SOME INVESTIGATIONS IN INDOXYL CHEMISTRY

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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106

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Pretka, John Edward, 1919" Some investigations in indoxyl chemistry. Hew York, 1950* v,87 typewritten leaves, diagrs.

29 era. Thesis (Ph.D.) - New York Unlversity* Graduate School, 1950® Bibliography: p.85-37* C57602

C Shelf List

Xerox University Microfilms,

Ann Arbor, Michigan 48106

THIS D ISSERTA TIO N HAS BEEN M IC R O FILM E D E X A C TLY AS RECEIVED.

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SOME INVESTIGATIONS IN INDOXYL CHEMISTRY

A DISSERTATION IN THE DET'RTMBNT OP CHEMISTRY SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF ARTS AND SCIENCE OF NEW YORK UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

JOHN E . PRETKA

1950

ACKNOWLEDGEMENT The a u th o r w ish e s t o e x p re s s h i s s i n c e r e s t a p p r e c i a t i o n t o P r o f e s s o r H. G. L in d w a ll who s u g g e s te d and d i r e c t e d t h i s i n v e s t i g a t i o n .

The r e s e a r c h was made

p o s s i b l e i n p a r t b y a o n e -y e a r f e llo w s h ip g r a n t from th e E . I . du P o n t de Nemours and Company*

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TABLE OP CONTENTS

Pag© ACKNOWLEDGMENT.........................................................................................

11

LIST OP PLOW SHEETS............................................................................

v

INTRODUCTION

1

.........................................................................................

DISCUSSION OP EXPERIMENTAL RESULTS .

.

.

.

S u b s t i t u t e d In d o x y ls • • • • • • • • • • 2,2* - D ia u b s tltu te d - 3 ,3 » - D ik e to - D I in d o lin y l- 2 ,2 * D e r iv a t iv e s ................................................. 2 - 8 u b a t l t u t e d - 3 - I n d o l e A c e tic A cids • • • • • S u b s t i t u t e d in d o le s • • • • • • • • • • M is c e lla n e o u s R e a c tio n s • • • • • • • • • M e ltin g P o i n t s .......................................................................... • EXPERIMENTAL SECTION.

•

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4 II 17 21 26 28

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A lp h a - ( o - c a r b o x y a n illn o ) - p r o p io n ic a c id ( I I I ) * • N - a c e ty l- a lp h a - ( o - c a r b o x y a n ilin o ) - p r o p io n ic a d d (V) 1 .3 - d 1a c e ty l- 2 - m e th y 1 In d o x y l (V II) • • • • • l - a c e t y l - 2 - m e t h y l In d o x y l ( I X ) . • • • • • • A lp h a -c h lo r o p h en y l a c e t i c a c id ( I I ) • • • • • A lp h a - ( o -c a r b o x y a n llln o ) -p h e n y l a c e t i c a c id ( I V ) . N -ace t y l - a l p h a - ( o - c a r b o x y a n l l i n o ) -p h e n y l a c e t i c a c id (VI) . . . . . . . . . . . . 1 . 3 - d i a c e t y l - 2 -p h e n y l In d o x y l ( V I I I ) . • • • • 1 - a c e t y l - 2 - p h e n y l In d o x y l (X) • • • • • • • P h en y l h y d ra zone o f 1 - a c e ty l- 2 - m e th y l in d o x y l (X I) • P h en y l h y d razo n e o f 1 - a c e ty l- 2 - p h e n y l In d o x y l ( X I I ) . M e th y l- a lp h a - c h lo r o p r o p io n a te ( X I I I ) . • • • • D im eth y l e s t e r o f a l p h a - ( o - c a r b o x y a n ilin o ) - p r o p io n ic a c id (XV) . . . . . . . . . . D im eth y l e s t e r o f N - a c e t y l - a l p h a - ( o - e a r b o x y a n i l i n o ) p r o p io n lc a c id ( X V I I ) ................................................. Sodium m e th y la te • • • • • • ............................. 2 ,2 * - d im e th y l- 3 , 3 ' - d ik e t o - d i i n d o l i n y l - 2 ,2 * fro m (XV) . . . . . . . . . . . 2,2* -d im e th y l- 3 , 3 M i k e t o - d i i n d o l i n y l - 2 , 2 1 fro m (XVII) • . . . . . . . . . . 2 , 2 ' -d im e th y l- 3 , 3 *- d l k e t o - d l l n d o l i n y l - 2 ,2» (XIX) fro m (IX ) . . . . . . . . . . . M ethyl m a n d e la te . . . . • • » » • • • ill

29 30 31 32 34 35 36 37 38 40 41 42 43 ■ 44 45 46 48 49 50

TABLE OP C O N TEN TS--C ontinued

Page M ethyl e a t e r o f a lp h a - c h lo r o p h e n y l a c e t i c a c id ( X I V ) ..................................................................... D im e th y l e s t e r o f a lp h a - ( o - c a r b o x y a n ilin o ) -p h e n y l a c e t i c a c id (XVI) • • • • • • • • • D im e th y l e s t e r o f N- a c e ty l - a lp h a - ( o - c a r b o x y a n i l i n o ) p h e n y l a c e t i c a c id (X V III) . . . . . . 2 ,2 * - d ip h e n y l- 3 , 3 ' - d i k e t o - d i l n d o l i n y l - 2 ,2* (XX) fro m ( X V I ) ...................................................................... 2 ,2 * - d ip h e n y l- 3 ,3 * - d i k e t o - d i i n d o l i n y l - 2 ,2 * (XX) fro m (X V III)...................................................................... 2 ,2 * - d ip h e n y l- 3 ,3 * - d i k e t o - d i i n d o l i n y l - 2 ,2 * (XX) fro m (X) . . . . . . . . . . . 2 - m e th y l- 3 - in d o le a c e t i c a c id (XXV) fro m (IX ) . 2 - m e th y l-3 - In d o le a c e t i c a c id (XXV) fro m 2 -m e th y l I n d o le ( X X I X ) .............................................................. 2 - p h e n y l- 3 - in d o le a c e t i c a c id (XXVI) fro m (X) • 2 - p h e n y l- 3 - I n d o le a c e t i c a c id (XXVI) fro m 2 -p h e n y l in d o le (XXX) . . . . . . . . . . l - a c e t y l - 2 , 3 - d i m e t h y l in d o l e (XXXII) fro m .(IX ) . 1 - a c e t y l - 2 , 3 -d im e th y l I n d o le (XXXII) v i a th e F is c h e r m ethod . . . . . . . . . . 2 . 3 - d ip h e n y l I n d o le (XXXVII) fro m (X) . . . . 2 .3 - d ip h e n y l in d o le (XXXVII) v i a th e Jap p -M u rray m ethod • • • • • • • • • • • A lp h a - ( o - c a r b o x y a n ili n o ) - a c e tic a c id • • • • N - a c e ty l- a lp h a - ( o - c a r b o x y a n il in o ) - a c e t i c a c id . 1 . 3 - d i a c e t y l in d o x y l. • • • • • • • • • 1 - a c e t y l In d o x y l . . . . • • • • • • D im e th y l e s t e r o f a lp h a - ( o - c a r b o x y a n i 11 no) a c e t i c a c id • • . • • • • • • • M ethyl in d o x y la te « . * • • • • • • •

51 52 53 54 55 56 57 60 63 66 69 72 74 77 78 79 80 81 82 83

SUM M ARY................................................................................................

84

BIBLIOGRAPHY........................................

85

iv

L IS T OP PLOW SHEETS

S heet 1* 2* S.

Page S y n th e s is o f S u b s t i t u t e d I n d o x y ls •

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5

2,2* - D i s u b s tit u te d - 3 ,3 * - D i k e t o - D i l n d o l l n y l - 2 ,2 , D e riv a tiv e s . • • • • • • • • • •

13

S y n th e s is o f 2 - S u b s t i t u t e d - 3 - I n d o l e A c e tic A c id s...................................................................................

18

4.

S y n th e s is o f 1 - A c e ty l- 2 ,3 - D i* e th y l In d o le *

5*

S y n th e s is o f 2 ,3 -D ip h e n y l In d o le *

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22 23

INTRODUCTION

ISTRODITCTIOy

I t seemed o f i n t e r e s t t o work o u t s u i t a b l e s y n th e s e s o f s u b s t i t u t e d in d o x y ls and t o s tu d y some o f t h e i r r e a c t i o n s * I t was b e l ie v e d t h a t b y v i r t u e o f th e r e a c t i v e c a rb o n y l group and th e " a c t i v e m e th y le n e 11 h y d ro g en s i n th e s e m o le c u le s , th e compounds w ould c o n s t i t u t e v a lu a b le in te r m e d ia te s f o r a c o e ss t o a v a r i e t y o f n it r o g e n h e t e r o c y c l e s , o th e rw is e made w ith d i f f i c u l t y o r in poor y ie ld s . B ecause o f th e s u s c e p t i b i l i t y t o o x id a tio n o f in d o x y l i t s e l f , i t was d e s i r a b l e t o f i n d d e r i v a t i v e s o f in d o x y l w hich w ere r e l a t i v e l y n o n - o x id iz a b le and y e t c o n ta in e d th e r e a c t i v e c e n t e r s f o r th e v e r y la r g e number o f s p e c u la te d r e a c t i o n s . I t had b e e n p r e v io u s l y r e p o r t e d t h a t th e p r e s e n c e o f an a c y l g ro u p on t h e n i t r o g e n g r e a t l y r e d u c e d th e s u s c e p t i b i l i t y o f in d o x y l t o o x l d a t l o n ( l ) •

i t was f u r t h e r a n t i c i p a t e d t h a t

th e p re s e n c e o f s u i t a b l e g ro u p s on t h e 2 -c a rb o n w ould f u r t h e r l e s s e n t h i s te n d e n c y b y a s t e r l c e f f e c t . The s u b s t i t u t e d in d o x y ls m ig h t w e ll p r o v id e s t a r t i n g p o i n t s f o r many I n t e r e s t i n g and u s e f u l r e a c t i o n s .

One p o s s i ­

b i l i t y i s th e f o rm a tio n o f 2 - s u b s tit u te d - ® —in d o le a c e t i c a c id s v i a th e R e fo rm a tsk y r e a c t i o n fo llo w e d b y d e h y d r a tio n and hy­ d ro ly s is .

The ad v a n ta g e o f t h e m ethod w ould b e t o make a v a i l ­

a b le th o s e a c id s w ith one s u b s t i t u e n t on th e 2 - c a r b o n and n o n e , o n e , o r two s u b s t i t u e n t s on th e a lp h a - c a r b o n o f t h e a c e t i c a c id s i d e c h a in .

The compounds w ould b e o f s p e c i a l

i n t e r e s t as p o t e n t i a l l y a c t i v e p l a n t h o rm o n es. W ith G rig n a rd r e a g e n ts a r i s e s th e p o s s i b i l i t y o f s y n th e 1

z. s i z i n g a la r g e number o f 2 , 3 - d i s u b s t i t u t e d in d o le s i n a f a a h io n s i a d l a r to th e above*

I n many e a s e s , i t v o u Id s e e n e x ­

c e e d in g ly d i f f i c u l t t o a r r i v e a t t h e s e d e r i v a t i v e s b y o th e r p a th s as com pared t o t h i s p ro p o sed method*

I t has a lr e a d y

b e e n r e p o r t e d t h a t in d ig o r e a c t s w ith a v id e v a r i e t y o f G rlg n a rd r e a g e n t s ( 2 ) • W ith th e s e th in g s I n m ind, th e c o u rs e o f v o rk was p la n n e d as fo llo v s *

(1) To p r e p a r e In d o x y ls v l t h a c y l g ro u p s s u b s t i t u t e d on th e n i t r o g e n , and e s t e r , a l k y l , o r a r y l g ro u p s on th e 2 - c a r b o n . (2) To p r e p a r e fro m t h e above s u b s t i t u t e d in d o x y ls v i a th e R efo rm at sk y r e a c t i o n , 2 - s u b s t l t u t e d - 3 - l n d o l e a c e t i c a c id s * (3) To p r e p a r e fro m t h e above s u b s t i t u t e d in d o x y ls v i a th e G rlg n a rd r e a c t i o n , 2 , 3 - d i s u b s t i t u t e d in d o le s * (4) To com pare th e p ro d u c ts fro m (2 ) and (3) w ith th o s e form ed b y o th e r m ethods* E x te n t o f R e a l i z a t i o n o f O b je c tiv e s M eth y l in d o x y la te was p re p a re d i n good y i e l d s b y a D ie c k mann r e a c t i o n as p r e v io u s l y r e p o r t e d (3 )» b u t vas fo u n d t o be to o u n r e a c t i v e f o r s y n t h e t i c p u rp o ses*

A ttem p ts t o c y c l i s e

i n t h e same way th e d im e th y l e s t e r s o f a lp h a - ( o - c a r b o x y a n i l i n o ) p r o p io n ic a c id (XV), i t s l - a e e t y l d e r lv a tiv e .( X V I I ) , and o f a l p h a - ( o - e a r b o x y a n llin e ) - p h e n y l a c e t i c acid (X V I) and i t s V a c e t y l d e r iv a tiv e ( X V I I I ) y ie ld e d 2 , 2 ' - d lm e th y l- d ,3 f - d i k e t o d i i n d o l i n y l - 2 ,2 * (X U ) and 2,2* - d ip h e n y l- 3 , 3 ' - d i k e t o - d l l n d o lin y l-2 ,2 * (X X ) r e s p e c t i v e l y r a t h e r th a n th e d e s ir e d s u b s t i t u t e d in d o x y la *

V -a e e ty 1 - 2 -m e th y l in d o x y l(IX ) and H -a c e ty l- 2 - p h e n y l

s in d o x y l(X ) wore p r e p a re d fro m N - a c e t y l - a l p h a - ( o - c a r b o x y a n i l i n o ) p r o p io n ic a c id (V ) and N - e c o ty l- a lp h a - ( o - c a r b o x y a n ilin o ) -p h e n y l a c e t i c a c id (V I) r e s p e c t i v e l y u n d e r P e rk in c o n d i t i o n s , fo llo w * ! by e e l e c t i T e h y d r o ly s is o f t h e r e s u l t i n g s u b s t i t u t e d d i& c e ty l in d o x y ls *

The i n te r m e d ia te s ( d i a c e t y l d e r i v a t i v e s ) had a l ­

re a d y b e e n r e p o r t e d b y v an A lp h en (4 ) •

By th e r e a c t i o n o f

th e a p p r o p r ia te R e fo rm a tsk y o r O rig n a rd r e a g e n ts w ith th e above m e n tio n e d s u b s t i t u t e d in d o x y ls , i t was fo u n d p o s s i b l e t o p r e p a r e 2 - « e t h y l - 3 - i n d o l e a c e t i c a c id (XXV), 2 - p h e n y l- 3 I n d o le a c e t i c acid(X X V I), 1 - a c e t y l - 2 ,3 - d im e th y l I n d o le (XXXII) , and 2 , 3 - d ip h e n y l in d o le (XXXVII),

These r e a c t i o n s i n d i c a t e

t h a t a v id e v a r i e t y o f s u b s t i t u t e d - 3 - i n d o l e a c e t i c a c id s and In d o le s c a n be p r e p a r e d b y t h i s r o u te *

DISCUSSION OP EXPERIMENTAL RESULTS

4 SUBSTITUTED INDOXYLS A la r g e number o f m ethods f o r s y n th e s iz in g in d o x y l h as b e e n c i t e d i n th e l i t e r a t u r e

(5 )*

The compound i s e s p e c i a l l y

im p o rta n t b e c a u se i t i s an in te r m e d ia te i n t h e s y n th e s is o f i n d i g o , and much w ork, b eg u n by B aeyer i n 1870 (6) i n a s tu d y o f th e s y n th e s is o f i n d i g o , h as b e e n d i r e c t e d to w ard s t h e s y n th e s is o f in d o x y l*

The p r e s e n t d ay m a n u fa c tu re o f in d ig o

i s l a r g e l y b y th e Heumamn p r o c e s s (7 ) i n w h ich p h e n y l g ly c in e i s f u s e d w ith a m ix tu re o f a l k a l i e s and o th e r a g e n ts , ear by th e c l o s e l y r e l a t e d m ethod, em ploying p h e n y l g l y c i n e - o - c a r b o x y lie a c id *

However, i n e i t h e r c a s e a p p lie d to la r g e s c a l e

p r o d u c tio n , th e f u s i o n m e lt i s d i r e c t l y o x id iz e d to in d ig o w ith o u t a tte m p tin g t o i s o l a t e th e in te r m e d ia te in d o x y l. As a l a b o r a to r y p r e p a r a t i o n , th e f u s i o n m ethods w ere found t o b e u n d e s ir a b le f o r th e p r e p a r a t i o n o f in d o x y l.

The

m e lt c o o ls t o a v e r y h a r d mass w hich c a n b e rem oved fro m th e i r o n c r u c i b l e o n ly w ith d i f f i c u l t y .

I n th e c a s e o f p h e n y l

g ly c in e -o -c a rb o x y 1 1 c a c id th e d e s ir e d p r o d u c t i s m ixed w ith a l a r g e e x c e s s o f a l k a l i n e a g e n ts w hich g r e a t l y f a v o r s th e o x i d a tio n t o I n d ig o , and a tte m p ts t o w ork u p t h e mass i n a i r - f r e e w a te r u n d e r n i t r o g e n atm o sp h ere l a r g e l y y ie ld e d In d ig o and n e g l i g i b l e am ounts o f In d o x y l o r in d o x y llc a c i d . M o reo v er, In d o x y l i s so s u s c e p t i b l e t o a i r o x id a tio n t h a t im m ediate u s e would be r e q u i r e d a lo n g w ith e l a b o r a t e p r e p a ­ r a t i o n s t o p r e v e n t th e d e c o m p o s itio n o f t h i s m a t e r i a l d u rin g th e r e a c t i o n s .

A tte m p ts t o s e c u re f u s i o n m e lt from th e dye

m a n u fa c tu re rs i n d i c a t e d t h a t ev en s m a ll am ounts c o u ld b e ob­ t a i n e d o n ly w ith a c o m p a r a tiv e ly g r e a t e x p e n d itu r e o f tim e .

5

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I I I , IV

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V, VI

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IX , X

I , I I I , V, V I I , IX , X Ii I I , IV , V I, V I I I , X, X II?

X I, X II

R = CHy- . R = CgH5 -

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FLOW SHEET X .— SYNTHESIS OP SUBSTITUTED INDOXYLS

6 l a b o r , and c o a t ( i n a b u t tin g down a l a r g e s c a le p r o c e s s ) , so o th e r s o u rc e s w ere deemed n e c e s s a r y . F o r our p u r p o s e s , th e most s u i t a b l e p r e p a r a t i o n o f su b ­ s t i t u t e d in d o x y ls seem ed t o b e one in v o lv in g th e r i n g c lo s u r e o f d e r i v a t i v e s o f N - a c e ty l p h e n y l g ly c in e - o - c a r b o x y lie a c id w ith f u s e d sodium a c e t a t e and a c e t i c a n h y d rid e ( 3 ) .

The la b o ­

r a t o r y m a n ip u la tio n s became su c h s im p le r* and s u i t a b l e amounts o f N - a c e ty l In d o x y ls c o u ld b e p r e p a r e d e a s i l y and s t o r e d i n ­ d e f i n i t e l y w ith o u t o x id a tio n ta k in g p l a c e . G e n e ra lly s p e a k in g , p h e n y l g l y c in e - o - c a r b o x y lie a c id and i t s d e r i v a t i v e s w ere p r e p a r e d i n a p p ro x im a te ly 60 p e r c e n t c ru d e y i e l d s b y th e r e a c t i o n o f a n t h r a n i l l c a c id w ith ap p ro p ­ r i a t e a lp h a c h lo r o a c id s i n w a te r c o n ta in in g an e x c e s s o f sodium c a r b o n a te .

I n a l l c a s e s , co m p lete p u r i f i c a t i o n b y

r e p e a te d r e c r y s t a l 11s a t i o n s fro m w a te r o r d i l u t e a lc o h o l r e ­ s u l t e d o n ly i n th e l o s s o f m a t e r i a l s w ith o u t co m p en satin g f a c t o r s i n o th e r s t e p s o f th e s y n t h e s e s .

