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The reductive condensation of 2,5-disubstituted pyrroles White, James David 1961

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THE REDUCTIVE CONDENSATION OF 2,5-DISUBSTITUTED PYRROLES by James D a v i d White B,A., Cambridge U n i v e r s i t y ,  1959  A TRESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE In t h e Department of CHEMISTRY  We accept t h i s t h e s i s as conforming t o t h e required standard  THE,UNIVERSITY OF BRITISH COLUMBIA June, 196l  In presenting  this thesis i n p a r t i a l fulfilment of  the requirements f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. f o r extensive  I f u r t h e r agree that permission  copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be  granted by the Head of my Department o r by h i s  representatives.  I t i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be alloived without my w r i t t e n permission.  Department o f C h e m i s t r y The U n i v e r s i t y of B r i t i s h Columbia, Vancouver 8, Canada. Date  J u  *  e  ^  1 9 6 1  ABSTRACT  The problem i n i t i a l l y presented was the s t r u c t u r a l e l u c i d a t i o n o f a compound obtained when 2 , 5 - d i m e t h y l p y r r o l e was subjected to conditions of a c i d i c reduction. had a s s i g n e d a molecular formula C ^ H ^ N  Previous workers  to t h i s product and a  p a r t i a l s t r u c t u r e had been put forward based on the i n d o l e n i n e system. In the course o f t h i s work i t was found t h a t the compound o b t a i n e d by these e a r l i e r workers was the r e s u l t o f a r e d u c t i v e s e l f - c o n d e n s a t i o n o f 2,5>-diraethylpyrrole, and I t s s t r u c t u r e was c o n c l u s i v e l y e s t a b l i s h e d as 1,3»h»7-tetramethylisoindoline.  The methods used i n the s t r u c t u r a l e l u c i d a t i o n o f  t h i s product i n c l u d e d elemental a n a l y s i s o f i t s d e r i v a t i v e s , measurement o f i t s b a s i c i t y and e q u i v a l e n t weight, ultraviolet  i n f r a r e d and  s p e c t r o s c o p i c evidence, o x i d a t i v e degradation, and  i t s p r o t o n magnetic resonance  spectrum.  Two r e l a t e d i s o i n d o l i n e s were prepared by d i f f e r e n t routes. analogous  2J4., 7 - t r i m e t h y l i s o i n d o l i n e was s y n t h e s i s e d by methods t o those a l r e a d y known, and the u l t r a v i o l e t . s p e c t r u m  of i t s methiodide, when compared w i t h that o f the raethiodide from 1>3»K»7-tetramethylisoindoline, ment o f the l a t t e r .  r e i n f o r c e d the s t r u c t u r a l a s s i g n -  1, 3-diphenyl-l|., 7 - d i m e t h y l i s o i n d o l i n e was  obtained by the r e d u c t i v e condensation o f acetonylacetone with 2 , 5 - d i p h e n y l p y r r o l e (which d i d not undergo s e l f - c o n d e n s a t i o n ) . ii  The  f a v o u r a b l e r e s u l t of t h i s r e a c t i o n suggested  condensation may  that a s i m i l a r  have o c c u r r e d t o g i v e the 1, 3, k-» 7-tetramethyl-  i s o i n d o l i n e and a l s o admitted the p o s s i b i l i t y of a g e n e r a l s y n t h e s i s of s u b s t i t u t e d i s o i n d o l i n e s by t h i s An attempt was  route.  made to r e s o l v e the mechanism o f the  2 , 5 - d i r a e t h y l p y r r o l e condensation,  f o r which e i t h e r a D i e l s - A l d e r  r e a c t i o n or a r i n g - o p e n i n g process may  be p o s t u l a t e d .  The  f a i l u r e of the d i m e t h y l p y r r o l e to show d i e n i c c h a r a c t e r , even i n the presence  of v e r y s t r o n g d i e n o p h i l e s , together with  positive  evidence f o r r i n g - o p e n i n g and k e t o n e - p y r r o l e condensation f o r c i b l y f o r the l a t t e r mechanism.  iii  argued  TABLE OP CONTENTS CHAPTER Ic  Ho  PAGE  INTRODUCTIONO  o  o  o  o  o  o  o  e  o  a  o  9  «  o  o  o  e  «  o  o  o  o  1  REDUCTIVE CONDENSATION OP 2,5-DIMETHYLPYRR0LE  9 . 10  S t r u c t u r a l E l u c i d a t i o n o f the Product .  P r e p a r a t i o n and A n a l y s i s o f D e r i v a t i v e s . . . . . 10 N-Methylation . . . .  . . . . . . . . . 10  I n f r a r e d Spectrum  , . . . 1 0  U l t r a v i o l e t Spectrum.  13  Electrometric Titration . . . . . . . . . . . . . lif Oxidative Degradation . . . . . . . . . . . . . .  llj.  P r o t o n Magnetic Resonance Spectrum. . . . . . . . 1 5 Stereochemistry o f the Product. III.  RELATED ISOINDOLINES.  ...........16  . . . . . . . . .  2,1^7-Trimethylisoindoline.  . . . 17  .............17  1,3~I iphenyl-i|j,7-dimethylisoindoline.  . . . . . . . . 21  )  DOI* iV3- t X V G S  0  0  0  0  0  0  0  0  0  4  0  0  0  0  0  0  0  0  23  6  2I4.  I n f r a r e d Spectrum . . . . . . . U l t r a v i o l e t Spectrum. IV.  THE MECHANISM OP THE 2,5-DIMETHYLPYRROLE CONDENSATION . . 26  . . . . . . . . . . . . . . . . 2 6  D i e l s - A l d e r Mechanism R i n g - o p e n i n g Mechanism. V.  . . . . . . . . . . . . . . 2 1 4 .  . . . . . . . . . . . . . . . 3 1  EXPERIMENTAL,  .  .  .  a  o  o  o  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  REFERENCES  o  «  o  o  a  o  .  .  .  o  o  o  .  o  o  o  .  .  .  o  o  .  o  iv  37 »  LIST OP TABLES PAGE  TABLE  I.  C h i e f F e a t u r e s o f t h e I n f r a r e d Spectrum o f 1,3 ,I(. ,7-Tetramethylisoindpline. . . . . . . . . . . .  12  The U l t r a v i o l e t S p e c t r a o f 1,3,1].,7-Tetramethyli s o i n d o l i n e and R e l a t e d Compounds . . . . . . . . . .  13  J  II. III. IV. V.  i  pK Values o f 1 , 3 , l j . , 7 - T e t r a m e t h y l i s o i n d o l i n e and R e l a t e d Compounds . . . . . . . . . . . . . . . . . . l l f The P r o t o n M a g n e t i c Resonance Spectrum o f 1n3>sh» 7 - T e t r a m e t h y l i s o i n d o l i n e . . . . . . . . . . . . The U l t r a v i o l e t Spectrum o f 1,3-Diphenyl-lj., 7-d.imethyli s o i n d o l i n e and R e l a t e d Compounds . . . . . . . . . .  v  15 2I4.  LIST OP FIGURES FIGURE 1, 2. 3« Ij..  '  PAGE  The P y r r o l e T r i m e r . .  e o o o o o o e o o o o o o o R e a c t i o n Sequence i n t h e C o n d e n s a t i o n o f 2,3-Disubstituted Pyrroles. . o e o o o o o o o o o o Schemes Proposed f o r t h e C o n d e n s a t i o n o f 2,ij.-Dimethylpyrrole . . . . . . . . . . . . . . . . . .  4  P l a n c h e r ' s Scheme f o r t h e R e d u c t i v e C o n d e n s a t i o n o f 2,5-Dimethylpyrrole . . . . . . . . . . .  6  5°  The R e d u c t i v e Condensation o f 2 , 5 - D i m e t h y l p y r r o l e j D e r i v a t i v e s and O x i d a t i v e D e g r a d a t i o n o f t h e P^OdUCt « o o o o o o o o o o o o o o o o o o o o o o o ^ ] ] _  6.  The S y n t h e s i s o f 2 , I ( . , 7 - T r i m e t h y l i s o i n d o l i n e . . . . . . . 18  7«.  The S y n t h e s i s o f 1, 3-Diphenyl-lj.j, 7 - d i m e t h y l l s o i n d o l l n e cLXlCl ID©! l V & t l V 6 S  8.  A Proposed D i e l s - A l d e r Mechanism f o r t h e R e d u c t i v e Condensation o f 2 , 5 - D i m e t h y l p y r r o l e . . . . . . . . . .  9.  Products o f the Reaction of C e r t a i n P y r r o l e s w i t h «Dl QX10 jptl i i © S  10.  0  0  0  0  0  0  0  4  0  0  0  0  0  0  0  0  0  0  0  0  0  A Proposed R i n g - o p e n i n g Mechanism f o r t h e R e d u c t i v e Condensation o f 2 5 - D i m e t h y l p y r r o l e . . . . . . . . . .  32  The C o n d e n s a t i o n o f A c e t o n y l a c e t o n e w i t h 2,5>-Dimethyl"t 111 Gjptl 0I"1©  12.  27 2^  0  S  11.  22  o o e o o « o o o o o o e o o o o © o o  1  o  o  o  o  9  o  o  o  o  o  o  o  o  «  o  o  a  o  e  6  o  o  o  3  ^  ~  The C o n d e n s a t i o n P r o d u c t o f Acetone and 2 = 5>-DimethylP Old o o e o o o e o o o o o o e o o o o o o o o o o 3 ^ "  vi  ACKNOWLEDGMENT  The w r i t e r would l i k e t o e x p r e s s h i s thanks t o Dr. R. Bonnett who p r o v i d e d much h e l p f u l a d v i c e and guidance i n t h e course of t h i s r e s e a r c h . Thanks a r e a l s o due t o Dr. D. McGreer f o r d e t e r m i n i n g t h e N.M.R. s p e c t r a . A n a l y s e s were c a r r i e d out by A. B e r n h a r d t , Mulheim.  vii  CHAPTER I INTRODUCTION  The life  importance o f p y r r o l e compounds i n p l a n t and animal  i s w e l l e s t a b l i s h e d and t h e i r chemistry has a t t r a c t e d a  p r o p o r t i o n a t e l y l a r g e share o f the a t t e n t i o n devoted to h e t e r o c y c l i c compounds. i n the m a c r o c y c l i c  The i n c o r p o r a t i o n o f the p y r r o l e nucleus  porphyrin  systems o f such molecules as  c h l o r o p h y l l and hemin t e s t i f i e s t o the s i g n i f i c a n t p a r t which i t plays  i n l i v i n g processes.  Other examples of b i o l o g i c a l l y  important p y r r o l e compounds i n c l u d e the enzyme c a t a l a s e , the b i l e pigment b i l i r u b i n and the mould pigment p r o d i g i o s i n o The  parent compound, p y r r o l e , has been known f o r some  time as a c o n s t i t u e n t  o f b o n e - o i l and i t s e a r l i e s t  preparations  c o n s i s t e d o f d i s t i l l a t i o n o f c o a l t a r , bones, and horn. i n lQ3k-> d e s c r i b e d  Runge,  a method f o r d e t e c t i n g p y r r o l e prepared i n  t h i s way u s i n g a p i n e - s p l i n t e r moistened with h y d r o c h l o r i c acid (1).  The p i n e - s p l i n t e r turned b r i g h t r e d i n t h e presence  of p y r r o l e and the name o f t h i s c l a s s o f compounds d e r i v e s the Greek e q u i v a l e n t  for this  from  colour.  P y r r o l e i s g e n e r a l l y regarded as intermediate i n a r o m a t i c i t y between f u r a n and thiophene, although p y r r o l e i s unstable  i n a i r , t u r n i n g r a p i d l y yellow  itself  and then orange.  presence o f a l k y l groups on the r i n g a c c e l e r a t e s  this  deter-  i o r a t i o n while electron-withdrawing substituents  i n h i b i t the  The  2  F i g u r e 2.  R e a c t i o n sequence i n the condensation o f 2,3-disubstituted pyrroles.  3 effect.  Among t h e r e a c t i o n s o f p y r r o l e i s one, f i r s t  i n 1888,  i n which p y r r o l e i s t r e a t e d w i t h a c i d t o g i v e a t r i m e r  (2).  reported  A f t e r s e v e r a l i n c o r r e c t assignments, the s t r u c t u r e of the  t r i m e r was e v e n t u a l l y e s t a b l i s h e d as ( I ) (3). A c i d t r e a t m e n t o f 2 - m e t h y l p y r r o l e was found t o g i v e a p r o d u c t , C]_oHnN, w h i c h Dennstedt c o n c l u d e d t o be 2,1^-dimethylindole (IV; R = C H 3 , R  = H) (ij.).  !  A similar reaction  occurred  w i t h 2,3-dimethylpyrrole g i v i n g the d i p y r r o l e ( I I ; R = R' = C H 3 ) and  s u b s e q u e n t l y 2,3*4s5-tetramethylindole (5), a l t h o u g h l a t e r  workers proposed a b i s s t r u c t u r e f o r t h i s compound (6). in  1938>  Allen,  suggested t h a t c o n d e n s a t i o n t o form i n d o l e s was a  general r e a c t i o n of 2,3-disubstituted p y r r o l e s  (7)»  scheme c o n s i s t e d o f an i n i t i a l l i n k a g e a t the f r e e to give the d i p y r r o l e ( I I ) . R i n g - c l o s u r e ,  Allen's (^-positions  g i v i n g the bridge-  compound ( I I I ) , f o l l o w e d by e l i m i n a t i o n o f ammonia would r e s u l t i n t h e 2,3>lw5-substituted  indole.  I n t h e case o f 2 - p h e n y l p y r r o l e  i t was found t h a t t h e d i p y r r o l e ( I I ; R = Ph, R' = H) was formed but no f u r t h e r r e a c t i o n o c c u r r e d I t was f i r s t  (8).  thought t h a t t h e c o n d e n s a t i o n o f  2 , l ) . - d i a l k y l p y r r o l e s follov*red t h e p a t t e r n o f the 2 , 3 - d i s u b s t i t u t e d pyrroles.  Plancher,  on t r e a t i n g 2 , k - d i m e t h y l p y r r o l e w i t h z i n c  and a c e t i c a c i d , o b t a i n e d  a s o l i d f o r which a n a l y s i s i n d i c a t e d a  molecular formula C ^ H ^ N  (9).  On t h e b a s i s o f an i n i t i a l  o ^ o t ' - l i n k a g e g i v i n g t h e d i p y r r o l e ( V I I ) , P l a n c h e r proposed t h a t r i n g - c l o s u r e occurred  between t h e s u b s t i t u t e d  p y r r o l e n u c l e u s and t h e f r e e F i g u r e 3)«  ^ - p o s i t i o n o f one  /3-position o f the other  ((a) In  Upon e l i m i n a t i o n o f ammonia t h i s would g i v e t h e  F i g u r e 3.  Schemes proposed f o r the condensation of 2,4-dimethylpyrrole.  