.  6.15; C l , 15.59.  17  H N O Cl : 24 2 8 2  C , 44.84; H , 5.31;  F o u n d : C , 4 5 . 0 1 ; H , 5. 38; N , 6.27; C l , 15.46.  N, N-DIMETHYL-N*. N'-DIBENZY L E T H Y LENEDIAMINE 1.  N ' - b e n z y l - N ' - (ft- N , N - d i m e t h y l a m i n o e t h y l ) - b e n z e n e carboxamide A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  mechanical stirrer,  dropping funnel (125 m l . ) with a d r y i n g tube, and  side a r m for setting a thermometer  (range - 1 0 0 ° C - 5 0 ° C ) .  N,N -  d i m e t h y l - N ' - b e n z y l e t h y l e n e d i a m i n e (17.83g, 0.1 mole) and r e d i s t i l l e d triethylamine (10. l g , 0. 1 mole) in 180 m l . dry ether were p l a c e d i n the f l a s k .  The solution was cooled to between.-5 and - 1 0 ° C in an i c e -  salt bath for 1 hour.  A solution of benzoyl chloride (14. l g , 0.1 mole)  in 30 m l . d r y ether was added v e r y slowly f r o m the dropping funnel to the r a p i d l y s t i r r e d solution so that the temperature of the solution r e m a i n e d below 0 ° C .  A f t e r the addition was completed,  the s t i r r i n g  92 was continued at r o o m temperature overnight.  30 m l . d i s t i l l e d water  was added and the mixture was s t i r r e d for 10 m i n u t e s .  The ethereal  layer was separated f r o m the aqueous one using a separatory funnel. The aqueous phase was extracted twice with 100 m l . portions of ether. T h e s e extracts were combined with the ether l a y e r and d r i e d over anhydrous m a g n e s i u m sulfate overnight.  The drying agent was suction  f i l t e r e d and the solvent was r e m o v e d using a r o t a r y evaporator.  The  r e s i d u a l crude product was d i s t i l l e d under reduced p r e s s u r e through a 9 inch V i g r e u x column wrapped in a heating tape. at 1 6 0 ° C (0.20 m m . Hg) was collected. . Y i e l d :  i r (neat) 2940, 2830, 2780 ( N ( C H ) ) , 3  nmr (CDCT ) 3  CH ),  2  T h e f r a c t i o n boiling  26. 8g (95%).  1632 c m "  1  (N-C=Q);  7. 60 - 7. 20 (m, 10, 2 phenyl), 4. 70 (s, 2, p h e n y l -  3.67 - 3.20 (m, 2, 0 = C - N - C H ) , 2.67 - 1.92 (m, 8,  2  2  CH -N 2  (CH ) ). 3  2  M o n o - h y d r o chloride derivatives The salt was p r e p a r e d by the same procedure as that d e s c r i b e d in E x p . A - 3 . m . p . : 1 6 8 ° C .  A n a l . C a l c d . for C N,  8.78; C l , 11.12.  2.  l  g  H  2  3  N  2  0 C l : . C , 6 7 . 8 ; H , 7.21;  F o u n d : C , 67.68; H , 7.18;. N , 8.74; C l , 11.01.  N , N - d i m e t h y l - N ' , N'-dibenzylethylenediamine A d r y 250 m l . three-necked flask was equipped with a  mechanical  s t i r r e r and dropping funnel ( 125 m l . ) with a drying tube.  93 150 m l . d r y ether was placed in the flask and lithium aluminum hydride ( 3 . 8 g ,  0.1 mole) was added to it.  refluxed with s t i r r i n g for 3 h o u r s .  The solution was gently  A solution of N ' - b e n z y l r N ' - ( ft -  N , N-dimethylaminoethyl) -benzenecarboxamide  (14. 1.2g, 0. 05 mole)  in 50 m l . d r y ether was added v e r y slowly to the flask f r o m the dropping funnel so as to maintain gentle r e f l u x . been completed,  A f t e r the addition had  the mixture was refluxed with s t i r r i n g for 30 h o u r s .  The heating mantle was r e p l a c e d by an i c e - w a t e r bath and the solution was cooled below 0 ° C . 20 m l . of d i s t i l l e d water was added dropwise to the r a p i d l y s t i r r e d mixture in the flask to decompose excess h y d r i d e . Sufficient 40% N a O H was added to b r i n g about clear separation of the ethereal l a y e r .  T h e mixture was centrifuged and the ether layer d r i e d  over anhydrous m a g n e s i u m sulphate overnight.  T h e d r y i n g agent was  suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y  evaporator.  The crude product was d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x column w a r m e d by a heating tape. 1 4 3 ° C ( 0. 75 m m . Hg) was collected. . Y i e l d :  T h e fraction boiling at 12. 7g (95%).  ir (neat) 3040 ( a r y l - H ) , 2940, 2800 ( N ( C H ) ) , 3  2  1600 c m "  1  (aromatic); n m r ( C D C 1 ) & 7 . 5 0 - 7.17 (m, 10, d i p h e n y l - H ) , 3.61 3  (s,  4, 2 p h e n y l - C H ) , 2  2.73 - 2.31 (m, 4, N - C H - C H - N ) , 2  2  2.17 (m,  6, N ( C H ) ) . 3  2  D i - p i c r a t e derivative 3. l g of the t e r t i a r y amine was d i s s o l v e d in 10 m l . of  °94 absolute ethanol and 5 m l . saturated p i c r i c acid solution was added. The mixture was w a r m e d for 15 m i n u t e s .  The salt was r e c r y s t a l l i z e d  f r o m d r y ethanol and ether m . p . : Z10.  •Anal. C a l c d . for C ,  H N O : C , 4 9 . 5 ; H , 4 . 1 5 ; H , 15.42. 30 o 14 C , 4 8 . 9 7 ; H , 4 . 0 4 ; N , 15.58. n  JU  Found:  J.  . N , N - D I M E T H Y L - N - 1 - CY C L O H E X E N Y L M E T H Y L - N C Y C L O H E X Y L E T HY L E N E D I A M I N E 1  1.  1  Cyclohexylcyanohydrin' A 500 m l . three-necked flask was equipped with a dropping  funnel and m e c h a n i c a l s t i r r e r .  Cyclohexanol (90. Og, 1 mole) in 100 m l .  ether and finely powdered potassium cyanide (97. 6g, 1.5 mole) were placed i n the flask in the fume hood.  The flask was cooled i n an i c e -  salt bath for 2 hours with r a p i d s t i r r i n g .  A s m a l l excess of fuming  H C l (150 cc) was added dropwise to the v i g o r o u s l y s t i r r e d reaction mixture and the s t i r r i n g was continued for 10 h o u r s .  The inorganic  salt was suction f i l t e r e d , and the l a y e r s were separated. layer was d r i e d over anhydrous sodium sulfate.  The ethereal  The drying agent was  suction f i l t e r e d and the ether solvent was d i s t i l l e d using a flash evaporator.  The oily residue was d i s t i l l e d under reduced p r e s s u r e in  the fume hood and r e c r y s t a l l i z e d f r o m cyclohexane.  Yield:  90g (72%),  m.p.: 31°C.  i r (neat) 3420 (OH), 2950, 2870 ( C H ) , 2260 c m " (C=N); n m r 2  1  (CDC1 ) S 3  3.03 (s, 1, O - H ) , 2.4 - 0.67 (m, 10, C  &  H  1 Q  ).  A n a l . C a l c d . for C . H N O : C , 6 7 . 2 ; H , 8.80; N , 11.2. ——— o 11 n  Found:  2.  C , 67.09; H , 8 . 8 1 ; N , 11.39.  Methyl 1 -hydroxy-cyclohexanecarboxylate Cyclohexylcyanohydrin'^ (87. 5g, 0. 7 mole) and 500 m l . d r y  methanol were placed in a one l i t r e round-bottomed flask equipped with a d r y i n g tube. for 2 h o u r s .  T h e solution was cooled below 0 ° C in an i c e - s a l t bath D r y HC1 gas was bubbled into the cooled reaction m i x t u r e  until it had been saturated. . T h e solution was protected f r o m m o i s t u r e by the d r y i n g tube and left to stand overnight in the fume hood. T h e drying tube was r e p l a c e d by an efficient reflux condenser. . The solution was slowly w a r m e d and refluxed on the heating mantle for 5 hours in the fume hood.  A f t e r the reaction was completed,  the a m m o n i u m  chloride was suction f i l t e r e d and the methanol flash evaporated. d i s t i l l e d water was added and the solution was s t i r r e d .  30 m l .  The mixture was  then extracted with three 150 m l . portions of ether and the ethereal solution was washed with 100 m l . • saturated sodium carbonate solution and d r i e d over anhydrous m a g n e s i u m sulfate.  The drying agent was  suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y evaporator. residue was d i s t i l l e d under reduced p r e s s u r e . 7 1 ° C (3 m m . Hg) was collected. . Y i e l d : 9 3 - 9 8 ° C / l 3 m m . . Hg).  The  The fraction boiling at  70g (63.4%).  (Lit. b . p . :  96 i r (neat) 3540 ( O - H ) ,  2970, 2890 ( C - H ) , 1735 c m 2  - 1  (-CO-O);  n m r ( C D C 1 ) o" 3. 77 (s, 3, C H j ) , 3. 20 (s, 1, O H ) , 2. 0 - 0. 92 (m, 3  10,  C  6  H  1 Q  ).  A n a l . . C a l c d . for C  g  H  1  4  0 :  C, 60.8; H , 8.85.  3  Found:  C, 60.93; H , 8. 83.  3.  M e t h y l 1 - cyclohexenecarboxylate M e t h y l 1 -hydroxycyclohexanecarboxylate  (55. 3g, 0. 352 mole)  was placed in a 250 m l . three-necked flask equipped with a m e c h a n i c a l stirrer,  dropping funnel (125 m l . ) and reflux condenser.  T h e condenser  and the funnel both c a r r i e d c a l c i u m chloride d r y i n g tubes. was placed in a cold water bath and s t i r r i n g was begun.  The flask  Thionyl  chloride (83. 4g, 0. 74 mole) was added v e r y slowly f r o m the dropping funnel over a p e r i o d of about an hour and the mixture was s t i r r e d for 3 hours on the hot water bath (  75°C).  T h e excess thionyl chloride was  r e m o v e d by c o - d i s t i l l a t i o n with two 80 m l . portions of d r y benzene. F i n a l l y , the residue was d i s t i l l e d under reduced p r e s s u r e and the f r a c t i o n boiling at 4 6 ° C (0.6 m m . Hg) was collected.  Yield:  42g  (78.25%).  i r (neat) 2950, 2880 ( C H & C H ) , 1715 ( - C O - O - ) , 2  (C=C); n m r ( C D C 1 ) 5 3  2.42 - 1.40 (m, 8, C  &  1650 c m  - 1  7 . 1 3 - 6.77 (m, 1, C=CH), 3.73 (s, 3, 0 - C H ) , 3  Hg).  A n a l . C a l c d . for Cg H C , 68.47; H , 8.41.  3  1  2  0  2  = C , 6 9 . 0 ; H , 9.00; F o u n d :  4.  1 - cyclohexenecarboxylic acid Sodium hydroxide (12g, 0.3 mole) and 120 m l . d i s t i l l e d  water were placed in a 250 m l . t h r e e - n e c k e d flask fitted with a dropping funnel and reflux condenser.  The solution was s t i r r e d with  a magnetic s t i r r e r and 35g of methyl 1-cyclohexenecarboxylate was slowly added.  When the^ester had been added, the solution was b o i l e d  gently for 3 hours until h y d r o l y s i s was complete ( i . e . , until a test portion could be completely d i s s o l v e d i n water).  T h e m i x t u r e was  diluted with 100 m l . d i s t i l l e d water, and about 100 m l . of liquid was r e m o v e d by distillation to ensure that alcohol f o r m e d during the h y d r o l y s i s had been completely r e m o v e d .  130 m l . 10% HC1 solution  was added to the cold residue in the flask with s t i r r i n g until the solution showed acidity with litmus paper.  The upper organic a c i d  layer was separated, and the aqueous phase extracted with three 150 m l . portions of ether. . The a c i d layer was combined with the ether extracts, washed with 40 m l . d i s t i l l e d water, and d r i e d over anhydrous sulphate.  magnesium  T h e ether was flash evaporated arid the residue d i s t i l l e d under  reduced p r e s s u r e .  Yield:  22g (87.3%).  i r (neat) 3200 - 2500 ( - C O O H ) , (C=C); n m r ( C D C 1 ) $ 3  1670 (-C=0),  4.17 (m, 1, C=CH),  A n a l . C a l c d . for C C , 66.50; H , 7. 94.  b . p . : 8 0 ° C / 2 m m . Hg.  ?  H  1  Q  1635 c m "  1  2.5 - 1.3 (m, 8, C  &  C> : C , 66.60; H , 7.90. . F o u n d : 2  H ). g  98 5.  1-cyclohexenecarboxyl  chloride  A d r y 125 m l . t h r e e - n e c k e d flask was equipped with a reflux condenser,  dropping funnel (125 m l . ) and m e c h a n i c a l s t i r r e r .  The  funnel and condenser both c a r r i e d drying tubes.  Cyclohexenecarboxylic  a c i d (16. 4g, 0. 13 mole) was placed in the flask.  T h i o n y l chloride  (23. 8 g, 0.2 mole) was added over a p e r i o d of 5 minutes to the acid, which was being s t i r r e d by a m e c h a n i c a l s t i r r e r .  The flask was p l a c e d  in an o i l bath at 1 5 0 ° C for one hour with r a p i d s t i r r i n g .  T h e reflux  condenser was then r e p l a c e d by a distillation head, 60 m l . of anhydrous benzene was added, and the mixture was d i s t i l l e d until the temperature of vapours reached 9 0 ° C .  The m i x t u r e was allowed to cool,  another  60 m l . of anhydrous benzene was added, and the distillation was c o n tinued until the temperature of the vapours again reached 9 0 ° C .  The  r e s i d u a l a c i d chloride was d i s t i l l e d under reduced p r e s s u r e to avoid p y r o l y s i s of the acid c h l o r i d e .  Yield:  13. 8g (74%).  b . p . : 5 0 ° C (6 m m .  Hg).  i r (neat) 3030 ( = C - H ) ,  1790 (C=0), 1651 (C=C), 650 c m "  1  (C-Cl).  6.  N - c y c l o h e x y l - N - (fi- N , N - d i m e t h y l a m i n o e t h y l ) - 1 - c y c l o hexenecarboxamide A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  side a r m for setting a thermometer (range -100 to 5 0 ° C ) , and  a dropping funnel (125 m l . ) with a drying tube.  N, N-dimethyl-N'-cyclo-  99 hexylethyldiamine .(13 . 6g,._ 0,. 08 . mole) and  triethylamine (15.18g,  0. 15 mole) in 150 m l . d r y ether were placed in the f l a s k .  The solution  was s t i r r e d in an i c e - s a l t bath for one hour until the temperature dropped below 0 ° C .  A solution of 1 - c y c l o h e x e n e - 1 - c a r b o n y l c h l o r i d e (11.53g,  0. 08 mole) in 50 m l . d r y ether was added very slowly f r o m the dropping funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C .  A f t e r the addition was completed, the reaction  was allowed to continue at 0 ° C for 2 hours and then overnight at r o o m temperature. separated, of ether.  50 m l . of d i s t i l l e d water was added, the l a y e r s were  and the aqueous phase was extracted with two 100 m l . portions The extracts were combined with the ethereal l a y e r , washed  with saturated sodium chloride solution, and d r i e d over 100 g of anhydrous m a g n e s i u m sulfate.  M o s t of the solvent was r e m o v e d by flash e v a p o r a -  tion, and the r e s i d u a l liquid was d i s t i l l e d under reduced p r e s s u r e using a 9 inch V i g r e u x c o l u m n .  Yield:  15.9g (74%).  i r (neat) 2920, 2850, 2770 ( N C C H ) ) , 3  K.  2  b.p. :  1 6 5 ° C (5 m m . Hg).  1630 c m " (C=C, C = 0 ) . / 1  N, N - D I M E T H Y L - N ' - 3 - C Y C L O H E X E N Y L M E T H Y L - N - C Y C L O HEXY LETHY LENEDIAMINE 1  1.  3 - C y c l o h e x e n e c a r b o x y l chloride A 250 m l . three-necked flask was equipped with a reflux con-  denser and dropping funnel, both of which c a r r i e d drying tubes. hexenecarboxylic acid (63g, 0. 5 mole) was p l a c e d in the f l a s k .  3-cycloThionyl  chloride (95. 184g, 0.8 mole) was added over a p e r i o d of 5 minutes to the  100 a c i d with s t i r r i n g .  T h e flask was p l a c e d in an o i l bath and heated at  a bath temperature of 1 5 0 ° C for one hour. then r e p l a c e d by a distillation head,  The reflux condenser was  150 m l . of anhydrous benzene  was added, and the mixture was d i s t i l l e d until the temperature of the vapours reached 9 5 ° C .  The m i x t u r e was cooled and another 150 m l .  of anhydrous benzene was added.  D i s t i l l a t i o n was continued until the  temperature of the vapours again reached 9 5 ° C .  The r e s i d u a l a c i d  chloride was r e d i s t i l l e d under reduced p r e s s u r e ,  and the fraction  boiling at 9 0 ° C (20 m m . Hg) was collected.  i r (neat) 3050 (=C-H), 1800 ( 0 = C - C T ) ,  2.  Yield:  655 c m "  56. 34g (78%).  1  (C-Cl).  . N-cyclohexyl-3-cyclohexenecarboxamide A d r y 250 m l . three-necked flask was equipped with a  mechanical stirrer,  a dropping funnel (125 m l . ) with a d r y i n g tube, and  a side a r m for setting a thermometer  (range -100 - 5 0 ° C ) .  A solution  of cyclohexylamine (40g, 0.4 mole) in 300 m l . d r y ether was placed in the f l a s k .  T h e solution was cooled to between -5 and - 1 0 ° C i n an i c e -  salt bath for one h o u r .  A solution of 3-cyclohexenecarboxyl  chloride  (28.92g, 0.2 mole) i n 60 m l . d r y ether was added dropwise f r o m the funnel to the r a p i d l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C .  A f t e r the addition was completed,  was continued for one hour at the same temperature, r o o m temperature.  the s t i r r i n g  and overnight at  50 m l . of d i s t i l l e d water was added and the mixture  was s t i r r e d for 20 minutes.  T h e white solid was suction f i l t e r e d and  101 the l a y e r s were separated.  T h e aqueous phase was extracted with two  100 m l . portions of ether.  The extracts were combined with the ether  l a y e r , and the solvent was r e m o v e d with a r o t a r y evaporator.  The  product was d r i e d under reduced p r e s s u r e in the e l e c t r i c a l oven ( 4 0 ° C ) and r e c r y s t a l l i z e d f r o m acetone in an ice bath. m.p.:  Yield:  157-158°C.  i r ( K B r ) 3280 ( Q = C - N - H ) , 3020 (=C-H), nmr ( C D C 1 )  5" 5. 