T h e r e f o r e , th e i n t e r ­

m e d ia te s were u s e d w ith o u t to o c a r e f u l p u r i f i c a t i o n . H a ll e r (9) h a s i n v e s t i g a t e d th e p r e p a r a t i o n o f p h e n y l g ly c in e - o - c a r b o x y lic a c id from a n t h r a n i l l c a c id and e h l o r a c e t i c a c i d , s tu d y in g t h e e f f e c t s o f c o n c e n t r a t i o n , tim e , r a t i o o f r e a c t a n t s , co n d e n sin g a g e n ts , and te m p e r a tu r e .

The r e s u l t s

o f h i s e x p e rim e n ts i n d i c a t e t h a t th e optimum c o n d itio n s f o r t h e r e a c t i o n c o n s i s t o f a two t o one mole r a t i o o f a n t h r a n i l l c a c id to e h l o r a c e t i c a c i d , 25 g . o f a n t h r a n i l l c a c id p e r 200 c e . o f w a te r , 2 .3 3 m. o f sodium c a r b o n a te p e r mole o f a n t h r a ­ n i l l c a c i d , and a te m p e r a tu r e o f n i n e t y d e g re e s f o r one h o u r . Somewhat s i m i l a r c o n d itio n s w ere u s e d i n our w o rk , e x c e p t t h a t

1

a mole p a t i o o f one t o one o f a n t h r a n i l l c a c id and a lp h a c h lo r o a c id was u s e d alo n g w ith some v a r i a t i o n s I n tim e and te m p e ra ­ tu r e c o n d itio n s .

I t was fo u n d t h a t th e y i e l d s v e re n o t s u b ­

s t a n t i a l l y changed fro m th o s e I n d ic a te d b y H a l l e r , and th e p r o c e s s a c h ie v e d a l a r g e s a v in g o f a n t h r a n i l l c a c id u sed * I n t h i s way were p r e p a r e d p h e n y l g l y c in e - o - c a r b o x y lic a c i d , a ip h a - ( o - c a r b o x y a n ilin o ) - p r o p io n ic a c i d ( I I I ) , and a l p h a (o - c a r b o x y a n llin o ) - p h e n y l a c e t i c a c id ( I V ) . I n ag reem en t w ith V o r la n d e r ( 1 0 ) , i t was fo u n d t h a t th e r i n g c l o s u r e o f th e above a c id s w ith sodium a c e t a t e and a c e t i c a n h y d rid e p ro c e d e d i n b e t t e r y i e l d s w ith th e N - a c e ty l d e r i v a ­ t i v e s th a n w ith th e a c id s th e m se lv e s*

V o rla n d e r b e lie v e d

t h a t t h i s a b i l i t y to c y c l l s e was a t t r i b u t a b l e to th e ab sen ce o f h y d ro g en on th e n i t r o g e n r a t h e r th a n t o th e p re s e n c e o f any p a r t i c u l a r ty p e o f g ro u p s in c e th e p re s e n c e o f a l k y l g ro u p s a l s o c a u se d th e same e f f e c t *

We fo u n d t h a t th e a c e t y l a t l o n

o f t h e s e a c id s p ro c e d e d e a s i l y , q u i c k l y , and i n good y i e l d s sim p ly b y a d d in g a c e t i c a n h y d rid e t o an aqueous sodium h y d ro x id e s o l u t i o n o f th e a c id and s h a k in g s e v e r a l m in u te s* R ing c l o s u r e o f th e s e N - a c e ty l a c id s t o d i a c e t y l in d o x y ls was p e rfo rm e d u n d e r d r y n i t r o g e n atm o sp h ere w ith r a p i d s t i r ­ r in g *

I t was fo u n d t h a t e x c e s s iv e te m p e r a tu r e and h e a tin g

tim e e i t h e r d u r in g th e r e a c t i o n p ro p e r o r d u r in g th e rem o v al o f e x c e s s s o lv e n t le d t o h ig h ly c o lo r e d p ro d u c ts w hich r e q u i r e d a d d i t i o n a l s te p s I n p u r i f i c a t i o n *

The c o n v e rs io n o f e x c e s s

a c e t i o a n h y d rid e t o a o e t l e a c id b y w a te r a d d i t i o n g r e a t l y d e c re a s e d th e tim e and te m p e ra tu re r e q u i r e d f o r rem o v al o f th e s o lv e n t u n d e r vacuum*

One h a l f h o u r o f r e f l u x tim e seemed

3 t o bo a s a t i s f a c t o r y com promise b etw e en p u r i t y and y i e l d o f cru d e 1 , 3 - d i a c e t y l - 2 -m e th y l In d o x y l(V II) and 1 , 3 - d i a c e t y l 2 -p h e n y l I n d o x y l(V I II ) o b ta in e d , w h ile c ru d e 1 , 3 - d l a e e t y l in d o x y l c o u ld be o b ta in e d o n ly aa a h ig h ly c o lo r e d s o l i d w hich r e s i s t e d c h a r c o a l d e c o lo n iz a ti o n . Methods in v o lv in g aqueous s o l u t i o n s o f sodium s u l f i t e , sodium b i s u l f i t e , and d iso d iu m h y d ro g en p h o sp h a te have a lr e a d y b e e n r e p o r t e d f o r s e l e c t i v e h y d r o ly s is o f 1 , 3 - d l a c e t y l in d o x y l t o 1 - a c e t y l In d o x y l ( 8 ) .

The u s e o f r e a g e n ts l i k e th e s u l f i t e s

seems t o have th e added ad v a n ta g e o f m ild r e d u c in g c o n d i tio n s . I t was fo u n d t h a t , b e c a u se o f th e o n ly s l i g h t s o l u b i l i t y o f th e d i a c e t y l in d o x y ls i n w a te r , lo n g h e a tin g was n e c e s s a r y t o fo rm even s m a ll amounts o f p r o d u c ts b y th e above m ethod.

The

u s e o f a d io x a n e -w a te r s o l u t i o n o f sodium s u l f i t e gave a n e a ii y homogeneous s o l u t i o n a t t h e b o i l i n g p o in t o f t h e m ix tu re and th e d e s i r e d h y d r o ly s is o c c u r r e d f a i r l y c o m p le te ly a f t e r ab o u t th re e h o u rs.

S u b seq u e n t vacuum d i s t i l l a t i o n o f th e s o lv e n ts

r e n d e r e d i s o l a t i o n o f th e p ro d u c ts e a s y .

I n t h i s way, o v e r a l l

y i e l d s o f 23 and 32 p e r c e n t (b a se d on N - a c e ty l a c id s u s e d , r e c r y s t a l l i z e d once from e th a n o l) w ere o b ta in e d o f 1 - a c e t y l 2 -m e th y l In d o x y l (IX) and 1 - a c e t y l - 2 -p h e n y l in d o x y l (X) r e ­ s p e c tiv e ly .

B ecause 1- a c e t y l in d o x y l c o u ld n o t b e p u r i f i e d

b y N o rlte d e c o l o r l z a t l o n and e t h a n o l r e c r y s t a l l i z a t i o n , i t s u s e i n f u r t h e r e x p e rim e n ts was aband o n ed . I t was n o te d t h a t th e c y c l i z a t i o n o f N - a c e t y l - a l p h a - ( o c a r b o x y a n ilin o ) - p h e n y l a c e t i o a e ld (V I) o c c u rr e d a p p r e c ia b ly more c o m p le te ly th a n N - a c e ty l- a lp h a - ( o - c a r b o x y a n il in o ) - p r o p ­ i o n i c a c id (V ).

One m ight s p e c u la te t h a t th e p re s e n c e o f an

9 e l e c t r o n a t t r a c t i n g g r o u p , su c h as th e p h e n y l r a d i c a l , may a c t i v a t e th e h y d ro g en a lp h a t o I t and th u s a i d th e c lo s u r e * A lp h a -c h lo ro p h e n y l a c e t i c a c id ( I I ) was p r e p a r e d from m a n d e lic a c id b y a p ro c e d u re d e s c r ib e d b y B ls c h o f f and Walden (11)*

The r e s u l t s w ere I n c lo s e ag reem en t w ith t h e i r o b s e r ­

v a tio n s * O th er m ethods w ere t r i e d i n an a tte m p t t o g e t th e d e s ir e d in d o x y ls more d i r e c t l y and i n b e t t e r y i e l d s .

Jo h n so n and

G le n n (12) h ave u s e d th e in v e r s e F r i e d e l - C r a f t s m ethod t o p r e ­ p a r e s u b s t i t u t e d 1 -h y d rin d o n e a i n e x c e l l e n t y i e l d s .

Our a t ­

te m p ts to a p p ly th e same c o n d itio n s t o th e e y e 11n a t io n o f N - a c e ty l p h en y l g ly c in e y i e l d e d o n ly s m a ll am ounts o f a n o n o ry s ta lllz a b le o i l .

I t had b e e n p r e v io u s ly c la im e d (13) t h a t

In d o x y l was fo rm ed b y th e a c t i o n o f anhydrous aluminum c h lo r id e on t h e a c id c h l o r i d e o f p h e n y l g l y c i n e , b u t t h i s was l a t e r d is p u te d (14)*

The l a t t e r r e p o r t , h o w ev er, c la im e d t h a t In d o x y l

c o u ld be form ed w ith aluminum c h l o r id e I f N - a c e ty l p h e n y l g ly c in e o r i t s a c id c h l o r id e r e a c t e d i n th e ab sen ce o f oxygen* An a tte m p t was made t o r e p e a t th e l a t t e r work u s in g N - a c e ty l p h e n y l g l y c i n e , b u t o n ly an u n i d e n t i f i e d h ig h m e ltin g brown s o l i d c o u ld be i s o l a t e d *

L ik e w is e , an a tte m p t t o d e h y d ra te

th e same compound w ith p h o sp h o ru s p e n to x ld e i n b en z en e gave u n i d e n t i f i e d h ig h m e ltin g brow n s o l i d s . Clemo and P e r k in (1 5 ,1 6 ) h av e o b se rv e d t h a t c e r t a i n b e t a a n l lln o p r o p io n lc a c id s u n d erg o r i n g c lo s u r e t o d ih y d r o - 4 q u ln o lo n e a w ith p h o sp h o ru s p e n to x ld e i f th e N - p - to lu e n e s u lf o n y l ( t o s y l ) d e r i v a t i v e s a r e used*

More r e c e n t l y , Jo h n so n and h is

10 c o l l a b o r a t o r s (17) have e y e liz e d t h e s e sa n e ty p e s o f compounds i n e x c e l l e n t y i e l d s b y f i r s t fo rm in g th e a c id c h l o r i d e s w ith p h o sp h o ru s p e n t a c h l o r i d e , and th e n c o m p le tin g th e r i n g c l o s u r e s w ith an h y d ro u s s t a n n i c c h l o r id e o r aluminum c h lo rid e *

E ld e rfie Id

and M aggiolo (18) have r e p o r t e d t h a t , w hereas th e N - t o s y l b e t a - ( p - c h l o r o a n i l i n o ) - b u t y r i c a c id u n d e rg o e s r i n g c l o s u r e r e a d i l y b y th e a c t i o n o f p h o sp h o ru s o x y c h lo r id e , t h e N - a c e ty l d e r i v a t i v e c o u ld n o t b e r i n g c lo s e d u n d e r a w ide v a r i e t y o f c o n d itio n s *

H oping to a p p ly t h i s in f o r m a tio n t o th e f o r m a tio n

o f N - to s y l in d o x y ls , we a tte m p te d t o t o s y l a t e p u re a l p h a ( o - c a r b o x y a n i lin o ) - p r o p io n ic a c i d , b u t abandoned t h i s b e c a u se o n ly o i l s were i s o l a t e d w hich w ould n o t c r y s t a l l i z e b y s c r a t c h ­ in g and v e ry lo n g c o o lin g * I t was fo u n d t h a t t h e f o rm a tio n o f p h en y l h y d ra z o n e s o f th e s u b s t i t u t e d in d o x y ls o c c u rre d r e l a t i v e l y e a s i l y , y i e l d i n g l i g h t y e llo w c r y s t a l l i n e s u b s ta n c e s (fro m a lc o h o l) w hich m e lte d s h a r p ly .

H ow ever, a tte m p ts to p r e p a r e th e oxlm es gave

h ig h ly c o lo re d n o n - c r y s t a l l i n e s o l i d s w h ile s e m ic a rb iz o n e s w ere i s o l a t e d b u t w ith g r e a t e r d i f f i c u l t y and i n s m a lle r y i e l d s th a n t h e p h e n y l h y d razo n es*

II 2.Z* -DISUBSTI TP TED-5,3* -DIKETO -P I INDOLINYL-2,2« DERIVATIVES A t th e b e g in n in g o f t h i s r e s e a r c h , i t was d e s ir e d t o f i n d a c o n v e n ie n t p r e p a r a t i o n o f s u b s t i t u t e d In d o x y ls su ch t h a t th e r e a c t i o n te m p e r a tu r e c o n d itio n s would b e as m ild as p o s s i b l e , y e t a llo w in g s u f f i c i e n t y i e l d s t o make t h e m ethod w o rth -w h ile # An id e a w hich o c c u rre d t o u s was th e p o s s i b i l i t y o f Dleckmann r i n g c l o s u r e s o f n e u t r a l e s t e r s of a l p h a - ( o - c a r b o x y a n ilin o ) p r o p io n ic a c i d , a lp h a —( o - c a r b o x y a n i11n o ) -p h e n y l a c e t i c a c i d , t h e i r N - a c e ty l d e r i v a t i v e s , and o th e r s i m i l a r l y s u b s t i t u t e d d e r i v a t i v e s o f p h e n y l g l y c in e - o - c a r b o x y lie acid * Auwers (3 ) h ad p r e v io u s l y r e p o r te d t h a t n e u t r a l e s t e r s o f p h en y l g l y c in e - o - c a r b o x y llc a c id co u ld b e c o n v e rte d a lm o st q u a n t i t a t i v e l y i n t o e s t e r s o f in d o x y lic a c id b y d ry sodium a l c o h o la te s i n benzene*

I n t h i s r e a c t i o n , f o r m a tio n o f a p u re

p ro d u c t I s f a v o r e d b y th e a b sen ce o f h y d ro g en on th e c a rb o n a lp h a t o th e a c y la t in g e s t e r g ro u p as e x i s t s i n th e s e compounds* However, th e u s e o f sodium a lc o h o la te s as c o n d e n sin g a g e n ts more o f t e n r e q u i r e s th e p r e s e n c e o f two h y d ro g en s a lp h a t o th e e s t e r g ro u p b e in g a c y l a t e d , and p re s e n c e o f o n ly one h y d ro g en i n t h i s p o s i t i o n o f t e n r e q u i r e s th e u se o f much s tr o n g e r b a s e s , l i k e t r i p h e n y l m e th y l sodium , t o d r iv e th e r e a c tio n *

E x c e p tio n s

have b e e n o b s e rv e d , f o r exam ple w ith th e compound e t h y l a lp h a - e th y 1- a l p h a ,a l p h a '- d i c a r b e t h o x y a d i p a t e ( 1 9 ) , and c e r t a i n e v id e n c e h a s b e e n p r e s e n te d t o show t h a t th e s e r e a c t i o n s may p ro c e e d by a m echanism I n v o lv in g h e m ia c e ta l f o rm a tio n fo llo w e d by e l i m i n a t i o n o f d i e t h y l c a rb o n a te *

A t any r a t e , i f th e

above m en tio n ed d e r i v a t i v e s o f p h en y l g ly c in e - o - c a r b o x y lie a c id

12 c o u ld n o t b e co n d en sed w ith sodium a l c o h o l a t e s , i t was a n t i c i ­ p a te d t h a t th e r e a c t i o n s w ould p ro b a b ly go i f b a s e s l i k e t r i p h e n y l m e th y l sodium o r m e s lty l magnesium brom ide w ere u sed * P ro v id in g th e r e a c t i o n s c o u ld b e c o n t r o l l e d s u f f i c i e n t l y , i t was b e lie v e d p o s s i b le t o p ro d u ce s u b s t i t u t e d In d o x y ls i n t h i s way. The d im e th y l e s t e r s o f a l p h a - ( o - c a r b o x y a n ilin o ) - p r o p io n ic a c id (XV) and o f a l p h a - ( o - c a r b o x y a n ilin o ) - p h e n y l a c e t i c a c id (XVI) w ere p r e p a r e d b y a m ethod d e s c r ib e d i n th e l i t e r a t u r e f o r th e p r e p a r a t i o n o f d im e th y l e s t e r o f p h e n y l g l y c i n e - o c a rb o x y llo M id (20)*

T h is c o n s i s t e d o f h e a t i n g i n two t o

one mole r a t i o f o r s e v e r a l h o u rs a t 150 d e g re e s C• , a s o l u t i o n o f m eth y l a n t h r a n l l a t e and th e c o rre s p o n d in g a lp h a c h lo ro e s te r re s p e c tiv e ly . A c e ty la t io n o f th e s e n e u t r a l e s t e r s was ac co m p lish ed by th e m ethod r e p o r t e d b y V o rla n d e r and W e issb re n n e r (21) f o r th e d i e t h y l e a t e r o f p h en y l g ly c in e - o - c a r b o x y lic a c i d .

The

e s t e r s w ere h e a te d o v er a ste a m b a t h s e v e r a l h o u rs w ith a c e t i c a n h y d rid e c o n ta in in g a few d ro p s o f c o n c e n tr a te d s u l f u r i c a c i d . The y i e l d s w ere s a t i s f a c t o r y f o r o u r p u rp o ses* B ecause o f th e com m ercial n o n - a v a i l a b i l i t y o f a lp h a c h lo ro p h e n y l a c e t i c a c id ( I I ) , i t s m eth y l e s t e r (XIV) was p r e p a r e d fro m m an d elie a c id i n th e way d e s c r ib e d b y F in d la y and T u rn e r (22) f o r th e e t h y l e s t e r * By Dleckmann r i n g c l o s u r e s o f XV, i t s N - a c e ty l d e r i v a t i v e (X V II), XVI, and i t s N - a c e ty l d e r i v a t i v e (X V III), we hoped t h a t w ith due p r e c a u t i o n s , we c o u ld o b ta in 2 -m e th y l in d o x y l,

IS

I^ V C O O C E +

ClCH(R)COOCH, S ^ -N H C H C R ) GOOCH, X I I I , XIV XV, XVI

3

H

l^ s / ,-RCH(R) GOOCH, COCHB

H

X IX , XX

X V II, X V III

A

-HR

COCHj IX , X I X , X I I I , XV, X V II, X IX :

R = CH3-

X , X IV , X V I, X V I I I , XX:

R — CgHg-

FLOW SHEET 2 . ~ 2,2* -DISTTBSTIT0TED-3,3» -DIKET0~D IIN D0Lim ,-2,2* DERIVATIVES

14 i t s N - a c e ty l d e r i v a t i v e ( I X ) , 2 -p h e n y l I n d o x y l, and i t s N a c e t y l d e r i v a t i v e (X)#

A ll r e a c t i o n s w ere co n d u c te d u n d e r d ry

n i t r o g e n atm o sp h ere w ith v ig o ro u s s t i r r i n g , and f r e s h , w a t e r f r e e and n e a r l y a l c o h o l - f r e e aodium m e th y la te was p r e p a r e d w ith e a c h r u n .

The d ry m e th a n o l u s e d was com m ercial C .P .

a b s o lu te m e th a n o l w hich was f u r t h e r d r i e d b y t h e a c tio n o f magnesium m e ta l as d e s c r ib e d b y P i e s e r ( 2 3 ) .

C o n tra ry t o o ur

w is h e s , compounds XV and XVII y ie ld e d 2 , 2 ' - d im e t h y l- 3 ,3 * - d i k e t o d i i n d o l i n y l - 2 , 2 » (XIX) w h ile XVI and X V III form ed 2 , 2 • - d ip h e n y l3 , $»- d i k e t o - d i i n d o l i n y l - 2 , 2 '( X X ) , th e l a t t e r b e in g form ed i n v e ry good y i e l d s .

The N - a c e ty l d e r i v a t i v e s c y c l i s e w ith much

g r e a t e r f a c i l i t y i n b o th c a s e s .