5  b i c y c l i c s t r u c t u r e ( V I I I ) ( 1 0 ) . T h i s s t r u c t u r e was l a t e r r e v i s e d t o an i n d o l e n i n e  ( I X ) which, ©lancher c l a i m e d , b e t t e r accounted  f o r the b a s i c i t y o f h i s p r o d u c t and a l s o a f f o r d e d a c l o s e r analogy w i t h a r e a c t i o n between a c e t o n y l a c e t o n e and p y r r o l e which gave [[.,7-dimethylindole  ( I I ) . The i n d o l e n i n e would r e s u l t  from c y c l i s a t i o n o f the d i p y r r o l e ( V I I ) by means o f the bond (b) i n F i g u r e 3°  S i n c e the s t r u c t u r e o f the i n t e r m e d i a t e  was n o t known ( a l t h o u g h  ( V I I ) would be most l i k e l y on s t e r i c  grounds) the p o s s i b i l i t y of t h r e e other had  dipyrrole  isomers o f the i n d o l e n i n e  t o be a d m i t t e d . The s t r u c t u r e o f t h e 2 , l ^ - d i m e t h y l p y r r o l e  condensation  p r o d u c t was l e f t i n doubt u n t i l 195>1, when S a x t o n took up t h e problem ( 1 2 ) . The p r o d u c t was shown t o be a p y r r o c o l i n e ( X ) , formed from t h e d i p y r r o l e by t h e l i n k a g e  (c) between t h e  c ( - p o s i t i o n o f one n u c l e u s and the n i t r o g e n atom o f t h e second. The p o s i t i o n s o f t h e m e t h y l groups i n the p y r r o c o l i n e ( V I I ) as t h e d i p y r r o l e I n t e r m e d i a t e .  established  S a x t o n found t h a t r e a c t i o n  of a c e t o n y l a c e t o n e w i t h 2,[}.-dimethylpyrrole  gave an i s o m e r i c  p y r r o c o l i n e ( V I ) , thus d i s m i s s i n g t h e i n d o l e n i n e s t r u c t u r e (V) proposed by P l a n c h e r f o r t h i s compound (11) C o n d e n s a t i o n p r o d u c t s have been r e p o r t e d t r i - and t e t r a s u b s t i t u t e d p y r r o l e s (13)« (2,]|-dimethyl-3-ethyl-)  for certain  Those f o r k r y p t o p y r r o l e  and p h y l l o p y r r o l e ( 2 , i ^ , 5 - t r i m e t h y l - 3 -  e t h y l - ) have been d u b i o u s l y  assigned  b i s s t r u c t u r e s (ll|.),  while  those from o t h e r t r i s u b s t i t u t e d p y r r o l e s have been f o r m u l a t e d i n d o l e s (l£).  as  Figure 4 .  Plancher's schemes f o r the r e d u c t i v e condensation o f 2 , 5 - d i m e t h y l p y r r o l e .  7  As e a r l y as 1897  i t was known t h a t 2 , 5 - d i m e t h y l p y r r o l e ,  on t r e a t m e n t w i t h z i n c and a c e t i c a c i d over a l o n g p e r i o d , gave a condensation product w i t h a molecular formula C^H^N The p r o d u c t was d e s c r i b e d as a b a s i c o i l which reddened i n a i r and e a s i l y s o l i d i f i e d . r e a c t i o n (10)  (16). rapidly  Plancher f i r s t explained t h i s  by an i n i t i a l r i n g - o p e n i n g o f one m o l e c u l e o f  2 , 5 - d i m e t h y l p y r r o l e , f o l l o w e d by c o n d e n s a t i o n o f the r e s u l t i n g a c e t o n y l a c e t o n e at the two  / 3 - p o s i t i o n s of a second p y r r o l e  m o l e c u l e t o g i v e the i s o i n d o l e ( X I ) .  On r e d u c t i o n , t h e i s o i n d o l e  would g i v e the Cj2 base by the s a t u r a t i o n o f one double bond, a l t h o u g h no s t r u c t u r e was proposed f o r t h e l a t t e r compound. A t the same time as he advanced the i n d o l e n i n e s t r u c t u r e ( I X ) f o r the 2,[}.-dimethylpyrrole c o n d e n s a t i o n p r o d u c t , P l a n c h e r suggested t h e i n d o l e n i n e ( X I I ) as the c o n d e n s a t i o n p r o d u c t o f a c e t o n y l a c e t o n e and 2 , 5 - d i m e t h y l p y r r o l e (11), h i s own p r e v i o u s i s o i n d o l e assignment.  thereby r e j e c t i n g  H i s r e a c t i o n scheme  i n v o l v e d c o n d e n s a t i o n o f the a c e t o n y l a c e t o n e ( i n t h e e n o l form) a t t h e oC- and  (5 - p o s i t i o n s o f the d i m e t h y l p y r r o l e . H i s reasons  f o r p r e f e r r i n g the i n d o l e n i n e ( X I I ) t o t h e i s o i n d o l e f o r m u l a t i o n (XI) were the same as .those which he p u t f o r w a r d i n f a v o u r o f the i n d o l e n i n e ( I X ) as the 2 , 1 ^ - d i m e t h y l p y r r o l e c o n d e n s a t i o n p r o d u c t namely, t h a t the i n d o l e n i n e ( X I I ) accounted more s a t i s f a c t o r i l y f o r the b a s i c i t y o f h i s p r o d u c t and t h a t the r e a c t i o n l e a d i n g t o i t s f o r m a t i o n p r e s e r v e d the a n a l p g y w i t h the a c e t o n y l a c e t o n e p y r r o l e condensation.  R e d u c t i o n o f one double bond o f the  i n d o l e n i n e ( X I I ) would g i v e a C ^ H j j N u n t i l now,  compound and t h i s base  a s s i g n e d the p a r t i a l s t r u c t u r e ( X I I I )  (17)«  was,  8  When S a x t o n , i n 1951|., showed t h a t P l a n c h e r ' s i n d o l e n i n e s t r u c t u r e (V) was i n c o r r e c t f o r the c o n d e n s a t i o n p r o d u c t o f a c e t o n y l a c e t o n e and 2 , 4 - d i m e t h y l p y r r o l e ( 1 2 ) , t h e i n d o l e n i n e ( X I I ) , f o r m u l a t e d as the 2,5>-dimethylpyrrole became q u e s t i o n a b l e .  condensation  product,  T h i s was e s p e c i a l l y so i n v i e w o f t h e l a c k  o f p o s i t i v e evidence f o r these i n d o l e n i n e s and P l a n c h e r ' s r e s e r v a t i o n s about h i s s t r u c t u r a l assignments  (11)»  I t seemed,  t h e r e f o r e , t h a t a r e i n v e s t i g a t i o n o f t h e 2,5-cTimethylpyrrole c o n d e n s a t i o n might prove f r u i t f u l immediate o b j e c t i v e o f condensing  0  T h i s was u n d e r t a k e n  with the  2 , 5 - d i m e t h y l p y r r o l e under  c o n d i t i o n s o f a c i d i c r e d u c t i o n t o o b t a i n t h e C12H.17N base. A f t e r t h e s t r u c t u r a l e l u c i d a t i o n o f t h i s compound and a s t u d y o f r e l a t e d r e a c t i o n s i t was hoped t h a t a mechanism f o r t h e condens a t i o n m i g h t be suggested.  CHAPTER I I REDUCTIVE CONDENSATION OP 2 , 5 - D l I IETHYLP YRR OLE V  2,5-dimethylpyrrole method (18)  and s u b j e c t e d  was p r e p a r e d by an e s t a b l i s h e d  t o c o n d i t i o n s o f a c i d i c reduction,,  F o r t h i s purpose i t was found c o n v e n i e n t t o r e p l a c e a c e t i c a c i d medium o f p r e v i o u s hydrochloric acid.  the z i n c and  workers (16) by t i n and d i l u t e  T h i s d e c r e a s e d r e a c t i o n time from s e v e r a l  days t o about 2lj. h o u r s .  B a s i f i c a t i o n of the r e a c t i o n mixture  f o l l o w e d by s t e a m - d i s t i l l a t i o n gave a r e d l i q u i d w h i c h was e x t r a c t e d w i t h e t h e r and 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 . p r o d u c t was a b a s i c o i l , b.p. 76-83°/0.7 mm., m o u s e - l i k e odour.  The  w i t h an u n p l e a s a n t ,  A l t h o u g h c o l o u r l e s s on d i s t i l l a t i o n , i t  reddened r a p i d l y i n a i r and, a f t e r p r o l o n g e d exposure t o t h e atmosphere, formed a powdery, w h i t e s o l i d - presumably by r e a c t i o n w i t h carbon d i o x i d e . Comparison o f these p r o p e r t i e s o f t h e base w i t h those of c e r t a i n i s o i n d o l i n e s revealed a s i m i l a r i t y .  For i n s t a n c e , the  p a r e n t compound i s o i n d o l i n e (19) and 1 - r a e t h y l i s o i n d o l i n e (20) a r e both r e p o r t e d as o i l s which redden i n a i r and absorb carbon d i o x i d e t o form s o l i d d e r i v a t i v e s .  The l a t t e r has a b p . o f 0  213°/758 mm. w h i l e t h a t o f N - m e t h y l i s o i n d o l i n e  (21)  i s g i v e n as  92-95°/25 mm. The densation  product o f the 2,5-dimethylpyrrole  p r o v e d , as p r e v i o u s l y r e p o r t e d  (16),  reductive  con-  t o be a C-^H-iyN  10 base and i t s s t r u c t u r e was shown t o be 1,3,1+s 7 - t e t r a m e t h y l i s o i n d o l i n e (XIV).  An account o f t h e e v i d e n c e which l e d t o t h i s  assignment f o l l o w s . I.  STRUCTURAL ELUCIDATION OP THE PRODUCT  P r e p a r a t i o n and a n a l y s i s o f d e r i v a t i v e s . The base r e a d i l y gave a n i t r a t e and a h y d r o c h l o r i d e , a n a l y s i s o f which i n d i c a t e d a molecular  f o r m u l a C12H17N f o r t h e base.  T i t r a t i o n of  the h y d r o c h l o r i d e w i t h s i l v e r n i t r a t e , u s i n g p o t a s s i u m chromate as i n d i c a t o r , gave an e q u i v a l e n t weight o f 208 ( c a l c . f o r c  1 2 H i 8 N C l , 212).  The n i t r o s o d e r i v a t i v e and the benzene-  sulphonamide o f t h e base were a l s o p r e p a r e d . p o s i t i v e r e s u l t t o Lieberraann's  The f o r m e r gave a  t e s t and t h e l a t t e r was i n s o l u b l e  i n a l k a l i ; hence, b o t h were d e r i v a t i v e s o f a secondary amine. R e a c t i o n o f t h e base w i t h c a r b o n d i o x i d e gave an adduct f o r w h i c h the carbamic a c i d s t r u c t u r e (XV) i s s u g g e s t e d . N-Methylation.  M e t h y l a t i o n o f t h e base was a c c o m p l i s h e d  using the Eschweiler-Clarke procedure.  The 1,2,3,^,7-pentamethyl-  i s o i n d o l i n e (XVI) was a b a s i c , v i s c o u s o i l which t u r n e d  yellow  i n a i r . I t s i n f r a r e d spectrum showed t h e absence o f NH a b s o r p t i o n and was c h a r a c t e r i s e d by t h e appearance o f a s t r o n g band a t 2760 cm." . 1  Wright (22) showed t h a t s t r o n g a b s o r p t i o n i n  t h i s r e g i o n can be a t t r i b u t e d t o t h e N-CH3 group o f a l i p h a t i c amines.  The p e n t a m e t h y l i s o i n d o l i n e gave a m e t h i o d i d e ( X V I I ) ,  a n a l y s i s of which confirmed I n f r a r e d spectrum.  t h e C12 m o l e c u l a r  f o r m u l a f o r t h e base.  The a b s o r p t i o n bands o f c h i e f  s i g n i f i c a n c e a r e shown i n T a b l e I .  •CH.  CH, N H  1  Sn + HCI  CH '  CK  }  .CCL.H CH.O +  NH  NCH.  HCO^H  X0 H 4  CO H  CH,  CH.  i  XVIII CH N X  cacH  XIV  XVI  CO,  X  CHjI  s  CO^CH, NCO H a  CO^CH, XIX  F i g u r e 5.  3  XVII  The r e d u c t i v e condensation o f 2 , 5 - d l m e t h y l p y r r o l e j d e r i v a t i v e s and o x i d a t i v e d e g r a d a t i o n of the product.  12  TABLE I CHIEF FEATURES OF THE INFRARED SPECTRUM OF 1, 3>k-» 7-TETRAMETHYLISOINDOLINE 3310 era."  (m) -  NH s t r e t c h  1865  (w) -  overtone  o f 931 era."  1603  (w) -  overtone  o f 806 cm."  ll).96  (s) -  a r o m a t i c C=C  931  (m) -  aromatic H (out-of-plane def.)  806  (s) -  The  1  "  1  "  s i n g l e , sharp NH a b s o r p t i o n suggested t h a t a  secondary amine group was p r e s e n t . and 806 cm.  1  S t r o n g bands a t llj.96 cm.  t o g e t h e r w i t h a s e r i e s o f peaks o f medium t o weak  i n t e n s i t y i n t h e 900-1225 cm." r e g i o n , supported 1  an a r o m a t i c  s t r u c t u r e , and t h e absence o f s t r o n g a b s o r p t i o n i n t h e 700-750 cm."  1  range suggested a s t r u c t u r e w i t h two a d j a c e n t  atoms on the benzene r i n g (23).  hydrogen  A, comparison was drawn between  a r o m a t i c a b s o r p t i o n i n t h e i n f r a r e d s p e c t r a o f the base and 1,2,3,l}.-tetramethylbenzene (2lj.), t h e l a t t e r showing fundamental a r o m a t i c bands a t 80I4. cm." and 936 cm." , and weak 1  bands c o r r e s p o n d i n g respectively.  1  overtone  t o these a t 1603 cm. ^ and 1865 cm.  The s i m i l a r i t y between t h e a r o m a t i c  absorptions  o f these two compounds was endorsed by t h e f a c t t h a t t e t r a a l k y l benzenes w i t h o t h e r s u b s t i t u t i o n p a t t e r n s show no a b s o r p t i o n i n the 1870 cm."*'" r e g i o n (2^).  I n f r a r e d evidence,  suggested t h a t a 1 , 2 , 3 , i | - - t e t r a s u b s t i t u t e d i n v o l v e d i n t h e s t r u c t u r e o f t h e base.  therefore,  benzene n u c l e u s was  13 U l t r a v i o l e t spectrum.  The u l t r a v i o l e t s p e c t r a o f t h e  base and i t s n i t r a t e and h y d r o c h l o r i d e d e r i v a t i v e s c o n f i r m e d t h e presence o f a benzene n u c l e u s , a l l showing the f i n e s t r u c t u r e c h a r a c t e r i s t i c o f the benzenoid methiodide  chromophoreo  The spectrum o f the  (XVII) (obtained from the base by E s c h w e i l e r m e t h y l a t i o n  and subsequent treatment w i t h m e t h y l i o d i d e ) a l s o showed t h e benzenoid  p a t t e r n o f a b s o r p t i o n and, moreover, c l o s e l y resembled  the spectrum o f 2 , i j . , 7 - t r i m e t h y l i s o i n d o l i n e m e t h i o d i d e  (XXIV)  (see F i g u r e 6, p. 1 8 ) ,  t h e s y n t h e s i s o f waich i s d e s c r i b e d i n  the f o l l o w i n g c h a p t e r .  A comparison was made w i t h the u l t r a (25)  v i o l e t spectrum o f ij.,7-dimethylindane  and a s i m i l a r i t y  noted.  The p o s i t i o n s o f a b s o r p t i o n maxima, w i t h e x t i n c t i o n c o e f f i c i e n t s i n parentheses,  are r e c o r d e d belows TABLE I I  THE ULTRAVIOLET SPECTRA OF 1,3,k>7-TETRAMETHYLIS0IND0LINE AND RELATED COMPOUNDS 1* 3j^>7-Tetramethyli s o i n d o l i n e (XIV)  265.5 m/*  271 m/A  H y d r o c h l o r i d e o f (XIV)  265 (377)  270.5 (322) 271* (307)  N i t r a t e o f (XIV)  265.5 (330)  270.5 (290) 27J4..5 (280)  w  1,2,3>sh» 7 - P e n t a m e t h y l i s o - 2 6 6 . 