73 (sharp m , 2, C H = C H - ) ,  3  N - H ) , 4.1 -  3.53 (m, 1, - C H - C = 0 ) ,  A n a l . C a l c d . for C Found:  3.  34. 84g.  1  2  H  2  1  1620 c m " (C=0 & C=C);  5. 63 -  1  5. 13 (broad s, 1,  5.6 - 0.57 (m, 17, C  f e  H  n  &C  N O : C , 74. 78; H , 1 0 . 1 3 ; N ,  &  H ).  6.74.  C , 74.29, H , 10.00; N , 6.92.  N - c y c l o h e x y l - N - 3-cyclohexenylmethylamine A d r y 250 m l . t h r e e - n e c k e d flask was equipped with a  m e c h a n i c a l s t i r r e r and Soxhlet apparatus with reflux condenser c a r r y i n g a drying tube.  200 m l . d r y ether was placed in the flask and l i t h i u m  aluminum hydride (11. 4g, 0.3 mole) was added to i t .  T h e solution was  refluxed gently with s t i r r i n g for 4 h o u r s . . N - c y c l o h e x y l - 3 - c y c l o h e x e n e carboxamide (31. l g , 0. 15 mole) was packed into the Soxhlet extractor with a round-bottomed columnar filter paper to prevent blockage of the siphon a r m . A glass r o d was placed in the powder i n o r d e r to maintain an efficient flow of solvent. . Refluxing was continued so as to maintain slow and steady dissolution of the amide in the Soxhlet.  A f t e r the  &  102 addition of amide was completed, with s t i r r i n g .  the mixture was refluxed for 48 hours  T h e reaction mixture was cooled in an i c e - w a t e r bath and  30 m l . of d i s t i l l e d water were added dropwise with s t i r r i n g to decompose excess h y d r i d e .  When the mixture had turned white,  sufficient 40% N a O H  was added with r a p i d s t i r r i n g to give clear separation of the ethereal layer.  T h e ether insoluble layer was separated by centrifugation.  The  ethereal layer was d r i e d over anhydrous m a g n e s i u m sulfate overnight. The solvent was r e m o v e d using a r o t a r y evaporator.  T h e crude product  was d i s t i l l e d under reduced p r e s s u r e and the fraction boiling at 7 5 - 7 8 ° C (0.2 - 0.3 m m . Hg) was collected).  Yield:  26.68g (92%).  i r (neat) 3300 (weak, N H ) , 2940,2860 ( C - H ) , 3040 ( = C H - ) , . 2  1655 c m  - 1  (C=C); n m r - ( G ' D C 1 )  & 5. 78 - 5. 60 (sharp m , 2, - H C = C H - ) ,  3  2.62 - 2.43 (m, 2, - C H ^ N ) ,  2.43 - 0.67 (m, 19, C  &  H  n  , C  &  H  ?  & NH).  M o n o - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as that d e s c r i b e d in E x p . A - 3 .  A n a l . - C a l c d . for C  —~~~— Cl,  1 -5  H  N C I : C , 68; H , 10.45; N , 6 . 1 ;  LAQ.  15. 49. • F o u n d : C , 67. 83; H , 10.32; N , 6.23; C l , 15.47.  4.  -Chloro-N-3-cyclohexenylmethyl-N-cyclohexylacetamide A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel (125 m l . ) with a drying tube, and side a r m for  setting a thermometer  (range - 1 0 0 ° - 5 0 ° C ) .  N-cyclohexyl-N-3-cyclo-  103 hexenylmethylamine (13.51g, 0.07 mole) and d r y triethylamine (8. O l g , 0. 08 mole) in 180 m l . d r y ether were p l a c e d in the f l a s k .  The  solution was cooled to between -5 and - 1 0 ° C i n an i c e - s a l t bath for one hour, and then a solution of c h l o r o a c e t y l c h l o r i d e (7. O l g , 0.07 mole) i n 40 m l . d r y ether was added dropwise to the vigorously s t i r r e d solution so as to keep the temperature of the reaction below 0 ° C . addition was completed, temperature.  A f t e r the  the mixture was s t i r r e d overnight at r o o m  30 m l . 5% H C l was added to the mixture and it was  s t i r r e d for 15 m i n u t e s .  The l a y e r s were separated and the aqueous  phase was extracted with two 100 m l . portions of ether.  T h e extracts  were combined with the ethereal layer and the solvent was r e m o v e d using a r o t a r y evaporator.  T h e product was d i s t i l l e d under reduced p r e s s u r e  using a 9 inch V i g r e u x column w a r m e d with a heating tape. boiling at 1 5 0 ° C (0. 2 m m . Hg) was c o l l e c t e d .  Yield:  T h e fraction  13.25g(80%).  i r ( K B r ) 3030 (=C-H),  1650 (C=C & C=0), 700 c m " ( C - C l ) ; O n m r ( C D C 1 , ) & 5. 70 (sharp m , 2, - C H = C H - ) , 4 . 15 (s, 2, C - C H - C l ) , ' 2 3.30 - 3.17 (m, 2, - C H ^ N - ) , 2.40 - 0.67 (m, 18, C H j & C H ) . 1  &  5.  l  f e  ?  p(--IDimethylamifio-N- 3- c y c l o h e x e n y l m e t h y l - N - c y c l o h e x y l acetamide A 250 m l . three-necked flask was e-quipped with a m e c h a n i c a l  s t i r r e r and a dropping funnel (125 m l . ) with a d r y i n g tube.  150 m l . d r y  ether was placed in the flask and cooled to between -5 and - 1 0 ° C in an i c e - s a l t bath for one hour.  Dimethylamine (6cc, 0.09 mole) was trapped  104 in a d r y graduated cylinder f r o m a dimethylamine gas tank using an acetone-dry i c e bath, and poured a l l at once into the reaction f l a s k . solution of o( (llg,  A  -chloro-N-3-cyclohexenylmethyl-N-cyclohexylacetamide  0.04 mole) in 60 m l . d r y ether was added dropwise to the reaction  mixture so as to keep the temperature of the solution below 0 ° C .  After  the addition was completed, the reaction was continued at a temperature below 0 ° C for 10 hours and then overnight at a temperature below 1 0 ° C . The dimethylamine salt was suction f i l t e r e d and the solvent r e m o v e d using a r o t a r y evaporator.  The crude product was d i s t i l l e d under  reduced p r e s s u r e through a 9 inch V i g r e u x c o l u m n .  T h e fraction boiling  at 1 6 0 ° C (0. 65-0. 75 m m . Hg) was collected.  10.9g(96%).  Yield:  i r (neat) 3040 (=C-H), 1642 c m " (C=C & C=0); n m r ( C D C l g ) 1  & 5.67 (m, 2, - C H = C H - ) , 3. 5 - VS'OJ^.j l } ( C H - N h s, 6., N C C H ^ , r  CJ,  M),  2.18 - 0 . 7 2 ( m , 1 8 , ( C  6  H  u  &C  f e  7  H )).. ,  '  ' "'  V  M e t h y l iodide derivative 2. 78g O.OJ(mole) of aminoacetamide was d i s s o l v e d i n 1 5 m l . of d r y ethanol and  1 Tft/,  of methyl iodide was added.  reacted at r o o m temperature.  T h e mixture  T h e salt was r e c r y s t a l l i z e d f r o m d r y  ethanol and ether. A n a l . C a l c d . for C I, 3 0 . 2 .  H  N I:  C , 51.45; H , 7.85; N, 6.66;  F o u n d : . C , 51.31; H , 7.93; N, 6. 74; I, 30.06.  105 6.  N , N - D i m e thy 1 - N - 3- cyclohexenylme t h y l - N ' - c y c l o h e x y l e t h y l enediamine 1  A d r y 250 m l . three-necked flask was equipped with a m e c h a n i c a l s t i r r e r and reflux condenser (125 m l . ) with a drying tube. 150 m l . d r y ether was p l a c e d i n the flask and l i t h i u m a l u m i n u m hydride (2.28g, 0.06 mole) was added to i t . . The solution was gently refluxed for 3 h o u r s .  A solution of  <^-dimethylamino-N-3-cyclohexenylmethyl-  N - c y c i o h e x y l a c t a m i d e (8. 34g, 0.3 mole) i n 30 m l . d r y ether was added dropwise f r o m the dropping funnel to the vigorously s t i r r e d solution so as to maintain gentle r e f l u x i n g .  A f t e r the addition was completed, the  reaction was continued for 30 h o u r s .  T h e n the flask was cooled to  below 0 ° C by an i c e - s a l t bath and 20 m l . of d i s t i l l e d water was added dropwise to decompose excess h y d r i d e . m i x t u r e turned white in c o l o u r .  S t i r r i n g was continued until the  Sufficient 40% sodium hydroxide was  added, with s t i r r i n g , to allow clear separation of the ethereal  layer.  The e t h e r - i n s o l u b l e m a t e r i a l was separated by centrifugation.  The  ethereal solution was d r i e d over anhydrous m a g n e s i u m sulfate overnight. The drying agent was suction f i l t e r e d and the ether was r e m o v e d using a r o t a r y evaporator. sure,  T h e crude product was d i s t i l l e d under reduced p r e s -  and the fraction boiling at 1 1 6 ° C (0. 6 m m . Hg) was collected.  Yield:  7. 6g (96%).  i r (neat) 3040 (=C-H), (m, C  1  3  2, - C H = C H - ) , 2.20 (s, 6, N - ( C H ) ) , 2. 8 - 0.77 (m, 3 0 C  6 11 H  1650 c m " (C=C); n m r ( C D C 1 ) '£> 5.66 3  -CH -N-CH -CH -N(CH ) ). 2  2  2  3  2  2  )  6  H , ?  106 Di-perchlorate  derivative  The salt was p r e p a r e d by the same procedure as that desc r i b e d i n E x p . B - 2 , except that two equivalents of p e r c h l o r i c a c i d was used,  o m . p . : 142-143 C . Anal.  N,  L.  C a l c d . for C  6.02; C l , 15.28.  1  ?  C l  2  O : C , 4 3 . 8 5 ; H , 7.31; g  F o u n d : C , 43. 75; H . 7.48; N , 5.87; C l , 15.09.  N , N - D I M E T H Y L - N ' - 3 - CY C L O H E X E N Y L M E T H Y L - N ' PHENY LETHY LENEDIAMINE 1.  o< - C h l o r o - N - p h e n y l a c e t a m i d e 223. 48g (2. 4 m l . ) of aniline and 1 300 m l . d r y ether were  placed i n a 2 l i t r e three-necked flask equipped with a dropping funnel, mechanical s t i r r e r ,  and thermometer (range - 1 0 ° C - 5 0 ° C ) .  The  solution was placed i n an i c e - s a l t bath for one hour to cool it to below 0 ° C . . C h l o r o a c e t y l chloride (1 35. 6g, 1. 2 m l . ) was added dropwise f r o m the funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the t e m p e r a ture of the reaction mixture below - 0 ° C .  After the addition was c o m -  pleted, the s t i r r i n g was continued for 3 hours below 0 ° C . another 5 hours at r o o m t e m p e r a t u r e .  and for  200 m l . 5% HC1 solution was  then added to the flask and the mixture was s t i r r e d for 10 minutes.  The  m i x t u r e was suction f i l t e r e d through a Buchner funnel, and a white product was obtained.  T h e anilide was washed i n the funnel using d i s -  tilled water until no HC1 could be detected with litmus paper. layer was d r i e d over m a g n e s i u m sulfate,  T h e ether  and the solvent was flash  107 evaporated to r e c o v e r the anilide it had d i s s o l v e d . m.p.:  Y i e l d : 191g (95%).  135-136°C.  i r ( K B r ) 3280 ( - C O N H ) ,  1670 (C=0), 625 c m " ( C - C l ) ; n m r 1  ( C D C 1 ) , & 8.50 - 7.80 (broad s, 1, N - H ) , 7.68.- 6.97 (m, 5, 3  phenyl-H)", 4. 17 (s, 2,  CH -C1). 2  A n a l . C a l c d . for C H„ N C I O : C , 56.6; H , 4. 7; N , 8 . 2 ; o o 0  Cl,  20.9.  2.  Found:  C , 56.66; H , 4. 78; N , 8.38; C l , 21.12.  oi- D i m e thy l a m i n o - N - p h e n y lac etamide A 2 l i t r e t h r e e - n e c k e d flask was equipped with a 500 m l .  dropping funnel with drying tube, m e c h a n i c a l s t i r r e r ,  and side a r m for  setting a thermometer (range - 1 0 0 ° C - 5 0 ° C ) .  250 m l . d r y methanol  and 750 m l . d r y ether were added to the f l a s k .  The solution was s t i r r e d  in an i c e - s a l t bath for one hour until it reached -5 to - 1 0 ° C .  Dimethyl-  amine (132. 4cc, 2 mole) was trapped i n a graduated c y l i n d e r f r o m a dimethylamine gas tank using an acetone-dry ice bath ( - 8 0 ° C ) . poured into the t h r e e - n e c k e d reaction flask a l l at once.  It was  A solution of  - c h l o r o - N - p h e n y l a c e t a m i d e (169. 5g, 1 mole) in 100 m l . d r y ether and 200 m l . d r y methanol was added v e r y slowly f r o m the dropping funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C .  When the addition had been completed, the m i x t u r e  was s t i r r e d continuously at 0 ° C for 10 hours, and overnight at r o o m temperature.  The white salt was suction f i l t e r e d and the solvent was  108 completely r e m o v e d using a flash evaporator.  30 m l . d i s t i l l e d water  was added to the product and it was shaken vigorously in a separatory funnel.  T h e mixture was extracted using two 200 m l . portions of ether,  and the ethereal solution was d r i e d overnight with anhydrous sulfate.  magnesium  The solution was suction f i l t e r e d and the solvent was r e m o v e d  by flash evaporation.  Yield:  152g (85%).  i r (neat) 3300 (CONH), (C=0); n m r ( C D C 1 ) 3  0=C-CH ), 2  b . p . : 1 3 5 ° C (2mm. Hg).  2940, 2825, 2780 ( N ( C H ) ) , 3  2  1680 c m "  <f 7 . 7 3 - 6.91 (m, 5, p h e n y l - H ) , 3 . 0 0 ( s ,  1  2,  2.33 (s, 6, N ( C H ) ) . 3  M o n o - h y d r o chloride  2  derivative  The salt was p r e p a r e d by the same p r o c e d u r e as that d e s c r i b e d in E x p . A - 3 . m . p . : 1 6 0 . 5 - 1 6 1 ° C .  • Anal.. Calcd. f o r - C . Cl,  16.5.  3.  Found:  n  H . _ N _ O C l : . C , 5 5 . 9 ; H , 6 . 9 ; N , 13;  C , 56. 05; H , 7.08; N , 12.87;. C l , 16.69.  . N , N - d i m e thy l - N ' - p h e n y l e t h y l e n e d i a m i n e A 2 l i t r e t h r e e - n e c k e d flask was equipped with a dropping funnel  (250 m l . ) , reflux condenser with drying tube,  and m e c h a n i c a l  stirrer.  1 l i t r e d r y ether and l i t h i u m aluminum hydride (41. 73g, 1. 1 m l . ) were placed in the flask. 3 hours.  The solution was gently refluxed with s t i r r i n g for  A solution of  o(-dimethylamino-N-phenylacetamide  (125g,  0. 7 mole) i n 150 m l . d r y ether was added to the flask f r o m the dropping funnel so as to maintain a gentle r e f l u x .  A f t e r the addition was c o m -  109 pleted, the mixture was refluxed with s t i r r i n g for 48 h o u r s . the reduction was over,  When  the flask was cooled in an i c e - s a l t bath for  30 minutes and excess lithium aluminum hydride was decomposed with d i s t i l l e d water.  Sufficient 40% N a O H solution was added to give good  separation f r o m ether insoluble substances.  T h e ethereal layer was  d r i e d over anhydrous m a g n e s i u m sulfate and the solvent r e m o v e d using a flash evaporator. on the o i l bath.  T h e product was d i s t i l l e d under reduced p r e s s u r e  Yield:  109g(95%).  b . p . : 8 5 ° C (1 m m . Hg).  i r (neat) 3380 ( N - H ) , 2970 - 2775  ( N ( C H  3  )  ),  1600 c m "  1  (aromatic); n m r ( C D C 1 ) & 7.33 - 6. 5 (m, 5, p h e n y l - H ) , 4 . 4 7 3  3.92  (broad s, 1, N - H ) , 3.57 - 2.80 (m, 2, N H - C H ) , 2.80 - 2.30 (m, 2, 2  CH -N(CH ) h 2  3  2  2. 25 (s, 6, N ( C H ) ) . 3  2  D i - h y d r o c h l o r i d e derivative The salt was p r e p a r e d by the same procedure as that d e s c r i b e d in E x p . A - 3 . m . p . : 133-133. 5 ° C .  • A n a l . C a l c d . for C . _ H , _ N _ C l : C , 5 0 . 6 ; H , 7. 5; N , 11.8; —"——  Cl,  29.9.  4.  Found:  1U  lo  Z  C , 50. 74; H , 7 . 4 3 ; N ,  L  12.01; C l , 2 9 . 7 1 .  . N ' - p h e n y l - N ' -( fi - N , N - d i m e t h y l a m i n o ethyl) - 3 - c y c l o he xe n e c a'r bo xarrii de A 500 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  stirrer,  a side a r m for setting a thermometer  ( range -50 -  100°C)  and a dropping funnel (125 m l . ) . . N , N-dimethyl-M'^-phenylethylene-  110 diamine ( 19. 71 g, 0. 1Z mole) , r e d i s t i l l e d triethylamine (15. 15g, 0.15  mole) and d r y ether ( 300 m l . ) were placed in the f l a s k .  The  solution was cooled to between -5 and - 1 0 ° C in an i c e - s a l t bath for one hour with s t i r r i n g . ( 17. 34g,  0. 1Z mole)  A solution of 3-cyclohexenecarboxyl  chloride  in 50 m l . d r y ether was placed in the dropping  funnel, and added v e r y slowly to the v i g o r o u s l y s t i r r e d solution in the flask so that the temperature of the solution always r e m a i n e d below 0 ° C . A f t e r the addition was completed, the reaction was continued at r o o m temperature overnight. . 30 m l . of d i s t i l l e d water was added to the reaction m i x t u r e ,  which was r a p i d l y s t i r r e d for 15 m i n u t e s .  l a y e r s were separated.  The  The aqueous phase was extracted using two  100 m l . portions of ether and the extracts were combined with the ether phase.  The ethereal solution was d r i e d over anhydrous m a g -  n e s i u m sulfate.  The drying agent was suction f i l t e r e d , and the solvent  was r e m o v e d by a r o t a r y evaporator.  The residue was d i s t i l l e d under  reduced p r e s s u r e through a 9 inch V i g r e u x column w a r m e d by a heating tape.  The fraction boiling at 1 Z 0 ° C ( 0 . 3  Yield:  27.4Zg (8Z%) .  i r (neat) 3050 ( = C - H ) , (C=C, m,  m m . Hg) was c o l l e c t e d .  C=0) ; n m r ( C D C 1 ) £ 3  Z930 - Z750 (N-( C H ) ) , 1640  7.57-  3  7.13  2  (m, 5, p h e n y l - H ) ,  cm"  1  5.63  Z, (HC=.CH), 4. 03 - 3. 73 (m, Z, 0 = C - N - C H ) , Z . 6 7 - Z . 3 3 (m, Z, 2  C - C H - N - ( C H ) ), 2  3  2  Z.30 (s,  6, N - ( C H ) ) , 2. Z0 - 1.5 (m, 7, 3  2  C  &  H ). ?  Ill 5.  N, N-dimethyl-N'-3-cyclohexenylmethyl-N'-ph e thy 1 ene diamine r  A 250 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l stirrer,  reflux condenser,  and dropping funnel.  