The m ethod h as n o t b e e n r e ­

p o r te d i n th e l i t e r a t u r e , and r e p r e s e n t s a r e l a t i v e l y good way o f p r e p a r in g th e s e s u b s t i t u t e d d i l n d o l i n y l com pounds. Thru th e u s e o f th e N - a c e ty l d e r i v a t i v e s (XV II, X V II I) , we h ad hoped t o b e a b le t o i s o l a t e th e r e l a t i v e l y n o n - o x id ls a b le l - a c e t y l - 2 - s u b s t i t u t e d in d o x y ls »

However, th e a c e t y l g ro u p s

a r e e l im in a te d e i t h e r b e f o r e o r a f t e r r i n g c l o s u r e s and p ro d u ce c y e liz e d in te r m e d ia te s w hich a r e a p p a r e n tly s u s c e p ti b le to d e h y d ro g e n a tio n ev en i n i n e r t gas a tm o sp h e re , lo s in g two atoms o f h y d ro g e n .

I t seems n e c e s s a r y t o c o n c lu d e t h a t th e f o r m a tio n

o f th e d i l n d o l i n y l d e r i v a t i v e s b y th e above p ro c e s s depends on th e e v o l u t i o n o f h y d ro g en g as r a t h e r th a n on th e p re s e n c e o f some p a r t i c u l a r o x i d i s i n g a g e n t. No a tte m p t was made t o th ro w any e x p e rim e n ta l l i g h t on th e m echanism in v o lv e d i n th e h y d r o ly s is o f th e amide g ro u p . A p l a u s i b l e e x p l a n a t io n , s im u la tin g th e i d e a o f Lowry ( 2 4 ) ,

15 m ight he th e a d d i t i o n o f th e m eth o x id e io n fo llo w e d b y e lim ­ i n a t i o n o f a m o le cu le o f e s t e r . The i n v e s t i g a t i o n s o f t h e s e D ieckm ann r e a c t i o n s f o r th e f o rm a tio n o f s u b s t i t u t e d in d o x y ls w ere n o t c a r r i e d o u t v e ry c o m p le te ly , b u t a p p l i c a t i o n o f Vor l e n d e r 's w ork (10) was m ade.

He h a s r e p o r t e d t h a t th e d i e t h y l e s t e r o f N - a c e ty l

p h en y l g ly c in e -o -c a rb o x y 1 1 c a c id form s th e N - a c e ty l d e r i v a t i v e o f e t h y l in d o x y la te i n 68 p e r c e n t y i e l d b y th e r e a c t i o n w ith a d ry a l c o h o li c s o l u t i o n o f sodium e th o x id e f o r tw e n ty - f iv e m in u tes a t room te m p e r a tu r e .

He s t a t e d t h a t th e same p ro d u c t

i s form ed i n 46 p e r c e n t y i e l d b y th e a c t i o n o f a lc o h o lic p o ta s s iu m h y d ro x id e f o r two h o u rs a t room te m p e r a tu r e , b u t t h a t th e d e a c e ty la t e d e t h y l I n d o x y la te form s on lo n g e r s ta n d in g . We t r i e d one r e a c t i o n in v o lv in g th e compound XVII w ith sodium m e th y la te i n b en zen e a t room te m p e r a tu r e f o r one h o u r , b u t fo u n d t h a t th e d e a c e ty la t e d d i l n d o l i n y l d e r i v a t i v e XIX a g a in fo rm e d .

I t was a ls o fo u n d t h a t , when X V III was t r e a t e d w ith

an a l c o h o li c s o l u t i o n o f sodium m e th y la te f o r o n e - h a lf h o u r a t room te m p e r a tu r e , th e s t a r t i n g compound was l a r g e l y re c o v e re d and o n ly a s m a ll amount was c o n v e rte d to th e d e a c e ty la t e d d i l n d o l i n y l d e r i v a t i v e XX. I n o r d e r to s u b s t a n t i a t e th e d i l n d o l i n y l p ro d u c ts form ed ab o v e , s e v e r a l th in g s w ere d o n e .

The a c t i o n o f aqueous sodium

h y d ro x id e on IX and X p ro d u ced y e llo w s o l i d s w hich showed no d e p r e s s io n b y m ixed m e ltin g p o in t d e te r m in a tio n s w ith th o s e p ro d ­ u c t s o b ta in e d b y th e Dieckmann r e a c t i o n s .

Van A lphen (4) c la im s

th e c o n v e rs io n o f 1 , 3 - d i a c e t y 1 -2 -m e th y l in d o x y l (V II) t o XIX

16 w ith a q u e o u s - a lc o h o lic s o l u t i o n o f a l k a l i , h u t a tte m p ts to c o n v e rt 1 ,S - d ia c e ty l- 2 - p h e n y l In d o x y l t o XX f a i l e d u n d e r a v a r i e t y o f c o n d itio n s *

Our e x p e rie n c e was t h a t X i s changed

v e r y n i c e l y to XX w ith aqueous sodium h y d ro x id e*

A m o le c u la r

w e ig h t d e te r m in a tio n o f XIX, o b ta in e d fro m compound XV, gave a v a lu e o f 237 b y d e p r e s s io n o f f r e e z i n g p o in t I n n a p h th a le n e a s com pared t o a t h e o r e t i c a l v a lu e o f 292*

D eterm in ed m olecu­

l a r w e ig h ts f o r IX and X w ere 186 and 246 as com pared t o th e c a l c u l a t e d v a lu e s o f 189 and 251 r e s p e c tiv e ly *

A ll n itr o g e n

a n a ly s e s ch eck ed t o w ith in 0*3 p e r c e n t o f c a l c u l a t e d v a l u e s , and p h y s i c a l and c h e m ic a l p r o p e r t i e s c o rre s p o n d e d t o th o s e c i t e d i n th e l i t e r a t u r e ( 4 , 27)*

17 2 -SUBSTITUTED- 3 -INDOLE ACETIC ACIDS B e t a - in d o le a c e t i c a c id h as a ro u se d i n t e r e s t i n th e p a s t as a p l a n t horm one, c a u s in g e lo n g a tio n o f c e l l s *

S ev eral

m ethods f o r p r e p a r in g i t have b een r e p o r t e d , b u t th e m ost c o n v e n ie n t one f o r l a b o r a t o r y p u rp o se s was r e c e n t l y r e p o r t e d by S ny d er e t a l . (28) and m o d ifie d b y S nyder and P ilg r im ( 2 9 ) . B r i e f l y , th e method c o n s i s t s o f c a r b o n - a l k y la ti o n o f q jia r te r n a r y ammonium s a l t s and t e r t i a r y a m in es, d e r iv e d from M annlch b a s e s o f i n d o l e , u s in g sodium c y a n id e as th e a l k y l a t i n g ag en t*

The

m ethod works w e ll f o r i n d o l e , b u t th e a u th o r s d id n o t e x te n d i t s u s e t o th e fo rm a tio n o f 2 - s u b s t i t u t e d - 3 - i n d o l e a c e t i c a c id s * A p a r t o f th e w ork on t h i s d i s s e r t a t i o n was d e v o te d to a c o m p ariso n o f t h e above m ethod w ith t h a t em ploying th e R e fo rm a tsk y r e a c t i o n w ith th e s u b s t i t u t e d in d o x y ls p r e p a r e d . Myers and L in d w a ll (30) h av e r e p o r t e d s u c c e s s of th e R e fo rm a tsk y r e a c t i o n w ith N - s u b s titu t e d i s a t I n s .

i t was b e lie v e d t h a t

t h i s r e a c t i o n w ith th e in d o x y ls w ould p e r m it g r e a t e r f l e x i b i l i t y i n p r e p a r in g v a r i o u s l y s u b s t i t u t e d 3 - in d o le a c e t i c a c i d s . The R e fo rm atsk y p r o c e d u r e , w hich u s e d l a r g e e x c e s s e s o f s in e and b r o m o e s te r , was t h a t d e s c r ib e d b y Bachmann a t a l . ( 3 1 ) . They r e p o r t e d v e ry good r e s u l t s w ith 7 -m ethoxy- 2 -m et hy 1 -2 c a r b o m e th o x y - l- k e to - 1 ,2 ,3 ,4 ,- te tr a h y d r o p h e n a n th r e n e .

By

e s s e n t i a l l y th e same m ethod, B ussey and Newman (32) h av e r e c e n t l y a p p lie d t h e r e a c t i o n w ith g r e a t s u c c e s s to k e to n e s c a p a b le o f e n o lis a tio n .

We c a r r i e d o u t th e d e h y d r a tio n o f th e in te r m e d ia te

b e ta - h y d r o x i e s t e r s i n th e f a s h i o n d e s c r ib e d b y Kon and Nargund

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PLOW SHEET 3* --SYNTHESIS OP 2 -SUBSTITOTID-3-INDOLE ACETIC ACIDS

19 (35) who r e p o r t t h a t , o f f o u r d e h y d r a tlu g a g e n ts t e s t e d , p h o sp h o ru s p e n to x id e i n b enzene g lT e s th e g r e a t e s t p r o p o r ti o n o f b e ta ,g a m m a -u n s a tu ra te d e s t e r i n a l l c a s e s s tu d ie d *

Sub­

s e q u e n t h y d r o ly s is w ith a l c o h o li c a l k a l i f i n a l l y gave th e c ru d e a c id s d e s ire d * One o f th e d i f f i c u l t i e s t h a t m a n ife s te d I t s e l f was t h a t th e R e fo rm a tsk y and d e h y d r a tio n I n te r m e d ia te s a l l seemed to be n o n - c r y s t a l l i z a b l e o ils *

Vacuum d i s t i l l a t i o n o f th e

R e fo rm a tsk y p r o d u c t, p re p a re d fro m 1 - a c e ty l- 2 - m e th y l in d o x y l ( I X ) , sim p ly gave a l i g h t c l e a r v is c o u s o i l w hich s t i l l would n o t fo rm c r y s t a l s i n a v a r i e t y o f s o lv e n ts *

Ho f u r t h e r a tte m p ts

w ere made to I s o l a t e p u re i n t e r m e d i a t e s . A n o th er d i f f i c u l t y was th e d a r k c o l o r a t i o n r e s u l t i n g i n th e c ru d e p ro d u c ts a f t e r p h o sp h o ru s p e n to x id e tre a tm e n t* H ow ever, a f t e r h y d r o l y s i s , H o r ite tr e a tm e n t and r e c r y s t a l l l z a t l o n o f th e r e s u l t i n g a c id s fro m a c e t i c a c id y ie ld e d l i g h t s o l i d s w hich c h e c k e d , b y n i t r o g e n a n a ly s is and r e p o r t e d m a ltin g p o i n t , w ith 2 - m e th y l- 3 - in d o le a c e t i c a c id (XXV) and 2 -p h e n y 1 -3 - in d o 1e a c e t i c a c id (XXVI). The 2 -m e th y l and 2 -p h e n y l in d o le s (XXIX, XXX) w ere p re p a re d b y th e c o n v e n tio n a l, z in c c h l o r i d e - c a t a l y z e d , F is c h e r In d o le s y n th e s is ( 3 4 ) .

The p r e p a r a t i o n o f 2 -m e th y l gram ine (XXVII)

and 2 -p h e n y l g ram in e (XXVIII) was r e a l i z e d b y th e M annlch p ro c e d u re d e s c r ib e d by Kuhn and S t e i n (35)*

S u p n iew sk i and

S e ra fln -G a je w a k l (36) c la im to have p r e p a re d XXVII I n t h i s way i n 88 p e r c e n t y i e l d s , b u t we w ere u n a b le t o c o n firm t h i s . Compound X X V III, an u n r e p o r te d M annlch b a s e , was p r e p a r e d i n

20 30 p e r c e n t c ru d e y i e l d s , end a n a ly z e d p r o p e r ly a f t e r two r e c r y s t a l l i s a t i o n s fro m e th a n o l* The S n y d er a l k y l a t l o n m ethod w orked q u i t e w e ll (64 p e r c e n t) f o r th e f o r m a tio n o f XXV, and no a tte m p t was made to h y d ro ly z e th e n e g l i g i b l e amount o f s o l i d s e p a r a te d p r i o r to th e p r e c i p i ­ t a t i o n o f t h i s p ro d u c t b y a c i d i f i c a t i o n *

I n th e c a se o f XXVI

▼ery p o o r r e s u l t s w ere o b ta in e d (6 p e r c e n t y i e l d ) , and a tte m p ts t o I n c r e a s e y i e l d s b y a l k a l i n e h y d r o ly s is o f th e la r g e amount o f p r e v io u s ly p r e c i p i t a t e d s o l i d s f a i l e d *

I n co m p a riso n , th e

in d o x y l p a th y ie ld e d much more s a t i s f a c t o r y r e s u l t s i n th e second c a s e (72 p e r c e n t c r u d e ) , and a p p ro x im a te ly e q u iv a le n t r e s u l t s i n th e f i r s t (47 p e r c e n t c ru d e )* Mixed m e ltin g p o in ts f o r th e a c id s o b ta in e d by th e two m ethods d id n o t p ro d u ce any d e p re s s io n *

21 SUBSTITUTED INDOLES The G rig n a rd r e a c t i o n vaa a p p lie d to th e s u b s t i t u t e d in d o x y ls b e c a u s e , a g a in , I t seemed to r e p r e s e n t a f l e x i b l e m ethod f o r o b ta in in g a la r g e number o f s u b s t i t u t e d i n d o l e s , l e s s a c c e s s i b l e b y o th e r m ethods*

W ith t h i s i n m in d , some

sim p le e a s e s w ere t e s t e d and checked a g a in s t p ro d u c ts fro m o th e r s y n th e s e s * We fo u n d t h a t th e m ost s u i t a b l e p ro c e d u re c o n s is te d o f p r e p a r in g th e G rig n a rd r e a g e n ts i n e t h e r i n a t h r e e to one m ole r a t i o

o v e r th e in d o x y l, and ad d in g a b en z en e s o l u t i o n

o f th e s u b s t i t u t e d in d o x y l d ro p w lae w ith v ig o ro u s s t i r r i n g * By u s in g an e x c e s s o f G rig n a rd m agnesium h a l i d e , we hoped to n o t o n ly g e t r e a c t i o n a t th e c a rb o n y l g ro u p , b u t a l s o t o s im u lta n e o u s ly d e h y d ra te and d e a e e t y l a t e t h e in te r m e d ia te s t o g e t th e d e s i r e d in d o le s d i r e c t l y *

H ow ever, i n t h i s w ay,

we o b se rv e d t h a t th e a o tlo n o f m e th y l magnesium io d id e on 1 - a c e t y l - 2 -m e th y l in d o x y l (IX) gave r i s e d i r e c t l y t o 46 p e r ­ c e n t y i e l d o f 1 - a c e ty 1 - 2 ,3 -d im e th y l in d o le (XXXII)*

D e h y d ra tio n

o f th e c ru d e p ro d u c t w ith p h o sp h o ru s p e n to x id e i n b en z en e r a i s e d t h i s s u b s t a n t i a l l y t o 60 p e r c e n t , and i t was d e c id e d to g e n e r a lly ad o p t t h i s l a s t s t e p i n t o th e p ro c e d u re * T h is same p ro d u c t was p r e p a r e d b y a F is c h e r s y n th e s is ( 5 4 ) , fo llo w e d b y a o e t y l a t l o n w ith a c e t y l c h l o r i d e i n a s ta n d a r d f a s h io n *

N itr o g e n a n a ly s is o f t h e G rig n a rd p r o d u c t and ab sen ce

o f d e p r e s s io n b y m ixed m e ltin g w ith th e F is c h e r p r o d u c t su b ­ s t a n t i a t e d th e i d e n t i t y o f th e su b s ta n c e *

I t was fo u n d t h a t

d e a c e t y l a t i o n to o k p la c e e a s i l y w ith a l c o h o li c a l k a l i e s t o g iv e

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24

2,Sfc-dim ethyl in d o le (X X X III), and m ixed m e ltin g p o in t w ith th e F is c h e r p r o d u c t a g a in co n firm e d th e s u b s ta n c e .

These

p r o d u c ts w ere r e a d i l y ste am d i s t i l l a b l e w hich made i s o l a t i o n and p u r i f i c a t i o n r e l a t i v e l y e a s y . I n th e same f a s h i o n , th e a c t i o n o f p h en y l m agnesium brom ide w ith 1 - a c e ty l- 2 - p h e n y l in d o x y l (X) fo llo w e d by d e h y d r a tio n and h y d r o ly s is i n a l c o h o li c p o ta s s iu m h y d ro x id e r e s u l t e d i n 80 p e r c e n t cru d e y i e l d o f 2 ,3 - d ip h e n y l in d o le (XXXVII) w h ich , u p o n r e o r y s t a l i i s a t I o n , a g re e d w ith th e c a l c u l a t e d n i t r o g e n c o n te n t and w ith th e r e p o r te d m e ltin g p o i n t .

T h is was th e n

p r e p a r e d b y th e m ethod o f Ja p p and M urray (37) as m o d ifie d b y F e n n e ll and P la n t (38) i n w h ich a m ix tu re o f b e n z o in , a n i l i n e , and a n i l i n e h y d r o c h lo r id e a r e r e f lu x e d w ith c o n tin u o u s re m o v a l o f w a te r as fo rm e d .

K o e ls c h (39) c la im s t h a t 2 , 3 -

d ip h e n y l in d o le i s o b ta in e d b y b o i l i n g a m ix tu re o f b e n z o in , a n i l i n e , and c o n c e n tr a te d h y d r o c h lo r ic a c i d , b u t t h i s was n o t co n firm ed b y u s .

I n s t e a d , we I s o l a t e d a w h ite s o l i d whose

m e ltin g p o i n t , a f t e r r e c r y s t a l l i z a t i o n from e t h a n o l , c o rre sp o n d e d t o t h a t o f " b e n z o in a n ilid e * ( 9 9 ° )• A c e ty la tio n o f S y S -d ip h e n y l I n d o le was fo u n d to b e ex ­ c e e d in g ly d i f f i c u l t , so a mixed m e ltin g p o i n t , w hich showed no d e p r e s s io n , was ta k e n o f th e 2 ,3 - d lp h e n y l I n d o le s o b ta in e d above • A t l e a s t ^ p - a l l t a t l v e l y , o t h e r r e a g e n ts t r i e d on IX were p h e n y l magnesium b ro m id e and b e n z y l magnesium c h l o r i d e .

In

b o th c a s e s , d e h y d r a tio n and d e a e e t y l a t i o n le d to s o l i d s w ith m e ltin g p o in ts i n th e g e n e r a l v i c i n i t y e x p e c te d f o r th e i n d o l e s . We fo u n d th e u s e o f b e n z y l m agnesium c h l o r id e p r e f e r a b l e o v er

25 t h e b ro m id e , b e c a u se a l a r g e p a r t o f t h e l a t t e r seem s t o b e r a p i d l y c o n v e rte d to d lb e n z y l.

26 MISCELLANEOUS REACTIONS M ethyl in d o x y la te was p r e p a re d I n good y i e l d s as p r e v io u s ­ ly re p o rte d ( 3 ) .