5 (34°) i n d o l i n e m e t h i o d i d e (XVII) 2,] ,7-Triraethylisoi n d o l i n e methiodide +  I4., 7-Dimethylindane  265.5 (300)  (XXIV)  26k  (290)  271 (282)  275.5 (313)  270.5 (25D 27l(..5 (272) 271 (200)  e x t i n c t i o n c o e f f i c i e n t s n o t determined o f carbon d i o x i d e . T  27I4. m;u  T  owing t o a b s o r p t i o n  shoulder. A l l s p e c t r a were determined w i t h e t h a n o l as s o l v e n t i n the case o f Ij.,7-dimethylindane ( i n isob'ctane).  except  Ik  The  c l o s e resemblance between t h e s p e c t r a o f the  t e t r a m e t h y l i s o i n d o l i n e and i t s s a l t s suggested t h a t n i t r o g e n was not a t t a c h e d d i r e c t l y t o t h e benzene r i n g (a r e s u l t i n c o n f o r m i t y w i t h the b a s i c i t y o f t h e i s o i n d o l i n e ) , s i n c e p r o t o n a t i o n o f t h e former produced no e v i d e n t e f f e c t on t h e e l e c t r o n i c a b s o r p t i o n of t h e l a t t e r .  The evidence from t h e u l t r a v i o l e t s p e c t r a o f  these compounds t h e r e f o r e s u p p o r t e d the f o r m u l a t i o n (XIV) as t h e s t r u c t u r e o f t h e base. Electrometric t i t r a t i o n .  The base i n 20% aqueous  e t h a n o l was t i t r a t e d a g a i n s t s t a n d a r d i s e d h y d r o c h l o r i c a c i d u s i n g a Beckmann pH meter.  The t i t r a t i o n curve gave a p K  a  value f o r  the base o f 8 . 9 , and an e q u i v a l e n t weight o f 178 ( c a l c . f o r C12H17N, 175)•  The f a i r l y s t r o n g l y b a s i c n a t u r e  o f t h i s compound  i s c o n s i s t e n t w i t h i t b e i n g an a l i p h a t i c amine, and a comparison w i t h known p K  a  values  showed t h a t I t s d i s s o c i a t i o n c o n s t a n t  was  o f t h e c o r r e c t o r d e r o f magnitude f o r an i s o i n d o l i n e such as (XIV). TABLE I I I pK  a  VALUES OP 1,3,1}-, 7-TETRAMETHYLISOINDOLINE AND RELATED COMPOUNDS  N-methylisoindoline cellosolve)  ( i n Q0% methyl  7»7  (26)  l , 3 , l j - , 7 - T e t r a m e t h y l i s o i n d o l i n e (XIV) ( i n 20% aqueous e t h a n o l )  8.9  Benzylamine ( i n w a t e r )  9.3  (27)  oC-Methylbenzylamine ( i n w a t e r )  9o5  (28)  Oxidative degradation.  F u r t h e r evidence f o r a 1,2,3,k~  t e t r a s u b s t i t u t i o n p a t t e r n around a benzene n u c l e u s was a f f o r d e d  15  by o x i d a t i o n o f t h e base.  Treatment w i t h a l k a l i n e permanganate  gave a 32$ y i e l d o f b e n z e n e - 1 , 2 , 3 , i + - t e t r a c a r b o x y l i c  acid (XVIII) .  E s t e r i f i c a t i o n o f t h i s a c i d w i t h diazomethane c o n v e r t e d i t t o the t e t r a m e t h y l e s t e r ( X I X ) , which was i d e n t i f i e d by a mixed m e l t i n g p o i n t and i n f r a r e d comparison w i t h an a u t h e n t i c sample ( p r e p a r e d b y o x i d a t i o n o f 1,2, 3, 4,-tetramethylbenzene). P r o t o n magnetic resonance  spectrum.  Confirmation of  the s t r u c t u r e o f t h e base was p r o v i d e d by i t s p r o t o n magnetic resonance  spectrum  ( n e a t , a t lf.0 mc. s e c . , u s i n g - 1  as e x t e r n a l s t a n d a r d ) .  Chemical  shifts  dichloromethane  (given i n T values),  s p i n - s p i n s p l i t t i n g , and a r e a r a t i o s s u p p o r t e d t h e t e t r a m e t h y l i s o i n d o l i n e f o r m u l a t i o n (XIV) as t h e s t r u c t u r e o f t h e r e d u c t i v e condensation product of 2,5-dimethylpyrrole. TABLE IV THE PROTON MAGNETIC RESONANCE SPECTRUM OP 1,3,k>7-TETRAMETHYLIS0INDOLINE Field  (T)  3olj.  Splitting sing.  6.0  quad.(J=7cps.)  8.2  sing.  8.9  doub.(J=7cps.)  Area  Assignment  1.0  armomatic H  1.0  H a t 1 & 3 s p l i t by CH3 at those p o s i t i o n s  2.9  CH3 a t I4. & 7  2.8  CH3 a t 1 & 3 s p l i t by H at those p o s i t i o n s  Comparison w i t h a comprehensive l i s t o f c h e m i c a l  shifts  g i v e n by T i e r s (29) showed t h a t the above v a l u e s were c o n s i s t e n t l y h i g h by about 0.5  T units.  This I s not s u r p r i s i n g i n view o f the  f a c t that T i e r s ' values are reported f o r d i l u t e s o l u t i o n , f o r i t  16  has been shown t h a t c h e m i c a l s h i f t s a r e g e n e r a l l y g r e a t e r f o r the pure l i q u i d t h a n f o r i t s d i l u t e s o l u t i o n , o f t e n b y c o n s i d e r a b l e amounts ( 3 0 ) .  I n a d d i t i o n t o any e f f e c t s due t o changes i n  b u l k d i a m a g n e t i c s u s c e p t i b i l i t y , each m o l e c u l e o f t h e pure l i q u i d i s i n a q u i t e s t r o n g l y b a s i c environment  and t h i s might be  e x p e c t e d t o make a f u r t h e r c o n t r i b u t i o n t o t h e d i a m a g n e t i c shielding. The r a t i o o f areas o f t h e s i g n a l s i s i n good agreement w i t h t h e s t a t i s t i c a l weight o f each type o f hydrogen, and t h e magnitude o f t h e s p l i t t i n g c o n s t a n t ( J ) i s c o n s i s t e n t w i t h c o u p l i n g between p r o t o n s l o c a t e d on a d j a c e n t carbons o f a saturated  system. II.  STEREOCHEMISTRY OP THE PRODUCT  The e v i d e n c e a l r e a d y p r e s e n t e d e s t a b l i s h e d t h e r e d u c t i v e c o n d e n s a t i o n p r o d u c t o f 2 , 5 - d i m e t h y l p y r r o l e as l,3,l4->7t e t r a m e t h y l i s o i n d o l i n e (XIV).  Examination of t h i s structure  r e v e a l e d the p o s s i b i l i t y o f c i s - t r a n s isomerism w i t h respect t o t h e m e t h y l groups a t p o s i t i o n s 1 and 3«  The c i s form has a p l a n e  of symmetry and i s t h e r e f o r e i n t h e meso c o n f i g u r a t i o n , w h i l e t h e t r a n s form s h o u l d be r e s o l v a b l e .  Attempts t o i s o l a t e such  by f r a c t i o n a l d i s t i l l a t i o n and vapour phase chromatography,  isomers as  w e l l as an attempted r e s o l u t i o n o f t h e base, have so f a r p r o v e d unsuccessful.  CHAPTER I I I RELATED ISOINDOLINES I.  2,1^7-TRIMETHYXrSOINDOLINE  Having e s t a b l i s h e d t h e s t r u c t u r e o f the 1,3,1)., 1t e t r a m e t h y l i s o i n d o l i n e (XIV) (see F i g u r e 5>, P» 11), the p o s s i b i l i t y o f s y n t h e s i s i n g t h i s o r a c l o s e l y r e l a t e d compound by an a l t e r n a t i v e r o u t e was considered,,  I n t h i s way  supplementary  evidence f o r t h e s t r u c t u r e o f t h e base would be o b t a i n e d .  The  r o u t e chosen i s shown i n F i g u r e 6 and was d e s i g n e d t o l e a d t o t h e 1,2,3,^,7-pentamethylisoindoline  (XVI).  A l t h o u g h t h i s was not  a c h i e v e d (a r e s u l t x-rtiich may be e x p l a i n e d i n terms o f the cons i d e r a b l e s t e r i c i n t e r f e r e n c e i n v o l v e d I n t h e 1,2,3,1}.,7-pentas u b s t i t u t e d system), i t d i d prove p o s s i b l e t o p r e p a r e 2,1}., 1trimethylisoindoline (XXIII).  The resemblance between t h e  u l t r a v i o l e t s p e c t r a o f the m e t h i o d i d e and the m e t h i o d i d e  (XXIV) o f t h i s compound  ( X V I I ) o f the p e n t a m e t h y l i s o i n d o l i n e (see  F i g u r e 5, P« 11) p r o v i d e d f u r t h e r support f o r (XIV) as t h e s t r u c t u r e of the 2,5-dimethylpyrrole r e d u c t i v e condensation product. The s y n t h e t i c scheme s t a r t e d w i t h t h e c o n v e r s i o n o f a c e t o n y l a c e t o n e t o 2 , 5 - d i m e t h y l f u r a n , w h i c h then underwent a smooth D i e l s - A l d e r r e a c t i o n w i t h m a l e i c a n h y d r i d e t o g i v e t h e adduct ( X X ) . T h i s compound may e x i s t i n e i t h e r an exo or endo  CH,  CH.  CH.CO II CH. CO-  CK  CH,  L;AIH  3  NCH, <-  4  XXIII  CH,NH  a  CH,  XXII •)CH M I z)LAIH 3  CHjl  9  4  CI  TJ V  O  ,  NCK  CH  C }  H  ,  °«  XXV  XXIV  F i g u r e 6.  The s y n t h e s i s  of^2,4-,7-trimethylisoindoline  19  c o n f i g u r a t i o n and, w h i l e e a r l y o p i n i o n s endo p r o d u c t s  (31) f a v o u r e d e x c l u s i v e l y  from D i e l s - A l d e r r e a c t i o n s , i t has been shown t h a t  a d d i t i o n o f m a l e i c a n h y d r i d e t o f u r a n i n e t h e r g i v e s an adduct w i t h t h e exo c o n f i g u r a t i o n (32). adduct w i t h c o n c e n t r a t e d 3,6-dimethylphthalic  Treatment o f the D i e l s - A l d e r  s u l p h u r i c a c i d a t - 8 ° gave  anhydride (XXI).  On warming t h e d i m e t h y l -  p h t h a l i c a n h y d r i d e w i t h methylamine, N-methyl-3,6-dimethylphthalimide  ( X X I I ) r e s u l t e d , and t h i s compound served as an  i n t e r m e d i a t e on which s e v e r a l a t t e m p t s a t t h e s y n t h e s i s o f 1,2,3,^.,7-pentamethylisoindoline  were based.  By a n a l o g y w i t h a known s y n t h e s i s o f a 1 - s u b s t i t u t e d i s o i n d o l i n e (33)*  t h e t r i m e t h y l p h t h a l i m i d e was t r e a t e d f i r s t  l i t h i u m m e t h y l and t h e n , w i t h o u t  with  i s o l a t i o n o f an i n t e r m e d i a t e ,  r e a c t e d w i t h l i t h i u m aluminium h y d r i d e .  E v i d e n t l y no r e a c t i o n  occurred w i t h the l i t h i u m methyl s i n c e the product,  a basic o i l  w h i c h t u r n e d y e l l o w on s t a n d i n g , p r o v e d t o be t h e r e s u l t o f d i r e c t reduction of (XXII).  T h i s p r o d u c t was i d e n t i f i e d as 2 , i i , 7 -  t r i m e t h y l i s o i n d o l i n e ( X X I I I ) by e l e m e n t a l  analyses  o f the  h y d r o c h l o r i d e and m e t h i o d i d e d e r i v a t i v e s . The c l o s e c o r r e s pondence between t h e u l t r a v i o l e t spectrum o f t h i s m e t h i o d i d e (XXIV) and t h e m e t h i o d i d e (XVII) has been p r e v i o u s l y n o t e d (see T a b l e I I , p. 1 3 ) . The  i n f r a r e d spectrum o f ( X X I I I ) as a t h i n f i l m showed  a s t r o n g band a t 2770 cm."" , a t t r i b u t e d t o N-CH3 (22), and s t r o n g 1  a b s o r p t i o n a t 805 cm." . 1  phthalimide  Both bands were absent i n t h e  and t h e l a t t e r appears t o be c h a r a c t e r i s t i c o f t h e  1 , 2 , 3 > l | - - t e t r a a l k y l s u b s t i t u t e d benzene system.  20  A G r i g n a r d r e a c t i o n on the t r i m e t h y l p h t h a l i r a i d e ( X X I I ) , f o l l o w e d by an a t t e m p t e d l i t h i u m aluminium h y d r i d e  hydrogenolysis,  produced a compound w h i c h i s p r o b a b l y the N-methyl-3,l|.,7-trimethyl-3-hydroxyphthalimidine  (XXV).  The  evidence  i n favour  of  t h i s s t r u c t u r e comprises a s a t i s f a c t o r y e l e m e n t a l a n a l y s i s and  an  -1 i n f r a r e d spectrum which showed a broad a b s o r p t i o n a t 3390 cm. corresponding of a  t o OH,  ,  and a s t r o n g c a r b o n y l band c h a r a c t e r i s t i c  J f - l a c t a m a t l 6 ? 8 cm.""'. 1  The p h t h a l i m i d i n e was  apparently  formed by r e a c t i o n o f the p h t h a l i m i d e w i t h one mole o f m e t h y l magnesium i o d i d e ( d e s p i t e the p r e s e n c e of a c o n s i d e r a b l e e x c e s s ) , the second c a r b o n y l f u n c t i o n r e m a i n i n g u n a t t a c k e d .  A reaction  o f t h i s type i s not w i t h o u t p r e c e d e n c e , f o r G r i g n a r d r e a c t i o n s w i t h N - s u b s t i t u t e d s u c c i n i m i d e s has been used as a g e n e r a l s y n t h e t i c route to 1 , 5 , 5 - t r i s u b s t i t u t e d 2-pyrrolidones.  Lukes,  f o r example, r e p o r t s a g e n e r a l r e a c t i o n between N-methyll-methyl-5,5'-  s u c c i n i m i d e and a l k y l magnesium bromides t o g i v e  a l k y l h y d r o x y p y r r o l i d o n e s (34.), and W a l t o n has used a s i m i l a r r e a c t i o n between N - s u b s t i t u t e d s u c c i n i m i d e s and reagents  to obtain pyrrolidones The  (35)«  f a i l u r e o f the p h t h a l i m i d e  two moles o f G r i g n a r d reagent  Grignard  (XXII) to r e a c t with  i s p r o b a b l y due t o s t e r i c  I n the case o f the p h t h a l i m i d e the m e t h y l r a d i c a l the c a r b o n y l f u n c t i o n o f the p h t h a l i m i d i n e (XXV)  factors.  approaching i s obstructed  by the m e t h y l group at the 7 - p o s i t i o n ( c o - p l a n a r w i t h the r i n g system) as w e l l as by the n e i g h b o u r i n g m e t h y l group a t n i t r o g e n and a 1 , 3 - i n t e r a c t i o n a c r o s s the five-membered r i n g . g e n o l y s i s o f (XXV)  I f hydro-  c o u l d be a c h i e v e d , f u r t h e r r e a c t i o n w i t h  21  G r i g n a r d r e a g e n t would become more f e a s i b l e . hydrogenolysis II.  have so f a r proved u n s u c c e s s f u l , however. 