and funnel c a r r i e d d r y i n g tubes.  Both the condenser  L i t h i u m a l u m i n u m hydride (5.7g,  0. 15 mole) and 180 m l . d r y ether were p l a c e d i n the f l a s k .  The  solution was gently refluxed for 3 hours on the heating mantle with stirring.  A solution of N - p h e n y l - N - ( ft-N, N - d i m e t h y l a m i n o e t h y l ) - 3 -  cyclohexenecarboxamide  (26. 2g, 0. 095 mole) i n 40 m l . d r y ether was  placed in the dropping funnel, and added dropwise to the s t i r r e d solution at a rate that maintained gentle r e f l u x . - A f t e r 30 minutes the addition was completed, 30 h o u r s .  and the m i x t u r e was s t i r r e d and refluxed for  The heating mantle was then r e p l a c e d by an i c e - s a l t bath,  and the solution was cooled below 0 ° C .  30 m l . of d i s t i l l e d water was  added dropwise to the v i g o r o u s l y s t i r r e d mixture in o r d e r to d e c o m pose excess h y d r i d e .  A sufficient amount of 40% N a O H solution was  added, with s t i r r i n g , to the mixture to allow for good separation of the ethereal layer f r o m the e t h e r - i n s o l u b l e r e s i d u e .  The ethereal layer  was decanted into an E r l e n m e y e r flask, and d r i e d over anhydrous m a g n e s i u m sulfate.  The drying agent was suction f i l t e r e d , and the ether  r e m o v e d by a r o t a r y evaporator.  The residue was d i s t i l l e d under  reduced p r e s s u r e through a 9 inch V i g r e u x column w a r m e d by a heating tape. Yield:  The fraction boiling at 1 6 2 - 1 6 4 ° C (2 m m . Hg) was c o l l e c t e d . 32g (94%).  112 i r (neat) 3040 (phenyl-H) 2980, 2940, 2830, 2780 ( N ( C H ) ) , 3  Z  1650 (C=C), 1600 (aromatic).  M.  N-CYCLOHEXYL-2, 5-CYCLOHEXADIENECARBOXAMIDE 1.  2, 5-cycl6hexadieriecarboxyTic  a c i d (1, 4-dihydrobenzbic a c i d  D r y benzoic a c i d (20g, 0. 164 mole) was added to 200 m l . anhydrous ethanol i n a 2 l i t r e t h r e e - n e c k e d flask equipped with a m e c h a n i c a l s t i r r e r and loose cotton plugs in the side n e c k s .  After  the benzoic a c i d had d i s s o l v e d , 800 m l . of liquid ammonia was passed d i r e c t l y f r o m an a m m o n i a tank through d r y heavy rubber tubing into the flask, which was cooled by an a c e t o n e - d r y ice bath. (0.54 mole) of sodium was added i n s m a l l p i e c e s .  T h e n 12. 4g  When about o n e - t h i r d  of the sodium had been added, the white sodium salt of the a c i d p r e c i pitated, and the mixture foamed f u r i o u s l y . been consumed,  After a l l the sodium had  as evidenced by the disappearance of the b l u e - b l a c k  colour, a m m o n i u m chloride (29. 2g, 0.54 mole) was added cautiously. The mixture was s t i r r e d for an additional hour and then allowed to stand until the a m m o n i a had evaporated.  T h e residue was d i s s o l v e d in 300 m l .  water and the solution poured into 300 g of ice and a c i d i f i e d to a p H of about 4 by addition of 150 m l . 10% h y d r o c h l o r i c a c i d .  The resulting  mixture was extracted with four 150 m l . portions of ether, and the combined extracts were washed with 50 m l . of a saturated aqueous solution of sodium c h l o r i d e . anhydrous m a g n e s i u m sulfate.  T h e solution was d r i e d over lOg of T h e solution was separated f r o m the  113 drying agent and concentrated at r o o m temperature under reduced p r e s s u r e by a f l a s h evaporator.  T h e r e s i d u a l o i l was d i s t i l l e d under  reduced p r e s s u r e through a 9 inch V i g r e u x c o l u m n . a c i d was obtained as a c o l o u r l e s s o i l . nitrogen in a closed f l a s k . Hg).  Yield:  1, 4 dihydrobenzoic  T h e product was stored under  15. 6g (78%).  b . p . : 9 0 ° C (0.2 m m .  ( L i t . b . p . : 8 0 - 9 8 ° C / 0 . 0 1 m m . Hg).  i r (neat) 2500 - 3500 ( - C O O H ) , nmr (CDC1 ) 3  6  11. 53 ( - C O O H ) ,  C H ) , 4.00 - 3.60 (t, J= 1 0 H , 2  2.  1  6. 20 - 5.62 (m, 4, C H = C H , CH=  CH-C=0),  2, 5-cyclohexadienecarboxyl  1690 (C=0); 1630 c m " (C=C);  3.00 - 2.55 (m, 2, C  4  H ).. 2  chloride  1, 4 - d i h y d r o b e n z o i c a c i d (14. 9g 10.1 mole) was placed i n a 250 m l . three-necked f l a s k . stirrer,  The flask was equipped with a m e c h a n i c a l  r e f l u x condenser and dropping funnel (125 m l . ) .  and funnel both c a r r i e d d r y i n g tubes.  The condenser  T h i o n y l chloride (28. 6g, 0. 24  mole) was added to the a c i d over a p e r i o d of five minutes, while the m i x t u r e was being r a p i d l y s t i r r e d .  T h e flask was p l a c e d in an o i l bath,  and heated to a temperature of 1 5 0 ° C for one hour.  T h e condenser was  r e p l a c e d by a distillation head, 80 m l . of anhydrous benzene was added, and the mixture was d i s t i l l e d until the temperature of the vapours reached 9 0 ° C .  T h e mixture was cooled and a further 80 m l . of  anhydrous benzene added. . The distillation was continued until the temperature of the vapours again reached 9 0 ° C .  T h e cooled r e s i d u a l  a c i d chloride was d i s t i l l e d under reduced p r e s s u r e to y i e l d the 2 , 4 -  114 cyclohexadienecarboxyl c h l o r i d e .  Yield:  13.5g (79%).  b . p . :9 5 ° -  1 0 0 ° C (0. 6 m m . Hg).  i r (neat) 3040, 2875, 2820 ( C - H ) ,  . 3.  . N-cyclohexyl-2,  1770 c m " (C=C, C=0). 1  5-cyclohexadienecarboxamide  A solution of cyclohexylamine (19.84g, 0.2 mole) in 180 m l . d r y ether was placed in a 250 m l . t h r e e - n e c k e d f l a s k .  T h e flask was  equipped with a m e c h a n i c a l s t i r r e r and a dropping funnel (125 m l . ) which c a r r i e d a drying tube.  T h e solution was cooled to between -5 and  - 1 0 ° C i n an i c e - s a l t bath for one hour with s t i r r i n g .  A solution of 2, 5-  cyclohexadienecarboxyl chloride (14. 2g, 0. 1 mole) i n 40 m l . d r y ether was p l a c e d in the dropping funnel, and added dropwise to the r a p i d l y s t i r r e d solution at such a rate so as to keep the temperature of the solution below 0 ° C . • A f t e r the addition was completed, the m i x t u r e was s t i r r e d at r o o m temperature for 5 h o u r s . added to the m i x t u r e ,  50 m l . of d i s t i l l e d water was  and it was s t i r r e d for a further 30 m i n u t e s .  white product was suction f i l t e r e d , and the l a y e r s separated. ethereal layer was f l a s h evaporated,  The  The  and the solid product combined  with the suction f i l t e r e d one. T h e product was d r i e d i n the a i r and then under reduced p r e s s u r e at r o o m temperature.  i r (neat) 3275 ( 0 = C - N - H ) ,  Yield:  16. 3g (79.5%).  1630 (C=0, C=C) ; n m r (CDC1 ^  & 6.2.  115 N.  N - 2 , 6 - D I M E T H Y L P H E N Y L - C Y C L O H E X Y L A M IN E 1.  N - 2 , 6-dime thy [phenyl- cyclohexanecarboxamide A 500 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel with a drying tube and thermometer  - 5 0 ° to 1 0 0 ° C ) .  2, 6-dimethylaniline (48. 27g,  ether was placed in the flask.  0. 4 mole in 300 m l . ) dry  The solution was cooled to between  and - 1 0 ° C in an i c e - s a l t bath for one hour with s t i r r i n g . cyclohexanecarboxyl  (range  chloride (29. 123g,  -5  A solution of  0.2 mole) in 50 m l . dry ether  was added dropwise f r o m the dropping funnel to the v i g o r o u s l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C . mixture was then s t i r r e d at r o o m temperature overnight.  The  50 m l . of  d i s t i l l e d was added to the flask and the mixture was s t i r r e d for 20 minutes.  The white product was suction f i l t e r e d using a Buchner funnel  and the l a y e r s were separated.  The ethereal phase was flash e v a p o r a -  ted to remove the solvent and the solids were combined with the suction f i l t e r e d product.  The product was m i x e d with 200 m l . 5% HC1 and  s t i r r e d for one hour on the magnetic s t i r r e r .  The solids were again  suction f i l t e r e d and washed with 500 m l . d i s t i l l e d water until no trace of HC1 could be detected with litmus paper. The solid was p r e d r i e d in the air and then under reduced p r e s s u r e in the e l e c t r i c a l oven ( 4 0 ° C , 20 m m . Hg).  The product was c r y s t a l l i z e d f r o m a mixture of ether  and a s m a l l amount of ethylacetate. 202°C.  Yield:  45. 2g (98%).  m.p. :  201-  116 i r ( K B r ) 3250 ( C O - N H ) , nmr ( C D C 1 )  7. 30 - 6.92  dimethyl), 2.07  - 0.68  3  (m,  3040 (phenyl-H), 1645 c m "  (m, 3, p h e n y l - H ) , 2.10 12,  C  &  Hj  2.  C , 77. 82; H , 9.05;  N,  6,  (C=0);  2,  6-  & NH).  - A n a l . - C a l c d . for C , _ H , . N O : . C , 77.6; ID C. 1 Found:  (s,  1  H , 9.05;  N,  6.04.  6.23.  N-2., 6 - d i m e t h y l p h e n y l - cyclohexylmethylamine A d r y 250 m l . three-necked flask was equipped with a  m e c h a n i c a l s t i r r e r and Soxhlet apparatus fitted with a r e f l u x condenser c a r r y i n g a d r y i n g tube.  200 m l . d r y tetrahydrofuran was placed in the  flask and lithium aluminum hydride (7.6g, 0. 2 mole) added to it. solution was refluxed with s t i r r i n g for 3 h o u r s . 2, 6-dimethylanilide (23g,  The  T h e n d r y cyclohexane-  0. 1 mole) was packed in the extractor, in  which a columnar filter had been placed to prevent blockage of the siphon a r m by the a m i d e .  A glass r o d was i n s e r t e d in the powder to  allow efficient flow of the solvent.  The rate of reflux was controlled  so that the amide would keep dissolving slowly.  The mixture was then  refluxed for 6 days until no unreduced amide could be detected. flask was cooled below 0 ° C in an i c e - s a l t bath.  The  50 m l . of d i s t i l l e d  w a t e r was added slowly to the mixture to decompose excess h y d r i d e . The s t i r r i n g was continued until the mixture became white in c o l o u r . Sufficient 40% sodium hydroxide solution was added to separate the ethereal layer f r o m the e t h e r - i n s o l u b l e r e s i d u e .  The residue was  separated by centrifugation and the ethereal layer was d r i e d over  117 anhydrous m a g n e s i u m sulfate overnight. using a r o t a r y evaporator reduced p r e s s u r e .  Yield:  T h e solvent was r e m o v e d  and the crude product was d i s t i l l e d under 20.6g(95%).  b . p . : 1 2 2 ° C / 0 . 5 m m . Hg.  ir (neat) 3380 (NH), 3050 ( a r y l - H ) , nmr  (CDC1 ) i 3  2.75(m, C  6  G.  H  l l  )  1600 c m "  1  (aromatic);  7.11 - 6.57 (m, 3, p h e n y l - H ) , 2.91 (s. 1, N H ) ,  2, C H - C H ) , 2  2.23 (s, 6, dimethyl), 2.00 - 0.80 (m, 11,  '  N, N-DIMETHY L - N ' - C Y C L O H E X Y L M E T H Y L E T H Y L E N E DIAMINE 1.  o£ - d i m e t h y l a m i h o e t h y l - N - c y c l o h e x a n e c a r b o x a m i d e A 250 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel (125 m l . ) with a d r y i n g tube, and side a r m  for setting a thermometer  (range -100 to 5 0 ° C ) .  N , N-dimethylethyl-  enediamine (26.45g, 0.3 mole) in 170 m l . d r y ether was placed in the flask.  T h e solution was cooled to between -5 and - 1 0 ° C in an i c e - s a l t  bath for one h o u r .  A solution of cyclohexanecarboxyl  chloride (21.85g,  0. 15 mole) i n 30 m l . d r y ether was added v e r y slowly f r o m the funnel to the r a p i d l y s t i r r e d solution so as to keep the temperature of the solution below 0 ° C .  A f t e r the addition was completed,  the s t i r r i n g was  continued at 0 ° C for one hour and at r o o m temperature overnight. 30 m l . d i s t i l l e d water was added and the m i x t u r e was s t i r r e d for 15 m i n u t e s . . The s o l i d was suction f i l t e r e d and the l a y e r s were  separated.  The aqueous phase was extracted with two 100 m l . portions of ether.  118 The extracts were combined with the ether layer and d r i e d with 50g of anhydrous m a g n e s i u m sulfate.  T h e drying agent was suction  f i l t e r e d and most of the solvent r e m o v e d using a r o t a r y evaporator. The crude product was r e c r y s t a l l i z e d f r o m a mixture of petroleum ether ( 3 0 ° - 6 0 ° C ) and ethylacetate.  i r (neat) 3280 (CONH), (C=0); n m r ( C D C 1 ) r> 3  28. l g (95%).  m . p . : 86°C.  2920, 2850, 2780 ( N C H ^ ) ,  1635 c m "  1  3. 47 - 3. 10 (m, 2, N H - C H ) , 2. 50 - 2. 22 (s, 2  6, N ( C H ) ) , 2.00 - 0.40 (m, 12, C 3  Yield:  2  &  H  & NH).  - A n a l . C a l c d . for C H N O : C , 66.65; H , 11. 1; N , 14. 15. " 11 ZZ F o u n d : C , 66.79; H , 11.05; N , 14.06.  2.  . N, N-dimethyl-N'-cyclohexylmethylethylenediamine A 250 m l . d r y three-necked flask was equipped with a  mechanical s t i r r e r ,  dropping funnel (120 m l . ) and reflux  The funnel and condenser both c a r r i e d drying tubes.  condenser.  180 m l . d r y  ether was placed i n the flask and l i t h i u m aluminum hydride (9.88g, 0. 26 mole) was added. with s t i r r i n g .  The solution was gently refluxed for 3 hours  A solution of d. - d i m e t h y l a m i n o e t h y l - N - c y c l o h e x a n e -  carboxamide (25. 65g, 0.13 mole) in 30 m l . d r y ether was added dropwise to the hydride solution f r o m the dropping funnel so as to maintain a gentle r e f l u x .  A f t e r the addition was completed,  mixture was refluxed for 36 h o u r s .  the  When the reduction was over, the  heating mantle was r e p l a c e d by an i c e - w a t e r bath and 20 m l . d i s t i l l e d  119 water was added slowly to the v i g o r o u s l y s t i r r e d m i x t u r e in the flask to decompose excess h y d r i d e . . S t i r r i n g was continued until the mixture became white.  Sufficient 40% N a O H was added to allow clear  separation of the ethereal layer f r o m the e t h e r - i n s o l u b l e r e s i d u e . The residue was separated by centrifugation.  T h e ethereal layer was  d r i e d over anhydrous sodium sulfate overnight. r e m o v e d using a r o t a r y evaporator,  T h e solvent was  and the product was d i s t i l l e d  under reduced p r e s s u r e through a 9 inch V i g r e u x c o l u m n . . Y i e l d : 22g(96.5%).  b . p . : 7 3 ° C (2. 0 m m . H g ) ; 6 6 ° C (0. 5 m m . Hg).  ir (neat) 3340 (NH), 2920, 2760, 2680 ( N ( C H ) ) ; n m r ( C D C l V 3  I  2.7-2.23  (m, 6, C H ^ N - C H - C H 2  2.03 - 0.6 (m, 12, C  &  H  u  2  3  )', 2.10 (s, 6, N ( C H ) ),  & NH).  D i - p e r c h l o r a t e derivatives The salt was p r e p a r e d by the same procedure as that desc r i b e d in E x p . B - 2 , except that two equivalents of p e r c h l o r i c a c i d was used.  m.p. :  183-184°C.  A n a l . C a l c d . for C N,  7.28; C l , 18.47.  11  Found:  H N O C l : C , 34.09; H , 6. 76; 26 2 8 2 C , 34. 13;. H , 6.81; N , 7.13; C l , 18.63.  P. . SINGLE REACTIONS 1.  3 - c h l o r o - 4 - c y c l o h e x e n e - l , 2 - d i c o r b o x y l i c a c i d anhydride 1-chlorobutadiene (17g, 0.2 m l . ) , m a l e i c anhydride (19g,  0. 2 ml.-), iodine (340 mg) and a s m a l l amount of hydroquinone with  120 ZOO m l . benzene were p l a c e d in a Z50 m l . flat-bottomed flask equipped with a reflux condenser.  T h e reaction mixture was refluxed  while being s t i r r e d on an o i l bath for 48 h o u r s . r e m o v e d with sodium hypochlrite.  T h e precipitated c r y s t a l was  separated to y i e l d 26g of the product. a mixture of benzene and acetone,  i r ( K B r ) 3040 (=C-H), cm  (C=C); n m r  - 1  (C$C1 )  4.77 (m, 1, C H - C 1 ) , (m,  2,  T h e n the iodine was  It was then r e c r y s t a l l i z e d f r o m  m.p. :  130-131°C.  1860, 1830, 1780 ( - C O - 0 - C O - ) , 1650  & 6.17 - 6.1 (m, 2, CH=CH), 5.08 -  3  3.6 - 3.27 (m, 2, 0 = C - C H - C H - C = 0 ) ,  2. 9 - 2.58  C=C-CH -C). 2  A n a l . C a l c d . for C  g  H  ?  C I O 3 :  . C , 5 1 . 5 ; H , 3.76; C l , 19.02.  F o u n d : . C , 51.63; H , 3.83; C l , 18.88.  2.  . C y c l o h e x y l p - to lime sulfonate A 500 m l . three-necked flask was equipped with a m e c h a n i c a l  s t i r r e r and thermometer  (range - 5 0 ° C to 1 0 0 ° C ) .  Cyclohexanol (50g,  0. 5 mole) and pyridine (158g, 2 mole); were placed i n the f l a s k .  