U sin g th e same c o n d itio n s as ab o v e , we

a tte m p te d t o r u n R e fo rm a tsk y and G rig n a rd (m e th y l magnesium io d id e ) r e a c t i o n s , b u t i n b o th c a s e s , s t a r t i n g m a te r ia l s w ere alm o st c o m p le te ly re c o v e re d *

The n o n - r e a c t i v i t y i s b e l ie v e d

to b e due t o th e n e a r l y co m p lete e n o l l s a t i o n o f th e compound* %

The s u b s ta n c e n o t o n ly g iv e s a f e r r i c c h l o r id e t e s t (g re e n ) * b u t a l s o c a u s e s p r e c i p i t a t i o n o f a s a l t u p o n a d d i tio n t o m e th y l magnesium io d id e *

S u b se q u e n t w orking u p o f th e G rig n a rd s a l t

s i n g l y p ro d u c e s u n r e a c te d e s te r * A ssusiing t h a t m e th y l in d o x y la te r e a c t s l a r g e l y as an e n o l , a tte m p ts were made to c a r r y o u t a D ie ls - A ld e r r e a c t i o n ( 4 0 , 4 1 ) , h o p in g t o p o s s i b l y d e v e lo p s a m ethod f o r p r e p a r in g s u b s t i t u t e d c a r b a s o le s *

We hoped t h a t th e e s t e r g ro u p would

s u f f i c i e n t l y a c t i v a t e th e d ie n o p h ile *

C y c lo p e n ta d le n e was

u se d as th e d le n e b e c a u s e o f i t s r e a c t i v i t y *

However, s t a r t i n g

m a t e r i a l s w ere r e c o v e re d a lm o st q u a n t i t a t i v e l y , ev en a f t e r lo n g h e a tin g i n a s e a le d tu b e* I t was d e s i r a b l e to p r e p a r e M annlch b a s e s o f l - a c e t y l - 2 m eth y l in d o x y l (IX) and 1- a c e t y l - 2 -p h e n y l in d o x y l (X ), b e c a u se su b se q u e n t R e fo rm a tsk y r e a c t i o n s and h y d r o ly s is would p ro d u ce amino a c id s w ith some p o s s i b l e p h y s io l o g ic a l a c t i v i t y *

I n th e

c a se o f X , s t a r t i n g m a t e r i a l s w ere l a r g e l y r e c o v e re d u n d e r a v a r i e t y o f c o n d itio n s *

By r e f l u x i n g IX w ith a s l i g h t m olar

e x c e ss o f d im e th y l amine h y d r o c h lo r id e and tw o - fo ld e x c e ss o f aqueous fo rm ald eh y d e (37 p e r c e n t) u n t i l th e d is a p p e a ra n c e

27 o f th e o r g a n ic l a y e r , good y i e l d s (77 p e r c e n t b a s e d on M annlch b a s e ) o f a l i g h t y e llo w o i l w ere o b ta in e d u p o n a l k a l i z i n g w ith c o n c e n tr a te d ammonium h y d ro x id e .

A tte m p ts to c r y s t a l l i z e

t h i s c ru d e by c o n v e n tio n a l m ethods f a i l e d *

By d is s o l v i n g I n

e t h a n o l , c o o lin g I n a to lu e n e - d r y I c e b a t h , and f i l t e r i n g as r a p i d l y as p o s s i b l e , a 21 p e r c e n t y i e l d o f n e a r l y w h ite s o l i d powder was o b ta in e d , m e ltin g p o in t ra n g e 6 2 - 5 ° ( u n c o r r . ) • R e c r y s t a l l i z a t i o n fro m e t h a n o l sim p ly e x te n d e d th e r a n g e to 5 9 -1 3 0 ° .

A ttem p ts to p r e p a r e th e h y d r o c h lo r id e I n e t h e r f a i l e d *

B ecause o f th e in h e r e n t d i f f i c u l t i e s and n o n - g e n e r a l i t y , t h i s v e in was n o t p u rs u e d .

I t i s q u e s tio n a b le w h eth e r a M annlch

b a s e a c t u a l l y form s o r w h e th e r sim p le a m ln a tio n o f th e c a rb o n y l o cc u rs*

28 MBLT1KG POINTS A ll m e ltin g p o in ts r e p o r t e d I n t h i s d i s s e r t a t i o n a re u n c o r r e c te d e x c e p t f o r th erm o m eter c a l i b r a t i o n c o r r e c t i o n s . M e ltin g p o i n t s o f th e new compounds V , V I, IX , X , X I, X I I , XVI, X V III, and XXVIII (s e e p p . 5 , 1 3 , 1 8 , 2 2 , 23) were d e te rm in e d w ith an e l e c t r i c a l l y h e a te d m e ta l b lo c k w ith good te m p e r a tu r e c o n t r o l s u p p lie d b y means o f a v a r l a c .

The

m e ltin g p o in ts o f s u b s ta n c e s a lr e a d y r e p o r t e d i n th e l i t e r a t u r e w ere d e te rm in e d w ith a c o n v e n tio n a l ty p e T h ie le tu b e w ith no m o d if ic a ti o n s .

EXPERIMENTAL SECTION

29 AlJ3h a - ( o - c a r b o x y a n l l l n o ) - p r o p i o n i c a c i d

(III)

-COOH

0

-NHCHCOOH CH3

To a s o l u t i o n o f 250 g .(2 .3 6 m * ) o f an h y d ro u s sodium c a rb o n a te i n 350 c e . o f w a te r , 68 g .( 0 .5 m .) o f a n t h r a n i l i c a c id ( p r a e t . , M .P .1 4 6 -7 °) was added w ith r ig o r o u s s t i r r i n g . When a l l th e s o l i d m a t e r i a l h ad d i s s o l v e d , 55 g*(0*51m .) o f a lp h a - c h lo r o p r o p io n ic a c id (B .P .8 2 -4 ° /l5 in m .) was added w ith s t i r r i n g a t a r a t e slow enough t o p r e v e n t e x c e s s iv e foam ing*

The s o l u t i o n was th e n h e a te d o v er a ste a m b a t h

f o r f o u r h o u rs*

The s o l u t i o n was h e a te d f i f t e e n a d d i t i o n a l

m in u te s w ith 75 g . o f N ofclte, f i l t e r e d h o t , th e n a c i d i f i e d w ith c o n c e n tr a te d h y d r o c h lo r ic a c id w h ile s t i r r i n g v ig o r o u s ly . The m ix tu re was c o o le d i n a r e f r i g e r a t o r (5 ° ) o v e rn ig h t* The s o l i d p r o d u c t was f i l t e r e d o f f , w ashed w ith 250 cc* o f w a t e r , p r e s s e d as d r y as p o s s i b l e w ith a r u b b e r dam, th e n o v e r - d r ie d (8 5 °) •

T h is cru d e p ro d u c t was a l i g h t g r e y pow der,

M .P .1 9 0 -2 0 0 ° , y i e l d 6 8 .5 g * (66 p e r c e n t) *

The m e ltin g p o in t

r e p o r t e d b y v a n A lphen (4) i s 216° ( r e c r y s t a l l i z e d fro m w a te r ) . T h is crude was u s e d w ith o u t f u r t h e r p u r i f i c a t i o n i n th e n e x t s te p *

30 N -a c e ty l-a lp h a - fo -c a rb o x v a n llin o ) -p r o p io n ic a c id

( f)

COOH ^^-N C H CCH gycO O H COCH

To a s o l u t i o n o f 159 g . (3 .9 8 m .) o f sodium h y d ro x id e In 1590 c c . o f w a te r , 318 g . (1 .5 2 m .) o f I I I waa added and s t i r r e d u n t i l c o m p le te ly d i s s o l v e d .

A c e tic a n h y d rid e (320 c c . , 3 .4 m .)

was added a l l a t once w ith o u t c o o lin g and th e m ix tu re was s t i r r e d f o r tw e n ty m in u te s .

A seco n d p o r t i o n o f a c e t i c an ­

h y d r id e (320 c c . ) was added and s t i r r e d tw en ty m in u te s more w ith o u t c o o lin g .

To co m p lete th e r e a c t i o n , th e r e a c t i o n

m ix tu re was h e a te d o v er a ste a m h a t h f o r h a l f an h o u r .

The

h o t s o l u t i o n was made d e f i n i t e l y a c i d i c w ith c o n c e n tr a te d h y d r o c h lo r ic a c i d , c o o le d , th e n s e t I n th e r e f r i g e r a t o r o v e r­ n ig h t.

The c ru d e was f i l t e r e d , w ashed q u ic k ly w ith 600 c c .

o f w a te r , p r e s s e d d r y w ith a dam, a i r - d r i e d s e v e r a l d a y s , f i n a l l y d r ie d u n d e r vacuum o v e r p h o sp h o ru s p e n to x id e .

The

c ru d e p ro d u c t was a w h ite , c r y s t a l l i n e pow der, M .P .1 8 4 -1 9 5 °, y i e l d 344 g . (90 p e r c e n t ) .

T h is c ru d e p ro d u c t was u s e d I n

t h e n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

A s m a ll sam ple

o f c ru d e was r e c r y s t a l 11 zed fro m aqueous h y d r o c h lo r ic a c id ( 5 p e r c e n t ) , th e n from 95 p e r c e n t e t h a n o l .

The p u re p ro d u c t

was a w h ite c r y s t a l l i n e s o l i d , M .P. 2 0 5 .3 - 2 0 5 .6 ° . A n a l.

C aled f o r

N, 5 .5 8

Found:

H, 5 .4 6 .

31 1 . 3 - d l ac e t y 1 - 2 -me t h y 1 I n d o x y l ( V l l )

-OCOCHg

A 500 c c . , ro u n d -b o tto m e d , th r e e - n e c k e d f l a s k was eq u ip p ed w ith a m e r c u r y - s e a le d , nlchrom e H ersh b erg s t i r r e r , a w a te r c o o le d c o n d e n se r p r o t e c t e d b y a c a lc iu m c h l o r id e t u b e , and a sy ste m f o r m a in ta in in g d r y , n i t r o g e n a tm o sp h e re .

I n t o th e

f l a s k was added 250 c c . (2 .6 5 m .) o f a c e t i c a n h y d r id e , th e n w ith s t i r r i n g 50 g . (0 .2 m .) o f V , f i n a l l y 50 g . (0 .6 1 m .) o f f r e s h l y f u s e d sodium a c e t a t e .

The v ig o r o u s ly s t i r r i n g m ix tu re

was h e a te d a t i t s r e f l u x te m p e r a tu r e o v e r an o i l b a t h ( b a th te m p e ra tu re 165°) f o r o n e - h a lf h o u r .

A f te r i n s e r t i n g a

th e rm o m e te r, th e f l a s k c o n te n ts w ere c o o le d to a b o u t 1 0 0 ° , th e n 75 c c . (4 .1 6 m .) o f w a te r was added d ro p w ise w ith c o o lin g and s t i r r i n g a t a r a t e s u i t a b l e t o m a in ta in th e te m p e r a tu r e n e a r 1 0 0 °.

The a c e t i c a n h y d rid e d e c o m p o sitio n was co m p leted

b y h e a tin g s e v e r a l m in u te s o v er a ste a m b a t h .

The so -fo rm e d

a c e t i c a c id was d i s t i l l e d o v e r a h o t w a te r b a t h u n d e r w a te r pump vacuum (20mm.) •

The re m a in in g r e s i d u e was t r i t u r a t e d

w ith 200 c c . o f w a t e r , 200 c c . o f f i v e p e r c e n t aqueous sodium c a r b o n a te , f i n a l l y w ith 200 c c . o f w a te r .

The c ru d e p ro d u c t

was a l i g h t y e llo w s o l i d , M .P .1 2 5 -1 3 6 °, y i e l d 1 3 .1 g . (28 p e rc e n t).

T h is c ru d e p ro d u c t was u s e d f o r th e n e x t s te p

w ith o u t f u r t h e r p u r i f i c a t i o n .

R e p o rte d m e ltin g p o in t 134° (4 )•

32 1 - a c e t y l - 2 - m e th y l I n d o x y l (IX )

ioC H j A, m ix tu re o f 73 g . (0 ,3 2 m .) o f V I I , 110 g , o f sodium s u lfite

(a n h y d ro u s ), 365 c c , o f d io x a n e , and 1100 c c , o f v a t e r

was r e f l u x e d o y e r a ste a m h a t h f o r t h r e e h o u r s .

Most o f th e

d io x a n e and v a t e r was d i s t i l l e d u n d e r vacuum (20mm,) i n n i t r o g e n atm osph ere o v e r a h o t v a t e r h a t h .

The r e s i d u e v a s t r i t u r a t e d

v i t h 3 -2 0 0 c c , p o r tio n s o f v a t e r , f i l t e r e d , p r e s s e d d r y v i t h a dam, th e n a i r - d r i e d a t room te m p e r a tu r e .

The cru d e p ro d u c t

v a s a f a i n t y e l l o v s o l i d , M .P .8 5 -9 8 ° , y i e l d 54 g , (91 p e r c e n t ) . The c ru d e m a t e r i a l (5 7 ,5 g« , 0 .3 0 m .) v a s d is s o lv e d i n 100 c c . o f h o t e th a n o l (95 p e r c e n t ) , h o i l e d s e v e r a l m in u te s v i t h 5 g , o f N o r i t e , f i l t e r e d h o t , th e N o r lte r i n s e d v i t h 10 c c , o f f r e s h , h o t e th a n o l and com bined v i t h th e h u lk o f s o l u t i o n . The c l e a r s o l u t i o n v as c o o le d s l o v l y to room te m p e r a tu r e , th e n p la c e d i n th e r e f r i g e r a t o r f o r s e v e r a l h o u rs u n t i l c r y s t a l l i z a t i o n v as c o m p le te .

The p r o d u c t v a s f i l t e r e d o f f , v ash ed v i t h 25 c c .

o f f r e s h e t h a n o l , p r e s s e d v i t h a dam, a i r - d r i e d a t room te m p e ra ­ t u r e , f i n a l l y l a s t t r a c e s o f s o lv e n ts v e r e rem oved u n d e r vacuum . The f i r s t h a tc h o f c r y s t a l s v e lg h e d 4 4 ,3 g , (75 p e r c e n t ) , M .P, 9 5 -9 3 ° , c o n s i s t e d o f n e a r l y v h i t e , i r r e g u l a r n e e d le s .

The

m other l i q u o r v as e v a p o ra te d t o d r y n e s s , th e re m a in in g s e m is o l i d m ix tu re v a s v ash ed q u ic k ly v i t h 5 c c , o f e t h a n o l , th e n

33

r e o r y a t a l i i z e d fro m 10 cc* of e t h a n o l .

The seco n d h a tc h

w eighed 6*3 g . , was a f a i n t y e llo w c r y s t a l l i n e s o l i d , M.P. 9 3 -9 7 °C .

Combined y i e l d o f th e s e r e c r y s t a l l i z e d p ro d u c ts

was 86 p e r c e n t .

P our r e c r y s t a l l i z a t i o n s o f a s m a ll sam ple o f

th e p r o d u c t fro m e th a n o l gave w h ite c r y s t a l s , M.P. 9 8 .3 -9 9 .3 ° C . A n a l.

C a lc d . f o r C^Hj^OgN?

C, 6 9 .7 8 ? H, 5 .8 2 ? N, 7 .4 1 .

Pounds

C , 6 9 .7 2 ? H, 6 .1 3 ? N, 7 .3 9 .

34 A lp h a -c h lo ro p h e n y l a c e t i c a c id ( I I )

-CHCOOH i Cl

D ry m a n d elic a c id ( C .P ., 100 g . , 0 ,6 6 m .) v as I n tro d u c e d I n to a 1 l i t e r , o n e -n e c k e d , ro u n d -b o tto m e d f l a s k e q u ip p ed w ith a c o n d e n s e r, c a lc iu m c h l o r id e tu b e , and r u b b e r tu b e t o th e s in k to remove th e h y d ro g en c h l o r i d e as i t v as fo rm ed . P hosphorus p e n ta c h lo r ld e (250 g . , 1 .2 m .) v a s a d d e d , th e th e equipm ent c o n n e c te d , and th e m ix tu re sh ak en th o ro u g h ly v i t h l o e - v a t e r c o o l in g .

When th e i n i t i a l e v o l u tio n o f h y drogen

c h l o r id e g as had s u b s id e d , th e m ix tu re v a s h e a te d o v e r a steam b a th f o r fo u r h o u rs.

The p h o sp h o ru s o x y e h lo rid e form ed v as

d i s t i l l e d u n d e r vacuum (25mm.) o v e r a ste am b a t h , th e n th e m ix tu re v as h e a te d one hour o v er an o i l b a t h a t 140°C.

T h is

v a s th e n vacuum d i s t i l l e d o v e r an o i l b a t h , and th e a c id c h l o r id e o f I I c o l l e c t e d a t 129-131°/50m m .

T h is m a t e r i a l

v a s a c o l o r l e s s o i l , w eighed 65 g . (52 p e r c e n t t h e o r e t i c a l ) . The a c id c h l o r id e v a s c o v e re d v i t h v a t e r , h e a te d c a r e f u l l y o v er a steam b a t h f o r a f e v m in u te s , sh ak en th o ro u g h ly * th e n s e t a s id e a t room te m p e ra tu re u n t i l th e o i l h ad c o m p le te ly s o lid ifie d .

The v h i t e s o l i d p r o d u c t v as f i l t e r e d , t r i t u r a t e d

th o ro u g h ly v i t h v a t e r , f i n a l l y a i r - d r i e d a t room te m p e ra tu re * The c o n v e rs io n o f th e a c id c h l o r i d e to I I v as q u a n t i t a t i v e . The p ro d u c t v a s a v h i t e s o l i d , had a p u n g en t o d o r , M .P .7 3 - 8 0 .5 ° . The r e p o r t e d m e ltin g p o in t i s 78p (4 2 )•

35 A lp h a -(o -c a rb o x v a n llin o )-p h e n y l a c e tic a c id

(IV )

rCOOH

A s o l u t i o n o f 372 g * (3 .5 m .) o f anhydrous sodium c a rb o n a te i n 2600 cc* o f w a te r was made u p I n a f i v e l i t e r * th r e e - n e c k e d , ro u n d -b o tto m e d f l a s k eq u ip p ed w ith a l i q u i d - s e a l e d s t i r r e r and co n d e n ser*

A n t b r a n l l l c a c id (322 g « , 2 . 35m .) was added w ith

s t i r r i n g and c o n tin u e d u n t i l a l l th e s o l i d m a t e r i a l had d is s o lv e d * A lp h a -c h lo ro p h e n y 1 a c e t i c a c id (400 g * , 2 .3 5 m .) was added w ith s t i r r i n g a t a r a t e slow enough to p r e v e n t e x c e s s iv e fo am in g . The s o l u t i o n was h e a te d f o u r h o u rs o v e r a ste a m b a t h , th e n 75 g* o f N o r lte a d d e d , th e m ix tu re h e a te d a n o th e r t h i r t y m in u tes* The h o t s o l u t i o n was f i l t e r e d , a c i d i f i e d w ith c o n c e n tr a te d h y d r o c h lo r ic a c i d .

Upon s ta n d in g i n th e r e f r i g e r a t o r o v e r n ig h t,

th e l i g h t y e llo w o i l w hich i n i t i a l l y s e p a r a te d became s o l i d . T h is was f i l t e r e d , t r i t u r a t e d w ith 2 -2 5 0 c c . p o r t i o n s o f w a te r , th e n w ashed r a p i d l y w ith 1 l i t e r o f w a te r , f i n a l l y a i r - d r i e d a t room te m p e r a tu r e .

The c ru d e p r o d u c t was a t a n s o l i d pow der,

M .P .1 6 0 -1 9 5 ° , y i e l d 359 g . (56 p e r c e n t) p o i n t o f p u re p r o d u c t i s 222° ( 4 ) . s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

R e p o rte d m e ltin g

T h is was u s e d i n th e n e x t

36

H - a c e tv l- a lp h a - ( o - o a r b o x y a n llin o ) - p h e n y l a c e t i c a c id (VI)

«^N-C00H S ^ -» C H ( C 6H5 )C00H COCHj

To a s o l u t i o n o f 110 g . (2 .7 5 m .) o f sodium h y d ro x id e i n 1500 c c . o f w a te r , 359 g . ( 1 .3 3 * .) o f cru d e IV was added and s t i r r e d u n t i l c o m p le te ly d i s s o l v e d .

A c e tic a n h y d rid e (300 c c . ,

3 .1 8 m .) was added a l l a t once w ith o u t c o o lin g and t h e m ix tu re was s t i r r e d f o r tw e n ty m in u te s .

A seco n d p o r t i o n o f a c e t i c

a n h y d rid e (300 c c . ) was added and s t i r r e d tw e n ty m in u te s more w ith o u t c o o lin g .

N o r ite (50 g . ) was ad d e d , t h e m ix tu re h e a te d

o v e r a steam h a t h f o r h a l f an h o u r , f i l t e r e d h o t , f i n a l l y made d e f i n i t e l y a c i d i c w ith c o n c e n tr a te d h y d r o c h lo r ic a c i d .

Upon

s ta n d in g i n th e r e f r i g e r a t o r o v e r n i g h t , th e l i g h t brow n o i l w hich i n i t i a l l y s e p a r a te d s o l i d i f i e d .