1, 3-DIPHENYL-l*, 7-DIMETHYLIS0IND0LINE 1,3,l+»7-tetramethylisoindoline  When t h e s t r u c t u r e o f (XIV)  Attempts a t such  (see F i g u r e 5 , p. 11 ) had been c o n f i r m e d  investigate the a p p l i c a t i o n of the reductive  i t was d e c i d e d t o condensation  r e a c t i o n t o other 2 , 5 - d i s u b s t i t u t e d p y r r o l e s .  I f successful,  t h i s would g i v e r i s e t o i s o i n d o l i n e s w i t h t h e same s u b s t i t u t i o n p a t t e r n as (XIV) but w i t h v a r i a t i o n s i n t h e s u b s t i t u e n t groups. To t h i s end, 2 , 5 - d i p h e n y l p y r r o l e  was p r e p a r e d  d i b e n z o y l e t h y l e n e by h y d r o g e n a t i o n ammonia.  from t r a n s -  and a u t o c l a v e r e a c t i o n w i t h  I t was o b t a i n e d as g r e e n i s h - y e l l o w f l a k e s and, u n l i k e  the 2 , 5 - d i a l k y l p y r r o l e s , was s t a b l e i n a i r . An attempt t o condense the d i p h e n y l p y r r o l e w i t h u s i n g the t i n and h y d r o c h l o r i c a c i d c o n d i t i o n s , f a i l e d ,  itself,  suggesting  t h a t e i t h e r e x c e s s i v e s t e r i c i n t e r a c t i o n i n an i n t e r m e d i a t e o r t h e c o n j u g a t i n g e f f e c t o f two phenyl r i n g s p r e v e n t e d analogous t o t h a t o f t h e 2 , 5 - d i m e t h y l p y r r o l e .  a reaction  E a r l i e r workers  (8) n o t i c e d a s i m i l a r l a c k o f r e a c t i v i t y i n 2 - p h e n y l p y r r o l e compared w i t h t h e 2 - a l k y l p y r r o l e s , t h e p h e n y l p y r r o l e f a i l i n g t o g i v e an i n d o l e a l t h o u g h  i t d i d form a d i p y r r o l e by c o u p l i n g a t  the f r e e c C - p o s i t i o n ( s e e p. 3 ) . When a m i x t u r e  of acetonylacetone  and 2 , 5 - d i p h e n y l -  p y r r o l e was s u b j e c t e d t o t h e same a c i d i c , r e d u c i n g c o n d i t i o n s a deep w i n e - r e d c o l o u r r e s u l t e d i n i t i a l l y .  On p r o l o n g e d  refluxing  t h i s f a d e d t o a p a l e y e l l o w as r e d u c t i o n o f t h e h i g h l y - c o l o u r e d  H /Pd  w H  /  2  ?kCO.CH .CH CO/Ph a  r  \o.Ph  XXVII  F i g u r e 7.  -y  XXVIII  The s y n t h e s i s o f l , 3 - d i p h e n y l - 4 , 7 - d i m e t h y l i s o i n d o l i n e and d e r i v a t i v e s .  23  i n t e r m e d i a t e took p l a c e .  A f t e r b a s i f i c a t i o n o f the r e a c t i o n  m i x t u r e and e x t r a c t i o n w i t h benzene, a p a l e y e l l o w s o l i d was  obtained.  T h i s p r o d u c t was  4,7-dimethylisoindoline  crystalline 1,3-diphenyl-  i d e n t i f i e d as  (XXVI), s u p p o r t i n g evidence  being  o b t a i n e d from e l e m e n t a l a n a l y s i s o f t h i s compound and d e r i v a t i v e s and from i t s i n f r a r e d and u l t r a v i o l e t s p e c t r a . Derivatives.  Treatment o f the  i s o i n d o l i n e (XXVT) w i t h sodium n i t r i t e d e r i v a t i v e (XXVII). t h a t t h i s was Reduction  diphenyldimethyl-  s o l u t i o n gave the n i t r o s o  A p o s i t i v e Liebermann's t e s t e s t a b l i s h e d (3&).  the d e r i v a t i v e of a secondary amine  o f the n i t r o s o amine w i t h z i n c and a c e t i c a c i d produced  the N-amino d e r i v a t i v e ( X X V I I I ) i n which the p r i m a r y was  d e t e c t e d by the appearance of WH  (w) and 3311  cm.  ^ (m)  f o r the p a r e n t isoindoline The  a b s o r p t i o n at 3378 cm."*'" 1  i n the i n f r a r e d spectrum.  these two d e r i v a t i v e s c o n f i r m e d  A n a l y s i s of  the C22H21N-molecular  compound which was  amino group  formula  i n d i c a t e d by a n a l y s i s o f the  itself. i s o i n d o l i n e (XXVT) showed a marked decrease i n  b a s i c i t y as compared w i t h 1 , 3 , 4 . , 7 - t e t r a r a e t h y l i s o i n d o l i n e (a f a c t w h i c h may  be a t t r i b u t e d t o the r e p l a c e m e n t o f the 1-  and  3-  m e t h y l groups by e l e c t r o n - w i t h d r a w i n g p h e n y l g r o u p s ) , but i t d i d form a s a l t w i t h hydrogen c h l o r i d e .  T h i s d e r i v a t i v e , when  t i t r a t e d against s i l v e r n i t r a t e (using potassium i n d i c a t o r ), gave an e q u i v a l e n t weight o f 336 C22H22NCI,  336).  chromate as  (calc. for  2i|.  I n f r a r e d spectrum. isoindoline  The i n f r a r e d spectrum o f t h e  (XXVI) showed an expected  increase i n complexity i n  the fundamental a r o m a t i c r e g i o n compared t o t h e spectrum o f 1>3ihs7-tetraraethylisoindoline at 698  (see p. 10).  Strong absorption  w i t h a s l i g h t l y weaker band a t 753  cm.  cm." i n d i c a t e d 1  benzene r i n g s (37)=  the presence o f m o n o s u b s t i t u t e d  The band  which p r e v i o u s l y c h a r a c t e r i s e d the 1,2,3,l4.-tetrasubstituted  -1 benzene system ( a t 800  cm.  what d i m i n i s h e d i n t e n s i t y . cm.  -1 ) had moved t o 817  cm. • w i t h some-  The NH a b s o r p t i o n o c c u r r e d a t ?>2>h)\  w i t h t h e s i m g l e , sharp band c h a r a c t e r i s t i c o f secondary  amines  (38). U l t r a v i o l e t spectrum.  The u l t r a v i o l e t s p e c t r a o f the  i s o i n d o l i n e (XXVI) and i t s h y d r o c h l o r i d e (both i n e t h a n o l ) showed t h e f i n e s t r u c t u r e o f t h e benzenoid  chromophore w i t h t h e  enhanced e x t i n c t i o n c o e f f i c i e n t expected f o r t h r e e benzene r i n g s .  unconjugated  A comparison was made w i t h t h e u l t r a v i o l e t  spectrum o f o-dibenzylbenzene  (39)  and the s i m i l a r i t y  noted.  P o s i t i o n s o f a b s o r p t i o n maxima, w i t h e x t i n c t i o n c o e f f i c i e n t s i n parentheses,  a r e shown i n Table V. TABLE V  THE ULTRAVIOLET SPECTRA OP 1,3-DIPHENYL-J+, 7-DIMETHYLIS0IND0LINE AND RELATED COMPOUNDS The  Isoindoline (XXVI)  Hydrochloride o f (XXVI)  o-Dibenzylbenzene  253  akk)  253 ™/± (ij.78)  258  (817)  258  (665)  257 ny* (813)  265  (7kk)  265 269  (712) (622)  263 269  (832) (692)  25  The u l t r a v i o l e t spectrum o f the d i p h e n y l p y r r o l e r e d u c t i v e condensation  acetonylacetone-  p r o d u c t e l i m i n a t e d the  p o s s i b i l i t y o f an i s o i n d o l e f o r m u l a t i o n , which seemed t h e most l i k e l y a l t e r n a t i v e t o (XXVI).  The r e p o r t e d spectrum o f  2-methyl-l,3-diphenylisoindole  i n dioxan  (I4.O) showed  Amax.  380 (£ 20,000) and 280 ny*. (£ 18,000) w i t h a s h o u l d e r a t 270 m/+  {£ l 4 , 0 0 0 ) o As i n t h e case o f 1 , 3 » h » 7 - t e t r a m e t h y l i s o i n d o l i n e ,  i t  was r e a l i s e d t h a t c i s - t r a n s i s o m e r i s m c o u l d occur a t t h e 1 , 3 - p o s i t i o n s o f t h e i s o i n d o l i n e (XXVI).  However, chromatography  of t h e 1 , 3 - d i p h e n y l 7 - d i m e t h y l i s o i n d o l e  on f l o r i s i l ,  as w e l l as  f r a c t i o n a l c r y s t a l l i s a t i o n o f i t and i t s d e r i v a t i v e s , f a i l e d t o r e v e a l any e v i d e n c e o f i s o m e r i c p r o d u c t s .  I n view o f t h e s t e r i c  i n t e r f e r e n c e w h i c h would be e x p e c t e d i f the p h e n y l (XXVT) were c i s t o each o t h e r , i t was concluded  groups i n  t h a t t h e more  s t a b l e t r a n s isomer was p r o b a b l y formed, perhaps w i t h t h e e x c l u s i o n of the c i s isomer. I t seems l i k e l y t h a t t h e r e a c t i o n between and 2 , 5 - d i p h e n y l p y r r o l e  acetonylacetone  i s a s p e c i a l case o f a more g e n e r a l  r e a c t i o n between l,lj.-diketones and 2 , 5 - d i s u b s t i t u t e d p y r r o l e s , e s p e c i a l l y s i n c e t h e r e i s some e v i d e n c e t h a t of these p y r r o l e s occurs by a r i n g - o p e n i n g  self-condensation  process  (see f o l l o w i n g  chapter).  I f t h i s i s s o , t h e n t h i s r o u t e a f f o r d s a n o v e l and  convenient  synthesis of substituted isoindolines.  The s i m p l e s t  and most u s e f u l a p p l i c a t i o n o f t h i s r e a c t i o n i s t h e case where the 2 , 5 - d i s u b s t i t u t e d p y r r o l e i s r e s i s t a n t t o s e l f - c o n d e n s a t i o n ( a s , f o r example, w i t h 2 , 5 - d i p h e n y l p y r r o l e ) , s i n c e , i n these circumstances,  o n l y one p r o d u c t may be e x p e c t e d .  CHAPTER IV THE MECHANISM OP THE 2,5-DIMETHYLPYRROLE CONDENSATION  In  c o n s i d e r i n g a mechanism f o r t h e s e l f - c o n d e n s a t i o n  of 2 , 5 - d i m e t h y l p y r r o l e two p o s s i b i l i t i e s have been f a v o u r e d . The f i r s t o f these i s a D i e l s - A l d e r type o f a d d i t i o n o f a protonated p y r r o l e molecule t o a n e u t r a l molecule, according t o the scheme shown I n F i g u r e 8 ( o v e r ) . mechanism was t h a t proposed  The second p o s s i b l e  o r i g i n a l l y by P l a n c h e r (10) (see p.  5) b u t l a t e r abandoned by him. T h i s i n v o l v e s r i n g - o p e n i n g o f a m o l e c u l e o f 2 , 5 - d i m e t h y l p y r r o l e t o form  acetonylacetone,  f o l l o w e d by c o n d e n s a t i o n o f t h e d i k e t o n e a t t h e another p y r r o l e m o l e c u l e .  -positions of  The r e s u l t i n g i s o i n d o l e i n t e r m e d i a t e  then undergoes r e d u c t i o n t o t h e t e t r a m e t h y l i s o i n d o l i n e . scheme i s shown i n F i g u r e 10, p. 32.  This  These two mechanisms  will  now be r e v i e w e d i n d e t a i l . I.  DIELS-ALDER  MECHANISM  E v i d e n c e from n u c l e a r magnetic resonance  s p e c t r a has  i n d i c a t e d that, i n a c i d i c s o l u t i o n , a l k y l p y r r o l e s are protonated p r e d o m i n a n t l y a t t h e ©(-position (1+1).  The r e s u l t i n g p y r r o l e n i n e  (XXIX) i s analogous  -unsaturated S c h i f f ' s  t o a protonated,  base and, as such, might be expected t o have some degree o f dienophilic character. of  A d d i t i o n of t h i s species t o a molecule  2 , 5 - d i m e t h y l p y r r o l e behaving as a diene i n t h e D i e l s - A l d e r  27  Figure  8.  A proposed D i e l s - A l d e r mechanism f o r the reductive  condensation  of  2,5-dimethylpyrrole.  28  f a s h i o n c o u l d l e a d t o the adduct (XXX)  w h i c h , on  reduction,  b a s i f I c a t i o n , and  e l i m i n a t i o n o f ammonia, might g i v e  isoindoline.  intermediate  The  (XXX), as i n the case o f  adduct of 2 , 5 - d i m e t h y l f u r a n and m a l e i c 6,  p. 18),  may  the  a n h y d r i d e ((XX)  have the exo or endo c o n f i g u r a t i o n .  o f the d i r a e t h y l p y r r o l e c o n d e n s a t i o n , ammonia was  the i n Figure  I n the case  detected  on  making the r e a c t i o n m i x t u r e a l k a l i n e and e l i m i n a t i o n had probably occurred had  i n the a c i d i c medium j u s t as the adduct  (XX)  r e a d i l y e l i m i n a t e d water under a c i d i c c o n d i t i o n s . U n l i k e the f u r a n s and  a considerable  thiophenes which are endowed w i t h  measure o f d i e n i c c h a r a c t e r , p y r r o l e s are  g e n e r a l l y a c t i v e as d i e n e s i n the D i e l s - A l d e r r e a c t i o n .  not The  u s u a l r e s u l t o f b r i n g i n g a p y r r o l e and d i e n o p h i l e i n t o c o n t a c t a d d i t i o n of the l a t t e r t o the (I4.2,i|/3,l|4).  The  few  o ( - p o s i t i o n of the p y r r o l e n u c l e u s  i s o l a t e d instances  of authentic  Diels-Alder  a d d i t i o n t o p y r r o l e s which are known have been r e p o r t e d p a r a t i v e l y r e c e n t l y and  is  com-  i n c l u d e the a d d i t i o n of dehydrobenzene t o  N - m e t h y l p y r r o l e g i v i n g (XXXI) ( 1 | 5 ) , and the r e a c t i o n between N-benzylpyrrole (i|.6).  and a c e t y l e n e d i c a r b o x y l i c a c i d to g i v e  (XXXII)  A t h i r d example i s the r e a c t i o n between N-carbomethoxy-  p y r r o l e and  the d i m e t h y l  e s t e r o f a c e t y l e n e d i c a r b o x y l i c a c i d (ij.7).  T h i s g i v e s 1 , 3 , ^ - t r i c a r b o m e t h o x y p y r r o l e and  acetylene  by  d e c o m p o s i t i o n o f the suggested i n t e r m e d i a t e  (XXXITI),  which  was  not i s o l a t e d . These cases o f p y r r o l e s u n d e r g o i n g a D i e l s - A l d e r r e a c t i o n appear to owe  t h e i r existence  t o an u n u s u a l c o n d i t i o n  o f decreased a r o m a t i c i t y and i n c r e a s e d d i e n i c c h a r a c t e r  of  the  XXXIV CN  H XXXV  Figure 9.  Products of the r e a c t i o n of c e r t a i n p y r r o l e with dienophiles.  