T h e flask  was i m m e r s e d in an i c e - s a l t bath to lower its temperature below 1 0 ° C . T h e n powdered p-tolunesulphonyl chloride (105g, 0.55 mole) was added in portions over a p e r i o d of 30 minutes so that the temperature did not exceed 1 0 ° C .  T h e mixture was then s t i r r e d for 5 hours below 1 0 ° C ,  after which it was diluted with 300 m l . of h y d r o c h l o r i c a c i d (SP g r . 1.19, 38%) in 1 l i t r e of ice water.  T h e c r y s t a l l i z e d ester was collected on a  121 c h i l l e d Buchner funnel and allowed to d r y in the a i r . . It was then d r i e d under reduced p r e s s u r e at r o o m temperature. c r y s t a l l i z e d f r o m petroleum ether ( 3 0 - 6 0 ° C ) . m.p.:  T h e ester was r e Yield:  101. 7g-(80%).  44-45°C.  i r ( K B r ) 3040 (phenyl-H), 1600 (aromatic) 1180 ( - S C ^ - O ) ; nmr ( C D C 1 ) 3  3, p - C H ) , 3  0  7.95 - 7.2 (m, 4), 4. 8 - 4. 3 (m, 1, O - C H ) ,  2.33 - 0.93 (m, 10, C  A n a l . C a l c d . for C Found:  3.  1  3  H  l  8  6  H  1 Q  2.4 (s,  ).  S 0 : C , 61.45; H , 7.08; S, 1 2 . 6 . 3  C , 6 1 . 3 1 ; H , 7. 18;. S, 12.44.  1 - C h l o r o 3-cyclohexene A d r y 500 m l . t h r e e - n e c k e d flask was equipped with a  m e c h a n i c a l s t i r r e r , reflux condenser with a drying tube, and l i e b i g condenser connected to a nitrogen inlet. (63. 3g, 0. 5 mole),  3-cyclohexenecarboxylic  acid  lead tetracetate (lOOg, 0. 2258 mole) and 300 m l .  d r y benzene were placed i n the flask under nitrogen g a s .  The powdered  l i t h i u m chloride (9. 55g, 0.2258 mole) was added to the solution and r e fluxed while being s t i r r e d until the powder disappeared and no carbon dioxide was evolved.  T h e solution became light yellow.  Two 200 m l .  portions of d i s t i l l e d water were added with r a p i d s t i r r i n g and the benzene layer was r e m o v e d with a separatory funnel. solution was d r i e d by anhydrous m a g n e s i u m sulfate.  T h e benzene T h e drying agent  was suction f i l t e r e d and the solvent was r e m o v e d using a r o t a r y e v a -  122 porator.  T h e crude product was d i s t i l l e d under reduced p r e s s u r e and  the fraction boiling at 1 4 0 - 1 4 1 ° C was collected.  Yield:  21g (80%).  i r (neat) 3040 (=C-H), 2940, 2910, 2830 ( C H ) , 1645 (C=C), 2  670 ( C - C l ) ; n m r ( C D C 1 ) 3  (m.  1, > C H - C 1 ) ,  2.87 - 1.55 (m, 6, C  A n a l . C a l c d . for C Found:  4.  5. 67 - 5. 3 (m, 2, CH=CH), 4. 37 - 3. 87  6  6  H  C , 61.95; H , 7 . 9 1 ; C 1 ,  ?  6  H ). &  C l j ! C , 61.90; H , 7.74;. C l , 30. 06. 30.23.  3- Cyclohexenylmethylamine A 250 m l . three-necked flask was equipped with a dropping  funnel (125 m l . ' ) , reflux condenser with d r y i n g tubes, stirrer.  150 m l . d r y ether and L A H (5. 7g, 0. 15 mole) were p l a c e d in  the fla.sk-. hours.  and m e c h a n i c a l  T h e solution was gently refluxed while being s t i r r e d for 3  A solution of 3-cyclohexene n i t r i l e (10. 7g, 0. 1 mole) i n 40 m l .  ether was added to the flask f r o m the dropping funnel so as to maintain a gentle r e f l u x .  A f t e r the addition was completed,  the mixture was  refluxed while being s t i r r e d for 40 h o u r s . . Then the flask was cooled in an i c e - s a l t bath for 30 minutes,  and excess l i t h i u m a l u m i n u m hydride  was decomposed with d i s t i l l e d water.  Sufficient 40% N a O H was added  to give good separation f r o m the ether insoluble r e s i d u e . layer was d r i e d over anhydrous m a g n e s i u m sulfate.  T h e ethereal  The solution was  suction f i l t e r e d through a Buchner funnel and the ether was r e m o v e d using a r o t a r y evaporator. (70%).  b . p . : 169-170°C.  T h e product was d i s t i l l e d .  Yield:  10.29g  123 i r (neat) 3360, 3280 ( N - H ) , 2  &  1650 c m " (C=C); nm4 ( C D C 1 ) 1  3  5 . 9 3 - 5.5 (m, 2, CH=CH), 2. 8 - 2. 5 (d, 2, J= 5, C H - N ) ,  0. 83 (m, 9, C  6  H  7  2.50-  k NH ). 2  M o n o - h y d r o chloride derivative The salt was p r e p a r e d by the same procedure as that d e s c r i b e d in E x p . A - 3 . m . p . :  216°C.  A n a l . C a l c d . for C H ?  Cl,  24.07.  5.  1 4  NC1:  C , 5 6 . 9 ; H , 9. 5;. N . 9 . 5 ;  F o u n d : C , 56.90; H , 9 . 6 1 ; N , 9 . 4 9 ; C l , 2 4 . 0 1 .  oj - C h l o r o - N , N-dirhethylacetamide A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  s t i r r e r and a dropping funnel with a d r y i n g tube.  140 m l . d r y ether  \was placed in the flask and cooled by an a c e t o n e - d r y ice bath for 30 minutes.  26.4 m l . of dimethylamine (0.4 mole) was added to the f l a s k .  • A 60 m l . solution of c h l o r o a c e t y l chloride (22. 6g, 0. 2 mole) in d r y *  ether was added v e r y slowly f r o m the dropping funnel so as to control vigorous r e a c t i o n .  A f t e r the addition was completed, the r e a c t i o n c o n -  tinued at the same temperature for 3 h o u r s . s t i r r e d at r o o m temperature for 2 h o u r s .  T h e n the m i x t u r e was  T h e white dimethylamine  hydro chloride was f i l t e r e d through a Buchner funnel. f l a s h evaporated, Yield:  The solvent was  and the product was d i s t i l l e d under r e d u c e d p r e s s u r e .  I 4 . 5 2 g (60%).  b . p . : 6 3 - 6 4 ° C (1.1 m m . Hg).  i r (neat) 2920 ( N ( C H ) ) , 3  2  1650 (C=Q) 790 c m " ( C - C l ) ; n m r 1  124 (CDC1 ) 3  6.  <S  4.13  (s,  2,  C1-CH ), 2  3.05  (d, 6,  J= 7 H z , N f C H ^ ) .  o£"- CKloro - N - 2, 6 - dime thy Ipheny 1 - N - cy clohexy Ime thyl acetamide (attempted) A 250 m l . t h r e e - n e c k e d flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel (125 m l . ) with d r y i n g tube, and a side a r m  for setting a thermometer  (range -50 to 1 0 0 ° C ) .  2, 5-dimethylamine (6.5g, 0.03 0.04  N - c y clohexy Ime thyl-  mole) and dry triethylamine (4. 04g,  mole) in 150 m l . dry ether were placed in the f l a s k .  The solution  was cooled to - 8 0 ° C in an acetone-dry ice bath for one hour. solution of  A  oc" - c h l o r o a c e t y l chloride (3. 642g, 0. 03 mole) in 40 m l .  d r y ether was placed in a dropping funnel and added dropwise to the v i g o r o u s l y s t i r r e d cold solution. . The product appeared to have been f o r m e d , but at the end of the reaction, f r o m a light brown c o l o u r .  the m i x t u r e started to darken  At r o o m temperature,  it was i m p o s s i b l e  to isolate the d e s i r e d product due to its further i n s t a b i l i t y .  7.  <xC - C h l o r o - N - d i p h e n y l a c e t a m i d e (attempted) A 250 m l . three-necked flask was equipped with a m e c h a n i c a l  stirrer,  dropping funnel (125 m l . ) with drying tube, and a side a r m  for setting a thermometer 0.05  (range -50 to 1 0 0 ° C ) .  mole) and d r y triethylamine (5. 05g,  (150 m l . ) , were placed in the f l a s k .  0.05  mole),  in d r y ether  The solution was cooled in an  acetone d r y ice bath ( - 8 0 ° C ) for one hour. acetylchloride (5. 65g,  0.05  Diphenylamine (8.45g,  A solution of °i - c h l o r o -  mole) in d r y ether (30 mole) was p l a c e d in  125 the dropping funnel, and added dropwise to the r a p i d l y s t i r r e d solution over a p e r i o d of 20 m i n u t e s .  The s t i r r i n g was continued in the acetone-  d r y ice bath for 5 hours at r o o m temperature.  The triethylamine salt  was suction f i l t e r e d , and the ether r e m o v e d by a r o t a r y  evaporator,  but the product r a p i d l y decomposed into a dark brown t a r r y  substance.  126  PART V HISTAMINE  The ubiquitous distribution of histamine in plants, lower animals and m a m m a l s ,  and the variety and significance of its b i o l o -  gical effects have interested physiologists, pharmacologists and chemists for a long time  (16).  jb - ( 4 - i m i d a z o l y l ) ethylamine (histamine) was synthesized as a c h e m i c a l c u r i o s i t y in 1907 by Windaus and Vogot, before its detection as a uterine stimulant and intense d e p r e s s o r and its i s o l a t i o n in pure f o r m f r o m extracts of ergot in 1910 ( B a r g e r and Dale, Histamine r e s e a r c h has expanded in many directions since Methods of synthesis of histamine and its analogues,  17).  1910.  estimation of  histamine in tissues and body fluids, h i s t o c h e m i c a l aspects of E h r l i c h ' s mast c e l l , association of histamine and heparine in c e l l s and tissues, and the relationship between structure and activity of analogues of histamine, have a l l been investigated. . The pharmacology of histamine, in p a r t i c u l a r its absorption and toxicity; its actions upon smooth muscle,  the c a r d i o v a s c u l a r system and on s a l i v a r y , b r a i n and gastric  s e c r e t i o n ; and its relationship with the autonomic have been investigated.  nervous system  The p r o b l e m of histamine r e l e a s e by venoms  and toxins, p h y s i c a l and c h e m i c a l agents, b a s i c compounds, and m a c r o m o l e c u l a r r e l e a s e r s like anaphylatoxin, dextran, in anaphylaxis has also been studied.  egg white,  The m e c h a n i s m of histamine  etc.  127 r e l e a s e and its relationship with r e s p i r a t i o n , carbohydrate m e t a b o l i s m and phosphorylation has been d i s c u s s e d in connection with the p r a c t i c a l p r o b l e m s of anaphylaxis and a l l e r g y .  The m e t a b o l i s m of histamine,  its c a t a b o l i s m and excretion in vivo, its m e t a b o l i s m in vitro (exclusive of diamine oxidase),  the enzymatic formation of histamine f r o m  histidine, pyridine coenzyme interactions,  the m e t a b o l i s m of histamine  in man and its distribution in the b r a i n have been investigated.  The  p h y s i o l o g i c a l significance of histamine, including the role of histamine in vasodilation; the effect of histamine on gastric s e c r e t i o n ; its role in inflammation, a l l e r g y and experimental asthma were other  challenges  that have been investigated in recent decades.  L i t t l e is known about the p h y s i o l o g i c a l role of histamine in humans.  Its function in most of the pathological conditions in which it  has been studied also r e m a i n s u n c e r t a i n .  In the late fifties,  Schayer  and K a h l s o n independently showed that there was a great difference in the rate of endogenous., histamine formation under, n o r m a l and pathological conditions, without any corresponding changes in tissue histamine content.  Two methods for determination of histamine g i v e consistently  reproducible r e s u l t s :  the whole body histamine formation m a y b e  deduced f r o m the u r i n a r y excretion of non-isotopic histamine and its metabolites; or one of s e v e r a l adaptations of S c h a y e r ' s isotopic method m a y be u s e d .  The actions of endogenously f o r m e d histamine cannot be  r e p r o d u c e d by injected e x t r a c e l l u l a r h i s t a m i n e .  Kahlson d i s c o v e r e d  128 the high "histamine f o r m i n g capacity" of embryonic and wound t i s s u e s . Histamine f o r m i n g capacity ( H F C ) r e f e r s to the rate at which histamine is f o r m e d in m i n c e d tissues,  c e l l suspensions, or the whole body; it  denotes histidine decarboxylase activity in n u m e r i c a l terms  (11).  K a h l s o n also proposed a functional difference between mast c e l l and non-mast cell histamine.  When methods of determining the rate of  histamine formation had been developed, and it was d i s c o v e r e d that m a r k e d alteration in histidine decarboxylase  activity o c c u r s under p a r t i -  cular conditions, new t e r m s were introduced to distinguish histamine l i b e r a t e d f r o m mast c e l l s f r o m histamine f o r m e d by histidine d e c a r boxylase activity.  Newly f o r m e d histamine, which results f r o m  elevated histidine decarboxylase activity and is believed to act at various sites in the body or in the c e l l where it is f o r m e d , is r e f e r r e d to as "induced h i s t a m i n e " by Schayer (13) and "nascent h i s t a m i n e " by Kahlson  (14).  The m a j o r source of stored histamine in m a m m a l i a n tissue is the m a s t c e l l (15) even though there are other,  and p o s s i b l y m o r e  important tissue sources of histamine f r o m the standpoint of n o r m a l physiology (18).  Recognition of the mast c e l l as a source of histamine  in blood and tissue has led to a better understanding of the location and binding of histamine,  and the m e c h a n i s m of its liberation by c h e m i c a l  substances and anaphylaxis in some s p e c i e s .  T h e r e are other areas of  the body such as the e p i d e r m i s which contain histamine not with mast c e l l s .  In the stomach of the rat,  associated  histamine is found in cells  129 in the s u p e r f i c i a l layer of m u c o s a which r e s e m b l e m a s t c e l l s , i n typical m a s t cells in the submucosa and m u s c u l a r l a y e r s , and in e n t e r o c h r o m a f f i n - l i k e cells in the m u c o s a (25).  M u c h of the histamine  in p e r i p h e r a l n e r v e s i s found i n the m a s t c e l l s . . T h e p o s t - g a n g l i o n i c f i b e r s of the sympathetic nervous system are e x t r a o r d i n a r i l y r i c h in histamine (27,  28).  The m a j o r i t y of histamine in the b r a i n is  associated with the phylogenetically o l d portions of the b r a i n , which also contain large amounts of serotonin and n o r - e p i n e p h r i n e .  Some of  the histamine associated with parts of the b r a i n such as the p o s t r e m a , c h o r o i d plexus, pineal body, and p o s t e r i o r pituitary gland is in the mast cells (29).  The histamine found in mast c e l l s , b a s o p h i l s , and the  b r a i n , i s held i n subcellular p a r t i c l e s .  . The particular characteristics presence of heparin in them.  of m a s t c e l l s depend on the  In rat mast c e l l s , histamine is stored in  basophil granules consisting m a i n l y (over 95% of the granule d r y weight) of a h e p a r i n - p r o t e i n complex; heparin is a p o l y m e r of glucuronic a c i d and glucosamine containing sulfate groups linked to some of the hydroxy and amino groups of the s u g a r s . most species,  In the blood of  a l l or most of the histamine is found in the b a s o p h i l l i c  leucocytes (26),  which sufficiently r e s e m b l e mast cells for them to be  r e f e r r e d to as blood mast c e l l s , just as m a s t cells have been c a l l e d tissue b a s o p h i l s .  The m a t r i x of the mast c e i l granules consists of an  insoluble h e p a r i n - p r o t e i n complex held together by strong attractive  130 f o r c e s between oppositely charged a c i d heparin and b a s i c protein macromolecules.  The sulphuric acid groups of the heparin were  COO Hep ^  „  NHS0  (  3  ^  ^H N—-^R-COO 3  'OSO3  H ^ C H ^ - C H ^ - C - N ^ ^  H,!^"""^  Figure 8 .  CH-NH  Hypothetical h e p a r i n - p r o t e i n histamine complex of mast c e l l granules at p H 7  thought to be essential in f o r m i n g the h e p a r i n - h i s t a m i n e complex since desulphated heparin lacks the ability to f o r m the complex (20); but it is questionable whether granular heparin present as part of the h e p a r i n - p r o t e i n complex has any sulphuric a c i d groups available for histamine binding, protein linkage.  since these groups are probably involved in h e p a r i n -  Recent observations indicate carboxyl groups, but not  sulphuric a c i d groups,are the most l i k e l y ionic binding sites for histamine in the mast c e l l granules (21).  Quantitative observations on  the formation of a complex of h e p a r i n - p r o t e i n with sodium, histamine and other biogenic amines, the nature,  as well as titration studies, y i e l d e d data on  number and location of ionic binding sites on the h e p a r i n -  p r o t e i n - h i s t a m i n e complex (?24).  If histamine was stored in the granules  in ionic linkage, the storage capacity should vary with the degree of dissociation.  The influence of p H was studied on granules isolated f r o m  131 14 m a s t c e l l s containing C ..-histamine which had been endogenously f o r m e d during incubation of mast cells in a m e d i u m containing 14 C  :-histidine.  