T h is was f i l t e r e d ,

t r i t u r a t e d w ith 2 -2 0 0 c c . p o r t i o n s o f w a te r , w ashed q u ic k ly w ith 600 c c . o f w a te r , f i n a l l y a i r - d r i e d a t room te m p e r a tu r e . The cru d e was a l i g h t t a n , o d o r le s s pow der, w e ig h t 330 g . (79 p e r c e n t ) , M .P .147-179°C .

T h is c ru d e was u s e d i n t h e n e x t

s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

A s m a ll sam ple was r e e r y s ta l*

U s e d fro m e t h a n o l (95 p e r c e n t) t o g iv e a w h ite c r y s t a l l i n e s o l i d , M .P .1 9 3 •0 -1 9 3 •5°C • A n a l.

C a lc d . f o r C17Hl g 0gN;

N, 4 . 4 7 .

Founds

V , 4 .H *

37 1 .S - d la o o ty l-2 -p h e n y l In d o x y l (V III)

OCOCHj

% ^ \ S ~ C6E5 iocH 3 The same p ro c e d u re v a s em ployed as I n th e s y n t h e s i s o f V II ( s e e p . 3 1 ) , u s in g th e same w e ig h t q u a n t i t i e s o f c ru d e a c id ( V I ) , a e e t l c a n h y d r id e , and f r e s h l y f u s e d sodium a c e t a t e . The c ru d e p ro d u c t v a s a l i g h t y e llo w s o l i d , y i e l d 2 2 .0 g . (47 p e r c e n t ) , li.P .1 1 6 -1 2 4 °C » th e p u re compound I s 126° ( 4 ) .

The m e ltin g p o in t r e p o r t e d f o r The c ru d e v as u s e d i n th e

n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

33 1 -a c e t v 1 - 2 - p h e n y l I n d o x y l (X)

/N

^ ^ / ■ HC6H5 I COCHg A m ix tu re o f 22 g . (0 .0 7 5 m .) o f V I I I , 33 g . o f anhydrous sodium s u l f i t e , 110 c c . o f d io x a n e , and 330 cc* o f w a te r was r e f l u x e d o r e r a ste a m b a t h f o r t h r e e h o u r s .

Most o f th e

d io x a n e wad w a te r was d i s t i l l e d u n d e r vacuum (20 mm.) i n n i t r o g e n atm o sp h ere over a h o t w a te r b a t h .

The r e s id u e v as t r i t u r a t e d

w ith 250 c c . o f v a t e r , f i l t e r e d , w ashed q u ic k ly w ith 50 c c . o f w a te r , p r e s s e d w ith a dam, a i r - d r i e d a t room te m p e ra tu re * The c ru d e p ro d u c t was a l i g h t y e llo w s o l i d , y i e l d 1 8 .0 g . (96 p e r c e n t ) , M .P .1 1 0 -1 3 5 °C . The c ru d e p ro d u c t was b o ile d s e v e r a l m in u tes w ith 36 c c . o f e t h a n o l and 0 .5 g . o f N o r l t e , f i l t e r e d h o t .

The c l e a r

s o l u t i o n was c o o le d s lo w ly to room te m p e r a tu r e , th e n p la c e d i n t h e r e f r i g e r a t o r o v e r n ig h t.

The p r o d u c t was f i l t e r e d o f f ,

w ashed q u ic k ly w ith 10 c c . o f f r e s h e t h a n o l , p r e s s e d w i t h a dam , a i r - d r i e d a t room te m p e r a tu r e . w ere rem oved u n d e r vacuum .

L a s t t r a c e s o f s o lv e n ts

The f i r s t b a t c h o f c r y s t a l s was

a l i g h t y e llo w c o l o r , y i e l d 1 2 .9 g . (68 p e r c e n t ) , M .P. 1 3 5 139°C•

R e p e a te d g e c r y s t a l l i z a t i o n s

(s e v e n tim e s) fro m e th a n o l

d id n o t change th e m e ltin g p o in t r a n g e .

A d d itio n a l p r o d u c t

m c o u ld be r e c o v e re d fro m th e m other li q u o r and w ash in g s A n a l.

C a lo d . f o r C ^H ^O gN ?

C, 7 6 .4 9 ; H , 5 .1 8 ? N , 5 5 8 .

F ound:

C , 7 6 .0 1 ? H, 5 .2 7 ? N, 5 4 7 .

#0 P h o n y 1 h y d r a zo n e o f l - a c e t v l - g ~ g e t h v l I n d o x y l (X I)

|= M H C 6 H g

iocH g I n 8 c c . o f e t h a n o l, 0 .5 g . (0 .0 0 2 6 m .) o f IX was d is s o lv e d a t room te m p e ra tu re and v a t e r v as added d r o p v is e t o th e p o in t of p r e c ip ita tio n .

To t h i s , 0 .5 c c . o f p h e n y l h y d ra z in e and

1 d ro p o f a c e t i c a c id v e r e ad d e d .

The m ix tu re v as h e a te d o v e r

a steam h a t h f o r h a l f an h o u r , c o o le d a t room te m p e ra tu re s e v e r a l m in u te s , more v a t e r added d r o p v is e u n t i l p r e c i p i t a t i o n j u s t s t a r t e d , th e n t h e s o l u t i o n v as s e t i n t h e r e f r i g e r a t o r se v era l days.

The y e l l o v c ru d e p ro d u c t v as f i l t e r e d o f f ,

v a sh e d v i t h 5 c c . o f v a t e r , f i n a l l y d r i e d a t room te m p e r a tu r e . The c ru d e m a t e r i a l v e ig h e d 0 .4 6 g . (62 p e r c e n t ) , M .P. 178-185°dec< T his v a s r e c r y s t a l l i z e d tv o tim e s fro m e th a n o l t o g iv e a l i g h t y e l l o v , c r y s t a l l i n e s o l i d , M .P. 1 8 4 .9 ° -1 8 5 .3 ° C • A n a l.

C a lc d . f o r

N, 1 5 .0 5 .

Founds

N, 1 4 .9 9 .

41

P h e n y l h y d r a z o n e o f 1 - a c e t y 1 - 2 -p h e n y 1 l n d o x y l ( X II)

^ S '|

rNNECgHg

V S r HC6E5 COCHj A s o l u t i o n o f 0*5 g . (0 .0 0 2 m .) o f X , 0 .5 c e . o f p h e n y l h y d r a z in e , 2 d ro p s o f g l a o i a l a c e t i c a c i d , and 7 .5 c c . o f e th a n o l v a s r e f l u x e d o v er a h o t w a te r b a t h f o r h a l f an h o u r . The u n d ls s o lw e d se d im en t was c e n tr if u g e d o f f end th e c l e a r , h o t s o l u t i o n c o o le d slo w ly t o room te m p e r a tu r e , th e n c o o le d i n an i c e b a t h and s c r a tc h e d w ith a g l a s s r o d u n t i l c r y s t a l f o rm a tio n j u s t s t a r t e d .

A f t e r two days I n t h e r e f r i g e r a t o r ,

th e l i g h t y e llo w c r y s t a l s w ere c e n tr if u g e d o f f , w ashed tw ic e w ith 1 .5 c c . p o r tio n s o f e t h a n o l . The c ru d e was r e f l u x e d th r e e m in u tes w ith 10 c c . o f e th a n o l and th e u n d i a s o l r e d , l i g h t y e llo w r e s i d u e s e p a r a te d fro m th e s o lu tio n by c e n tr if u g in g .

T h is r e s i d u e I s p u re p ro d u c t X I I ,

M .P.170.6°C w ith s l i g h t d a r k e n in g .

R e c r y s t a l l i z a t i o n fro m

e th a n o l d id n o t change t h e m e ltin g p o in t* A n a l.

C a lc d . f o r CggH^gOHgS

N, 1 2 .3 2 .

Founds

N, 1 2 .1 5 .

42

M e th y l- a lp h a -c h lo ro p r o p lo n a te ( X I I I )

CH3CHC00CH3 Cl A m ix tu re o f 400 g* (3 .6 8 m .) o f a lp h a - c h lo r o p r o p io n ic a c i d , 400 cc* o f a b s o lu te m e th an o l ( U .S .P .) , and 28 cc* of c o n c e n tr a te d s u l f u r i c a c id was r e f l u x e d e le v e n h o u rs o v er a h o t w a te r b a th *

Most o f t h e e x c e s s m eth an o l was d i s t i l l e d

o v er a steam b a th *

The o i l y r e s i d u e was w ashed w ith 1 l i t e r

o f c o ld w a te r , 500 cc* o f 5 p e r c e n t aqueous sodium c a r b o n a te , f i n a l l y w ith 500 cc* o f w ater*

The cru d e was d r i e d s e v e r a l

h o u rs o v e r c a lc iu m c h l o r i d e , f i l t e r e d , th e n d i s t i l l e d a t a t ­ m o sp h eric p r e s s u r e *

The p r o d u c t was a c o l o r l e s s l i q u i d , y i e l d

342 g . (76 p e r c e n t ) , B .P . 129-131°C* I s 132*5° ( 4 4 ) .

R e p o rte d b o i l i n g p o in t

D im e th y l e s t e r o f a lp h a - f o - c a r b o x y a n illn o ) - p r o p io n ic a c id

(XV)

•^^'C O O C H j -NHCHCOOCHj ch3

A m ix tu re o f 302 g* (2m .) o f m e th y l a n th r a n ila te ( M .P .2 3 - 4 ° ) and IBS*5 g . ( lm .) o f X I I I was h e a te d tw e lv e h o u rs o v e r an o i l h a t h a t 150°C*

The m ix tu re was c o o le d , sh a k en s e v e r a l

m in u te s i n a s e p a r a to r y f u n n e l w ith 500 cc* o f w a te r t o d is s o lv e th e fo rm ed h y d r o c h lo r id e o f m e th y l a n t h r a n i l a t e * aqueous la y e r was d e c a n te d o ff*

Most o f th e

The o r g a n ic l a y e r was washed

w ith a s o l u t i o n o f 110 cc* o f c o n c e n tr a te d h y d r o c h lo r ic a c id i n 500 cc* o f w a te r , f i n a l l y t e s t i n g th e aqueous la y e r t o be s u r e I t was a t i l l d e f i n i t e l y a c id ic *

The c ru d e p r o d u c t was

draw n o f f , d r ie d o v e r c a lc iu m c h l o r i d e , d i s t i l l e d u n d e r vacuum* The p r o d u c t was c o l l e c t e d a t 169-1710C /6 mm* as a c o l o r l e s s o i l , w e ig h t 95*5 g* (40 p e r c e n t) * The com bined aqueous w ashings w ere made s l i g h t l y b a s i c b y ad d in g s o l i d sodium c a rb o n a te *

I n t h i s way, 212*g* o f

im pure m e th y l a n t h r a n i l a t e was re c o v e re d *

F ra c tio n a tio n of

t h i s o i l u n d e r vacuum s u b s e q u e n tly gave p u re m eth y l a n t h r a n i l a t e * A nal*

Calod* f o r C^gHigO^N}

H, 5*91*

F ound:

H, 6 .0 9 .

44

D im eth y l e s t e r o f H - a c o ty l- a lp h a - ( o - e a r b o x y a n llin o ) - p r o p io n ic a c id (XVII)

^ ^ “ COOCHg

■NCH(GH3 )C00CH3 COCH_ V

A m ix tu re o f 20 g* (0.084m *) o f XV, 100 cc* o f a c e t i c a n h y d r id e , and 10 d ro p s o f c o n c e n tr a te d s u l f u r i c a c id vas h e a te d o y e r a steam h a t h f o r tw e lv e h o u rs*

To th e h o t s o lu tio n *

enough w a te r (38 cc*) was added d ro p w ise w ith c o o lin g to j u s t decompose a l l th e a c e t i c an h y d rid e*

A f te r h e a tin g a few m in u tes

o v e r th e ste a m h a t h , th e form ed a c e t i c a c id was d i s t i l l e d u n d e r vacuum o ver a h o t w a te r h a th *

The r e s i d u e was d is s o lv e d

I n 130 cc* o f h e n z e n e , t r a n s f e r r e d t o a s e p a r a to r y f u n n e l , s a t u r a t e d aqueous sodium b ic a r b o n a te s o l u t i o n added u n t i l th e aqueous la y e r t e s t e d s l i g h t l y b a s i c a f t e r s h a k in g th e m ix tu re v ig o ro u s ly *

The h en z en e e x t r a c t was w ashed w ith 100 cc* o f

w a te r , d r i e d over c a lc iu m c h l o r i d e , th e s o lv e n t rem oved u n d e r vacuum o v e r a h o t w a te r h a th *

The c r u d e , d a rk brown o i l was

f i n a l l y vacuum d i s t i l l e d and th e p ro d u c t c o l l e c t e d a t 175-176°/2.5m m . Y ie ld o f p ro d u c t was 18 g* (76 p e r c e n t ) • A nal*

Caled* f o r C^HppOgMj

C , 60* 2 2 ;

H, 6*09;

N, 5*02*

Poundr

C,

60*54; H, 6*40*

N, 5*17*

45

Sodium m etfaviate CEjONa I n th e Dieekmann r i n g c l o s u r e s to b e d e s c r ib e d I n th e f o llo w in g p a g e s , a s u s p e n s io n o f sodium me th y l a t e I n d ry b e n se n e was p r e p a r e d as f o l l o w s , u s in g an e q u im o la r amount o f d i b a s i c e s t e r p er mole o f sodium m e th y la te p re p a re d * A 200 c c . , ro u n d -b o tto m e d , th r e e - n e c k e d f l a s k was e q u ip p e d w ith a m e r c u r y - s e a le d , n lch ro m e H ersh b erg s t i r r e r , a w a te r c o o le d c o n d e n se r p r o te c te d b y a c a lc iu m c h l o r i d e t u b e , and a sy stem f o r m a in ta in in g d r y , n i t r o g e n atm o sp h ere*

Powdered

sodium (2*3 g . , 0 .1 m .) was p r e p a r e d i n 40 c c . o f d ry x y le n e by h e a tin g t h e m ix tu re a t I t s r e f l u x te m p e r a tu r e o v e r a f r e e flam e f o r s e v e r a l m in u tes u n t i l th e sodium was c o m p le te ly m o lte n , th e n c o o lin g th e m ix tu re w h ile s t i r r i n g as v ig o r o u s ly as p o s s i b l e .

The x y le n e was d e c a n te d , th e sodium washed w ith

20 cc* o f d ry th io p h e n e - f r e e b e n s e n e , th e n c o v e re d w ith 30 cc* o f b en sen e*

A s o l u t i o n o f 3 .2 g . (0 .1 m .) o f a b s o lu te m eth an o l

i n 10 c c . o f b e n se n e was added d ro p w lse w ith s t i r r i n g , th e n th e m ix tu re was r e f lu x e d u n t i l a l l th e sodium had r e a c t e d . I n a l l c a s e s , s o d lu m -d r le d , th io p h e n e - f r e e b e n se n e sa d x y le n e w ere u s e d .

The a lc o h o l was d r ie d w ith magnesium m e ta l

as d e s c r ib e d b y F l e s e r (23) •

The r e a c t i o n s w ere r u n I n t h e

above s e t - u p w ith o u t a l t e r a t i o n *

46

2 , 2 * - d im e th y 1 - 5 , 3 1« d l k c t o - d l l n d o l l n y l - 2 . 2 t (XIX) f ro m XV ( c f . p . 4 3 )

H

H

A s u s p e n s io n o f 5 .7 8 g . (0 ,1 0 7 m .) o f sodium m e th y la te I n 50 c c , o f d ry b en sen e was p r e p a r e d as p r e v io u s ly d e s c rib e d * A s o l u t i o n o f 25*4 g , (0 .1 0 7 m .) o f th e d im e th y l e s t e r o f a lp h a ( o - c a r b o x y a n ilin o ) - p r o p io n ic a c id (XV) i n 70 c c . o f b e n se n e was added a l l a t once i n d ry n i t r o g e n atm o sp h ere*

T hen, th e

m ix tu re was h e a te d f i f t y m in u te s a t i t s r e f l u x te m p e ra tu re w ith s t i r r i n g o v e r a steam b a th *

The f l a s k c o n te n ts w ere

c o o le d , p o u red slo w ly w ith s t i r r i n g i n t o an i c e - c o l d s o l u t i o n o f 6 cc* o f a c e t i c a c id i n 54 cc* o f w ate r* s e t a s id e one h o u r i n th e r e f r i g e r a t o r *

The m ix tu re was

The s o l i d form ed

was f i l t e r e d fro m th e two p h ase l i q u i d s y s te m , y i e l d i n g 2*50 g* o f y e llo w powder*

The aqueous la y e r was s e p a r a t e d , th e b en z en e

la y e r washed w ith 50 cc* o f aqueous sodium c a rb o n a te (10 p e r c e n t ) , f i n a l l y w ith 50 cc* o f w ater*

The b en z en e s o l u t i o n was e v a p ­

o r a te d a t room te m p e r a tu r e y i e l d i n g 15*0 g , o f brow n s e m i- s o lid * The y e llo w s o l i d and brow n s e m i- s o lid w ere com bined and r e c r y s t a l 11zed once fro m b e n z e n e , y i e l d i n g 2 ,5 5 g* (16 p e r c e n t) o f b r i g h t y e llo w p o tid e r, M.F. 174°C dec*

A se co n d r e c r y s t a l ­

l i z a t i o n fro m e th a n o l gave y e llo w e r y s t a l s w ith no change I n

47

m e ltin g p o i n t .

R e p o rte d m e ltin g p o in t i s 174° d e c . (4 )•

Ho o th e r s o l i d s u b s ta n c e s c o u ld b e I s o l a t e d fro m t h e b en z en e m other l i q u o r . A n a l.

C a lc d . f o r c i8 Hig ° 2 ll2 5: Pound:

9 *58. N, 9 .5 1 .

48

2 . 2 1- d im e th y 1 - 5 , 3 1- d l k e t o - d l l n d o l l n v l - 2 , 2 »

(XIX)

f ro m X V II ( o f . p . 4 4 )

A su a p e n a lo n o f 3*48 g* (0 .0 6 5 m .) o f sodium m e th y la te I n 25 c c . o f d ry "benzene was p r e p a re d as p r e v io u s ly d e s c r ib e d * A s o l u t i o n o f 1 3 .6 g . (0 .0 4 9 m .) o f t h e d im e th y l e s t e r o f Nac e t y 1 - a lp h a - ( o - c a r b o x y a n l l i n o ) - p r o p i o n i c a c id (XVII) I n 40 cc* o f b e n z e n e was added a l l a t once I n d r y , n i t r o g e n a tm o sp h e re . Some y e llo w s o l i d a p p e a re d Im m e d ia te ly .

The m ix tu re was s t i r r e d

v ig o r o u s ly a t room te m p e r a tu r e f o r one h o u r .

The f l a s k c o n te n ts

w ere p o u red slo w ly i n t o a c o l d , s t i r r e d s o l u t i o n o f 10 cc* o f a c e t i c a c id I n 100 c c . o f i c e w a te r .

The b en z en e was ev ap o ­

r a t e d fro m th e m ix tu re b y s e t t i n g a s id e a t room te m p e ra tu re f o r s e v e r a l h o u rs*

T h is g ave a s u s p e n s io n o f b ro w n -o ran g e

s e m i- s o lid i n th e y e llo w , aqueous s o l u t i o n .

The c ru d e p ro d u c t

was f i l t e r e d , w ashed w ith 50 c c . o f w a te r , w ashed q u ic k ly w ith 50 c c . o f c o ld e t h a n o l , f i n a l l y o v e n - d r ie d a t 85°C . The cru d e p ro d u c t was a b r i g h t y e llo w , s o l i d pow der, y i e l d 3 . 3 g . (46 p e r c e n t ) , M .P.168-174°C d e c .

A p o r t i o n o f c ru d e

was r e c r y s t a l l i z e d fro m 15 cc* o f e t h a n o l , g iv in g a p u re p r o d u c t m e ltin g a t 174°C d e c . The d i i n d o l i n y l p ro d u c ts o b ta in e d from XV and XVII showed no d e p r e s s io n b y m ixed m e ltin g p o i n t . A n a l.