30  p y r r o l e n u c l e u s i n the compounds involved,, p y r r o l e t h i s has been e x p l a i n e d  W i t h N-carbomethoxy-  (1*7) by the  electron-withdrawing  e f f e c t of the e s t e r group, w h i c h thus i n h i b i t s c o n j u g a t i o n the n i t r o g e n e l e c t r o n p a i r w i t h the the system.  of  t r - e l e c t r o n s o f the r e s t o f  A decrease i n a r o m a t i c i t y o f the p y r r o l e n u c l e u s  a l s o been p o s t u l a t e d as r e s p o n s i b l e f o r the a d d i t i o n (1*6).  has  N-benzylpyrrole  No comparable e f f e c t s appear t o o p e r a t e t o  enhance the d i e n i c c h a r a c t e r o f 2 , 5 - d i m e t h y l p y r r o l e  and a D i e l s -  A l d e r r e a c t i o n i n v o l v i n g t h i s compound would, t h e r e f o r e , be somewhat unexpected. A f u r t h e r o b j e c t i o n t o a D i e l s - A l d e r mechanism f o r the 2,5-dimethylpyrrole solvent.  The  condensation  concerns the n a t u r e  of the  aqueous c o n d i t i o n s o f the i s o i n d o l i n e p r e p a r a t i o n  are not t h o s e i n w h i c h D i e l s - A l d e r syntheses are n o r m a l l y c a r r i e d out - an I n e r t h y d r o c a r b o n o r e t h e r e a l s o l v e n t b e i n g most commonly preferred. The  a b i l i t y of 2,5-dimethylpyrrole  A l d e r r e a c t i o n was d i e n o p h l l e s known.  t e s t e d w i t h two  t o undergo a D i e l s -  o f the most r e a c t i v e  M a l e i c a n h y d r i d e gave o n l y a d a r k r e d , p o l y -  m e r i c substance ( c f . 1*8),  while tetracyanoethylene  g i v e a compound which was  not an a d d u c t .  to  T h i s l a t t e r compound,  the o n l y p r o d u c t observed i n t h e r e a c t i o n , was 2,5=dimethyl-3-tricyanovinylpyrrole  reacted  considered  to be  (XXXV) on t h e b a s i s of i t s  a n a l y s i s , i t s i n f r a r e d spectrum (which  showed NH a b s o r p t i o n ) ,  the a n a l o g y w i t h the r e a c t i o n o f p y r r o l e and  and  tetracyanoethylene  which g i v e s (XXXIV) ( 1 * 9 ) . Since tetracyanoethylene,  which would be expected to be  a s t r o n g e r d i e n o p h i l e t h a n the p r o t o n a t e d  pyrrolenine  (XXIX),  31  f a i l e d t o e l i c i t any d i e n i c c h a r a c t e r from  2,5-dimethylpyrrole,  an a d d i t i o n r e a c t i o n o f the type shown i n F i g u r e 8 must be r e g a r d e d as u n l i k e l y .  In f a c t , the product  (XXXV), which i s the  r e s u l t of e l e c t r o p h i l l c s u b s t i t u t i o n by t e t r a c y a n o e t h y l e n e , t e s t i f i e s t o the a r o m a t i c r a t h e r t h a n d i e n i c n a t u r e of the p y r r o l The  e v i d e n c e , t h e r e f o r e , argues a g a i n s t a D i e l s - A l d e r mechanism  f o r the c o n d e n s a t i o n process„ II.  RING-OPENING MECHANISM  Pyrroles exhibit a c e r t a i n f a c i l i t y with regard to r i n g - o p e n i n g by aqueous a l k a l i , a r e a c t i o n which i s a c c e l e r a t e d by a l k y l groups but r e t a r d e d by p h e n y l , a c y l , and c a r b o x y l groups (50).  Plancher  (10),  as e a r l y as 1905,  of t h i s b e i n g the i n i t i a l 2,5-dimethylpyrrole  r e a l i s e d the  possibility  step i n t h e c o n d e n s a t i o n r e a c t i o n o f  (see p. 5)•  A l t h o u g h r i n g - o p e n i n g by a c i d ,  as i n the f u r a n s e r i e s , i s not g e n e r a l l y p o s s i b l e w i t h p y r r o l e s , i t has been shown t h a t w i t h Brady's reagent  2,5-dimethylpyrrole  s u f f e r s c l e a v a g e t o g i v e a p r o d u c t which i s f i x e d as 2,lj.-dinitrophenylhydrazone d e r i v a t i v e T h i s r e s u l t was  the  (Ij.8).  v e r i f i e d and extended by comparing the  r e a c t i o n of 2 , 5 - d i m e t h y l p y r r o l e , 2 , 5 - d i p h e n y l p y r r o l e , acetonylacetone w i t h 2,l|.-dinitrophenylhydrazine.  and  I t was  found  t h a t a c e t o n y l a c e t o n e and 2 , 5 - d i m e t h y l p y r r o l e gave d e r i v a t i v e s i m m e d i a t e l y ; t h e s e were i d e n t i c a l (by mixed m e l t i n g p o i n t and  a  comparison o f i n f r a r e d s p e c t r a ) and, by a n a l y s i s , were shown t o be the b i s - 2 , [ { . - d i n i t r o p h e n y l h y d r a z o n e of a c e t o n y l a c e t o n e 2,5-Diphenylpyrrole  ( c f . (I4.8  gave no d e r i v a t i v e even a f t e r s e v e r a l weeks  32  Figure  10.  A proposed r i n g - o p e n i n g mechanism f o r the r e d u c t i v e condensation o f 2 , 5 - d i m e t h y l p y r r o l e .  33 and i t appeared t h a t r i n g - o p e n i n g was c o m p l e t e l y i n h i b i t e d i n t h i s case.  Thus, a p a r a l l e l between r i n g - o p e n i n g and c o n d e n s a t i o n  i s e v i d e n t w i t h these two 2 , 5 - d i s u b s t i t u t e d p y r r o l e s s i n c e t h e d i m e t h y l p y r r o l e gave an i s o i n d o l i n e w h i l e the d i p h e n y l p y r r o l e was r e c o v e r e d unchanged from t h e r e a c t i o n m i x t u r e . F o l l o w i n g r i n g - o p e n i n g o f a p y r r o l e molecule acetonylacetone  to give  ( o r i t s e q u i v a l e n t ) , the second stage o f the  c o n d e n s a t i o n p r o c e s s i s presumed t o i n v o l v e r e a c t i o n o f t h e two c a r b o n y l f u n c t i o n s w i t h t h e £-positions  o f a second p y r r o l e  molecule  I t Is s i g n i f i c a n t that  t o g i v e t h e i s o i n d o l e (XXXVI).  a r e a c t i o n e x a c t l y analogous t o t h i s o c c u r r e d i n t h e c o n d e n s a t i o n o f a c e t o n y l a c e t o n e w i t h 2 , 5 - d i p h e n y l p y r r o l e , an account has been g i v e n i n t h e p r e v i o u s c h a p t e r .  o f which  This r e a c t i o n e n t a i l e d  c o n d e n s a t i o n o f the d i k e t o n e w i t h the two $ - p o s i t i o n s o f t h e d i p h e n y l p y r r o l e , p r o b a b l y t o form an i s o i n d o l e i n t e r m e d i a t e , which was t h e n reduced  i n t h e r e a c t i o n medium t o  1,3-diphenyl-  l ) . , 7 - d i m e t h y l i s o i n d o l i n e (XXVI) (see f i g u r e 7, p. 2 2 ) . A s i m i l a r c o n d e n s a t i o n has been shown t o occur i n t h e thiophene  s e r i e s ( 5 l ) , i n w h i c h a c e t o n y l a c e t o n e and 2 , 5 - d i m e t h y l -  thiophene a r e t r e a t e d w i t h h y d r o f l u o r i c a c i d t o g i v e lj>3*4*7-tetramethylisothionaphthene  (XXXVIII).  This product i s  e v i d e n t l y c o n s i d e r a b l y more s t a b l e than t h e c o r r e s p o n d i n g i s o i n d o l e , f o r attempts  t o i s o l a t e t h e l a t t e r from an e t h e r e a l  s o l u t i o n o f 2 , 5 - d i m e t h y l p y r r o l e t r e a t e d w i t h hydrogen c h l o r i d e have so f a r r e s u l t e d i n o n l y h i g h l y - c o l o u r e d , p o l y m e r i c p r o d u c t s , the n a t u r e o f w h i c h remains  obscure.  A f u r t h e r p i e c e o f evidence i n support o f the ketonep y r r o l e c o n d e n s a t i o n was a f f o r d e d by a r e a c t i o n between acetone  XXXVIII F i g u r e 11.  F i g u r e 12.  Condensation of acetonylacetone w i t h dimethylthiophene  2,5-  Condensation product of acetone and dimetnylpyrrole.  2,5-  35  and 2 , 5 - d i m e t h y l p y r r o l e o  T h i s r e a c t i o n , w h i c h was  c a r r i e d out  i n the p r e s e n c e of h y d r o c h l o r i c a c i d , y i e l d e d a p i n k compound f o r which a n a l y s i s i n d i c a t e d a molecular The  formula  C15H22N2 ( c f .  p r o d u c t gave a p o s i t i v e E h r l i c h r e a c t i o n ( s u g g e s t i n g  (l|8))o  an  u n s u b s t i t u t e d p o s i t i o n on a p y r r o l e n u c l e u s ) , and the i n f r a r e d spectrum showed HH a b s o r p t i o n a t 3413  cm.""'* w i t h t h e  i n t e n s i t y c h a r a c t e r i s t i c o f the p y r r o l e system. spectrum was  enhanced  The  ultraviolet  a l s o s i m i l a r to t h a t o f 2 , 5 - d i m e t h y l p y r r o l e  and  t h i s e v i d e n c e l e d t o the p r o p o s e d s t r u c t u r e (XXXIX) f o r t h i s compound.  A r e a c t i o n between acetone and 2 - m e t h y l i n d o l e  a l s o been r e c e n t l y r e p o r t e d The  (52).  i s o i n d o l e (XXXVI) thus seems t o be a  i f h y p o t h e t i c a l , intermediate 2,5-dimethylpyrrole.  The  has  reasonable,  i n the r e d u c t i v e c o n d e n s a t i o n o f  a c t u a l r e d u c t i o n o f the i s o i n d o l e  take p l a c e d i r e c t l y from (XXXVI) (by s a t u r a t i o n of one  may  double  bond and rearrangement or by a d d i t i o n o f hydrogen a c r o s s the ends o f the c o n j u g a t e d system a t the 1v i a the a r o m a t i c Imine i n t e r m e d i a t e  and  3-positions) or, p o s s i b l y ,  (XXXVII).  T h i s second c o u r s e  would r e s u l t f r o m p r o t o n a t i o n of the i s o i n d o l e a t the  1-position  (which would be e x p e c t e d t o o c c u r r e a d i l y s i n c e i t l e a d s  to  a r o m a t i s a t i o n ) , f o l l o w e d by r e d u c t i o n of the i m i n e double bond. The  formation  o f the a r o m a t i c imine would depend on whether  p r o t o n a t i o n or d i r e c t r e d u c t i o n o f the i s o i n d o l e took p l a c e  the  more r a p i d l y . As y e t , the n a t u r e o f the r e d u c t i o n p r o c e s s has been a s c e r t a i n e d s i n c e i t has proved i m p o s s i b l e t o  obtain  c o n c l u s i v e r e s u l t s from p r o d u c t s i s o l a t e d by t r e a t m e n t of  not  36  2 , 5 - d i r a e t h y l p y r r o l e and the a c e t o n y l a c e t o n e - d i p h e n y l p y r r o l e mixture w i t h a c i d alone.  However, the evidence a v a i l a b l e i s  considered to support a r i n g - o p e n i n g r a t h e r than a D i e l s - A l d e r mechanism pyrrole.  f o r the i n i t i a l  c o n d e n s a t i o n p r o c e s s o f 2,5>-dimethyl  CHAPTER V EXPERIMENTAL  M e l t i n g p o i n t s were determined on a h e a t e d b l o c k and a r e uncorrected,,  U n l e s s o t h e r w i s e s t a t e d , i n f r a r e d s p e c t r a were  determined as l i q u i d f i l m s o r n u j o l m u l l s between s a l t p l a t e s on a Perkin-Elmer I n f r a c o r d spectrophotometer.  In general, only  bands o f medium t o s t r o n g i n t e n s i t y have been r e p o r t e d .  Ultra-  v i o l e t s p e c t r a were determined u s i n g a Cary ll+ r e c o r d i n g spectrophotometer. 2,5-Dimethylpyrrole 2 , 5 - D i m e t h y l p y r r o l e was p r e p a r e d from a c e t o n y l a c e t o n e and ammonium carbonate by t h e method o f Young and A l l e n ( 1 8 ) .  It  was o b t a i n e d as a c o l o u r l e s s , s l i g h t l y v i s c o u s l i q u i d , b.p. o 2^ 72-75  (22 mm.),  i n 3$% y i e l d .  n  D  1.502  The p y r r o l e s l o w l y t u r n e d r e d i n a i r .  i n f r a r e d spectrum  Its  ( o f t h e pure l i q u i d ) showed a b s o r p t i o n a t 31+25  (NH), 2933 (CH3), 1590, (ring  ( a l t h o u g h t h i s i n c r e a s e d on s t a n d i n g ) ,  1511  (both C=C), 1035,  927,  and 768  cm."  1  hydrogen). The p r o t o n magnetic resonance  spectrum o f 2 , 5 - d i m e t h y l -  p y r r o l e ( d e t e r m i n e d neat a t 1+0 mc. s e c . " , u s i n g 1  hexamethyl-  d i s i l o x a n e as e x t e r n a l s t a n d a r d ) d i s p l a y e d resonances (on t h e T s c a l e ) o f 3»3  at f i e l d s  (broad and l o w due t o NH), 4.06 ( r i n g  h y d r o g e n s ) , and 8 . 3 (methyl h y d r o g e n s ) .  The s i g n a l a t 1+.6 on  38  the *t s c a l e was s p l i t ( J , 2.1 cps.)  i n t o an almost s y m m e t r i c a l d o u b l e t  and has been a t t r i b u t e d t o c o u p l i n g between  hydrogens a t t h e 1- and 3 - p o s i t i o n s  .  (A s p l i t t i n g o f t h e  same magnitude and a s c r i b e d t o t h e same cause has a l s o been observed i n t h e spectrum o f  2,3,5-trimethylpyrrole  1 , 3 , U - , 7 - T e t r a m e t h y l i s o i n d o l l n e (XIV) and D e r i v a t i v e s 25 g. o f 2 , 5 - d i m e t h y l p y r r o l e  was added i n s m a l l  lots  t o a m i x t u r e o f 125 g . o f t i n and 500 m l . o f 6N h y d r o c h l o r i c a c i d b o i l i n g under r e f l u x .  R e f l u x i n g was c o n t i n u e d  f o r 22 h o u r s .  E x c e s s o f ]\Q% c a u s t i c soda s o l u t i o n was added t o t h e c o o l e d r e a c t i o n mixture,  which was t h e n s t e a m - d i s t i l l e d . A c o l o u r l e s s  o i l appeared w i t h t h e d i s t i l l a t e w h i c h , a f t e r a d d i t i o n o f 20 g. of s o l i d sodium h y d r o x i d e , for  10 h o u r s .  was c o n t i n u o u s l y  i n n i t r o g e n under reduced p r e s s u r e ,  n  D  ether  The e x t r a c t was d r i e d over anhydrous sodium  s u l p h a t e and t h e e t h e r d i s t i l l e d o f f .  