The granules were isolated by h y d r o l y s i s of the cells,  and the stores of endogenously f o r m e d histamine showed the same p H dependence as that o b s e r v e d for exogenous? histamine (ZZ, Z3).  At  p H 7 histamine is monobasic, but the ionization i n c r e a s e s r a p i d l y below neutrality and it becomes dibasic at p H 3-4.  Consequently, the affinity  of histamine for cationic binding sites w i l l increase with falling p H . On the other hand, the ionization of carboxyl groups in the granules w i l l be reduced with i n c r e a s i n g acidity, thereby diminishing the h i s t a m i n e - b i n d i n g capacity of the granules.  Therefore,  histamine  uptake of the granules should be expected to show a p H dependence curve with two i n v e r s e l y changing d i s s o c i a t i o n curves reflecting a falling d i s s o c i a t i o n of carboxyl groups and i n c r e a s i n g dissociation of amino groups (Z4).  The assumption that mast c e l l histamine is stored  in ionic linkage with C O O groups and can be exchanged with other cations ( e . g .  sodium ions) means that the mast c e l l granules should  have the p r o p e r t i e s of a weak cation exchange m a t e r i a l with carboxyl groups as m a x i m a l binding sites  (24).  T h e r e are many substances that r e l e a s e histamine f r o m tissues (25,  Z6).  T h o s e that r e l e a s e histamine f r o m the mast c e l l can  be placed in two groups.  Agents of one group r e q u i r e oxygen to induce  histamine r e l e a s e in cat and rat t i s s u e s .  A n example of a compound  132 belonging to this group is "compound 48/80','a condensation product of p-methoxy-phenethyl methyl amine and formaldehyde.  Histamine  r e l e a s e d by these agents is blocked by anoxia and metabolic glucose. The other group;  is composed of organic bases such as morphine and  aliphatic bases like octylamine which cause histamine r e l e a s e under anoxic conditions, p r e s u m a b l y by d i s p l a c i n g histamine f r o m its binding in the m a s t c e l l granules.  Uvnas proposed that histamine r e l e a s e is in p r i n c i p l e a two-stage p r o c e s s .  The f i r s t event is degranulation of the m a s t c e l l  which results in exposure of the h i s t a m i n e - c o n t a i n i n g granules to the extra-cellular fluid.  The second event is the r e l e a s e of histamine f r o m  these granules by a simple cation exchange between granular histamine and e x t r a c e l l u l a r sodium ( F i g . 9  and r e f . 32).  Electron microscopic  observation may help to c l a r i f y the relationship between degranulation and histamine r e l e a s e (33,  34).  The exocytosed granules of the mast  cells become exposed to the e x t r a c e l l u l a r fluid and r e l e a s e their histamine and 5-hydroxytryptamine.  Other granules r e m a i n inside the  m a s t c e l l ( F i g , 10 ).  About 90 y e a r s after the d i s c o v e r y of m a s t c e l l s , they were c l e a r l y differentiated f r o m other varieties of connective tissue c e l l s , but no function for them has yet been demonstrated.  No evidence has  been produced to show that histamine is r e l e a s e d f r o m mast cells under physiological conditions.  The d i s c o v e r y of the presence of large amounts  133 R e l e a s e r attaches 2. to mast c e l l membrane  Granules are discharged  Histamine is r e l e a s e d from discharged granules by cation exchange  Heparin -j _ P t c u i n V COO-HI Complex 1 +  Figure  Figure  9 .  10.  Degranulation and histamine r e l e a s e in mast c e l l s : suggested m e c h a n i s m of action of compound 48/80 (ref. 3G> ).  Schematic drawing to show the sequential exocytosis of histamine-containing granules (ref. ).  + • Ha  134 of histamine in the mast c e l l , the high m a s t c e l l content of manytissues,  and the finding that v i r t u a l l y a l l the blood histamine is present  within the basophils or "blood m a s t c e l l s " leads to the b e l i e f that the m a j o r i t y of the body histamine r e s i d e s in these c e l l s 036).  The exact  proportion of the total body histamine contained in m a s t c e l l s has not been established. . D u r i n g histamine r e l e a s e in anaphylaxis,  the  excretion and c a t a b o l i s m of histamine do not keep pace with its  release.  T h e r e is no evidence that the p h y s i o l o g i c a l importance of the mast cells is connected with their content of h i s t a m i n e .  The role of histamine and  heparin in the m a m m a l i a n mast c e l l would appear to warrant further investigation. . Schayer d i s c o v e r e d that mast cells collected f r o m the • 14rat peritoneal cavity f o r m e d histamine f r o m C  -histidine.  He i n f e r r e d  that the histamine f o r m e d by rat mast c e l l s was bound in a stable condition and that exogenous:': histamine was not bound.  Although the  mast c e l l s contain a lot of histamine, p r e s u m a b l y owing to the long l i f e time of the amine f o r m e d in them, their histamine f o r m i n g capacity is not p a r t i c u l a r l y high c o m p a r e d with some other t i s s u e s .  In the skin,  which is r i c h in mast c e l l s , the histamine f o r m i n g capacity is low.  In  fact, the H F C is so low that on r e m o v i n g the histamine f r o m the mast cells of the skin, it takes 2-3 weeks to r e s t o r e the o r i g i n a l content of histamine. The mast c e l l is not unique in that the histamine f o r m e d in it has a long l i f e .  N o n - m a s t cells exist in rat lungs and intestines  135  15  14-  U;<Uae\eaeet:c acid  F i g u r e 11.  l.4-M«tHy|iimda*o»« *.e«U\4hyd«  T h « catlbol'ism of histemiive.  136 which r e s e m b l e mast c e l l s i n their complement of l o n g - l i v e d h i s t a m i n e . T h e s e n o n - m a s t cells differ f r o m r e a l mast cells in that their histamine is resistant to m o b i l i z a t i o n by compound 48/80.  Also,  the histamine  of intestine cells is not r e l e a s e d in anaphylaxis.  T h e r e are considerable differences between species r e garding the c a t a b o l i s m of histamine both i n vitro (36) and i n vivo (37, 38).  T h e s e differences have also been found in studies of histamine  formation. of h i s t a m i n e .  Figure  11  shows the m a i n pathways for the catabolism  A n important pathway i n most species,  including m a n , is  direct oxidative deamination to imidazoleacetaldehyde (2 in F i g . 11 ) by diamine oxidase,  or histaminase which m a y not be the same as  diamine oxidase (39, 40, 41). diamine oxidase i n h i b i t o r s .  T h i s pathway in vivo is blocked by  T h e end products of the reactions  by diamine oxidase and monoamine oxidase a r e the same (52,  catalyzed 53).  However, monoamine oxidase does not seem to be important in the f i r s t step of histamine catabolism i n vivo (54).  T h e f i r s t evidence for the  participation of diamine oxidase in the c a t a b o l i s m of p h y s i o l o g i c a l quantities of histamine i n vivo was seen in the rat (42).  In vitro i n h i -  b i t o r s of diamine oxidase which do not inhibit monoamine oxidase, i s o n i a z i d (43) and aminoguanidine (44), prevent the formation of the m a j o r metabolite 1 - r i b o s y l i m i d a z o l e acetic a c i d , as o b s e r v e d by K a r j a l a _et al.(45) and independently by T a b o r and H a y a i s h i (46).  The  test for diamine oxidase activity r e q u i r e d aminoguanidine to be used i n  137 a dose that n e a r l y caused complete inhibition in vivo (56),  and the  14 intestinal C  - h i s t a m i n e l e v e l was m a r k e d l y i n c r e a s e d .  Diamine  oxidase probably dominates intestinal histamine c a t a b o l i s m . conclusion was drawn f r o m in vitro studies (57).  A similar  Since aminoguanidine  14 also reduces total intestinal C  - h i s t a m i n e , it is conceivable that the  n e w l y - f o r m e d endogenous histamine accumulates,  p a r t i a l l y f i l l s the  binding sites,  1  and reduces the uptake of injected C ^ - h i s t a m i n e ; or  that aminoguanidine m a y occupy histamine binding sites in the intestine 14 and reduce uptake of injected C  -histamine.  A l m o s t a l l the i m i d a z o l e -  acetaldehyde - (2 in F i g . 11 ) i:s converted to i m i d a z o l e a c e t i c acid (3 in F i g . 11 ) by aldehyde dehydrogenase.  Only a s m a l l portion of the  aldehyde is reduced by alcohol dehydrogenase to histidol ( i m i d a z o l e ethanol (4 in F i g . 11. , 47)).  Some of the i m i d a z o l e a c e t i c acid is con-  verted to ribotide ( 5 ' - p h o s p h o r i b o s y l i m i d a z o l e a c e t i c a c i d (5 in F i g . 11 )). The formation of this ribotide r e q u i r e s 5 ' - p h o s p h o r i b o s y l - 1 - p y r o p h o s phate and s t o i c h i o m e t r i c amounts of adenosine triphosphate  (48).  The most important pathway for histamine m e t a b o l i s m c o m p r i s e s methylation of the r i n g nitrogen to l - m e t h y l - 4 ( ^  -amino-  ethyl)imidazole (7 in F i g . 11 ) by histamine methyl t r a n s f e r a s e . product of this reaction is usually c a l l e d methylhistamine or  The  sometimes  1, 4 - m e t h y l h i s t a m i n e (7 in F i g . 11 ) to differentiate it f r o m the 1 , 5 - i s o m e r (8 in F i g . 11).  The i m i d a z o l e N - m e t h y l t r a n s f e r a s e acts  on no substrate except histamine so far as is known (49, S-adenosylmethionine is the m e t h y l donor.  50).  M e t h y l i m i d a z o l e (7 in  /  138 F i g . 11 ) is oxidatively deaminated to f o r m the c o r r e s p o n d i n g m e t h y l i m i d a z o l e acetaldehyde (9 in F i g . 11 ) in vivo l a r g e l y by a monoamine oxidase or monoamine o x i d a s e - l i k e enzyme but not by a diamine oxidase (51).  In m i c e l i v e r , the monoamine oxidase inhibitor a m i n o -  guanidine has little effect. oxidase,  T h e s e facts suggest  not diamine oxidase,  methylhistamine  that monoamine  is the catalyst in the formation of  (55).  Methylhistamine is the in vivo inhibitor of the histamine methylating enzyme that has been known longest.  The inhibition of  histamine methylation by methylhistamine made it possible to use u r i n a r y histamine levels as c r i t e r i a of histamine formation and release.  B y the action of aldehyde dehydrogenase, m e t h y l i m i d a z o l -  acetic acid (11 in F i g . 11) is f o r m e d , and this is the major u r i n a r y product of histamine c a t a b o l i s m .  Therefore,  catabolism are methylation and oxidation.  the two major routes, of  Quantitative analysis of the  14 urine of animals injected with C i . - h i s t a m i n e show that acetylation of the amino group of the side chain is a m i n o r reaction in m a m m a l i a n tissues (58).  Intestinal b a c t e r i a acetylate histamine (59) and a c e t y l -  histamine m a y be present in the urine of some species in considerable amounts (60).  N - a c e t y l h i s t a m i n e (13 in F i g . 11 ) has been shown to be  identical with the conjugated histamine that becomes p h y s i o l o g i c a l l y active after acid h y d r o l y s i s (60).  Methylation of the p r i m a r y amino  group ( l a in F i g . 11 ) and the nitrogen of the tautomer (lb) yields  139 N - m e t h y l h i s t a m i n e (14) and 1, 5-methylhistamine (8 i n F i g . 11 ), pectively.  Other catabolic pathways are d e s c r i b e d in r e f .  res-  61.  Injected histamine cannot r e v e a l p r e c i s e l y what is happening to endogenously f o r m e d histamine, because injected histamine is catab o l i z e d p r i m a r i l y by those organs with the greatest m a s s and blood flow, like the kidney and l i v e r .  The actions of endogenously f o r m e d histamine  cannot be r e p r o d u c e d by injected extracellular h i s t a m i n e .  T h i s applies  p a r t i c u l a r l y to nascent histamine, the metabolic action of which appears to be linked to the v e r y p r o c e s s of its f o r m a t i o n .  Again,  it  should be e m p h a s i z e d that the indications are that endogenously f o r m e d histamine is catabolized in a different way f r o m injected h i s t a m i n e . circumstance  This  should encourage m o r e extensive development of n o n - i s o t o p i c  methods of determining the p r i n c i p a l histamine  catabolites.  Many cells can take up histamine that is ingested or f o r m e d f r o m histidine by the b a c t e r i a l f l o r a . . However, almost a l l the histamine that is found in tissues is f o r m e d in the c e l l s by decarboxylation of histidine, a p r o c e s s which r e q u i r e s p y r i d o x a l - 5 - p h o s p h a t e (62, 63).  Histidine d e c a r -  boxylating enzyme ( L - h i s t i d i n e carboxylase) was f i r s t d i s c o v e r e d i n m a m m a lian tissue by W e r d l e .  The enzyme is now known to be identical with  D O P A - d e c a r b o x y l a s e (3, 4 - d i h y d r o x y - L - p h e n y l a l a n i n e - d e c a r b o x y l a s e ) . M o r e recently,  Schayer has found that at least two enzymes capable of  decarboxylating histidine occur in m a m m a l s (74).  One is a nonspecific  140  CH -CH-NH 2  N  -co  2  CH -CH -NH 2  2  COOH  A  Histamine  F i g u r e 12.  Decarboxylation of histidine  L - a m i n o acid decarboxylase, decarboxylase.  and the other is a specific histidine  These two enzymes are  affinities, different p H optima, and their inhibitors (75) .  distinguished by their substrate sensitivities  The specific decarboxylase  mast c e l l s ,  and fetal, l i v e r of the rat  acts only on histidine,  enzyme, named a r o m a t i c L - a m i n o acid decarboxylase decarboxylate histidine in v i t r o .  to different  which is found in the  which is responsible for induced or nascent h i s t a m i n e .  Another (76), can also  It has a low affinity for histidine and  is c l o s e l y related to, or identical with, enzyme or  2  H  Histidine  stomach,  2  DOPA-decarboxylase.  enzymes with low affinity for histidine are  s p e c i f i c " histidine decarboxylase.  The  called "non-  K a h l s o n , though, is against r e f e r r i n g  to enzymes with a low affinity for histidine as histidine decarboxylase, even with the prefix " n o n - s p e c i f i c " .  In rats fed on a partly synthetic  h i s t a m i n e - f r e e diet without p y r i d o x a l - 5 - p h o s p h a t e , HFC  the whole body  can be reduced to approximately 50% within 2 weeks and to 20%  in 6-7 weeks (1£). S e m i c a r b a z i d e  is*  shown to inhibit histamine  formation in vivo, but when it is given to rats in conjunction with a  141 p y r i d o x i n e - d e f i c i e n t diet,  its effect is v e r y potent  (12).  Inhibition of histamine formation in vivo was f i r s t r e p o r t e d by Schayer et a l .  who found that injection of cortisone inhibits  histamine formation in the skin but not in the stomach of r a t s .  It was  also demonstrated that prednisolone greatly reduces the histidine decarboxylase  activity of p a r t i c l e - f r e e extracts of rat lung (64),  these steroids  are r e l a t i v e l y weak inhibitors (<12).  ^»  but  -3,4-  dihydroxyphenyl- Ok. -methylalanine ( Ok - m e t h y l - D O P A ) in vitro strongly inhibits histamine formation in kidney of the guinea pig and rabbit. contrast, E h r l i c h ascites tumor ( 70) is not inhibited by DOPA.  By  £><. - m e t h y l -  Neither does significant reduction of the whole-body H F C  o c c u r in rats after they are given toxic dosages of subcutaneously ( 12 , 69).  £K - m e t h y l D O P A  4 - B r o m o - 3 - h y d r o x y b e n z y l o x y a m i n e was  r e c o g n i z e d as an inhibitor of histidine decarboxylase in vitro ( 70) and in vivo ( TV>, 76).  H y d r a z i n e derivatives of carbonyl reagents, which  engage p y r i d o x a l phosphate, are also known to inhibit amino acid decarboxylase in vitro (73).  In r a t s , in vivo isonicotinic hydrazide even  in high daily doses over a p e r i o d of two weeks caused only a slight reduction in whole-body H F C , and even this reduction subsided during the course of injections (1S).  Ok - H H , the  CK - h y d r a z i n o analogue of  histidine, is reported to be an inhibitor of histidine decarboxylase both in vitro and in vivo ( 78).  