C a lc d . f o r C Founds

*

H, 9.58* N, 9*30*

49

2 . 2 » - d l m e t h v l - 3 ,3 * - d l k e t o - d l l n d o l l n y l - 2 , 2 '

(XIX)

fr o m IX ( c f . p .3 2 )

A m ix tu re o f 1 g . (0*0053 m .) o f 1 - a c e ty 1 -2 -m e th y l ln d o x y l (IX)

and 15 c c . o f 20 p e r c e n t aqueous sodium h y d ro x id e was

h e a te d one h o u r over a ste am b a t h .

The d a r k b lu e - g r e e n s o l u t i o n

mas c o o le d , th e s m a ll amount o f u n d is s o lv e d r e s i d u e f i l t e r e d o f f and d i s c a r d e d .

A c i d i f i c a t i o n o f th e f i l t r a t e ca u sed a

re d -b ro w n s o l i d t o p r e c i p i t a t e .

A f t e r s ta n d in g I n th e r e f r i g e r ­

a t o r o v e r n i g h t , th e c ru d e p r o d u c t was f i l t e r e d o f f , w ashed th o ro u g h ly w ith w a te r , d r i e d a t room te m p e r a tu r e to g iv e 0 .5 5 g . (71 p e r c e n t) o f d i r t y y e llo w p o w d er, M .P.160-173°C d e c .

A

p o r t i o n o f c ru d e was r e c r y s t a l l i s e d fro m b e n s e n e , g iv in g a y e llo w c r y s t a l l i n e s o l i d , M .P.168-174°C d e c .

A seco n d r e c r y s t a l -

11s a t i o n fro m b e n se n e g av e a y e llo w c r y s t a l l i n e s o l i d m a ltin g a t 173-4°C d e c . A n a l.

C a lc d . f o r c x8H16°2N2 J P ound:

9 *58 H , 9 .4 4 .

50

M ethyl m a n d e la ta

M M B M M h H M M B H H M M V M H M M M

G

S ^ /G,~CH(OH)COOCH3

a

m ix tu re o f 400 g . (2.63m *) o f m an d ellc a c id ( C .P .) ,

1200 c c . o f a b s o lu te m eth an o l ( U .S .P .) , and 06 c c . o f co n cen­ t r a t e d s u l f u r i c a c id v as r e f l u x e d e le v e n h o u rs o v e r a h o t v a te r h a th .

The ex e esa m e th an o l v a s d i s t i l l e d o v er*

The

r e s i d u e v a s p o u re d i n t o 1 .5 l i t e r s o f v a t e r , sh a k e n th o r o u g h ly , th e n th e m ix tu re v a s made b a s i c b y ad d in g s o l i d sodium c a rb o n a te * The tv o la y e r s v e r e s e p a r a t e d , t h e aqueous la y e r e x t r a c te d v l t h 400 cc* o f e t h e r and t h e e t h e r e x t r a c t v a s added to th e c ru d e e s t e r .

The s o l u t i o n v a s d r i e d o v er sodium s u l f a t e ,

t h e e t h e r v a s d i s t i l l e d , th e c ru d e e s t e r p o u red i n t o a l a r g e e v a p o r a tin g d i s h , and l a s t t r a c e s o f s o lv e n t v e r e rem oved b y b y e v a p o r a tio n , f i n a l l y u n d e r vacuum*

The cru d e p ro d u c t

c r y s t a l l i z e d u p o n c o o lin g t o a v h i t e s o l i d , y i e l d 356 g* (82 p e r c e n t ) , M .P .57-58°C .

R e p o rte d m e ltin g p o in t i s 58°0* (4 5 )*

The c ru d e p r o d u c t v a s u se d w ith o u t f u r t h e r p u r i f i c a t i o n *

51

M e tte tl e a t o r o f a l p h a - c h l o r o p h e n y l a c e t i c a d d

(XIV)

0^ ^ -C H (C 1 )C 0 0 C H 3

To a s o l u t i o n o f 162 g . (0 .9 7 5 m .) o f m eth y l m a n d ela te I n 250 cc* o f d r y c h lo ro fo rm , 208 g« (lo u ) o f p h o sp h o ru s p e n t a c h l o r I d s was added slo w ly w ith c o n tin u o u s sh ak in g *

The

h y d ro g en c h l o r id e e v o lv e d was d i r e c t e d t o th e s in k w ith ru b b e r tu b in g *

When t h e a d d i t i o n was co m p lete# th e f l a s k c o n te n ts

w ere h e a te d s lo w ly and c a u t i o u s l y u n t i l r e f l u x te m p e ra tu re v a s re a c h e d (one h o u r)*

The r e a c t i o n m ix tu re was r e f l u x e d

u n t i l h y d ro g en c h l o r id e e v o lu tio n was co m p lete (one and o n e h a l f h o u rs )* th e n was r e f lu x e d an a d d i t i o n a l hour*

The e x c e ss

c h l o r i d e s o f p h o sp h o ru s were decom posed by c a u t i o u s l y ad d in g 250 cc* o f w a te r d ro p w lse w ith s h a k in g and c o o lin g i n an ic e b a th *

When th e d e c o m p o sitio n was com plete* 1 1* o f w a te r was

added a l l a t once* th e m ix tu re was sh a k e n th o ro u g h ly * and th e aqueous la y e r s e p a r a te d by d e c a n ta tlo n *

The c ru d e p ro d u c t

was v a sh e d a seco n d tim e w ith 1 1* o f w a te r .

The s o lv e n ts

w ere d i s t i l l e d * th e n t h e p ro d u e t was e o l l e e t e d as a c o l o r l e s s o i l a t 159°C/25mm.

Y ie ld was 122*5 g* (68 p e r c e n t) *

b o i l i n g p o in t i s 248°C/760mm. ( 4 3 ) .

R e p o rte d

sa D im eth y l e a t e r o f

mmtmmmmmmmmmmmmmmmmmmmmmrnmmmmmmmmmmmmm

a l p h a - ( o - c a r b o x y a n llln o ) - p h e n y l a c e t i c a c id (XVI)

^ n -c o o c ^ -NGH ( C6H5 ) C000H3 H A m ix tu re o f 200 g* ( l * 3 2 a . ) o f m e th y l a n t h r a n i l a t e and 122*5 g* (0»66m*) o f XIV v a s h e a te d t e n h o u rs o v er an o i l h a t h a t 150°C.

The m ix tu re was c o o le d , d is s o lv e d I n 400 cc*

o f h e n z e n e , washed v l t h 250 c c . o f v a t e r , v l t h 500 c c . o f 10 p e r c e n t aqueous h y d r o c h lo r ic a d d , v l t h 250 cc* o f 5 p e r c e n t sodium c a rb o n a te s o l u t i o n , f i n a l l y v l t h 250 cc* o f w ater* The b en z en e s o l u t i o n v as d r i e d o v e r c a lc iu m c h l o r i d e , th e s o lv e n ts d i s t i l l e d , th e p ro d u c t c o l l e c t e d u n d e r vacuum a t 1 9 0 -2 2 1°C/15mm* as a t h i c k , v is c o u s o i l *

T h is o i l v a s

r e c r y s t a l l i z e d fro m 200 cc* o f e t h a n o l , y i e l d i n g 82 g* (42 p e r c e n t) o f a w h ite , c r y s t a l l i n e s o l i d , H*F*0O-1°C*

A seco n d

r e c r y s t a l l l z a t l o n gave a sw eet s m e llin g , w h ite s o l i d m e ltin g a t 91*3—92*0°C.

F u r th e r r e c r y s t a l l i z a t i o n s fro m e th a n o l d id

n o t change th e m e ltin g p o in t ran g e* The com bined aqueous a c id w ash in g s v e r e made s l i g h t l y b a s i c b y ad d in g s o l i d sodium c a rb o n a te *

I n t h i s w ay, 83*5 g*

o f im pure m eth y l a n t h r a n i l a t e v as r e c o v e r e d as an o i l * A nal*

C aled* f o r

N, 4*68*

F ound;

N, 4.7 6 *

53

D im eth y l e a t e r o f N - a c e ty l- a lp h a - f o - c a r b o x y a n llln o ) -p h e n v l a c e t i c a c id (X V III)

^ N co o c^ \ J - y c u ( c 6 R5

) C00CH3

C0CH3 A m ix tu re o f 30 g . (0 .1 m .) o f XVI, 150 cc* o f a c e t i c a n h y d rid e , and 15 d ro p s o f c o n c e n tr a te d s u l f u r i c a c id was h e a te d o y er a ste am b a t h f o r tw e n ty -f o u r h o u r s , t h e c o n d e n ser b e in g eq u ip p ed w ith a c a lc iu m c h l o r i d e tu b e *

The e x c e ss a c e t i c

a n h y d rid e was decomposed b y ad d in g 30 cc* o f w a te r t o th e h o t s o l u t i o n w ith s h a k in g and c o o lin g *

The form ed a c e t i c

a c id was d i s t i l l e d u n d e r vacuum (25mm*) o v er a h o t w a te r b a th * The r e s id u e was c o o le d , 75 cc* o f w ater a d d e d , s o l i d sodium b ic a r b o n a te added u n t i l th e aqueous la y e r t e s t e d n e u t r a l a f t e r v ig o ro u s s h a k in g o f th e two p h ases*

The cru d e p ro d u c t was

f i l t e r e d , w ashed w ith 100 cc* o f w a te r , th e n a i r - d r i e d at room te m p e ra tu re *

T h is y ie ld e d 33*3 g* (97 p e r c e n t) o f l i g h t

y e llo w s o l i d , M *P*118-133°C.

The im pure p ro d u c t was r e c r y s t a l ­

l i s e d fro m 50 ec* o f e t h a n o l , w ashed q u ic k ly w ith 20 cc* o f f r e s h e t h a n o l , d r ie d

i n an o v ea (80°C) f o r one h o u r , f i n a l l y

d r ie d u n d e r vacuum o v er p h o sp h o ru s p e n to x id e *

Y ie ld o f

r e c r y s t a l l i s e d p ro d u c t was 23*6 g* (69 p e r c e n t) o f l i g h t y e llo w c r y s t a l s , M*P*132-6°C*

R e p e a te d r e c r y s t a l l i s a t i o n s fro m e th a n o l

gave w h ite c r y s t a l s , M*P*135*0-135*8°C. Anal*

C a lc d .f o r Cx9H1905H?

c » 66•S6 ? H, 5*57*

N, 4*11*

Pounds

C,

H, 3 .9 6 .

6 6 .8 9 ; H, 5 .7 3 ;

2 . 2 1- d l p h e n y l - 3 .3 f - d l k e t o - d l l n d o l l n y l - 2 . 2 t (XX) fro m XVI ( c f . p . 52)

C6H5H5C6 Nv X /N k H

H

A s u s p e n s io n o f 3 .6 2 g . (0 .0 6 7 m .) o f sodium m e th y la te i n 25 c c . o f d ry b en zen e v as p r e p a re d as p r e v io u s ly d e s c r ib e d . A s o l u t i o n o f 20 g . (0 .0 6 7 m .) o f th e d im e th y l e s t e r o f a lp h a ( o - c a r b o x y a n ilin o ) - p h e n y l a c e t i c a c id (XVI) i n 35 c c . o f b e n z e n e was added a l l a t once i n d ry n it r o g e n a tm o sp h e re . The m ix tu re v a s s t i r r e d v ig o r o u s ly f o r o n e - h a lf h o u r a t room te m p e r a tu r e , th e n one ho u r a t r e f l u x te m p e r a tu r e .

The f l a s k

c o n te n ts v e re c o o le d , p o u red s l o v l y v l t h s t i r r i n g i n t o a s o l u t i o n o f 6 c c . o f a c e t i c a c id i n 200 c c . o f i c e v a t e r . The m ix tu re v a s s e t a s id e a f e v m in u te s f o r co m p lete d e c o m p o s itio n . The y e l l o v s o l i d v h lc h s e p a r a te d v as f i l t e r e d , v ash ed v l t h 50 c c . o f v a t e r , v ash ed q u ic k ly v i t h 25 c c . o f e t h a n o l, d r ie d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum .

The p ro d u c t v as

a b r i g h t y e l l o v s o l i d p o v d e r, M .P.212-224°C d e c . , y i e l d 1 0 .0 g . (72 p e r c e n t ) .

A p o r t i o n ( 3 .5 g . ) v a s r e c r y s t a l l i z e d

fro m 200 c c . o f b e n z e n e , g iv in g a b r i g h t y e l l o v s o l i d p o v d e r, M .P. 224°C d e e . A n a l.

The r e p o r t e d m e ltin g p o in t i s 2 2 4 -5 °C ( 2 5 ) .

C a lc d . f o r C28H20°2K2 J Pounds

6 .7 3 . H, 6 .6 0 .

55 2 , 2 * - d i p h e n y l - 3 ,3 » - d l k e t o - d l l n d o l l n y l - 2 , 2 »

(XX)

fr o m X V III ( c f , p . 5 5 )

A s u s p e n s io n o f 3*04 g . (0 .0 5 6 m .) o f

sodium m e th y la te i n

20 c c . o f d ry b en zen e was p r e p a r e d as p r e v io u s ly d e s c r ib e d . A s o l u t i o n o f 13 g . (0 .0 3 8 m .) o f th e d im e th y l e s t e r o f N - a o e ty la lp h a - ( o - c a r b o x y a n ilin o ) - p h e n y l a c e t i c a c id (X V III) i n 40 c c . o f b en zen e was added a l l a t once i n d r y , n i t r o g e n a tm o sp h e re . The m ix tu re was s t i r r e d v ig o r o u s ly f o r one - h a l f h o u r a t room te m p e r a tu r e , th e n one hour a t th e r e f l u x te m p e r a tu r e .

The

f l a s k c o n te n ts w ere c o o le d , p o u red s lo w ly w ith s t i r r i n g i n t o a s o l u t i o n o f 6 c c . o f a c e t i c a c id i n 100 c c . o f i c e w a te r . A f t e r s t i r r i n g a few m in u te s , th e y e llo w s o l i d w hich s e p a r a te d was f i l t e r e d o f f , w ashed w ith 50 c c . o f w a te r , w ashed q u ic k ly w ith 25 c c . o f e t h a n o l , d r ie d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum .

The c ru d e p r o d u c t was a y e llo w pow der, y i e l d

8 .0 g . ( q u a n t i t a t i v e ) , M .P. 200-225°C d e c .

A s m a ll p o r tio n

was r e c r y s t a l l i z e d tw ic e from b e n z e n e , g iv in g a b r i g h t y e llo w s o l i d , M .P.224-5°C d e c . A n a l.

C a lc d . f o r ^28^20^2^2^

N, 6 .V 3 .

F ound;

N, 6 .5 8 ,

The d i l n d o l l n y l p ro d u c ts o b ta in e d from XVI AHD X V III showed no d e p r e s s io n b y mixed m e ltin g p o i n t .

56 2 .2 * - d l p h e n y l - g .3 t - d i k e t o - d l l n d o l l n y l - 2 .2 '

(XX)

fr o m X ( c f . p . 3 8 )

A m ix tu re o f 1 g . ( 0 .0 0 4 m .) o f l - a c e t y l - 2 - p h e n y l in d o x y l (X)

and 15 c c . o f 20 p e r c e n t aqueous sodium h y d ro x id e was h e a te d

one h o u r o v er a ste am h a t h . s o lu tio n .

T h is gave a c l e a r , l i g h t brow n

The s o l u t i o n was c o o le d I n i c e , a c i d i f i e d w ith

c o n c e n tr a te d h y d r o c h lo r ic a c i d . to p r e c ip ita te o u t.

T h is ca u sed a y e llo w s o l i d

A f t e r s ta n d in g i n th e r e f r i g e r a t o r o v e r­

n i g h t , th e cru d e p r o d u c t was f i l t e r e d o f f , w ashed th o ro u g h ly w ith w a t e r , d r i e d a t room te m p e r a tu r e .

T h is y ie ld e d 0 .8 1 g .

(98 p e r c e n t) o f y e llo w p o w d er, M .P. 175-205°C d e c .

A s m a ll

sam ple was r e c r y s t a l l i z e d from h e n z e n e to g iv e a b r i g h t y e llo w po w d er, M.P. 215-225°C d e c .

A seco n d r e c r y s t a l l i z a t i o n from

h en z en e p ro d u ced a p u re p r o d u c t, M.P. 224-5°C d e c . A n a l.

C a lc d . f o r C2aH20 °2 N2 ?

N' 6#73#

P ound:

N, 6 .4 8 .

57

2 - m e th y l- 5 - ln d o le a c e t i c a c id (XXV) fro m IX ( c f . p . 32)

CE

E R e fo raiatak y r e a c t i o n w ith l - a c e t y l - 2 - m e t h i l In d o x y l ( IX ) : k d r y 200 c c . , th r e e - n e c k e d , ro u n d -b o tto ra e d f l a s k vaa e q u ip p e d v l t h a m e r c u r y - s e a le d , nichrom e H ersh b erg s t i r r e r and a c o n d e n se r p r o t e c t e d v l t h a c a lc iu m c h l o r id e tu b e .

I n to

th e f l a s k v a s I n tro d u c e d 2 g . (0 .0 1 0 6 m .) o f IX , 25 c c . o f d ry e t h e r , 25 c c . o f d r y , th io p h e n e - f r e e b e n z e n e , 5 g . o f c le a n (v ash e d tv o m in u te s v l t h 2 p e r c e n t aqueous h y d r o c h lo r ic a c i d , th e n v l t h v a t e r , a c e to n e , a b s o lu te m e th a n o l, a b s o lu te e t h e r , oven d r i e d , th e n u n d e r vacuum ), tv e n ty -m e a h g r a n u la r z i n c , 0 .1 5 g . o f I o d in e , f i n a l l y 1 .6 c c . o f d ry e t h y l b ro m oa c e ta te .

The v ig o r o u s ly s t i r r i n g m ix tu re v as r e f lu x e d f o r t y -

f i v e m in u te s .

F iv e more a d d i tio n s o f s in e and Io d in e v e r e

siade a t f o r t y - f i v e m in u te I n t e r v a l s and tv o more a d d itio n s o f e t h y l b ro m o a c e ta te v e r e made a f t e r one and o n e - h a lf and t h r e e hour I n t e r v a l s .

The m ix tu re vas r e f l u x e d f o r a t o t a l

o f f o u r h o u rs v l t h c o n tin u o u s s t i r r i n g .

The g re y a d d i t i o n

p ro d u c t v a s d is s o lv e d b y a d d in g 2 c c . o f m e th a n o l- a c e tic a c id s o l u t i o n ( 1 :1 volume r a t i o ) , and th e s o l u t i o n v a s d e c a n te d from th e z in c I n t o 50 c c . o f I c e v a t e r .

The z in c r e s id u e I n th e

f l a s k v a s r i n s e d v l t h 20 c c . o f f r e s h e t h e r c o n ta in in g a f e v

58 d ro p s o f m e th a n o l- a c e tic a c id s o l u t i o n , and t h i s was added t o th e above*

The m ix tu re was a c i d i f i e d w ith a c e t i c a c id

(7 c c * ) t o congo r e d p a p e r .