obtained 25  extracted with  The r e s i d u e was d i s t i l l e d  and t h e i s o i n d o l i n e was  as an i n i t i a l l y c o l o u r l e s s o i l , b.p. 76-83° ( 0 . 7 mm.),  1.5271,  i n y i e l d s v a r y i n g from 6.50 g. (28$) t o 11.Ij. g. ( 5 0 $ ) .  The major l o s s o c c u r r e d  a t t h e s t e a m - d i s t i l l a t i o n stage f o r i t  was found t h a t y i e l d s were improved by making t h e r e a c t i o n m i x t u r e more s t r o n g l y b a s i c p r i o r t o d i s t i l l a t i o n .  Even under  these c o n d i t i o n s t h e i s o i n d o l i n e s t e a m - d i s t i l l e d r e l u c t a n t l y , a r e l a t i v e l y l a r g e volume o f d i s t i l l a t e b e i n g r e q u i r e d t o c a r r y over a l l t h e p r o d u c t . Hydrochloride.  When anhydrous hydrogen c h l o r i d e was  passed through an e t h e r e a l s o l u t i o n o f t h e base a w h i t e p r e c i p i t a t e r e s u l t e d immediately.  R e c r y s t a l l i s a t i o n of the  39 product from a dichloromethane-hexane mixture gave the h y d r o c h l o r i d e as C, 68.3;  H,  8.75j  n i t r a t e ) , 208). 16.8$; M,  colourless  212.  6.8;  N,  C, 68.1;  12  2674., 2488, 2l|21, 2037  I 4 I 6 , 1353, Nitrate.  1168,  1067,  1035,  n i t r a t e was  C,  60.8;  H,  7.^;  N,  11.8$).  The  (both NHj), 821  cm.  1  8.6;  6.6;  N,  ( a l l NH*>), 896,  and  With d i l u t e n i t r i c a c i d the  a copious white p r e c i p i t a t e which was The  H,  CI,  11.9$.  N,  1585,  809  cm." . 1  i s o i n d o l i n e gave  b l a d e s , m.p.  C12H18N2O3 r e q u i r e s  C,  176-8° (Pound;  60.5;  1292,  (both C=C),  1266,  1031,  7.6;  H,  2703, 2500  i n f r a r e d spectrum showed a b s o r p t i o n at 14.93  I499  r e c r y s t a l l i s e d from e t h a n o l .  obtained as c o l o u r l e s s  1605,  silver  i n f r a r e d spectrum of the h y d r o c h l o r i d e showed  a b s o r p t i o n bands at (both C=C),  (dec.) (Pounds  CI, 16.1$; M (by t i t r a t i o n with  C H"i8NCl r e q u i r e s The  267-8°  prisms, m.p.  isoindoline  84I,  and  „ Nitrosamine.  Addition  of a f r e s h l y prepared  o f sodium n i t r i t e i n d i l u t e h y d r o c h l o r i c p r e c i p i t a t e d the n i t r o s o d e r i v a t i v e . r e c r y s t a l l i s e d from ethanol as on a d d i t i o n of phenol and g r e e n i s h - b l u e colour  solution  a c i d to the base  The  nitrosamine  was  colourless  prisms, m.p.  94°,  concentrated s u l p h u r i c  a c i d , gave  and, the  (changing to r e d on d i l u t i o n ) which i s  c h a r a c t e r i s t i c o f n i t r o s o d e r i v a t i v e s of secondary amines (Liebermarm's T e s t ) . the n i t r o s a m i n e a t 1053,  1032,  978,  Bands occurred i n the  1495,  870,  I n t e n s i t y at 1299 dialkylnitrosamines  ll|12, 1299,  817,  cm.  737  and  1250, cm."  appears to be  1  i n f r a r e d spectrum of  1166, The  1099,  broad band of h i g h  c h a r a c t e r i s t i c of  i n the diraeric s t a t e , f o r which the  frequency i s r e p o r t e d to f a l l at about 1310 Benzenesulphonamide. the Schotten-Baumann method.  This  1073,  N=0  cm.~" (51+)« L  d e r i v a t i v e was  prepared  by  A f t e r r e c r y s t a l l i s a t i o n from e t h a n o l  lj.0  i t was H,  127-8° (Pounds C, 68.5j 68.5,* H, 6.7; N, k>k?°) °  o b t a i n e d as c o l o u r l e s s b l a d e s , ra.p.  6.5; N,  lj.o35$.  C18H21NO2S r e q u i r e s C,  The i n f r a r e d spectrum of the benzenesulphonyl d e r i v a t i v e showed  11*90, 1339  1279, 1161* ( - S O 2 - ) , 1125, 1091*, 1081, 1065, 816, 761, 7l*8 ( C 6 H 5 ) , 716, and 698 cm." ( C H £ ) . A b s o r p t i o n i n the r e g i o n s of 13I4.O cm." and 1165 cm. has been a b s o r p t i o n at  (-S0 -), 2  1  6  1  -1  shown to be c h a r a c t e r i s t i c of sulphonamides Carbon d i o x i d e adduct (XV).  (55).  A white p r e c i p i t a t e s l o w l y  separated when carbon d i o x i d e was passed through an e t h e r e a l s o l u t i o n of the i s o i n d o l i n e .  The product was  washed s e v e r a l times  with ether but could not be r e c r y s t a l l i s e d without decomposition. On h e a t i n g the adduct, decomposition o c c u r r e d (at r e g e n e r a t i o n of the i s o i n d o l i n e C  13 17 2 H  N0  r  e  <  l  u  i  r  e  s  c  »  71.2;  H,  (Pounds C, 71»0;  7»8; N,  6.1$).  85-90°)  H, 7«8;  with  N,  6.2$.  A n a l y s i s thus  e l i m i n a t e d the p o s s i b i l i t y of t h i s compound b e i n g the carbonate or b i c a r b o n a t e d e r i v a t i v e of the i s o i n d o l i n e . spectrum, which had bands a t 260l+,  1372, IO36,  8ll+, and 777 cm.  -1  2l+8l,  1639  The  infrared  (C=0), 1553, 11+90,  , revealed a s i g n i f i c a n t  absence  of a b s o r p t i o n a s s o c i a t e d w i t h the carbonate i o n at lij.50-lij.10  and 880-860 cm."  1  (56).  1  Picrate. d i s s o l v e d i n 1+-5  cm."  2 drops of the t e t r a m e t h y l i s o i n d o l i n e were  drops o f ether and a s o l u t i o n of p i c r i c  ( i n moist ether) added u n t i l the s o l u t i o n was  acid  just a c i d i c .  p i c r a t e , which p r e c i p i t a t e d w i t h some d i f f i c u l t y , was  collected  and r e c r y s t a l l i s e d from ethanol to g i v e y e l l o w p l a t e s , m.p. 2,ii-Dinitrophenyl d e r i v a t i v e . equimolecular q u a n t i t i e s o f the base and  The  187-9°.  Approximately 2,11-dinitrochlorobenzene  1*1  were d i s s o l v e d i n a l i t t l e  a l c o h o l and a s m a l l excess o f anhydrous  p o t a s s i u m carbonate added. b a t h f o r a few minutes  The m i x t u r e was h e a t e d on a steam-  and poured  p r o d u c t which s e p a r a t e d was  i n t o water.  The  brownish-yellow  washed w i t h sodium carbonate  and w i t h d i l u t e h y d r o c h l o r i c a c i d and, a f t e r from acetone, gave g o l d e n y e l l o w p r i s m s , m.p. 1,2,3,1*,7-Pentamethylisoindoline  solution  recrystallisation 235-6°.  (XVI)  E s c h w e i l e r m e t h y l a t i o n o f the t e t r a m e t h y l i s o i n d o l i n e (XIV) was  c a r r i e d out f o l l o w i n g t h e procedure  and A l l e s ( 5 7 ) . mixture of 2.1  of Icke, Wisegarver,  On a d d i n g 2 g. o f the i s o i n d o l i n e (XIV) t o a g. 90$ f o r m i c a c i d and 1 . 3  g. 37$ formaldehyde,  vigorous exothermic r e a c t i o n occurred w i t h e v o l u t i o n of dioxide.  When t h e r e a c t i o n was  complete  carbon  ( a f t e r h e a t i n g f o r 9|-  hours a t 9 0 - 1 0 0 ° ) , d i l u t e h y d r o c h l o r i c a c i d was  added and  r e m a i n i n g f o r m i c a c i d was removed under reduced p r e s s u r e steam.  The  s o l u t i o n , on c o o l i n g , formed a g l u e which was  any over taken  up i n a l i t t l e water and 3 m l . o f 1*0$ c a u s t i c soda added. upper, dark brown l a y e r was e x t r a c t e d w i t h benzene.  a  The ,  s e p a r a t e d and the l o w e r aqueous l a y e r  T h i s e x t r a c t was d r i e d over  potassium  c a r b o n a t e and t h e benzene was removed u s i n g a r o t a r y e v a p o r a t o r ( d i s t i l l a t i o n was p r e v e n t e d by e x c e s s i v e f r o t h i n g ) .  For  d i s t i l l a t i o n o f the r e s i d u e under r e d u c e d p r e s s u r e a b a t h temperature  of 180°  i s o i n d o l i n e at 5 6 ° occurred).  The  was n e c e s s a r y t o d i s t i l the ( 0 . 2 mm.)  (considerable frothing again  I s o i n d o l i n e (XVI) was  a y i e l d o f 0.1*8 g. (22$)  was  pentamethyl-  obtained.  a pale yellow, basic o i l ; The i n f r a r e d spectrum  ( X V I ) , r e c o r d e d as a l i q u i d f i l m on a P e r k i n - E l m e r Model 21  of  1+2  double-beam I n s t r u m e n t , showed a b s o r p t i o n a t  2950,  2863,  (N-CH3), 1622,  1225,  1170,  1I4.98,  1061}., 9l+l, 806,  and  1339,  1290,  1325,  1260,  1  M e t h y l i o d i d e was  added d r o p w i s e  t o the f r e s h l y d i s t i l l e d p e n t a m e t h y l i s o i n d o l i n e m i x t u r e became warm and  solidified.  (XVI) u n t i l  H  N I  rs^" *® 11  8  c  *  decomposed i n a i r . 1196,  1076,  m.p.  2 6 l j . - 6 ° (dec.) (Pounds C, 5 1 . 0 ;  50.8,•  H,  Infrared absorption  lOkh, 921)., 822,  A m i x t u r e of 0 . 9 8  and 808  i n 100 m l . of water was The m i x t u r e was  occurred  a t l l + 9 7 , 11+06,  1  a c i d (XVTII)  g. o f  allowed  1,3,1+,  7-tetramethylisoindoline,  3 . 8 g. of p o t a s s i u m carbonate  t o s t a n d a t room temperature f o r  t h e n r e f l u x e d f o r l\. hours and made  weakly a c i d i c w i t h 6N h y d r o c h l o r i c a c i d .  Sulphur dioxide  passed t h r o u g h the s o l u t i o n to f i r s t p r e c i p i t a t e and r e d i s s o l v e the manganese d i o x i d e formed.  The  extracted with ether f o r 8 hours.  then  continuously  T h i s removed b y - p r o d u c t s  v e r y l i t t l e o f the t e t r a c a r b o x y l i c a c i d .  The  s o l u t i o n was  a c i d i f i e d to a s t r e n g t h o f 6N w i t h c o n c e n t r a t e d a c i d , upon which some i n o r g a n i c m a t e r i a l was  ether f o r 8 6 hours.  was  s o l u t i o n was  a c i d i f i e d t o pH 1+ w i t h h y d r o c h l o r i c a c i d and  f i l t e r e d o f f and  6.5$.  H,  cm." .  1 5 g. o f p o t a s s i u m permanganate, and  was  In  The m e t h i o d i d e s l o w l y  6.65$).  Benzene-1,2,3,ij.-tetracarboxylic  3 days.  t a k e n up  S e v e r a l r e c r y s t a l l i s a t i o n s from e t h a n o l gave  c o l o u r l e s s needles, ll4- 22  the  A few drops of excess m e t h y l  i o d i d e were added and the brown s o l i d m a t e r i a l was  C  1127,  7 8 3 cm." .  Methiodide (XVII).  hot e t h a n o l .  2760  further  hydrochloric  precipitated.  the f i l t r a t e c o n t i n u o u s l y  but  extracted  A f t e r d r y i n g over sodium s u l p h a t e ,  This  with the  1*3  e t h e r e a l e x t r a c t was e v a p o r a t e d down t o g i v e crude benzenetetracarboxylic acid.  R e c r y s t a l l i s a t i o n from d i l u t e h y d r o c h l o r i c  a c i d gave 0.1*5 g. (32$) o f ( X V I I I ) as c o l o u r l e s s p r i s m s , 236-1*1° ( l i t . 236-8° ( 5 8 ) , 2 3 6 . 5 - 8 ° ( 5 9 ) ) .  The i n f r a r e d spectrum  o f t h e a c i d showed a b s o r p t i o n a t 2688 ( b r o a d , OH), 1701 1272,  and 763 cm.  m.p.  (C=G),  1  I t was found t h a t a l a r g e excess o f permanganate was needed f o r complete o x i d a t i o n o f t h e i s o i n d o l i n e , as a s m a l l e r excess gave o n l y p a r t i a l o x i d a t i o n t o 3 , 6 - d i m e t h y l p h t h a l i c anhydride.  The a n h y d r i d e was among t h e p r o d u c t s  e x t r a c t e d a t pH  1* and was i d e n t i f i e d by comparison w i t h t h e s y n t h e t i c compound (XXI)  (see F i g u r e 6, p. 18). Tetramethyl  (61),  ester (XIX).  Diazomethane was  prepared  and a s o l u t i o n o f O.O38 g. o f t h e t e t r a c a r b o x y l i c a c i d i n  e t h e r was added.  On c o o l i n g , 0.032 g. (70$) o f the t e t r a m e t h y l  e s t e r (XIX) c r y s t a l l i s e d .  R e c r y s t a l l i s a t i o n from e t h e r gave  c o l o u r l e s s n e e d l e s , m.p. 1 2 9 - 3 2 ° ( l i t . 1 3 1 - 3 ° ( 5 8 ) , 129-30° ( 6 0 ) ) . M i x e d m.p. w i t h an a u t h e n t i c sample o f 1 , 2 , 3 , 1 * - t e t r a c a r b o m e t h o x y benzene gave 1 3 0 - 2 ° .  The i n f r a r e d s p e c t r u m o f (XIX)  a b s o r p t i o n a t 1721*, 1305, 1266, 12l*8, 1192, 1167, 1000,  showed  lll*3,  1110,  983, 9l+3, 868, 816, 807, 756, and 730 cm." , and was 1  i d e n t i c a l w i t h t h e spectrum o f t h e a u t h e n t i c sample o f t h e tetramethyl ester. 2,1*,6-Trimethylphthalimide  (XXII)  2 , 5 - D i m e t h y l f u r a n was p r e p a r e d t h e method o f Gaertner  from a c e t o n y l a c e t o n e  by  and Tonkyn ( 6 2 ) , and was o b t a i n e d i n 37$  y i e l d as a c o l o u r l e s s l i q u i d , b.p. 86-88° ( l i t .  92.5-91*°  (62)).  17 g. o f t h e 2 , 5 - d i m e t h y l f u r a n was d i s s o l v e d i n 1 0 0 m l . o f anhydrous e t h e r and 1 8 g. o f m a l e i c anhydride added.  The  r e s u l t i n g y e l l o w s o l u t i o n was shaken a t room temperature  f o r 2l+  hours and r e f r i g e r a t e d , on which c o l o u r l e s s c r y s t a l s o f t h e D i e l s A l d e r adduct (XX) s e p a r a t e d from e t h e r t o g i v e The  17  (63).  (lj.9$)  g o  The p r o d u c t was r e c r y s t a l l i s e d  o f ( X X ) , m.p.  74-5°  (lit.  78°  (6l)).  i n f r a r e d spectrum o f (XX) showed a b s o r p t i o n a t 1 8 5 5 , 1779  ( b o t h C=0 o f a n h y d r i d e ) , 926,  863, 834,  and  7l+5  c m  1582..  °  (C=C),  13L3, 1238,  1209, 1098, 978,  (the c a r b o n y l bands a r e d i s c u s s e d  below). D e h y d r a t i o n o f t h e D i e l s - A l d e r a d d i t i o n p r o d u c t (XX) was  accomplished  by t h e method o f Newman and L o r d (61}.).  After  r e c r y s t a l l i s a t i o n of. the p r o d u c t from benzene, a 2 6 $ y i e l d o f 3 , 6 - d i r a e t h y l p h t h a l i c anhydride p r i s m s , m.p.  11+4.-6°  (lit.  shotted a b s o r p t i o n a t  (XXI) was o b t a i n e d as c o l o u r l e s s  I4I4.-6  1 8 3 8 , 1757  0  The i n f r a r e d  (6I4.)).  spectrum  ( b o t h C=0 o f a n h y d r i d e ) ,  11+95,  -1 121+1,  1192,  1161,  901,  and  890  cm.  . The double  carbonyl  a b s o r p t i o n has been p o i n t e d out as c h a r a c t e r i s t i c o f a n h y d r i d e s j moreover, t h e p o s i t i o n s o f these bands i n t h e D i e l s - A l d e r adduct (XX) and t h e d i m e t h y l p h t h a l i c a n h y d r i d e  (XXI) c o r r e s p o n d  closely  w i t h t h e p o s i t i o n s o f t h e c a r b o n y l a b s o r p t i o n s i n s u c c i n i c and p h t h a l i c a n h y d r i d e r e s p e c t i v e l y , t h e r e b e i n g a s h i f t t o lower f r e q u e n c y f o r b o t h c a r b o n y l bands g o i n g from the a l i p h a t i c t o t h e a r o m a t i c system ( 6 5 ) .  The c o n s t a n t s e p a r a t i o n o f t h e two c a r b o n y l  bands o f a n h y d r i d e s , d e s p i t e o v e r a l l s h i f t s i n f r e q u e n c y , has a l s o been noted  ( 6 5 ) and i s borne out i n t h i s  case.  45 3 , 6 - D i m e t h y l p h t h a l i c a n h y d r i d e was c o n v e r t e d t o N-methyl-3,6-dimethylphthalimide  ( X X I I ) by a r e a c t i o n s i m i l a r t o  t h a t d e s c r i b e d f o r p h t h a l i c anhydride d i m e t h y l p h t h a l i c anhydride  i t s e l f (66).  lj..6 g. o f  (XXI) was d i s s o l v e d i n I4.O m l , o f 20$  methylamine i n water and t h e s o l u t i o n warmed t o 5 0 ° . s e p a r a t e d which was f i l t e r e d o f f and c o l l e c t e d . ,  A slurry  The f i l t r a t e  was r e f l u x e d u n t i l t h e s l u r r y a g a i n became t o o heavy t o a l l o w smooth b o i l i n g .  The c y c l e o f f i l t e r i n g and r e f l u x i n g was  r e p e a t e d f o u r t i m e s , a f t e r which no f u r t h e r s o l i d  separated.  The m a t e r i a l , which had been f i l t e r e d and c o l l e c t e d , was heated a t 130° f o r 2 hours and d r i e d i n vacuo t o g i v e a q u a n t i t a t i v e y i e l d o f the p h t h a l i m i d e ( X X I I ) .  The p r o d u c t  sublimed above  150° and, p u r i f i e d i n t h i s way, gave a w h i t e s u b l i m a t e , m.p. 1 7 6 - 7 ° (Pounds C , 7 0 . 1 ; H, 5 . 6 : N , 7»5$. C, 69«8j H, 5«9j N, 7»4$)° absorption at 174 , 8  893,  CnHnNOg r e q u i r e s  The i n f r a r e d spectrum showed  1701+ ( b o t h C=0 o f i m i d e ) , 1264, 1163,  8 2 0 , and 755 cm."  1  As w i t h t h e a n h y d r i d e s  1010,  (XX) and (XXI)  p r e v i o u s l y noted, the carbonyl absorption of the phthalimide ( X X I I ) was d o u b l e d , b u t was now a t lower f r e q u e n c y .  The  p o s i t i o n s o f these bands a r e i n agreement w i t h t h e v a l u e s r e p o r t e d f o r compounds c o n t a i n i n g t h e N - s u b s t i t u t e d imide grouping  (67).  2 , 4 , 7 - T r i m e t h y l i s o i n d o l i n e ( X X I I I ) and D e r i v a t i v e s M e t h y l l i t h i u m was p r e p a r e d by t h e method o f G i l l m a n , Z o l l n e r and S e l b y ( 6 8 ) .  To 50 m l . o f t h i s f r e s h l y  s o l u t i o n was added 0 . 2 5 g« o f  prepared  N-methyl-3,6-dimethylphthaiimide  ( X X I I ) i n 8 m l . o f anhydrous e t h e r .  A f t e r standing overnight the  m i x t u r e was r e f l u x e d on a steam b a t h f o r 2 h o u r s .  The  p r e c i p i t a t e d l i t h i u m h y d r o x i d e was f i l t e r e d o f f and t h e d r i e d e t h e r e a l s o l u t i o n was r e f l u x e d w i t h 0.5 g. o f l i t h i u m h y d r i d e f o r 10 h o u r s .  aluminium  A f t e r d e c o m p o s i t i o n o f t h e excess  lithium  aluminium h y d r i d e w i t h m o i s t e t h e r t h e s o l v e n t was e v a p o r a t e d , l e a v i n g 0.11 g. {l\B%) o f crude 2 , 4 , 7 - t r i m e t h y l i s o i n d o l i n e  (XXIII).  T h i s p r o d u c t was o b t a i n e d as an i n i t i a l l y c o l o u r l e s s , b a s i c o i l , which t u r n e d y e l l o w on s t a n d i n g , and was t h e r e s u l t o f d i r e c t r e d u c t i o n o f t h e i m i d e ( X X I I ) (see pp. 18-19).  The i n f r a r e d  spectrum o f ( X X I I I ) as a l i q u i d f i l m showed a b s o r p t i o n a t 2770, 1855 1220,  and l 6 8 l  ( b o t h weak), 1590, 1495, 1372, 1316, 1297, 1253,  1189, 1153, 1116, lOij.0, 1000, 935, 868, 805, and 726 cm." Methiodide.  1  The crude t r i m e t h y l i s o i n d o l i n e ( X X I I I )  r e a c t e d e x o t h e r m i c a l l y w i t h m e t h y l I o d i d e and t h e brown s o l i d formed was t a k e n up i n and c r y s t a l l i s e d from e t h a n o l . R e c r y s t a l l i s a t i o n from e t h a n o l gave 2 , 4 , 7 - t r i m e t h y l i s o i n d o l i n e (XXIV) as c o l o u r l e s s p l a t e s , m.p. 2 3 1 - 2 ° (Pound: C ,  methiodide  1+7.3J H, 6 . 0 ; I , 1+1.5; N, 4..!$.  H, 6 . 0 ; I , l j l . 9 j 1337, 1316,  W, !|..6$).  1264, 1166,  C 2%8 1  I N  r e q u i r e s C , 47*5;  I n f r a r e d a b s o r p t i o n o c c u r r e d a t 1502,  1038, 988, 923, 897, and 844 cm." ( s e e 1  T a b l e I I , p. 13 f o r t h e u l t r a v i o l e t spectrum o f t h i s p r o d u c t ) . Hydrochloride.  When anhydrous hydrogen c h l o r i d e was  passed through an e t h e r e a l s o l u t i o n o f t h e t r i m e t h y l i s o i n d o l i n e , s o l i d m a t e r i a l separated immediately.  The p r o d u c t was c o l l e c t e d  and r e c r y s t a l l i s e d from acetone t o g i v e 2 , 4 , 7 - t r i m e t h y l i s o i n d o l i n e h y d r o c h l o r i d e as c o l o u r l e s s , s l i g h t l y h y g r o s c o p i c n e e d l e s , m.p. 2 1 3 - 6 ° (Pounds C I , 17.9; N, 7.1$.  C H 6C1N r e q u i r e s C I , 17o9| 11  1  N, 7 » 1 $ ) .  A q u a l i t a t i v e u l t r a v i o l e t spectrum o f the  X  c h l o r i d e ( i n methanol) showed v a l u e s o f 275 nyu.(cf. T a b l e I I , p Picrate.  0  RAAJC<>  hydro-  at 266,  271,  and  13).  On adding a s o l u t i o n o f the t r i m e t h y l -  i s o i n d o l i n e i n ether to a s o l u t i o n of p i c r i c a c i d i n moist a y e l l o w p r e c i p i t a t e s l o w l y formed.  ether  This p i c r a t e d e r i v a t i v e 182-4°.  r e c r y s t a l l i s e d from e t h a n o l as y e l l o w p l a t e s , m.p.  was Its  i n f r a r e d spectrum showed a b s o r p t i o n a t 2 6 9 5 ( b r o a d ) , 1621, (N0 ), 2  706  1357  cm."  (N02),  1304,  1256,  1155,  1070,  819,  791,  1558,  747,  and  1  N-methyl-3,4,7-trimethyl-3-hydroxyphthalimidine M e t h y l magnesium i o d i d e was  (XXV) from 3 g«  prepared  of  magnesium t u r n i n g s i n 25 ml. o f anhydrous e t h e r and 7»5 g« m e t h y l i o d i d e I n 30 m l . o f anhydrous e t h e r .  1.0  of  g. o f N-methyl-  3 , 6 - d i m e t h y l p h t h a l i r a i d e (XXII). i n 60 ml. o f anhydrous e t h e r added d r o p w i s e ,  w i t h s t i r r i n g , t o the G r i g n a r d r e a g e n t ,  w h i c h the s o l u t i o n t u r n e d y e l l o w and s o l i d was w a l l s o f the f l a s k . w i t h water,  T h i s s o l i d m a t e r i a l was  and e x t r a c t e d w i t h e t h e r .  The  was  during  d e p o s i t e d on  the  removed, t r e a t e d  e t h e r e x t r a c t was  t h o r o u g h l y d r i e d over anhydrous sodium s u l p h a t e and  then  r e f l u x e d f o r 10 hours w i t h 2 g. o f l i t h i u m aluminium h y d r i d e . D e c o m p o s i t i o n of the excess l i t h i u m aluminium h y d r i d e w i t h m o i s t e t h e r , f o l l o w e d by e v a p o r a t i o n o f the s o l v e n t gave a y e l l o w , c r y s t a l l i n e product.  T h i s crude m a t e r i a l was  t w i c e from a dichloromethanejhexane g. (56$)  o f a p r o d u c t presumed t o be  3-hydroxyphthalimidine  (XXV).  mixture  recrystallised  ( l s l O ) to give  0,74  N-methyl-3,4,7-trimethyl-  T h i s compound was  obtained  as  1+8  c o l o u r l e s s n e e d l e s , m.p  0  C Hi5N0 12  2  159-62° (Pound; C, 70.0;  70.2;  r e q u i r e s C,  H,  7°1+; N, 6.8$). The  1590, 11+99, 1258, 121+2, 1172,  (C=0),  1009, 962, 862, 81+7, 821, 802, 769,  cm."  6 8$. 0  3390  (OH),  1116, 1083,  1152,  and 715  N,  infrared  spectrum o f the p h t h a l i m i d i n e showed a b s o r p t i o n a t  1678  7.2;  H,  1055,  The  1  phthalimidine ( i n ethanol) e x h i b i t e d absorption i n i t s u l t r a v i o l e t spectrum w i t h X M A X O (6  2,700),  and  292  (e  m/A,  231 {€ 8,100), 2l+6,  5,570),  (C  282  2,250).  1, 3-Diphenyl-l+, 7 - d i m e t h y l i s o i n d o l i n e (XXVI) and D e r i v a t i v e s F o l l o i i r i n g the method d e s c r i b e d by K r e u t z b e r g e r  f o r the p r e p a r a t i o n o f 2 , 5 - d i p h e n y l p y r r o l e , t r a n s -  K a l t e r (69)  1,2-dibenzoylethylene The r e a c t i o n was temperature,  was  f i r s t hydrogenated t o  dibenzoylethane.  c a r r i e d out i n a Magne-Dash a u t o c l a v e a t room  u s i n g p a l l a d i s e d c h a r c o a l as c a t a l y s t .  symmetrical dibenzoylethane m.p.  and  was  The  o b t a i n e d as c o l o u r l e s s p r i s m s ,  11+5-8° ( l i t . 11+7-8° (69)), i n 61$ y i e l d . The  d i b e n z o y l e t h a n e was  t r e a t e d w i t h ammonia-saturated  e t h a n o l i n a Magne-Dash a u t o c l a v e (69) pyrrole.  The p y r r o l e , a f t e r r e c r y s t a l l i s a t i o n from aqueous  e t h a n o l , was ll+3-l+°  t o o b t a i n 2,5-diphenyl-  o b t a i n e d as p a l e y e l l o w p l a t e s , m.p.  (69)),  in  96$  yield.  a b s o r p t i o n a t 3581+ ( N H ) ,  The  ll+3-5° ( l i t ,  i n f r a r e d spectrum showed  1957, 1869  (both weak a r o m a t i c  overtones),  1608, 1582, 1520, 1282, 1156, 1101+, 1078, 1055, 9l+2, 907, 781+, 760,  751+,  and 69I  n o r m a l l y weak C=G  cm.  1  The  increased i n t e n s i t y of the  a b s o r p t i o n a t 1582  cm.  1  i s consistent with  the enhanced c o n j u g a t i o n e f f e c t i n 2 , 5 - d i p h e n y l p y r r o l e The unusual  s p l i t t i n g of the m o n o s u b s t i t u t e d  (70).  benzene a b s o r p t i o n  1*9  i n t o two components a t 760 and 754 cm."  i s noteworthy ( c f . ( 7 1 ) ) .  The u l t r a v i o l e t spectrum o f 2 , 5 - d i p h e n y l p y r r o l e  ( i n e t h a n o l ) had  A a x . 230 (£ 10,900) and 329 m/*. (£ 3 0 , 1 0 0 ) . m  A m i x t u r e o f 10 g. o f 2 , 5 - d i p h e n y l p y r r o l e , 6 g. o f a c e t o n y l a c e t o n e and 150 m l . o f a b s o l u t e e t h a n o l was added i n s m a l l l o t s t o 65 g. o f t i n , 250 m l . o f 6N h y d r o c h l o r i c a c i d , and 125 m l . o f a b s o l u t e e t h a n o l b o i l i n g under r e f l u x .  The p y r r o l e m i x t u r e  t u r n e d a deep r e d c o l o u r when i t came i n t o c o n t a c t w i t h t h e a c i d i c medium b u t t h i s g r a d u a l l y f a d e d t o a p a l e y e l l o w as r e d u c t i o n took p l a c e .  R e f l u x i n g was c o n t i n u e d f o r l\.0 h o u r s ,  a f t e r w h i c h e t h a n o l was d i s t i l l e d from t h e r e a c t i o n m i x t u r e a heavy s l u r r y formed.  until  The m i x t u r e was made s t r o n g l y b a s i c w i t h  i*0$ sodium h y d r o x i d e and s o l i d m a t e r i a l p r e c i p i t a t e d a t the i n t e r f a c e between an upper, dark r e d l a y e r and the l o w e r aqueous layer.  The s o l i d m a t e r i a l and aqueous l a y e r were drawn o f f and  e x t r a c t e d w i t h 50 m l . o f benzene.  The benzene l a y e r took up t h e  s o l i d , organic m a t e r i a l forming a yellow s o l u t i o n , while the r e m a i n i n g i n o r g a n i c m a t e r i a l d i s s o l v e d i n t h e aqueous l a y e r on dilution.  The aqueous l a y e r was f u r t h e r e x t r a c t e d with  three times.  benzene  E v a p o r a t i o n o f t h e benzene e x t r a c t gave a y e l l o w ,  c r y s t a l l i n e p r o d u c t which was r e c r y s t a l l i s e d from e t h a n o l t o y i e l d 8 . 8 g. (64$) o f 1 , 3 - d i p h e n y l ~ 4 , 7 - d i m e t h y l i s o i n d o l i n e ( X X V I ) , o b t a i n e d as o f f - w h i t e n e e d l e s , m.p. 1 7 2 - 4 ° C, 8 8 . 0 ; H, 6 . 9 ; N, 4»85$; M 2 9 5 . 7.1; N, 4 - 7 $ ; M 2 9 9 ) .  1027,  8 9 3 , 849, 817,  f o r the u l t r a v i o l e t  C22H21N r e q u i r e s C, 8 8 . 2 ; H,  The i n f r a r e d spectrum o f (XXVI) showed  a b s o r p t i o n a t 3344 (NH), 1595, 1066,  (Pounds  1493,  l4l4,  130ij., 1267,  784, 753, and 698 cm.'  spectrum).  