W e i s s b a c h et a l . found that in vitro  c( -methylhistidine inactivated the histidine decarboxylase of both mouse mast c e l l s and guinea pig kidney.  It was later shown that  histidine decarboxylase converts these inhibitors to  c<* - m e t h y l h i s t a m i n e  142 which is l i k e l y to stimulate histamine, thereby concealing any inhibition that might have taken p l a c e .  K a h l s o n et a l . have demonstrated that  - m e t h y l h i s t i d i n e is a powerful inhibitor of histidine decarboxylase in vitro and in vivo and have come up with evidence suggesting that the mode of action of substrate  (<1£).  , ^ - m e t h y l h i s t i d i n e is by competition with the o(.-methylhistidine has been shown to be a specific  and nontoxic inhibitor of histamine fo rma t i o n in vitro and in vivo using both non-isotopic and isotopic methods.  ^ - m e t h y l h i s t i d i n e is a safe  means for identifying the presence of histidine decarboxylase  activity  and distinguishing this activity f r o m that of D O P A decarboxylase  (7*3).  In work oniinhrbition of histamine formation, the distinction between m a s t c e l l and n o n - m a s t c e l l histamine must again be m a d e . • Schayer, and K a h l s o n et a l . showed that a consistent relationship between tis sue histamine content and histamine f o r m i n g capacity ( H F C ) of tissues does not exist.  A n initial lowering of tissue histamine content p r e s u m a b l y  elevates tissue H F C by a feed-back relationshipbetween his tamine content and histidine decarboxylase activity, but not in v i t r o .  a r e p r e s s i o n which operates i n vivo  A c c o r d i n g l y , the degree of inhibition manifested in vivo  would represent the balance r e s u l t i n g f r o m inhibited and newly f o r m e d enzyme m o l e c u l e s .  In the inhibition study  (-12), a feed-back relationship  was f i r m l y established as operating in the gastric m u c o s a (77,  78).  Information concerning turnover rate (lifetime of i n t r a c e l l u l a r histamine) has been obtained by two different approaches. Schayer injected C ^ - h i s t i d i n e into guinea pigs and rats and determined the amounts of C^^-his  tamine present in e x c i s e d tissues at various  143 time intervals  (1 $5,186 )  #  K a h l s o n et a l . made use of the finding that  using a combination of pyridoxine deficiency and s e m i c a r b a z i d e a d m i n i s t r a t i o n in vivo inhibits the whole body H F C of rats to within 1020% of its n o r m a l value.  T h e y examined various tissues of the rat for  histamine content every day for 90 daysfoir inhibition of histamine f o r m a tion.  In tissues like abdominal skin and tongue, which are r i c h in mast  cells,  inhibition of histamine formation to a s m a l l fraction of its n o r m a l  rate for s e v e r a l weeks was not followed by a significant drop in histamine content; but in the gastric m u c o s a , c e l l tissue,  which is a predominantly n o n - m a s t  the histamine content fell to low levels within 24 hours of  the start of the experiment (7*8., 1£ ). r  mast c e l l tissues,  1  T h i s was taken to indicate that in  a histamine molecule, once formed, is f i r m l y held and  has a long i n t r a c e l l u l a r l i f e t i m e ; whereas in the gastric m u c o s a the reverse applies.  In the rat lung which is believed to be poor in mast  c e l l s , the H F C was found to be r e l a t i v e l y high. was low and its lifetime exceptionally long.  The histamine content  T h i s situation indicates  that the m a j o r i t y of n e w l y - f o r m e d histamine is pooled so as to be able to leave the c e l l e a s i l y .  A s m a l l portion appears to be retained in cells  that p o s s e s s a type of binding which provides for a long l i f e t i m e .  H a r r i s et a l .  (i!31') d i s c o v e r e d that high concentrations of  histamine occur in c e r e b r a l regions related to the hypothalamus and hypophysis, e s p e c i a l l y in the hypophyseal stalk.  White  (-187) showed  that the cat b r a i n f o r m s histamine.by perfusing it with radioactive  144 histidine.  T h e s e experiments m a r k e d the beginning of the i n v e s t i g a -  tion into the o c c u r r a n c e and distribution of histamine in the whole b r a i n and its regional t i s s u e s .  White (13£ ) determined the in vitro H F C in  m i n c e d b r a i n tissue of the cat,  pig, and dog and found that in the three  species studied, H F C was highest in the hypothalamus.  He also found  that r i n g N - m e t h y l a t i o n is the p r i n c i p a l pathway for histamine c a t a b o l i s m in cat b r a i n in v i v o .  It is l i k e l y that almost a l l histamine, at least in  m a m m a l s such as guinea pig, rat,  baby rat,  rabbit, mouse,  chick and ?  frog (188 ), o c c u r s in n e u r a l tissues and not in mast c e l l s , for mast cells are not found in the central nervous tissues of those species that have been examined ( ] £ ? ' ,  164).  The rabbit, which is deficient in m a s t  c e l l s , has less histamine in the p o s t e r i o r lobe of its hypophysis than have other s p e c i e s .  It would appear too, that the histamine of the  anterior lobe of the hypophysis, though it is not in mast c e l l s , is held differently f r o m histamine in the b r a i n .  T h i s is because r e s e r p i n e ,  c h l o r o p r o m a z i n e and i p r o n i a z i d did not change the levels of histamine in the hypophysis while they did alter levels in b r a i n (1134}.  Schayer came up with a new theory for the p h y s i o l o g i c a l function of histamine under some n o r m a l conditions and various a b n o r m a l conditions in laboratory a n i m a l s . a v a r i e t y of c i r c u m s t a n c e s  He was i m p r e s s e d by the fact that in  an a r t i f i c i a l l y induced i n c r e a s e in histidine  decarboxylase activity is accompanied by changes in tone and p e r m e a b i l i t y of t e r m i n a l blood v e s s e l s .  The c o r r e l a t i o n between changes in  145 decarboxylase activity and m i c r o c i r c u l a t i o n was the basis for the hypothesis that induced histamine, state of the t e r m i n a l v e s s e l s .  s e r v e s as a governor of the functional  In o r d e r to understand m o r e fully the  relationships between these things, the following experimentally supported postulates are r e q u i r e d ; v i z , histamine is continuously p r o duced within the smooth m u s c l e and endothelial c e l l s of s m a l l blood vessels;  histamine acts p r i m a r i l y on i n t r i n s i c or i n t r a c e l l u l a r r e c e p t o r s ,  and the m e c h a n i s m for histamine production can adapt to environmental requirements ( i . e . histidine decarboxylase is an inducible enzyme). A c c o r d i n g to these postulates,  histamine is f o r m e d within smooth  m u s c l e c e l l s , and diffuses out through the c e l l w a l l .  A moderate  excess of histamine then i n c r e a s e s nutritive blood flow and p e r m i t s cells to r e a c h their full potentialities.  C o n v e r s e l y , a histamine i n s u f f i -  ciency w i l l lead to i m p a i r e d c e l l nutrition and development of a b n o r m a l i ties in c e l l c h e m i s t r y and function (  K a h l s o n (?£.) demonstrated e x t r e m e l y r a p i d formation of histamine during pregnancy in the r a t .  It was also shown that fetuses  of the rat contained an extremely active histidine decarboxylase ($3). T h i s led to the hypothesis that the p r o c e s s of histamine formation was in some way connected with r a p i d growth.  T h i s hypothesis is  further supported by observations made on wound healing and l i v e r regeneration (8Z). In an attempt to identify the tissues responsible for the i n c r e a s e d formation of histamine during pregnancy in the rat,  it  146 seemed to be l o g i c a l to study the effect of r e m o v a l of the fetuses on the u r i n a r y excretion of the a m i n e .  On r e m o v a l of the fetuses,  u r i n a r y histamine f e l l sharply and r a p i d l y r e v e r t e d to the nonpregnant l e v e l or even lower, indicating that i n c r e a s e d formation of histamine during pregnancy depends on the presence of the fetuses.  Detailed  studies of the sites of histamine formation in the fetus in vitro r e v e a l e d that the fetal l i v e r is the most important location for histamine p r o d u c tion: more.  the H F C exceeds that of adult l i v e r by up to 1, 000 times or even The histamine content of the fetal tissues was low, even below  that of the mother, . i n spite of the high tissue H F C . H e r e is a situation c h a r a c t e r i z e d by high H F C , but low histamine content and low capacity to bind h i s t a m i n e . involved.  T h e s e factors suggest that nascent histamine is  Other fetal tissues also displayed histidine decarboxylase  activity at m u c h higher levels than those found in the tissues of young or adult a n i m a l s (25,  87')-  A  s  T h i s was also c o n f i r m e d by other pregnancy of the mouse p r o c e e d s ,  investigators  histamine  excretion r i s e s to values up to 100 times the nonpregnant value. d e l i v e r y , the u r i n a r y histamine f a l l s , at f i r s t steeply,  After  then m o r e slowly,  and the nonpregnant l e v e l is not attained until a few weeks after d e l i very  Striking differences exist in the regional distribution of  histidine decarboxylase in fetal m i c e and r a t s :  in the mouse fetus the  H F C r e s i d e s m a i n l y in the skin, whereas in the rat fetus the l i v e r is the p r i n c i p l e site of histamine f o r m a t i o n .  In the pregnant h a m s t e r ,  the  site of elevated histamine formation is not the fetus but the placenta  147 The histidine decarboxylase activity determined i s o t o p i c a l l y in vitro i n the extra-uterine  tissues of the pregnant hamster (abdominal... skin,  lung, l i v e r , spleen, gastric m u c o s a ,  s m a l l intestine, kidney and  skeletal muscle) did not show significantly elevated histamine f o r matiori 08$). -  Studies of histamine formation i n the human embryo have been far less comprehensive than i n the other s p e c i e s .  Blood was  collected f r o m the u m b i l i c a l a r t e r y and vein while the embryo was in place, and then f r o m a c a r o t i d a r t e r y after the embryo had been removed.  P l a s m a histamine was found in significant amounts in the  u m b i l i c a l a r t e r y and in the e m b r y o n i c carotid a r t e r y .  Maternal plasma,  like human p l a s m a generally, was devoid of histamine in m e a s u r a b l e concentration.  T h e r e was m o r e histamine in the u m b i l i c a l a r t e r y  p l a s m a than in the p l a s m a of the u m b i l i c a l vein (  90).  M o r e direct  evidence of histamine formation in human embryonic tissues was o b tained by isotopic in vitro determinations (:*?!)).  M o s t of the fourteen  e m b r y o n i c tissues examined displayed histidine decarboxylase  activity,  although at rather low l e v e l s ; highest in o r d e r of magnitude were spleen, hypothalamus, stomach,  abdominal skin, and l i v e r .  Healing skin and some tumors show enhanced formation of histamine.  The rate of wound healing, as e x p r e s s e d in the tensile  strength of the wound and the rate at which collagen f o r m e d i n it, was m e a s u r e d in the n o r m a l state and after the H F C of the skin had been  148 a r t i f i c i a l l y lowered or elevated ( 93,  94 , :  95.).  The histamine content  of wound and granulation tissue is v e r y low in c o m p a r i s o n with that of n o r m a l skin.  T h e s e tissues then, share with embryonic tissues the  p r o p e r t i e s of H F C and high turnover rate of h i s t a m i n e .  Histidine de-  carboxylase activity in human skin has been demonstrated i s o t o p i c a l l y (19.6)-.  T h i s change is not caused by mast cells because the number of  mast cells is not i n c r e a s e d in the region of the wound.  L i n d e l l et a l . ( ^ 1 )  also found the H F C to be low in n o r m a l human skin, but high in healing skin wounds.  Injection of " l o n g - a c t i n g " histamine, however,  did not  enhance the rate of healing, nor did injections of a histamine antagonist r e t a r d the n o r m a l p r o c e s s of healing (.93).  T h u s , the role played by  nascent histamine cannot be s e r v e d by e x t r a c e l l u l a r histamine nor eliminated by antihistamine agents. A f t e r a high H F C had been r e c o g n i z e d as being concomitant with certain kinds of r a p i d tissue growth, it appeared likely that a s i m i l a r phenomenon might also be found in malignant t i s s u e s .  Riley  et a l . found that female rats b e a r i n g a subcutaneously implanted hepatoma had m a r k e d l y elevated u r i n a r y histamine excretion levels which returned to n o r m a l i m m e d i a t e l y after r e m o v a l of the tumor ( 9 8 ) .  K a h l s o n et a l .  have investigated various t u m o r s ; in the E h r l i c h a s c i t e s tumor in m i c e they determined mitotic index, growth curve, H F C , histamine binding capacity and histamine content ( (08).  A s p e c i a l i n q u i r y into H F C , as it  is related to growth, has been conducted using two different kinds of  149 tumors.  A h l s t r o m et a l . (100) examined a transplantable,  virus-  induced rat s a r c o m a and the enlarged l i v e r of the t u m o r - b e a r i n g host. The H F C of the tumor was high; there was a tendency for higher H F C to be associated with m o r e frequent m i t o s i s and younger tumors tended to have a higher H F C . A rat Walker c a r c i n o s a r c o m a  studied by  Johnston U6I") grew r a p i d l y , and the l i v e r became e n l a r g e d .  The H F C  of the tumor and enlarged l i v e r was high.  That histamine is a powerful stimulant of gastric  secretion  was d i s c o v e r e d f i r s t in experiments on dogs conducted during 19191920.  A s i m i l a r action in humans was demonstrated in 1922.  It was  subsequently shown that histamine stimulates gastric secretion in a l l species that have been adequately tested.  The work on this subject up  to 1963 has been reviewed extensively by Ivy and B a c h r a c h (102-') and by Code (\0ih)f" The gastric m u c o s a of a l l species studied (man, dog, cat,  rat,  guinea pig, hamster,  decarboxylase (f7d). In the rat,  mouse, mouse,  much higher than in the other tissues,  and frog) are r i c h in histidine and cat,  m u c o s a l H F C is  and is exceeded only by the  high l e v e l s in certain tissues of pregnant animals and some malignant tissues.  R e s u m e d feeding of fasted rats, m i c e , and frogs evokes  a m o b i l i z a t i o n of histamine and concurrent a c c e l e r a t i o n of the rate of histamine formation in the p a r i e t a l region of the gastric  mucosa.  T h e s e changes in m u c o s a l histamine are not m e r e l y a product of s e c r e t o r y activity since they do not occur when a c i d secretion is  150 excited by injection of h i s t a m i n e .  N o r do they o c c u r in regions of the  m u c o s a that are devoid of n o n - p a r i e t a l cells (18).  F e e d i n g , or the  p r i n c i p a l individual excitatory components operating subsequent to feeding, such as vagal excitation,  production of g a s t r i n , or distention  of the stomach w a l l , induce an a c c e l e r a t e d rate of histamine f o r m a t i o n that p e r s i s t s for s e v e r a l hours (78).  T h i s sharp and l o n g - l a s t i n g  elevation of histidine decarboxylase activity is b e l i e v e d to be brought about by an initial lowering of the p r e f o r m e d histamine content of the m u c o s a , with the levels of the enzyme and the end product i n t e r r e l a t e d by feedback coupling.  U s i n g fluorescence m i c r o s c o p y to v i s u a l i z e gastric m u c o s a l histamine in the rat,  Thunfeerg; found fluorophores of histamine in  cells located at the base of the gastric gland and in the few submucosal mast cells,  2.. . In s e r i a l sections,  H F C was shown to be a property  of that part of the gland which contains h i s t a m i n e .  