A f te r s h a k in g th o r o u g h ly , th e

aqueous la y e r was s e p a r a te d and e x t r a c t e d w ith 50 cc* o f e th e r* The com bined o r g a n ic e x t r a c t s w ere w ashed w ith 2 -6 0 cc* p o r tio n s o f 5 p e r c e n t aqueous ammonium h y d ro x id e , f i n a l l y w ith 50 cc* o f w ater*

The s o l u t i o n was d r i e d o v e r c a lc iu m c h l o r i d e , th e n

th e s o lv e n ts rem oved by d i s t i l l a t i o n , f i n a l l y rem oving l a s t t r a c e s u n d e r vacuum*

T his y ie ld e d 3*1 g* o f a y e llo w , n o n *

c r y s t a l l l s a b l e o i l (XXI)•

T h is was u s e d i n t h e n e x t s te p

w ith o u t f u r t h e r p u r i f i c a t i o n * The above c ru d e XXI was d is s o lv e d i n 10 ee* o f d ry b e n s e n e , 3 g* o f p h o sp h o ru s p e n to x ld e was ad d e d , and th e m ix tu re was r e f l u x e d ( p r o t e c t e d w ith a c a lc iu m c h l o r id e tu b e ) o v e r a steam b a t h f o r t h r e e h o u rs*

The e x c e s s p h o sp h o ru s p e n to x ld e was

d e s tro y e d b y ad d in g 10 cc* o f w a te r w ith s t i r r i n g and c o o lin g * To th e m ix tu r e , 50 cc* o f e t h e r was ad d ed , th e n i t was f i l t e r e d t o s e p a r a te th e s m a ll amount o f p u r p le s o l i d fro m t h e two l i q u i d system *

The aqueous la y e r was s e p a r a t e d , e x t r a c t e d

w ith 50 cc* more o f e th e r*

The com bined o r g a n ic e x t r a c t s

w ere w ashed w ith 20 cc* o f 5 p e r c e n t aqueous sodium b ic a r b o n a te s o l u t i o n , f i n a l l y w ith 20 cc* o f w ater*

The o r g a n ic s o lv e n ts

w ere rem oved by d i s t i l l a t i o n o v e r a steam b a t h , f i n a l l y u n d e r vacuum*

A p p ro x im a te ly 2 g . o f b ro w n , n o n - c r y s t a l 11s a b le o i l

(X X III) was o b ta in e d *

T h is was u s e d i n th e n e x t s t e p w ith o u t

f u r th e r p u rific a tio n * A m ix tu re o f t h e above c ru d e X X III, 15 cc* o f w a te r , 5 cc* o f e t h a n o l , and 2 g* o f sodium h y d ro x id e was r e f lu x e d one

«

59

h o a r o v e r a ste am b a th *

The m ix tu re was c o o le d , t h e s m a ll

amount o f u n d is s o lT e d , p u r p le s o l i d f i l t e r e d o f f , th e f i l t r a t e t r e a t e d w ith 0*5 g . o f N o r ite f o r te n m in u tes o v e r a ste am b a t h , th e n f i l t e r e d .

The d a rk r e d s o l u t i o n was a c i d i f i e d w ith

c o n c e n tr a te d h y d r o c h lo r ic a c id , c o o le d i n i c e f o r o n e - h a lf hour*

The medium brown p r e c i p i t a t e was f i l t e r e d o f f , washed

th o r o u g h ly w ith w a te r ,

d r ie d u n d e r vacuum* The c ru d e p ro d u c t

was a b ro w n , g r a n u la r s o l i d ,

y i e l d 0*95 g* (47 p e r c e n t b a s e d

on amount o f IX u s e d ) , M .P. 158-170°C dec*

Two r e c r y s t a l l i z a t i o n s

fro m a c e t i c a c id y i e l d e d 0*42 g* (2 1 p e r c e n t) o f l i g h t t a n c r y s t a l s , M .P .1 9 5 -2 00°C d e c .

T h is m e ltin g p o in t ch eck s w ith

t h a t r e p o r t e d b y F i s c h e r (34)* A n a l.

C a lcd f o r

N, 7 .4 1 .

Foundr

N, 7 .4 8 .

60

£ -m e th y l-3 « -ln d o le a c e t i c a c id (XXV) fro m 2 -m e th y l I n d o le (XXIX) A cetone p h e n y l h y d razo n e? To a f i l t e r e d s o l u t i o n o f 20 g* (0 .1 4 m .) o f p h e n y l h y d ra z in e h y d r o c h lo r id e ( C .P .) and 30 g . o f sodium a c e t a t e i n 200 c o . o f w a te r was added 5 .8 g . (0 .1 m .) o f a c e to n e w ith v ig o ro u s s h a k in g . a y e llo w o i l *

The p ro d u c t s e p a r a te d im m e d ia te ly as

A f t e r o n e - h a l f h o u r , 100 c c . o f e t h e r was a d d e d ,

th e m ix tu re s h a k e n , and t h e aqueous la y e r s e p a r a te d *

The

o r g a n ic la y e r was w ashed t h r e e tim e s w ith 50 c c . p o r tio n s o f w ater*

The e t h e r s o l u t i o n was d r ie d o v er c a lc iu m c h l o r i d e ,

th e e t h e r d i s t i l l e d o v er a steam h a t h , and l a s t t r a c e s o f s o lv e n t rem oved u n d e r vacuum* of lig h t red o i l .

T h is y i e l d e d 1 4 .3 g* (96 p e r c e n t)

The c ru d e was u s e d Im m e d ia te ly I n th e n e x t

s te p * 2 -m e th y l I n d o le (XXIX) An I n tim a te m ix tu re o f 5 g . (0 .0 3 4 m .) o f a c e to n e p h e n y l h y d razo n e and 25 g* o f d r y , pow dered z in c c h l o r i d e was h e a te d w ith s t i r r i n g o v er a Wood’ s m e ta l h a t h a t 180°C f o r t e n m in u te s . The d a r k brow n m ix tu re was c o o le d , 50 c c . o f w a te r added and h e a te d o v er a steam b a t h u n t i l th e two l i q u i d and s o l i d p h a se s becam e s e p a r a b le .

The m ix tu re was c o o le d , a c i d i f i e d w ith

c o n c e n tr a te d s u l f u r i c a c id (4 c c * ) , t r a n s f e r r e d to a s e p a r a to r y f u n n e l , acd e x t r a c t e d w ith 100 c c . o f e th e r *

The o r g a n ic

e x t r a c t was w ashed w ith 50 cc* o f w a te r , t h e e th e r was d i s t i l l e d , and th e r e s i d u e was ste a m d i s t i l l e d *

The p ro d u c t came o v er as

a c o l o r l e s s o i l w hich q u ic k ly s o l i d i f i e d I n t o a w h ite ,

61

c r y s t a l l i n e s o li d *

The ste a m d i s t i l l a t e v a s c o o le d s e v e r a l

h o a rs i n th e r e f r i g e r a t o r , th e p ro d u c t v a s f i l t e r e d , v ash ed v l t h a l i t t l e v a t e r , a i r - d r i e d o v e r n ig h t, f i n a l l y u n d e r vacuum* The p r o d u c t, v h ic h had become l i g h t y e l l o v on s ta n d in g , v e ig h e d 6 g* (91 p e r c e n t ) , M*P.56-60°C*

T h is v a s u s e d i n th e n e x t

s te p v ith o u t f u r th e r p u r ific a tio n *

The r e p o r t e d m e ltin g p o in t

i s 60°C (34)* 2 -m eth y l g ram in e (XXVII) A s o l u t i o n o f d im e th y l amine (4*1 g . o f 33 p e r c e n t aqueous s o l u t i o n , 0*03m .) v as c o o le d t o 5°G*

M a in ta in in g th e te m p e ra ­

t u r e a t 5°G , th e fo llo w in g com ponents v e re added i n o r d e r ; 4*1 g . o f g l a c i a l a c e t i c a c i d , fo rm a ld eh y d e ( 2*42 g* o f 36 p e r c e n t aqueous s o l u t i o n , 0 .0 2 9 m .) v l t h s l i g h t a g i t a t i o n , f i n a l l y 3*8 g . (0*029m .) o f 2 -m e th y l in d o le .

The m ix tu re

v a s sh a k en by hand f o r tv e n ty m in u te s , th e n s e t a s id e a t room te m p e ra tu re o v e r n ig h t.

The u n d ls s o lv e d s o l i d v as f i l t e r e d

o f f , th e f i l t r a t e v as d i l u t e d v l t h 60 cc* o f v a t e r , u n r e a c te d XXIX v as f i l t e r e d o f f*

The l i g h t y e l lo v f i l t r a t e v as made

s l i g h t l y a l k a l i n e v l t h 10 p e r c e n t sodium h y d ro x id e , c a u s in g th e p r e c i p i t a t i o n o f th e v h l t e s o l i d p r o d u c t.

The m ix tu re

v a s c o o le d i n ic e f o r tv e n ty m in u te s , th e s o l i d v as f i l t e r e d , v ash ed th o ro u g h ly v l t h v a t e r , d r i e d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum.

T h is y ie ld e d 1*99 g* (36*5 p e r c e n t) o f v h l t e

p o v d er (XXVII), M .P .117-121°C .

T h is vas u s e d i n th e n e x t

s te p v ith o u t f u r th e r p u r ific a tio n *

The r e p o r t e d m e ltin g p o in t

i s 120-1°C ( 3 6 ) . a - m e th y l- 3 - in d o le a c e t i c a c id (XXV) A m ix tu re o f 1*99 g . (0*0106m .) o f XXVII, 3 .5 g . o f sodium

6Z

c y a n id e , 28 cc* o f e t h a n o l , and 7 cc* o f w a te r was r e f l u x e d e i g h ty h o u rs o v e r a ste a m h a th *

The m ix tu re was c o o le d , u n ­

d is s o lv e d s o l i d ( n e g l i g i b l e amount) was f i l t e r e d o f f , th e f i l t r a t e t r e a t e d b y b o i l i n g t e n m in u te s w ith 0*5 g* o f N orite*. The c l e a r s o l u t i o n was c o n c e n tr a te d u n d e r vacuum u n t i l a l l th e a lc o h o l was rem o v ed , s u f f i c i e n t w a te r added to b r in g th e t o t a l volume t o ab o u t 7 c c * , th e n th e m ix tu re was c o o le d i n an i c e b a th *

The w h ite s o l i d w hich s e p a r a te d was f i l t e r e d

o f f and d is c a r d e d .

The c o ld f i l t r a t e was a c i d i f i e d w ith

c o n c e n tr a te d h y d r o c h lo r ic a c i d , c a u s in g a l i g h t brow n o i l to p r e c i p i t a t e o u t*

T h is o i l s o l i d i f i e d i n th e r e f r i g e r a t o r

a f t e r s e v e r a l h o u rs*

The c ru d e p r o d u c t was f i l t e r e d , washed

th o r o u g h ly w ith w a te r , d r i e d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum*

The c ru d e p ro d u c t was a l i g h t brown pow der,

y i e l d 1*27 g* (64 p e r c e n t ) , M *F.94-165°C*

Two r e c r y s t a l ­

l i s a t i o n s fro m g l a c i a l a c e t i c a c id gave a l i g h t p in k pow der, M*P*182-195°C dec*

An a d d i t i o n a l r e c r y s t a l l i s a t i o n fro m a

minimum o f a c e to n e gave a n e a r l y w h ite p r o d u c t, M.P. 195-200°C dec* Mixed m e ltin g p o in t o f p r o d u c ts o b ta in e d fro m IX and XXIX showed no d e p re s s io n *

63 2 -p h e n y l-a » ln d o le a c e t i c a c id

(XXVI)

f ro m X ( c f . p . 38)

||

J'CHgCOOH

V V ^ ° 6 H5

H R efo rm atak y r e a c t i o n w ith 1 - a c e t y l - 2 -p h e n y l In d o x y l (X ): The r e a c t i o n p ro p e r vaa c a r r i e d o u t i n e x a c tl y th e same way as p r e v io u s l y d e s c r ib e d f o r IX ( s e e p . 5 7 ) , u s in g 2 g . o f X (0 .0 0 8 m .) .

At th e end o f t h e r e f l u x i n g p e r i o d , 6 c c . o f a

1 :1 volum e s o l u t i o n o f m eth an o l and a c e t i c a c id was a d d e d , b u t th e g r e y a d d i t i o n p ro d u c t was in c o m p le te ly d i s s o l v e d . The r e a c t i o n m ix tu re was c o o le d i n i c e and 50 c c . o f i c e w a te r was added r a p i d l y w ith s t i r r i n g . d is s o lv e d e x c e p t th e u n r e a c te d z i n c .

A ll th e s o l i d m a t e r i a l The m ix tu re was made

a c i d i c t o congo r e d p a p e r w ith a c e t i c a c id ( 1 0 c c . ) .

The c l e a r

s o l u t i o n was d e c a n te d fro m th e z in c I n t o a s e p a r a to r y f u n n e l . The re m a in in g r e s i d u e was w ashed w ith 20 c c . o f e t h e r c o n ta in in g a few d ro p s o f th e m e th a n o l- a c e tic a c id s o l u t i o n , and t h i s was com bined w ith t h e b u lk o f o r g a n ic m a t e r i a l .

The aqueous

l a y e r was s e p a r a t e d , e x t r a c t e d w ith 50 c c . o f f r e s h e t h e r . The com bined o r g a n ic e x t r a c t s w ere w ashed w ith 2*100 c c . p o r tio n s o f c o l d , 5 p e r c e n t aqueous ammonium h y d r o x id e , f i n a l l y w ith 50 c c . o f w a te r .

The s o l u t i o n was d r i e d o v er c a lc iu m

c h l o r i d e , th e s o lv e n ts rem oved by d i s t i l l a t i o n , f i n a l l y l a s t t r a c e s w ere rem oved u n d e r vacuum.

The n o n - c r y s t a l l i z a b l e o i l

(XXII) was u se d i n th e n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

64

The above c ru d e XXII v a i d is s o lv e d I n 10 c c . o f d r y b e n z e n e , 4 g . o f p h o sp h o ru s p e n to x ld e v a s a d d e d , and t h e m ix tu re v a s r e f l u x e d ( p r o t e c t e d v i t h a c a lc iu m c h lo r id e tu b e ) o v er a ste am b a t h f o r t h r e e h o u r s .

A f te r d e s tr o y i n g th e

e x c e s s p h o sp h o ru s p e n to x ld e v l t h 20 c c . o f v a t e r , th e m ix tu re vas v o rk ed u p i n e x a c tl y t h e same v ay as i n th e d e h y d r a tio n o f XXI ( c f . p . 5 8 ) .

The cru d e p ro d u c t v a s a r e d d le h - b r o v n ,

n o n - c r y s t a l l l z a b l e o i l (XXIV).

T h is v a s u s e d i n th e n e x t

s te p v ith o u t f u r th e r p u r if i c a t io n . The above c ru d e XXIV v a s r e f lu x e d one h o u r o v er a ste am b a t h i n a s o l u t i o n o f 4 g . o f p o ta s s iu m h y d ro x id e i n 20 c c . of e th a n o l.

F o r ty c c . o f v a t e r v as ad d e d , and th e e th a n o l

vas rem oved b y h e a tin g u n d e r vacuum .

The medium b ro v n ,

aqueous s o l u t i o n v as h e a te d t e n m in u te s o v e r a steam b a t h v i t h 1 g . o f N o r i t e , f i l t e r e d , th e N o r ite v a sh e d v i t h 5 c c . o f h o t v a t e r and t h i s combined v i t h th e b u lk o f t h e aqueous s o l u t i o n . The s o l u t i o n v a s c o o le d i n i c e , a c i d i f i e d v i t h c o n c e n tr a te d h y d r o c h lo r ic a c i d .

T h is c a u se d t h e p r e c i p i t a t i o n o f a l i g h t

b r o v n , o i l y s e m i- s o lid .

A f te r c o o lin g i n th e r e f r i g e r a t o r

o v e r n ig h t, th e cru d e had c o m p le te ly s o l i d i f i e d .

T h is v as

f i l t e r e d , v a sh e d th o ro u g h ly v i t h v a t e r , d r i e d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum.

The c ru d e p ro d u c t v a s a l i g h t t a n p o v d e r,

y i e l d 1 .4 4 g . (72 p e r c e n t ) , M .P .166-177°C d e c .

The c ru d e v as

d is s o lv e d i n 40 c c . o f a c e to n e , th e s m a ll amount o f b la c k u n d is s o lv e d m a t e r i a l f i l t e r e d o f f ,$ h e n th e s o l u t i o n v a s b o i l e d o n e - h a lf h o u r o v er a ste a m b a t h v i t h 2 g . o f N o r l t e .

The

c h a r c o a l v a s f i l t e r e d , v a s h e d v i t h 20 c c . o f f r e s h a c e to n e . T h is tr e a tm e n t gave a n e a r l y v a t e r - v h l t e s o l u t i o n .

The s o lv e n t

65

was e v a p o ra te d a t room te m p e r a tu r e , and l a s t t r a c e s w ere rem oved u n d e r vacuum*

T h is y ie ld e d 1*21 g* (61 p e r c e n t) o f n e a r l y

w h ite c r y s t a l l i n e s o l i d , M .P.170-5°C *

A s m a ll sam ple was

r e c r y a t a l i i zed tw ic e from g l a c i a l a c e t i c a c i d , y i e l d i n g n e a r l y w h ite c r y s t a l s , M .P .174-6°C .

The r e p o r te d m e ltin g p o in t i s

174°C ( 4 6 ) . A nal*

C a lc d . f o r C^gH^OgN;

N, 5*58*

Pound:

N, 5.37*

6S 2 -p h en y 1 - 3 - ln d o 1e a c e t i c a c id (XXVI) from 2 -p h e n y l in d o le (XXX) A cetophenone p h e n y l h y d ra z o n e t To a f i l t e r e d s o l u t i o n o f 20 g . (0 .1 4 m .) o f p h e n y l h y d ra z in e h y d r o c h lo r id e (C .P .) and 30 g . o f sodium a c e t a t e i n 200 c c . o f w a te r was added 1 1 .6 g . (0 .1 m .) o f aceto p h en one w ith v ig o ro u s s h a k in g . a l i g h t y e llo w s o li d *

The p ro d u c t s e p a r a te d im m e d ia te ly as A f te r f o r t y m in u tes* th e c ru d e was

f i l t e r e d * w ashed w ith 150 c c . o f w a te r* d r i e d a t room te m p e ra ­ tu r e * f i n a l l y u n d e r vacuum .

T h is y ie ld e d 19*5 g« (96 p e r c e n t)

o f l i g h t y e llo w pow der, M .P .9 7 -1 0 5 °C .

T h is was u s e d a t once

i n th e n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n .

The r e p o r te d

m e ltin g p o in t i s 105°C ( 4 7 ) . 2 -p h e n y l in d o le (XXX)? An in tim a te m ix tu re o f 5 g . (0 .0 2 4 m .) o f aceto p h en o n e p h e n y l h y d razo n e and 25 g . o f d ry pow dered z in c c h l o r id e was h e a te d w ith s t i r r i n g o v er a Wood*s m e ta l b a th a t 180°C f o r f i v e m in u te s .

The d a r k brown m ix tu re was c o o le d , a s o l u t i o n

o f 5 c c . o f c o n c e n tr a te d h y d r o c h lo r ic a c id i n 50 c c . o f w a te r was added* th e n th e m ix tu re was h e a te d c a r e f u l l y o v e r a f r e e fla m e u n t i l a l l th e s o l i d was i n f r e e s u s p e n s io n .

The m ix tu re

was t r i t u r a t e d i n a m o rtar* th e n e x t r a c t e d w ith 125 c c . o f e th e r * y ie l d i n g a c le a r * two l i q u i d p h ase sy sta m .

The aqueous

la y e r was s e p a r a te d * th e e t h e r s o l u t i o n was f i l t e r e d t o remove th e s m a ll t r a c e s o f u n d is s o lv e d s o l i d .

The e t h e r was d i s t i l l e d *

and l a s t t r a c e s w ere removed u n d e r vacuum .

The l i g x t y e llo w

s o l i d c ru d e was d r i e d I n an oven (85°C) f o r h a l f an h o u r .

The

67

c ru d e p r o d u c t w eighed 3 .9 g . (85 p e r c e n t ) , M .P .1 7 0 -1 8 1 OC .

One

r e c r y s t a l l i z a t i o n fro m e t h a n o l gave a n e a r l y w h ite c r y s t a l l i n e s o l i d , M .P. 1 8 1 -5 °C .

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 fro m e th a n o l

y i e l d e d a w h ite s o l i d , M.P. 187-8°C . i s 186°G ( 3 4 ) .

R e p o rte d m e ltin g p o i n t

The r e c r y s t a l l i s e d p r o d u c t (M .P. 1 8 7 -8 °) was

u s e d i n th e n e x t s t e p . 2 -p h e n y l g r amine (X X V III): A t 5°C , th e s e com ponents w ere mixed i n th e f o llo w in g o r d e r w ith a g i t a t i o n ; 1*9 c c . (0 .0 1 4 m .) o f 33 p e r c e n t aqueous d im e th y l am in e, 6 c c . o f g l a c i a l a c e t i c a c i d , 1 c c . (0 .0 1 2 m .) o f 36 p e r c e n t aqueous fo rm a ld e h y d e , f i n a l l y 2 .2 6 g . (0 .0 1 2 m .) o f 2 -p h e n y l I n d o le (XXX) •

The m ix tu re was sh a k en b y hand

v ig o r o u s ly f o r tw e n ty m in u te s , th e n s e t a s id e a t room te m p e r a tu r e o v e r n ig h t.