1  1185,  (see T a b l e V  50  Nitrosamine procedure was  (XXVII).• A m o d i f i c a t i o n of the u s u a l  necessary  f o r the p r e p a r a t i o n of t h i s d e r i v a t i v e  on account o f the l a r g e q u a n t i t y of e t h a n o l used t o d i s s o l v e the i s o i n d o l i n e , the n i t r o s a m i n e b e i n g ( r e l a t i v e l y ) s o l u b l e i n 2.1  ethanol.  g. of the i s o i n d o l i n e was  a b s o l u t e e t h a n o l and the s o l u t i o n was c o n c e n t r a t e d h y d r o c h l o r i c a c i d was by an i c e - c o o l e d s o l u t i o n o f 1.5 of water.  The m i x t u r e was  d i s s o l v e d i n 120 1.5  cooled i n i c e .  added, f o l l o w e d  ml.  of  ml.  of  immediately  g. o f sodium n i t r i t e i n 3 ml. 15  allowed to stand i n i c e f o r  m i n u t e s , d u r i n g which some sodium n i t r i t e was  precipitated.  T h i s was  p r e c i p i t a t e d by  f i l t e r e d o f f and the n i t r o s a m i n e was  a d d i t i o n o f water.  The  d e r i v a t i v e was  from an ethanol:benzene (3*1)  c o l l e c t e d and  m i x t u r e t o g i v e 2.05  recrystallised  g. (89$)  1,3-diphenyl-i4.,7-dimethylisoindoline nitrosamine, obtained 1 8 3 - 5 ° (Pound: C, 8 0 . 7 ;  p a l e y e l l o w b l a d e s , m.p. C  2 2 2 0 2 ° r e q u i r e s C, 8 0 . 5 ; H  H , 6.1;  N  N, 8 . 5 $ ) .  H, 6 . 0 ; The  7l(.6, 733,  1236, 712,  1206,  and 698  1176, cm." , 1  1076,  1030, 855, 831,  1  15  group i n  (XXVII) and 15  The m i x t u r e was  strong  g. o f g l a c i a l a c e t i c  added s l o w l y t o a s t i r r e d m i x t u r e o f 2.7  nitrosamine  769,  (54).  N-Amino d e r i v a t i v e ( X X V I I I ) . a c i d was  li+88,  821,  d i s t i n g u i s h e d by the appearance of the v e r y  band at.1292 cm."  8.5$.  N,  As w i t h the 1 , 3 , 4 , 7 - t e t r a m e t h y l -  i s o i n d o l i n e n i t r o s a m i n e , the presence o f the N=0 (XXVII) was  as  infrared  spectrum o f the n i t r o s a m i n e showed a b s o r p t i o n a t 1590,  lq.14, 1292,  of  g. o f the  g. o f z i n c dust i n 30 ml. o f water  (72).  s t i r r e d i n i c e f o r 3 hours and t h e n a t room  temperature f o r 3 days.  F i n a l l y , the r e a c t i o n m i x t u r e was  heated  51  on a steam b a t h f o r 1 hour and f i l t e r e d h o t .  The r e s i d u e , which  c o n t a i n e d the p r o d u c t , was d i g e s t e d w i t h warm benzene and f i l t e r e d a g a i n t o remove t r a c e s o f z i n c .  Evaporation o f the  benzene gave a y e l l o w s o l i d w h i c h , on r e c r y s t a l l i s a t i o n from a n ethanol:benzene  mixture  (9:1), produced 0.9 g. (35$) o f 2-amino-  1,3-diphenyl-!|.,7-dimethylisoindoline derivative of hydrazine).  ( X X V I I I ) (which i s a l s o a  T h i s compound was o b t a i n e d as o f f -  w h i t e p r i s m s , m.p. 177-9° (Pound: C, 83.6; H, 7.1; N, 8.9$. C  22 22: 2 r e q u i r e s C, 81+.0; H, 7.05; N, 8.9$). H  N  spectrum  Its infrared  showed a b s o r p t i o n a t 3378, 3311 (both NH2),  3178 (weak),  1597, 11+95, 131+0, 1309, 1261, 1238, 1115, 1Q79, 1031, 975, 935, 895,  81+1, 828, 815, 80l+, 789, 750, 7l+l, and 698 cm." , 1  The f a c t  t h a t t h e f r e q u e n c i e s o f t h e symmetric mode (3311 cm." ) and t h e 1  a n t i s y m m e t r i c mode (3378 c m . ) o f the amino group obey t h e -1  e m p i r i c a l r e l a t i o n c o n n e c t i n g these two q u a n t i t i e s (73) i s s t r o n g evidence f o r the presence Hydrochloride.  o f a f r e e NHg group i n ( X X V I I X ) . As anhydrous hydrogen c h l o r i d e was  passed through a n e t h e r e a l s o l u t i o n o f 1,3-diphenyl-l+,7-dimethyli s o i n d o l i n e a w h i t e p r e c i p i t a t e s l o w l y formed. r e c r y s t a l l i s e d from a benzene:chloroform  T h i s was  (10:1) m i x t u r e t o g i v e  c o l o u r l e s s prisms which decomposed above 210° (Pound: C I , 10.8; N,'l+.5$; M (by t i t r a t i o n w i t h s i l v e r n i t r a t e ) , 336.  C22H22CTN  r e q u i r e s C I , 10.55; N, l+» $; M, 336). The h y d r o c h l o r i d e showed 2  i n f r a r e d a b s o r p t i o n a t 2625, 21+88, 2183 ( a l l NH ),  1558, ll+95, -1 1277, 1192, 1029, 923, 81+0, 767, 752, 737, 727, and 697 cm. 2  Benzenesulphonamide.  The i s o i n d o l i n e (XXVI) was  d i s s o l v e d i n a s m a l l q u a n t i t y o f p y r i d i n e and b e n z e n e s u l p h o n y l  52  c h l o r i d e was added.  The s o l u t i o n t u r n e d g r e e n and, on s t a n d i n g ,  solid precipitated.  R e c r y s t a l l i s a t i o n from e t h a n o l gave a  c o l o u r l e s s p r o d u c t , m.p. 1 7 7 - 9 ° , which showed i n f r a r e d a b s o r p t i o n a t ll+93, 1333 ( - S 0 - ) , 1311, 2  736, and 695 cm."  1  1160 ( - S 0 - ) , 1088, 988, 839, 756, 2  (cf. (55)).  2,5-Dimethyl-3-tricyanovinylpyrrole  (XXXV)  0 . 7 5 g. o f f r e s h l y d i s t i l l e d 2 , 5 - d i m e t h y l p y r r o l e i n 5  ralo  o f d r y t e t r a h y d r o f u r a n was added t o 1 g. o f t e t r a -  cyanoethylene  i n 10 m l . o f t e t r a h y d r o f u r a n .  The s o l u t i o n t u r n e d  deep b l u e i n i t i a l l y and then underwent a s t r i k i n g s e r i e s o f c o l o u r changes from deep g r e e n t o p a l e green and f i n a l l y t o orange.  The t e t r a h y d r o f u r a n was evaporated  l e a v i n g an orange-  c o l o u r e d p r o d u c t w h i c h was r e c r y s t a l l i s e d from a 1$ s o l u t i o n o f e t h a n o l i n benzene.  1.2  g. (77$) o f 2 , 5 - d i m e t h y l - 3 - t r i c y a n o v i n y l -  p y r r o l e (XXXV) was o b t a i n e d as b r i c k - r e d n e e d l e s , m.p. 192-1+° (Pounds C, 67.1; H, l+.l; N, 2 8 . 6 $ .  C H s N ^ r e q u i r e s C, 6 7 . 3 j 1 1  H, l+.l; N, 2 8 . 5 5 $ ) . The  i n f r a r e d spectrum o f (XXXV) showed a b s o r p t i o n a t  3236 (NH), 2217 970,  (C=N), 1590, 1515,  807, 769, 72lf., and 700 cm." , 1  1393, 1267,  1131+, 1028, 9 9 5 ,  The band a t 3236 cm." had 1  the enhanced i n t e n s i t y c h a r a c t e r i s t i c o f t h e p y r r o l e NH a b s o r p t i o n (71+) and e s t a b l i s h e d t h a t s u b s t i t u t i o n b y t e t r a cyanoethylene nucleus.  had not o c c u r r e d a t the n i t r o g e n atom o f t h e p y r r o l e  The s t r o n g CsN a b s o r p t i o n f e l l a t t h e lower end o f t h e  range quoted f o r o t / i - u n s a t u r a t e d n i t r i l e s  (75).  The v i s i b l e and u l t r a v i o l e t spectrum o f t h e t e t r a cyanoethylene  d e r i v a t i v e had a b s o r p t i o n maxima a t 251.5  (€ 1|.,610),  53  362  ( e 1 3 , 6 0 0 ) , and 1+33 m/uc (& 16,1+00)  ( c f . 1+9).  Acetonylacetone bis-2,l+-dinitrophenylhydrazone 0 . 5 go o f s o l i d 2 , l + - d i n i t r o p h e n y l h y d r a z i n e was d i s s o l v e d i n 25 m l . o f warm e t h a n o l , and 0 . 2 5 g. q u a n t i t i e s o f a c e t o n y l a c e tone and 2 , 5 - d i r a e t h y l p y r r o l e added t o s e p a r a t e p o r t i o n s o f t h e solution.  The m i x t u r e s were h e a t e d t o b o i l i n g and 1 m l . o f 10$  s u l p h u r i c a c i d was added t o each.  A y e l l o w p r e c i p i t a t e formed  i m m e d i a t e l y i n b o t h cases and, a f t e r s t a n d i n g a few m i n u t e s , these were c o l l e c t e d and r e c r y s t a l l i s e d from p y r i d i n e .  The  a c e t o n y l a c e t o n e d e r i v a t i v e was o b t a i n e d as y e l l o w p r i s m s , m.p. 269-72° (dec.) and t h e 2,5-d i m e t h y l p y r r o l e gave a s i m i l a r , y e l l o w , c r y s t a l l i n e p r o d u c t , m.p. 2 7 2 - 3 ° (dec.) d e r i v a t i v e , 262° ( 1 + 8 ) ) .  (lit.  f o r "mono"  Mixed m.p. gave 270-3° ( d e c ) ,  e s t a b l i s h i n g t h e i d e n t i t y o f t h e s e two compounds (Pounds C, 1+5.6; H, 3 . 9 5 ; N, 2 3 . 7 5 $ . N, 2 3 . 6 $ ) .  c  i 8 i 8 8 ° 8 r e q u i r e s C, 1+5.6; H, 3 . 8 ; H  N  These two d e r i v a t i v e s were, t h e r e f o r e , t h e b i s -  2 , l + - d i n i t r o p h e n y l h y d r a z o n e o f a c e t o n y l a c e t o n e ( c f . (1+8)). i n f r a r e d s p e c t r a (which c o n f i r m e d t h e i r i d e n t i t y )  Their  showed  a b s o r p t i o n a t 3322 (NH), 1608, 1585, 1529, 1508, 11+16, 13 59 , 1330, 1 3 0 0 , 1259, 1131+, 1075, 911, 8 3 9 , 71+1, and 72i+ cm."  1  S i m i l a r treatment o f 2 , 5 - d i p h e n y l p y r r o l e w i t h 2 , l + - d i n i t r o p h e n y l h y d r a z i n e r e a g e n t gave no d e r i v a t i v e , even a f t e r s t a n d i n g f o r s e v e r a l weeks, from which i t was c o n c l u d e d t h a t no r i n g - o p e n i n g t o t h e diketone occured i n t h i s  case.  2 , 2 - B i s - b - ( 2 , 5 - d i m e t h y l p y r r o l y l ) ] propane (XXXIX) 2„5  g. o f f r e s h l y d i s t i l l e d 2 , 5 - d i m e t h y l p y r r o l e  was  t r e a t e d w i t h acetone and h y d r o c h l o r i c a c i d a c c o r d i n g t o the method d e s c r i b e d by A l l e n , and Young (lj.8).  An  orange-coloured  p r o d u c t r e s u l t e d w h i c h , a f t e r t h r e e r e c r y s t a l l i s a t i o n s from aqueous e t h a n o l , y i e l d e d 1<>9  g. (63$)  o f a compound, f o r which  the s t r u c t u r e (XXXIX) appears most l i k e l y . o b t a i n e d as p i n k n e e d l e s , m.p. H, 9 . 6 ;  (Pounds C, 78.71 C, 7 8 . 2 ;  H, 9 . 6 ;  60$  The  compound  was  177-8° (dec.) ( l i t . 1714.° (1+8))  N, 1 2 . 1 $ ; M, 2l+5.  N, 1 2 . 2 $ ; M, 2 3 0 ) .  C ^ H ^ I ^ requires  A l l e n and Young, on t h e b a s i s  of a n i t r o g e n a n a l y s i s and m o l e c u l a r weight d e t e r m i n a t i o n , a s s i g n e d a m o l e c u l a r f o r m u l a C ^ H ^ N ^ to t h i s p r o d u c t of acetone w i t h 2 , 5 - d i m e t h y l p y r r o l e  condensation  but d i d not propose  a s t r u c t u r e (1+8). The ^1^22^2  P  r o c  * ct u  o b t a i n e d i n t h i s case decomposed  s l o w l y , d e t e r i o r a t i o n b e i n g accompanied by r e d d e n i n g  of colour  and r e g e n e r a t i o n o f 2 , 5 - d i m e t h y l p y r r o l e ,  the odour o f which soon  became d e t e c t a b l e .  compound gave a  The  f r e s h l y prepared  p o s i t i v e E h r l i c h r e a c t i o n , s u g g e s t i n g an u n s u b s t i t u t e d / 5 - p o s i t i o n on a p y r r o l e n u c l e u s , and i t s i n f r a r e d spectrum showed a b s o r p t i o n a t 3I+25 (NH), 1582, 793,  708,  and 692  cm." . 1  The  li+97, 1391,  1199,  1166,  1073,  NH a b s o r p t i o n at the same p o s i t i o n  and w i t h the enhanced i n t e n s i t y w h i c h c h a r a c t e r i s e d the spectrum of 2 , 5 - d i m e t h y l p y r r o l e , s a t i o n product  supported  a s t r u c t u r e f o r the conden-  i n which t h i s n u c l e u s was r e t a i n e d .  The u l t r a v i o l e t spectrum of (XXXIX) below 270 m^, common w i t h t h a t o f 2 , 5 - d i m e t h y l p y r r o l e  (76),  in  showed a b s o r p t i o n  55 i n c r e a s i n g t o an e x t i n c t i o n c o e f f i c i e n t o f 9,900 a t 220rayw-( w i t h no maximum i n t h i s r e g i o n ) . spectrum had  X  raax<>  a t 307  Towards l o n g e r wavelength t h e VHJA.  (£ 80)„  A s t r u c t u r e such as  (XXXIX), t h e r e f o r e , seems t o be i n a c c o r d w i t h t h e e v i d e n c e a v a i l a b l e so f a r  0  REFERENCES  1.  Runge, Ann. P h y s i k , I83I+, 31,  2.  Dennstedt and Zimmerman, B e r . , 1888, 2 1 ,  3.  P i e r o n i and Moggi, G a z z e t t a , 1923,  1+.  D e n n s t e d t , B e r . , 1888, 2 1 ,  31+29.  5.  Dennstedt, Ber., I889, 22,  1920.  6.  P i l o t y and W i l k e ,  7.  A l l e n , G i l b e r t , and Young, J . Org. Chem., 1938,  8.  I b i d . , p. 227.  9.  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W l t t i g and S t r e i b , Annalen, 1953, 5§l+_, 1 1 .  3l+.  Lukes, C o l l . Czech. Chem. Comm., 1932, Ij., 35l«  35.  Walton, J . , 1 9 4 ° , 1*38.  36.  V o g e l , " P r a c t i c a l Organic Chemistry," Longmans, London, 1951, p. 621. B e l l a m y , "The I n f r a r e d S p e c t r a o f Complex M o l e c u l e s , "  37.  Methuen, London, 1958, p. 76. 38.  I b i d . , p. 2 5 1 .  39.  G i l l e t , B u l l . Soc. chim. F r a n c e , 1950, 1139.  40.  T h e i l a c k e r and Schmidt, Annalen, 1957, 6 0 5 , 43-  41.  Abraham, B u l l o c k ,  1+2.  D i e l s and A l d e r , A n n a l e n , 1 9 3 1 , 4 8 6 , 2 1 1 .  43.  D i e l s and A l d e r , A n n a l e n , 1931, 1+90, 2 6 7 .  44.  D i e l s and A l d e r , Annalen, 1932, 1^98, 1.  45.  W i t t i g , Angew. Chem., 1957, 6 9 , 2 4 5 .  46.  M a n d e l l and B l a n c h a r d , J . Amer. Chem. Soc., 1957, 79, 6198.  and M i t r a , Canad. J . Chem., 1959, 37, 1859.  58  lj.7.  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