The distribution of  p a r i e t a l cells appeared to be unconnected with the distribution of histamine and the enzyme which synthesizes it.  H i s t a m i n e approaching  the p a r i e t a l c e l l f r o m the outside causes the c e l l to secrete H C l , as seen f r o m the stimulatory efficiency of injected h i s t a m i n e . of the stomach,  In sections  the number of a c i d - s e e r eting c e l l s p a r a l l e l s the amount  of histamine held in e n t e r o c h r o m a f f i n - l i k e cells in the gastric m u c o s a . Furthermore,  the output of histamine into the g a s t r i c juice p a r a l l e l s  the volume of h y d r o c h l o r i c a c i d secretion whether this secretion is  151 induced by injection of gastrin, ingestion of food, or injection of cholinergic drugs.  CAfcBACHOL M6THACHOHW  ( VAGUS  .1  Q-AVT-RIM  F i g u r e 13.  Schematic representation.of .the approach of histamine to the p a r i e t a l c e l l of the stomach (ref. 94>).  The phenomenon of anaphylaxis was d e s c r i b e d by P o r t i e r and Richet (1902) in a dog r e c e i v i n g s u b - l e t h a l doses of an extract of salt-water A c t i n i e s  It appeared to them that instead of being  . . " i m m u n i z e d " , the dog developed a condition just the r e v e r s e , developed a h y p e r s e n s i t i v i t y to the toxic agent. (Gk. a n a - i n v e r s e ,  i . e . it  The name " a n a p h y l a x i s "  phylaxis-protection) was coined to convey this idea  of "reverse^, i m m u n i t y " .  In 1910 Dale and L a i d l o w  that histamine might be involved in anaphylaxis.  (.1.1:2..) f i r s t suggested  R e l e a s e of histamine  in anaphylaxis has recently been extensively reviewed by R o c h a e S i l v a • >  ( \0t) and s e v e r a l others ( lO?,. < 10S" \CR ?  >  M O , U.H). Anaphylaxis in  most animal species and human a l l e r g y , r e g a r d l e s s of the precipitating  152 antigen, involve s i m i l a r p h y s i o l o g i c a l r e a c t i o n s :  increased capillary  p e r m e a b i l i t y (hence the development of edema and even hemorrhage), hemodynamic changes such as a m a r k e d fall in a r t e r i a l blood p r e s s u r e , and contraction of smooth m u s c l e (  12/J, 128). T h e s e endogenous  observations have p r o v i d e d considerable impetus to the s e a r c h for endogenous p r i n c i p l e s of anaphylaxis.  F o r some y e a r s it was thought  that histamine was the only mediator of anaphylactic reactions,  but  m o r e recent study indicates that histamine alone cannot account for a l l the symptoms of a l l e r g i c manifestations.  In 1941,  Dragstedt defined  anaphylaxis as a phenomenon of " a u t o - i n t o x i c a t i o n " by p h y s i o l o g i c a l l y active substances.  B e s i d e s h i s t a m i n e , w h i c h s t i l l r e m a i n s the most  important c h e m i c a l m e d i a t o r , many other endogeneous p r i n c i p l e s such as h e p a r i n  (11.2),  serontin (5-hydroxytryptamine),  polypeptides such as  b r a d y k i n i n , and an unidentified slowly reacting substance (SRS) have been i m p l i c a t e d in anaphylaxis in animals catecholamines,  (J06).  A c e t y l c h o l i n e (113 ),  and adenyl compounds m a y be involved to a l e s s e r  degree.  The precipitating factor in a l l e r g y and anaphylaxis involves the interaction of two m a c r o m o l e c u l e s :  an antigen and an antibody.  An  antigen m a y be a p o l y s a c c h a r i d e , protein, or a simple compound that is covalently bound to protein as defense against the specific antibody (I IS").  The m a m m a l i a n o r g a n i s m manufactures a specific antibody  f r o m the globulin fraction of the b l o o d .  Renewed contact of antigen and  153 antibody at a later date initiates a chain of events r e s u l t i n g in r e l e a s e of histamine and other compounds such as serotonin, SRS and b r a d y k i n i n f r o m mast c e l l s (lo&j Il6 ), b a s o p h i l i c leucocytes, platelets.  and  Some agents that selectively r e l e a s e histamine and other  substances f r o m mast cells a r e : amines (d-tubocurarine, compound 48/80.  antigen-antibody, cationic proteins,  stilbamidine, m o r p h i n e , p o l y m i x i n B) and  In the selective r e a c t i o n ,  the constituents of the  granules are rreileased without any apparent damage to the c e l l m e m b r a n e s '(I'M;  N o n - s e l e c t i v e agents that r e l e a s e substances f r o m mast  cells are proteolytic enzymes, venoms and tissue i n j u r y .  T h e r e are  many indications that the r e l e a s e of histamine f r o m the sensitized guinea pig lung is blocked by anoxia, low temperature, p r e s u m a b l y act by antagonizing enzymatic m e c h a n i s m s , Ca ions.  inhibitors which and r e m o v a l of  Renewed contact of antigen and antibody involves the fixation  of bivalent immunoglobulin and activation of p r o c e s s e s leading to the r e l e a s e of vasoactive m e d i a t o r s f r o m the c e l l .  In a study of the anaphylactic reaction in isolated guinea-pig tissues based on histamine r e l e a s e and D a l e - S c h u l t z type responses OU^). Mongar and Schild proposed a general scheme for a c e l l u l a r anaphylactic histamine r e l e a s e m e c h a n i s m which involves interaction of the antigen-antibody complex with a "heat-sensitive enzyme p r e c u r s o r " . this reaction,  respiratory  C a ions and a narrow p H range are r e q u i r e d for  which is inhibited by S H reagents and other enzyme  154 inhibitors ( II? , \2>0 ). 4  T h i s reaction produces the "active e n z y m e " ,  which, in turn, is inactivated by a number of s t r u c t u r a l l y unrelated compounds such as phenol, cyanide, cinnamate,  and some a n t i p y r e t i c s .  It is this active enzyme that liberates bound histamine.  M o t a (|I7) proposed that the mast cells play a v e r y important role in guinea-pig anaphylaxis, due to the high sensitivity of this species to histamine; but he believes that mast cells probably play an insignificant role in rat anaphylaxis due to the low sensitivity of this species to histamine and 5-hydroxytryptamine.  B r o n c h o s p a s m is the  most important symptom of anaphylaxis in the g u i n e a - p i g .  In the n o r m a l  state, the guinea-pig tissues examined exhibited H F C in order of dec r e a s i n g magnitude as f o l l o w s : s m a l l intestine, lung, aorta,  uterus,  spleen, l i v e r ,  skin; but a c c o r d i n g to K a h l s o n et a l . ( I T9),  tissues with  p a r t i c u l a r l y high H F C in the n o r m a l state do not have c o r r e s p o n d i n g l y high levels in anaphylaxis, and vice v e r s a .  Nor do the tissues in  which anaphylaxis i s predominant (for example,  guinea-pig lung and  rat intestine) exhibit s t r i k i n g l y high elevations of H F C . It is now known whether there is a p a r a l l e l between sensitivity of tissues to the effects of i n t r a c e l l u l a r histamine generated by elevated H F C and sensitivity to histamine acting f r o m outside. in some tissues that are poor in mast c e l l s ,  K a h l s o n et a l . c l a i m e d that the o b s e r v e d elevation of  H F C during anaphylaxis is on the same scale, is in tissues that are r i c h in mast c e l l s .  or even greater, than it  Histamine f o r m e d during  155 anaphylaxis in the rat and the guinea-pig i s , in their view, l a r g e l y of non-mast cell origin.  The d i s c o v e r y that histamine is not m e r e l y  r e l e a s e d , but is also newly f o r m e d in hypersensitivity and anaphylaxis reactions,  caused investigators to look at histamine in a new way again.  H i s t a m i n e f o r m e d at a high rate and acting i n t r a c e l l u l a r l y may at least p a r t i a l l y account for manifestations which f o r m e r l y were not believed to be associated with histamine.  In dogs, the m o r e pronounced effects  of anaphylatic shock are hypotension, portal venous constriction and hemorrhage of the G - I tract.  It has been demonstrated that histamine is also r e l e a s e d in human a l l e r g y and anaphylaxis (12^), which conditions m a y be manifested by a combination of u r t i c a r i a , hypotension, and b r o n c h o - c o n s t r i c t i o n (.l-tOVTfl'j).  L i l j a et a l . found that human lung tissue f o r m s histamine,  i . e. it is endowed with H F C . The comparatively low rate of formation was of the same o r d e r of magnitude as that seen in the skin of n o r m a l rats ( 130).  The d i s c o v e r i e s that i n c r e a s e d histamine formation takes place in a l l tissues investigated i n the anaphylactic a n i m a l , and that the elevated H F C p e r s i s t s for a long time after histamine r e l e a s e has ceased,  seem to be helpful in explaining the failure of histamine  antagonists to afford protection in the later stages of anaphylaxis. Histamine antagonists may not interfere with actions caused by histamine f o r m e d and acting within tissue c e l l s .  It is p r e s u m e d that in anaphylaxis,  156 agents other than histamine (serotonin etc. ) are responsible for symptoms which are not alleviated by histamine antagonists  (T0(>).  The histamine antagonists do not interfere with the important actions of endogenous histamine in gastric secretion and in the metabolic p r o c e s s e s of tissue growth and protein synthesis.  T h i s is p r e s u m a b l y  because histamine is not engaging r e c e p t o r s of the f a m i l i a r sort in these functions.  The limitation is that the feed-back relation between  histidine decarboxylase and histamine, by its v e r y nature,  is likely to  exclude the f e a s i b i l i t y of inhibiting histamine formation e n t i r e l y .  E n d e a v o u r s of the last ten y e a r s have not succeeded in demonstrating histamine r e l e a s e in any p u r e l y p h y s i o l o g i c a l event. One case of p h y s i o l o g i c a l histamine r e l e a s e has been shown to o c c u r : the histamine content of the g a s t r i c m u c o s a of a rat deprived of food is lowered when the animal is fed.  T h i s phenomenon was interpreted  in t e r m s of alterations in a chain of events in the m u c o s a l histamine m e t a b o l i s m designed to stimulate and sustain the secretion of h y d r o chloric acid.  A solid body of observations provides the b a s i s of theories  which causally associate gastric m u c o s a l histamine r e l e a s e and f o r m a tion with excitation of the p a r i e t a l c e l l s , and nascent histamine with the anabolic p r o c e s s e s of growth and protein synthesis in various tissues.  The foregoing is a s u m m a r y of developments in some areas of histamine r e s e a r c h .  The d e s i r e to treat a l l e r g y m o r e effectively is  157 the p r i m a r y reason for our interest in h i s t a m i n e . included with this in m i n d .  T a b l e VIII  is  It details the various stages of a l l e r g i c  reaction and the treatments that can be given along the way.  158 T a b l e VIII ACTION O F DRUGS,ON T H E A L L E R G I C RESPONSE (Ref. Sequence of A l l e r g i c Reaction  192)  Anti-allergic Action: : Stage and T y p e  A n t i - a l l e r g i c drugs  Antigen Antibody f o r m i n g cells  Ab + A g  R e l e a s e of h u m o r a l agents  Immediate response of target tissue: V a s c u l a r dilatation Broncho constriction Resulting disturbance in organism: Change in mucus Cough E d e m a and itching L a c r i m a t i o n and rhinorrhea Insomnia.nervousness, exhaustion Hypoxia Hypercapnea A c i d - b a s e imbalance Shock Infection  Medication  P r e v e n t i o n of antibody formation  Immunosuppr es sants  Prevent formation of h u m o r a l agent (histamine) Stabilize l y s o s o m e s  Histidine decarboxylase inhibitor Steroids  Depletion of h u m o r a l agents Interference with action of h u m o r a l agents  Histamine (et a l . ?) liberators A n tihi s t am in e s et a l .  Reverse undesired effects  Adrenergics  ;  Theophylline  Supportive treatment Expectorants and mucolytics Antitussives Analgesics T r a n q u i l i z e r s and sedatives Oxygen A c i d - b a s e buffers Vasopressors Antibiotics  159 P A R T VI HISTAMINE " R E C E P T O R S "  L i t t l e is known about the " r e c e p t o r s " for histamine in the a n i m a l body, but two facts can be deduced f r o m studies of s t r u c t u r e activity relationships and the effects of specific blocking agents (7). F i r s t , wherever histamine r e c e p t o r s are located in the body (in smooth muscle,  c a p i l l a r y endothelium, n e r v e s ,  g a s t r i c glands, etc. ),  they  are distinct f r o m each of the other " r e c e p t o r s " activated by other autacoids like the catecholamines, b r a d y k i n i n and angistensin.  5-hydroxytryptamine,  acetylcholine,  The other thing known for c e r t a i n about  histamine r e c e p t o r s is that there is m o r e than one type.  The specific  antagonism of some ractions of histamine by low concentrations of antihistaminic drugs c h a r a c t e r i z e s which A s h and Schild (174)  one type of histamine receptor,  to  give the symbol H ^ . . Receptors of this type  o c c u r in guinea-pig i l e u m and b r o n c h u s .  Other actions of histamine  like: stimulation of gastric acid secretion and stimulation of isolated rat uterus are not antagonized by common antihistaminic agents (775). T h e s e actions are likely to be mediated by r e c e p t o r s other than those designated Hj, .  T h e r e c e p t o r s involved in these actions are designated  as H ^ -  K i e r (176) proposed that two conformations of histamine are p r e f e r r e d ; one with the t e r t i a r y nitrogen of the side chain and the  160 pyridine nitrogen of the molecule (a) 4. 55 A with these nitrogens separated by 3.60  H 1  \ / C— M  H  H•  M  T  1  A°.  apart, the other (b) He suggested that the  H / H  1  (b)  (a) 6  CC  = |80»,  Sec = 3 0 0 ° ,  £v-.-^ - C =120"  ' F i g u r e 14.  ConformationsJof  ©i-;^ - C  =120"  histamine  c o n f o r m e r s attach to different types of r e c e p t o r s , H ^ and H ^ . therefore,  Kier,  postulated that two distinct b i o l o g i c a l responses depend on  the presence of one or the other complementary r e c e p t o r .  The H ^  receptor would be complementary to the internitrogen relationship (a) in F i g .  14 , whereas H-, receptor would be complementary to the  internitrogen relationship (b) in F i g . 14 .  K i e r ' s calculations were  based on the extended Huckel method for m o l e c u l a r o r b i t a l calculation.  G r e e n et a l . (177)  severely criticized K i e r ' s work,saying  that the Huckel method gives " h o p e l e s s l y inaccurate r e s u l t s " and is "worthless as a procedure for predicting the structure or c h e m i c a l behaviour of m o l e c u l e s . "  In K i e r ' s work, too, the dihedral angle was  rotated every 6 0 ° , a procedure that could m i s s important  conformers.  G r e e n et a l . used the INDO (Intermediate Neglect of D i f f e r e n t i a l Overlap) m o l e c u l a r o r b i t a l method.  The total energy of the molecule was m i n i -  m i z e d as a function of two dihedral angles,  ^ and 0 ^ ^ for  161 histamine.  The angles were rotated at 3 0 ° intervals and at 1 5 ° when  4.  N  rr  this was n e c e s s a r y .  CH* -  <*  CH ~WH* 2  The result is that 98% of histamine free base  should exist in the configuration with © ,  „ = 1 5 0 ° and © .  „ = 330°.  In this configuration, a suitable distance o c c u r s between one of the s i d e - c h a i n amino hydrogens and N - 3 of the i m i d a z o l e r i n g to p e r m i t hydrogen bonding. f o r m e r with ©^  A n a l y s i s of the histamine cation showed the c o n -  p = 1 8 0 ° (in the plane of the i m i d a z o l e ring) and  p = 3 0 ° or 3 3 0 ° had least energy. . The quaternary nitrogen in  this structure was close enough to N - 3 of the i m i d a z o l e r i n g to p e r m i t hydrogen bonding.  P u l l m a n et a l . (178)  c o n f i r m e d this result by  finding that the folded structure of the cationic f o r m of histamine at p h y s i o l o g i c a l p H most stable; it included an i n t r a m o l e c u l a r hydrogen bond.  A l l this information about the conformations of histamine has  done v e r y little for our understanding of the receptor for h i s t a m i n e . One way to conceptualize the receptor is to speak in general t e r m s and say that the receptor for a cationic molecule should incorporate an anionic part so that ionic bonding is p o s s i b l e .  Since the action radius  of ionic groups are r e l a t i v e l y large (the e l e c t r i c a l field around the ions decreases with the square of the distance),  it is postulated that the  162 amino group s e r v e s as a guiding group leading the drug to its receptor site,  and then the r e l a t i v e l y weak forces whose action r a d i i  decrease with the seventh power of the distance, and V a n der Waals f o r c e s ,  hydrogen bonding  come into action and stabilize the complex  and make possible a close fit at the receptor surface (179).  Another model for the histamine receptor was suggested by R o c h a e S i l v a (106).  A c c o r d i n g to his scheme, histamine attaches to  its receptor by means of two sites:  the imino group of the i m i d a z o l e  r i n g and the free amino group of the side chain.  T h e imino group f o r m s  a transitory bond with the p o l a r i z e d carbonyl group of a peptide linkage of the r e c e p t o r ; the second one f o r m s a hydrogen bond with a protein residue of histidine or a r g i n i n e .  Other f o r c e s ,  m a i n l y hydrophobic ones,  may a s s i s t in the interaction.  F i g u r e 15 . . Schematic representation of histamine receptor (ref. 106).  163 P A R T VII ANTIHISTAMINES  A n t i h i s t a m i n e s a r e drugs with the ability to antagonize in varying degrees most, but not a l l , of the p h a r m a c o l o g i c a l actions of histamine (179).  T h e y seem to share with many other p h a r m a c o l o -  gical antagonists the property of competitively occupying the receptor sites on the effector c e l l s to the exclusion of the agonist.  This implies  that the effects of the presence of a certain amount of histamine w i l l be countered by a sufficiently high dose of an antihistamine, and vice versa.  A n t i h i s t a m i n e s apparently bind with the histamine receptor  without initiating a r e s p o n s e .  In this manner,  they avoid the full impact  of i n c r e a s e d h i s t a m i n f o r m i n g capacity ( H F C ) and the resulting presence of elevated concentrations of histamine in the blood and t i s s u e s . h i s t a m i n i c s d i m i n i s h , in v a r y i n g degrees,  Anti-  the b r o n c h i o l a r and intestinal  s p a s m , i n c r e a s e d c a p i l l a r y p e r m e a b i l i t y , salivation, cutaneous wheal, and r e l e a s e of epinephrine f r o m the adrenals caused by h i s t a m i n e . ever,  How-  antihistaminics have no effect on gastric secretion induced by  histamine.  A new class of compounds which competitively inhibit actions  of histamine on gastric secretion has recently been reported (174). . The symptoms of elevated histamine content of tissues m a y also be alleviated by the a d m i n i s t r a t i o n of p h y s i o l o g i c a l antagonists,  e . g . , ephedrine or  epinephrine, which have an effect d i a m t r i c a l l y opposed to that of histamine.  ' .  S T R U C T U R E - ACTIVITY RELATIONSHIPS AMONG T H E ANTIHISTAMINES M a x i m u m antihistaminic activity is found in the following structure,  where R^ and R-, are aromatic or heteroaromatic  one of which m a y be separated f r o m  F i g u r e 16.  X  by a methylene group.  cyclohexyl) without loss of activity (181, an oxy ether to carbon. (  taminics.  One  G e n e r a l structural f o r m u l a of antihistamines  of the a r o m a t i c rings m a y be r e p l a c e d by an a l i c y l i c s y s t e m ,  activity (5).  rings,  ^ICH-O-).  6).  (e.g.  X may be N , C H , or  The use of a thio ether  reduces  The nature of X is commonly used to c l a s s i f y a n t i h i s Except i n cases where  Y  to attain good antihistaminic activity. chain m a r k e d l y d e c r e a s e s activity.  is present,  R^ must be ethylene  Lengthening or branching the The antihistaminics are then  named as p r o p y l a m i n e , ethylenediamine, or ethanolamine  derivatives.  Two subclasses of the ethylenediamines are the piperazine and phenothiazine d e r i v a t i v e s .  E x a m p l e s of antihistaminics belonging to each  c l a s s are given in F i g u r e 16. positions by  4  7  2  m a y be linked in the o r t h o -  Y , which is a methylene, heteroatom,  heteroatom function. -N(R )  R^ and R  or methylene-  R^ and Rg are u s u a l l y methyl groups,  m a y be i n c o r p o r a t e d into a s m a l l r i n g s y s t e m .  although  The use of  165 ethyl groups for R  and R 5 d e c r e a s e s the antihistaminic activity.  A  distance of 5 - 6A f r o m the amino nitrogen to the center of one of the a r o m a t i c rings gives the strongest competitive activity.  Substitution  of one of the aromatic rings with a p - m e t h y l or p - c h l o r o group g e n e r a l l y i n c r e a s e s activity. activity.  O r t h o - substitution on one or both rings d e c r e a s e s  Nauta (2) has explained this relationship in alkylsubstituted  diphenhydramine derivatives by proposing that the  TC  electrons of  one of the aromatic rings interact with the oxygen lone pair electrons, resulting in an a l t e r e d electron density on the oxygen atom.  Para-  alkyl substitution enhances the o v e r l a p interaction, while ortho- and m e t a - substitution decrease the interaction.  T a b l e IX  166  ANTIHISTAMINES  E T H A N O L A M IN E  DERIVATIVES Chemical Formula  C h e m i c a l Name ( G e n e r i c ; Brand) Thymoxyethyldiethylamine ( ; 929F) CH,  O-CH -CH -N-CH 'T'CH 2  2  2  C H — GH3 2  CH-CH3  2-(Benzohydryloxy)-N, N dimethylethylamine (Diphenhydramine; Benadryl) CH-O-CH  -CH -N-CH 2  CH  3  3  2 - ( p - b r o m o - ck - p h e n y l b e n z y loxy)N, N - d i m e t h y l e t h y l a m i n e (Bromodiphenhydramine; A m b r o d r y l )  CH-O-CH--CH--N-CH, 1 2 2 3 CH,  Br-  2-( ck -(2-Dimethylaminoethoxy)- ^ -methylbenzyl)-pyridine (Doxylamine; Decapryn) ,—N  CH C-0-CH -CH -N-CH 2  2  CH  ( 2 - B e n z y l p h e n y l ) - /S - d i m e t h y l am ino - e thyle the r (Phenyltoloxamine; B r i s t a m i n ) //  \  O-CH -CH -N-CH 2 2 J  3  3  167 T A B L E IX ETHANOLAMINE DERIVATIVES  (Continued)  C h e m i c a l Name ( G e n e r i c ; Brand)  Chemical Formula  2-(p-Chloro-ek - (2-dimethylaminoethoxy)benzyl)-pyridine (Carbinoxamine; Clistin)  0-CH -CH -N-CH 2  2  CH  3  3  Piperidinomethyl-2-benzodioxane ( ; F933)  CH  (  2  - N;  )  ((llime^Kyo"-?^  CH  I  \\_CH-0-CH -CH -NH 2 2 I CH,  7  9  CH  7  O-  TABLE ETHYLENEDIAMINE  ( (  DERIVATIVES  )  ; 2325RP)  CH -CH -N-CH -CH -N-CH 3  N-benzyl-N-phenyl-N'-N dimethylethylenediamine ( ; Antergan) 1  2  2  2  9  M'  0  3  168 T A B L E IX E T H Y L E N E D I A M I N E D E R I V A T I V E S (Continued) Chemical Formula  C h e m i c a l Name i (Generic *;TBrand) N-phenyl-N-(2-thenyl)-N\ N dimethylethylenediamine (Methaphenilene; Diatrin) 1  CH -N 2  -CH -CH -N-CH 2  2  3  CH. 2 - (2 - dime thy 1 amino e thy 1 - (pmethoxybenzyl) amino) pyridine ( P y r i l a m i n e ; Neo-Antergan) CH -0-(/  CH -  \-  3  2  N-CH -CH -N-CH 2  2  CH  N-benzyl-N', N'-dimethyl-N-2pyridylethylenediamine (Tripelennamine; Pyribenzamine) CH -N-CH -CH -N-CH 2  2  2  3  CH,  2 - £ ( j3 - dime thylamino ethyl)-2thenylamino^-pyridine (Methapyrilene; Thenylene, Histadyl) CH -N-CH -CH -N-CH 2  2  2  CH,  N', N -dimethyl-N-(2-pyridyl)-N(5-chloro-2-thenyl)-ethylenediamine (Chlorothen; Tagathen) ,  CH -N-CH -CH -N-CH 2  2  N  2  CH,  3  3  3  T A B L E IX E T H Y L E N E D I A M I N E D E R I V A T I V E S (Continued) Chemical Formula  C h e m i c a l Name ( G e n e r i c ; Brand) 2-(2-dimethylaminoethyl)p-methoxybenzyl) amino) p y r i m i d i n e ( T h o n z y l a m i n e ; Neohetramine) CH -0^7  V CH -N-CH -CH -N-CH H  3  2  2  2  3  CH.  N  N , N'-diethyl-N-ethyl-N-phenylethylenediamine ( ; 1571F) 1  CH -CH -N-CH -CH -N-C H 3  2  2  2  2  C  5  2 5 H  ( ( T h e n y l d i a m i n e ; Thenfadil)  // \N  CH, - N -CH.- CH. -N- CH. CH,  TABLE PROPYLAMINE  DERIVATIVES  N, N-dimethyl-3-phenyl-3-(2pyr i d y l ) - p r o p y l a m i n e (Pheniramine; Trimeton) CH-CH,-CH,.-N-CH_ 2 2 | i 3 CH. 2 - ( p - c h l o r o - tf( ( 2 - d i m e t h y l /—N aminoethyl) b e n z y l ) - p y r i d i n e (Chlorpheniramine ; C h l o r - T r i m e t o n ) \ / (Dexchlorpheniramine; Polaramine)  CH-CH -CH -N-CH CH-, 2  2  3  170 T A B L E IX PROPYLAMINE DERIVATIVES  (Continued) Chemical Formula  C h e m i c a l Name ( G e n e r i c ; Brand) 2-(p-bromo-(2-dimethylaminoethyl)benzyl)-pyridine ( B r o m p h e n i r a m i n e ; Dimetane) (Dexbrompheniramine; D i s o m e r ) r—  <^  N y-CH-CH -CH -N-CH CH, 2  2  3  1 - i^:-(p-chlorophenyI)-3-phenyl2-butenyl^-pyrrolidine (Pyrrobutamine; Pyronil)  V//  • C=CH-CH  2  N'  .CH,  Cl-  Trans-2-(3-(l -pyrrolidinyl)-1 (p-to l y l ) p r o p e n y l ) - p y r i d i n e (Triprolidine; Actidil) , — N <^  ^ > ~ C = C H - C H , — IM  CH-  TABLE  PHENOTHIAZINE DERIVATIVES  10- (2-dimethylamino- 1 - p r o p y l ) phenothiazine ( P r o m e t h a z i n e ; Phenergan)  C H  3  CH_-CH-N-CHo 2 , 3 CH.  171 TABLE  IX  PHENOTHIAZINE DERIVATIVES  (Continued) Chemical Formula  Cehneemr ii cc a; l Brand) Name G 10-(2-(l-pyrrolidyl)ethyl)phenothiazine (Pyrathiazine; Pyrrolazote)  //  \\  N— C H - C H - N' 2  10 - (3 - dime thy lamino - 2 - me thy 1 p r o p y l )phenothiazine (Trimeprazine; Temaril)  2  CH M-CH -CH-CH -N-CH 2  2  CH 10-(l - m e t h y l - 3 - p y r r o l i d y I m e t h y l ) phenothiazine (Methodilazine; T a c a r y l ) // \\ N-CH-  N-CH,  10-(2-dimethylaminopropyl)-9thia-1, 1O-diaza-anthracene (Isothipendyl; Theruhistin)  CH, -CHo-CH-N-CH-: I  CH,  3  T A B L E IX (Continued) XYCLIZINES AND OTHER DERIVATIVES Chemical Formula  Chemical Name (Generic; Brand) 2- (N-benzylanilinomethyl)- 2imidazoline (Antazoline; Antistine)  CH -N -CH 2  C  2  1 -diphenylmethyl-4me thy lpipe r a zine (Cyclizine; Marzine)  1 -(p-chlorobenzhydryl)-4methylpiperazine (Chlorcyclizine; Perazil) -CH  1 - (p- c h l o r o p h e n y l b e n z y l ) - 4 (m-methylbenzyl)-piperazine ( M e c l i z i n e ; Bonamine)  N-CH,  Cl CH,  \  2 - m e t h y l - 9 - p h e n y l - 2 , 3, 4, 9tetrahydro-1 -pyridinedene (Phenindamine; Thephorin)  /  2  N-CH,  \-  173  !  T A B L E IX CYCLIZINES AND OTHER DERIVATIVES C h e m i c a l Name ( G e n e r i c ; Brand)  (Continued) Chemical Formula  2 - (1 - (2 - (2 - dimethylamino ethyl)3 -indenyl)e thy 1)-pyridine (Dimethpyrindene; F o r h i s t a l )  >CH -CH -N-CH 2  //  \)-CH-CH  2  CH3  3  174  CONCLUSION  Nauta et a l . have reported the significance of overlap interactions (homoconjugation) between heteroatoms like oxygen and sulphur and the  TC electrons of the phenyl group in diphenhydramine  and thiodiphenhydramine. mesomeric,  T h e s e interactions are m o d i f i e d by  inductive, and steric effects. . Changing the amount of  interaction changes the antihistaminic activity ( £ , S ).  The following compounds were p r e p a r e d to allow m o r e information to be obtained regarding the effects of homo- and p T C conjugation and lack of conjugation on the antihistaminic activity of antergan analogues:  N, N-dimethyl-N'-cyclohexylmethyl-N'-o -methyl-  phenylethylenediamine;  N, N-dimethyl-N'-cyclohexylmethyl-N'-m-  methylphenylethylenediamine;  N, N-dimethyl-N'-cyclohexylmethyl-N*-  p-methylphenylethylenediamine;  N , N - d i m e t h y l - N - cyclohexylmethyl-  N'-p-bromophenylethylenediamine;  1  N , N-dimethyl-N'-3-cyclohexenyl-  methyl-N'-cyclohexylethylenediamine;  N, N-dimethyl-N'-3-cyclo-  hexenylmethyl-N'-phenylethylenediamine; methylethylenediamine;  N, N-dimethyl-N'-diphenyl-  N , N - d i m e t h y l - N ' , N'-dibenzylethylenediamine;  N, N-dimethyl-N'-benzyl-N'-cyclohexylethylenediamine; N -cyclohexylmethyl-N'-cyclohexylethylenediamine. 1  N , N-dimethyl-  T h e s e analogues  were p r e p a r e d by reacting the appropriate p r i m a r y amines with a c i d chlorides like  <<-chloroacetylchloride and benzoyl c h l o r i d e ,  to f o r m  175  °k - chloro ace tamide derivatives and benzenecarboxamide.  The  oC -  chloroacetamide derivatives were then substituted n u c l e o p h i l i c a l l y with dimethylamine to f o r m vatives.  c<-N, N - d i m e t h y l a m i n o a c e t a m i d e d e r i -  The aminoacetamides and N ' - ( / - N , N - d i m e t h y l a m i n o e t h y l ) -  benzenecarboxamide were then reduced with lithium a l u m i n u m hydride to f o r m the ethylenediamine d e r i v a t i v e s .  The ethylene diamines were  reacted with the following c a r b o x y l i c a c i d c h l o r i d e s : carboxyl, phenylcarboxyl, 3-cyclohexenecarboxyl,  cyclohexane-  and  1-cyclohexene-  c a r b o x y l c h l o r i d e i n the presence of triethylamine to obtain the N l-(fi N, N-dimethylaminoethyl)-carboxamide derivatives. were also reduced with l i t h i u m aluminum h y d r i d e .  The carboxamides T h i s sequence of  reactions generally gave a good y i e l d for a l l the analogues. tion was the p - b r o m o p h e n y l d e r i v a t i v e .  A n excep-  A worse p r o b l e m was the  reduction of the olefinic bond in the oC , fi -unsaturated  aminocar-  boxamide, N ' - c y c l o h e x y l - N ' - ( fi - N , N - d i m e thy lamino ethyl)- 1 - c y c l o hexenecarboxamide:  when this compound was reduced with l i t h i u m  aluminum h y d r i d e , both the c a r b o x y l group and the olefinic bond of the 1-cyclohexenyl moiety were r e d u c e d .  N ' - 3 , 5 - d i m e t h y l p h e n y l - N ' - ( fi -  N , N-dimethylaminoethyl)cyclohexanecarboxamide was also p r e p a r e d , but subsequent p u r i f i c a t i o n and reductions were not completed i n this work because of a time  shortage.  The preparation of the following cyclohexadiene of antergan was attempted:  -  analogues  N , N-dimethyl-2, 5-cyclohexadienylmethyl-  176 N - c y c l o h e x y l e t h y l e n e d i a m i n e and N , N - d i m e t h y l - N - 1 , 4 - c y c l o h e x a d i e n y l 1  1  . m e t h y l - N - cyclohexylethylenediamine. 1  2 , 5 - cy clohexadiene-1 - c a r b o x y l i c  a c i d was p r e p a r e d by B i r c h reduction of benzoic a c i d . of 1, 4 - c y c l o h e x a d i e n e - 1 - c a r b o x y l i c 3-chloro-4-cyclohexene-1,  The p r e p a r a t i o n  a c i d began f r o m preparation of  2 - d i c a r b o x y l i c a c i d anhydride using the  D i e l s - A l d e r synthesis of 1-chlorobutadiene and m a l e i c anhydride. Due to spontaneous aromatization of the cyclohexadiene a c i d when it was p r e p a r e d ,  it would have been extremely difficult to isolate these  acids in the pure f o r m .  B u t 2, 5 - c y c l o h e x a d i e n e - l - c a r b o x y l  was p r e p a r e d in order to get N - c y c l o h e x y l - 2 , amide.  chloride  5-cyclohexadienecarbox-  The reduction of this compound with lithium a l u m i n u m hydride  r e s u l t e d in reduction of the c a r b o x y l group and oxidation (aromatization) of the cyclohexadiene s y s t e m .  C h l o r o a c e t y l chloride was also employed  in the reaction of N - 2 , 6-dimethylphenylcyclohexylmethylamine p r e p a r e d in this work and c o m m e r c i a l l y available diphenylamine.  The product  could not be isolated due to its instability; a t a r r y m i x t u r e was f o r m e d .  A l k y l a t i o n using cyclohexyl-p-toluenesulphonate^  1-chloro-  3-cyclohexene and chlorocyclohexane hWijth''"" N , N - d i m e t h y l - N ' - c y c l o hexylmethylethylenediamine^and N ' - b e n z y l e t h y l e n e d i a m i n e i m p r a c t i c a l method of obtaining antergan analogues.  was an  A l s o , the t e r t i a r y  amine site of ethylenediamine appeared to be m o r e active than the secondary amine site of the m o l e c u l e .  Identification of most intermediates and final products was  177 done by i n f r a - r e d , nuclear magnetic resonance, '  r.  elemental a n a l y s i s .  E l e m e n t a l analysis of liquid amines  and aminoacetamide derivatives were p e r f o r m e d on h y d r o c h l o r i d e , picrate,  per chlorate,  r .1 m e t h y l iodide d e r i v a t i v e s .  178  BIBLIOGRAPHY  R o m m , P . , Guryanova, E . N . , and Koche sko v, K . A . , T e t r a h e d r o n 25, 2455-2468, P e r g a m o n P r e s s , (19691 Nauta, W . 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