The u n d is s o lv e d m a t e r i a l was f i l t e r e d o f f , th e

f i l t r a t e d i l u t e d w ith 100 c c . o f w a te r , c o o le d , f i l t e r e d . The c o l o r l e s s f i l t r a t e was made a l k a l i n e w ith 10 p e r c e n t aqueous sodium h y d r o x id e , c a u s in g th e p r e c i p i t a t i o n o f a w h ite s o l i d . The m ix tu re was c o o le d i n i c e f o r o n e - h a lf h o u r , th e c ru d e p ro d u c t was f i l t e r e d , w ashed th o ro u g h ly w ith w a t e r , d r i e d a t room te m p e r a tu r e u n d e r vacuum o v er p h o sp h o ru s p e n t o x id e .

The

c ru d e was a n e a r l y w h ite pow der, M .P. 128-131°C , y i e l d 0 .8 4 g . (89 p e r c e n t ) .

A f t e r two r e c r y s t a l l i z a t i o n s fro m e t h a n o l , th e r e

was no f u r t h e r change i n m e ltin g p o i n t r a n g e .

The p u re p ro d u c t

was a w h ite c r y s t a l l i n e s o l i d (s m a ll n e e d l e s ) , M.P. 1 3 0 .0 - 1 3 9 .8°C. A n a l.

C a lc d . f o r C17H8JI2 ;

C , 8 1 .6 0 ;

H, 7 .2 1 ;

N, 1 1 .1 9 .

F ound:

C,

8 1 .7 0 ; H, 7 .4 6 ;

N, 1 1 .0 7 .

68 2 - p h e n y l- 3 - ln d o le a c e t i c a c id (XXVI): A m ix tu re o f 0 .9 5 g . (0 .0 0 4 m .) o f c ru d e X X V III, 1 .0 g . o f sodium c y a n id e , 9 c c . o f e t h a n o l , and 2 c c . o f w a te r was r e f l u x e d e i g h t y h o u rs o v er a steam b a t h .

The m ix tu re was

c o o le d , u n d is s o lv e d s o l i d ( 0 .5 8 g . ) f i l t e r e d o f f , th e f i l t r a t e d e c o lo r is e d b y b o i l i n g te n m in u te s w ith a s m a ll amount o f N o r i te . The c l e a r s o l u t i o n was c o n c e n tr a te d u n d e r vapuum u n t i l a l l th e a lc o h o l was rem oved, s u f f i c i e n t w a te r was added to make th e t o t a l volume 2 c c . , th e n th e m ix tu re was c o o le d i n an i c e b a th .

The w h ite s o l i d (0 .2 6 g . ) w hich s e p a r a te d was f i l t e r e d

o ff.

The c o ld f i l t r a t e was a c i d i f i e d w ith c o n c e n tr a te d h y d ro ­

c h l o r i c a c id w ith s t i r r i n g , c a u s in g a w h ite powder to p r e c i p i t a t e o u t.

The m ix tu re was c o o le d I n th e r e f r i g e r a t o r s e v e r a l h o u r s ,

th e s o l i d f i l t e r e d , washed th o ro u g h ly w ith w a te r , d r ie d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum o v er p h o sp h o ru s p e n to x ld e . The y i e l d o f c ru d e p r o d u c t was 0 .0 6 g . (6 p e r c e n t) o f l i g h t p in k s o l i d , M .P. 174-6°C .

S u f f i c i e n t p ro d u c t was n o t o b ta in e d

f o r p u r i f i c a t i o n by r e c r y s t a l l i s a t i o n . The two s o l i d s o b ta in e d p r i o r t o s e p a r a t i o n o f th e p ro d u c t b y a c i d i f i c a t i o n w ere ea c h r e f l u x e d w ith 10 p e r c e n t aqueous sodium h y d ro x id e f o r f o u r h o u r s .

A f te r f i l t r a t i o n , N o r lte

t r e a t m e n t , and a c i d i f i c a t i o n w ith c o n c e n tr a te d h y d r o c h lo r ic a c i d , no more p ro d u c t c o u ld b e o b ta in e d . Mixed m e ltin g p o in t o f p r o d u c ts o b ta in e d from X and XXX showed no d e p r e s s io n .

69 l - a c e t v l - 2 .3 - d i m e t h y l i n d o l e (XXXII) fr o m IX ( c f . p .3 2 )

Orr-%

VV*C H 3 (bCH3 A c tio n o f m e th y l magnesium io d id e on 1 - a c e t y 1 - 2 -m ethy 1 in d o x v l(IX ) A 100 c c . , th r e e - n e c k e d , ro u n d -b o tto m e d f l a s k was eq u ip p ed w ith a c o n d e n s e r, c a lc iu m c h l o r id e d r y in g t u b e , a nlchrom e H e rs h b e rg , m e rc u ry - s e a le d s t i r r e r , a d ro p p in g f u n n e l , and a sy ste m f o r m a in ta in in g d r y , c a rb o n d i o x i d e - f r e e , n i t r o g e n a tm o sp h e re .

I n t o t h e f l a s k was in tr o d u c e d 0*78 g . (0 .0 3 2 m .)

of

c l e a n , d r y m agnesium t u r n i n g s , a l s o a s m a ll io d in e c r y s t a l , and 4 c c . o f e t h e r .

To t h i s was added w ith s t i r r i n g and a t

a r a t e s u f f i c i e n t to m a in ta in r e f l u x i n g , a s o l u t i o n of 4 .5 2 $ (0 .0 3 2 m .) o f m e th y l io d id e ( C .P .) i n 10 c c . o f e t h e r .

When

a d d i t i o n was c o m p le te , th e d ro p p in g f u n n e l was r i n s e d w ith 2 c c . o f f r e s h e t h e r , th e n th e s t i r r i n g m ix tu re was r e f lu x e d u n t i l a l l th e m e ta l had r e a c t e d ( f o r t y - f i v e m in u te s ) .

To

t h i s was added d ro p w lse w ith v ig o ro u s s t i r r i n g , 2 .0 g . (0 .0 1 0 6 m .) o f IX d is s o lv e d i n 4 c c . o f h o t , d r y , th io p h e n e - f r e e b en zen e ( f i v e m in u te s ) , th e n th e a d d i t i o n f u n n e l was r i n s e d w ith 4 c c . more o f h o t b e n z e n e .

A g re y a d d i t i o n p ro d u c t p r e c i p i t a t e d

a lm o st im m e d ia te ly .

The m ix tu re was r e f l u x e d one hour o v e r

a h o t w a te r b a t h w ith s t i r r i n g , c o o le d i n an i c e b a t h , 50 c c . o f e t h e r a d d e d , th e n p o u red w ith s t i r r i n g i n t o an i c e - c o l d

70

s o l u t i o n o f 3*6 cc* o f c o n c e n tr a te d s u l f u r i c a c id I n 60 cc* o f w ater*

The r e a c t i o n f l a s k was r i n s e d w ith a l i t t l e w a te r*

and com bined w ith th e above*

The w a te r la y e r was drawn o f f ,

e x t r a c t e d w ith 50 cc* o f e t h e r .

The com bined e th e r e x t r a c t s

w ere washed w ith 20 cc* o f w a te r , 20 cc* o f 5 p e r c e n t aqueous sodium b ic a r b o n a te , f i n a l l y w ith 20 c c . o f w a te r .

The o rg a n ic

s o lv e n ts were d i s t i l l e d and l a s t t r a c e s removed u n d e r vacuum* T h is y ie ld e d 1*87 g . o f a v i s c o u s , y e llo w s e m i- s o lid (XXXI) w ith an in d o le odor* P a r t o f t h i s c ru d e (1*15 g*) was steam d i s t i l l e d d i r e c t l y , g iv in g a w h ite o i l w hich g r a d u a lly c r y s t a l l i z e d *

A f te r s ta n d ­

in g o v e r n ig h t i n th e r e f r i g e r a t o r , t h e s o l i d was f i l t e r e d , d r i e d a t room te m p e ra tu re i n tlss a i r , f i n a l l y u n d e r vacuum* The p ro d u c t was a w h ite c r y s t a l l i n e s o l i d , y i e l d 0*56 g . (46 p e r c e n t o f X X X II), M .P. 7 3-4°C . F a r t o f t h e c ru d e XXXI (0 .5 2 g .) was d is s o lv e d i n 3 cc* o f b e n z e n e , 2 g . o f p hosphorus p e n to x ld e add ed , and th e m ix tu re r e f l u x e d ( p r o t e c t e d b y a c a lc iu m c h l o r i d e tu b e ) f o r t h r e e h o u rs* The e x c e ss p h o sp h o ru s p e n to x ld e was decomposed w ith 10 cc* o f w a te r w ith c o o lin g *

E th e r (15 cc* ) was ad d e d , and th e

m ix tu re sh ak en th o ro u g h ly *

The u n d is s o lv e d r e s id u e was f i l t e r e d

o f f , and th e aqueous la y e r s e p a ra te d * e x t r a c t e d w ith 15 c c . more e th e r *

The aqueous la y e r was

The combined o r g a n ic e x t r a c t s

w ere w ashed w ith 10 cc* o f w a te r , 10 cc* o f 5 p e r c e n t aqueous sodium b ic a r b o n a te , f i n a l l y w ith 10 cc* o f w ater*

The o rg a n ic

s o lv e n ts were d i s t i l l e d , and l a s t t r a c e s removed u n d e r vacuum t o g iv e a d a rk bro w n , c o m p le te ly s o l i d r e s id u e (0*45 g*)»

71

T h is was ste a m d i s t i l l e d , t h e d i s t i l l a t e c o o le d i n th e r e f r i g e r ­ a t o r o v e r n ig h t, th e w h ite c r y s t a l l i n e s o l i d f i l t e r e d , d r i e d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum. was 0 .3 3 g . (60 p e r c e n t ) , M .P. 7 3 -4 °C .

The y i e l d o f XXXII

Two r e c r y s t a l l i z a t i o n s

fro m e th a n o l gave w h ite c r y s t a l s , m e ltin g s h a r p ly a t 74°C. The r e p o r t e d m e ltin g p o in t i s 74°C ( 4 8 ) . A n a l.

C a lc d . f o r C^gH^ON;:

N, 7 .4 8 .

Found:

N, 7 .4 2 .

7a

I - a e e t y l - 2 .5 - d lm e th y l in d o le (XXXII) v i a th e F is c h e r method P h en y l h y d razo n e o f m eth y l e t h y l k e to n e (XXXIV) : To a f i l t e r e d s o l u t i o n o f 20 g . (0 .1 4 m .) o f p h en y l h y d ra z in e h y d r o c h lo r id e (C .P .) and 50 g . o f sodium a c e t a t e I n 200 c c . o f w a te r was added 7 g . (0 .1 m .) o f m e th y l e t h y l k e to n e w ith v ig o r o u s s h a k in g . once.

A y e llo w o i l s e p a r a te d a t

A f t e r t h i r t y m in u te s , t h e m ix tu re w§s t r a n s f e r r e d

t o a s e p a r a to r y f u n n e l , 100 c c . o f e t h e r a d d e d , and th e aqueous la y e r draw n o f f .

The e t h e r e x t r a c t was w ashed

w ith t h r e e -5 0 c c . p o r tio n s o f w a t e r , d r ie d o v e r c a lc iu m c h l o r i d e , th e e t h e r d i s t i l l e d , and l a s t t r a c e s o f s o lv e n t w ere rem oved u n d e r vacuum .

The p r o d u c t was a l i g h t brown

o i l (XXXIV), y i e l d 1 1 .3 g . (72 p e r c e n t ) .

T h is c ru d e o i l

was u se d a t once i n th e n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n . 2 . 5 -d im e th y l I n d o le (X X X III): An in ti m a t e m ix tu re o f 2 .0 g . (0 .0 1 2 m .) o f XXXIV and 10 g . o f d r y , pow dered z in c c h l o r i d e was h e a te d w ith s t i r r i n g o v e r a W ood's m e ta l b a t h a t 130°C f o r t e n m in u te s .

The

d a r k brown m ix tu re was c o o le d , a s o l u t i o n o f 2 c c . o f c o n c e n tr a te d s u l f u r i c a c id i n 20 c c . o f w a te r was ad d e d , th e n 50 c c . o f e t h e r .

The m ix tu re was sh a k en u n t i l a l l th e

s o l i d d i s s o l v e d , g iv in g a c l e a r , tw o - liq u id p h a se sy s te m . The aqueous la y e r was draw n o f f , th e n th e o r g a n ic la y e r was w ashed w ith 20 c c . o f f r e s h w a te r . and l a s t t r a c e s rem oved u n d e r vacuum .

The e t h e r was d i s t i l l e d , The r e s i d u e was steam

d i s t i l l e d , th e d i s t i l l a t e c o o le d i n th e r e f r i g e r a t o r s e v e r a l

73

h o u r a , th e w h ite c r y s t a l l i n e s o l i d was f i l t e r e d , o v e n - d r ie d (8 5 °) f o r a few m in u te s , f i n a l l y u n d e r vacuum .

T h is y ie ld e d

1 .2 g , (66 p e r c e n t) o f c ru d e X X XIII, M.P. 100-106°C . r e p o r t e d m e ltin g p o in t i s 106°C (3 4 )*

The

F iv e r e c r y s t a l l i z a t i o n s

fro m l i g r o i n gave th e p u re p r o d u c t, M.P. 105-6°C. 1 - a c e ty 1 - g . 3 -d lm e th y l I n d o le (XXXII): A s o l u t i o n o f 0 .5 6 g . (0 .0 0 4 m .) o f XXXIII I n 3 c c . o f a c e t y l c h l o r id e was r e f lu x e d f o u r h o u rs o v e r a h o t w a te r h a t h . The e x c e s s a c e t y l c h l o r id e was rem oved u n d e r vacuum .

The

re m a in in g d a rk brow n o i l was w ashed w ith w a te r , th e n was ste a m d i s t i l l e d .

The ste a m d i s t i l l a t e was c o o le d i n th e

r e f r i g e r a t o r s e v e r a l h o u r s , th e w h ite c r y s t a l s w ere f i l t e r e d , d r i e d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum .

The cru d e

y i e l d o f XXXII was 0 .3 4 g . (47 p e r c e n t ) , M .P, 7 1 -6 °C .

T h is

c ru d e was r e c r y s t a l l i z e d once from 1 c c . o f e t h a n o l , w ashed w ith a few d ro p s o f f r e s h a l c o h o l , d r i e d u n d e r vacuum .

T h is

gave w h ite n e e d le s , M.P. 73**76.5°C. M ixed m e ltin g p o in t o f p ro d u c ts o b ta in e d fro m IX and fro m th e F is c h e r m ethod showed no d e p r e s s io n .

74 2 ,5 -d ip h e n y l In d o le

(XXXVII)

f r o m X ( c f . p . 38)

i^ N —

„

I

6 5

V A nJ~C6 H5 H A c tio n o f p h e n y l magnesium b ro m id e on 1 - a c e ty l- 2 - p h e n y l In d o x y l(X ): A 100 cc* , th r e e - n e c k e d , ro u n d -b o tto m e d f l a s k vas eq u ip p ed w ith a c o n d e n s e r, c a lc iu m c h l o r id e d r y in g t u b e , a nichrom e H e rs h b e rg , m e rc u ry -s e a le d s t i r r e r , a d ro p p in g f u n n e l , and a sy ste m f o r m a in ta in in g d r y , c a rb o n d i o x i d e - f r e e , n it r o g e n atm osphere*

I n t o th e f l a s k was in tr o d u c e d 0*29 g .

(0*012m*) o f c l e a n , d ry magnesium t u r n i n g s , th e n a sm a ll io d in e c r y s t a l , and 2 cc* o f e th e r *

To t h i s was added w ith

s t i r r i n g and a t a r a t e s u f f i c i e n t to m a in ta in r e f l u x i n g , a s o l u t i o n o f 1*88 g* (0*012m*) o f d ry brom obenzene i n 8 cc* of e th e r.

When a d d i t i o n was c o m p le te , th e d ro p p in g f u n n e l

was r i n s e d w ith 2 cc* o f f r e s h e t h e r , th e n th e s t i r r i n g m ix tu re was r e f l u x e d u n t i l a l l th e m e ta l h ad r e a c t e d ( te n m in u tes m ore)*

To t h i s was added d ro p w ise w ith v ig o ro u s

s t i r r i n g , 1 g . (0*004«u) o f X d is s o lv e d i n 4 cc* o f h o t , d r y , th io p h e n e - f r e e b en zen e ( f i v e m in u te s ) , th e n th e a d d i tio n f u n n e l was r i n s e d w ith 2 cc* more o f h o t b enzene* a d d i t i o n p ro d u c t p r e c i p i t a t e d a t once*

A w h ite

The m ix tu re was

r e f lu x e d one h o u r o v er a h o t w a te r b a th w ith s t i r r i n g .

The

75

f l a s k c o n te n ts w ere c o o le d , 30 c c . o f e t h e r a d d e d ,th e n pou red w ith s t i r r i n g i n t o an i c e - c o l d s o l u t i o n o f 2 c c . o f co n cen ­ t r a t e d s u l f u r i c a c id i n 30 c c . o f w a te r .

The w a te r la y e r

was draw n o f f , n e u t r a l i z e d w ith aqueous sodium h y d ro x id e (5 p e r c e n t ) , e x t r a c t e d w ith 50 c c . o f e t h e r .

The combined

e t h e r e x t r a c t s w ere w ashed w ith 20 c c . o f w a te r , 20 cc* o f aqueous sodium b ic a r b o n a te (5 p e r c e n t ) , f i n a l l y w ith 20 c c . o f w a te r .

The o r g a n ic s o lv e n ts w ere d i s t i l l e d , and l a s t

t r a c e s were rem oved u n d e r vacuum . u n d e r vacuum .

Then th e c ru d e was d r ie d

T h is y ie ld e d 1 .3 0 g . o f a l i g h t brow n s o l i d

(XXXV), M.P. 5 6 -7 2 °C .

I t was fo u n d d i f f i c u l t t o p u r i f y t h i s

by o r d in a r y c r y s t a l l i z a t i o n m e th o d s. A p o r t i o n o f c ru d e XXXV ( 0 .5 0 g .) was d is s o lv e d i n 2 cc* o f d ry b e n z e n e , 1 .2 g . o f phosp h o ru s p e n to x ld e was a d d e d , and th e m ix tu re r e f lu x e d ( p r o te c te d b y a c a lc iu m c h lo r id e tu b e ) th r e e h o u rs.

fo r

The e x c e ss p h o sp h o ru s p e n to x ld e was decomposed

w ith 5 c c . o f w a te r w ith c o o lin g .

E th e r (15 c c .) was ad d ed ,

th e m ix tu re sh ak en th o r o u g h ly , th e u n d is s o lv e d r e s id u e f i l t e r e d o f f , th e n th e aqueous la y e r s e p a r a t e d . e x t r a c t e d w ith 15 c c . more e t h e r .

The aqueous la y e r was

The com bined o r g a n ic e x t r a c t s

w ere w ashed w ith 10 c c . o f 5 p e r c e n t aqueous sodium b ic a r b o n a te , f i n a l l y w ith 10 c c . o f c o n c e n tr a te d sodium c h lo r id e s o l u t i o n . The o r g a n ic s o lv e n ts w ere d i s t i l l e d , l a s t t r a c e s rem oved u n d e r vacuum .

T h is y ie ld e d 0 .5 0 g . o f a n o n - c r y s t a l l i z a b l e o i l (XXXVI)

w hich was u s e d i n th e n e x t s te p w ith o u t f u r t h e r p u r i f i c a t i o n * P a r t of c ru d e XXXVI (0 .3 5 g . ) was d is s o lv e d i n 5 c c . o f e t h a n o l , th e n 1 g . o f p o ta ss iu m h y d ro x id e ad d ed , and th e s o l u t i o n was r e f lu x e d o v er a ste am b a th f o r tw e n ty m in u te s .

W ater (10 c c .)

76

was a d d e d , th e e th a n o l was removed u n d e r vacuum o ver a ste am h a th *

The o i l - w s t e r m ix tu re re m a in in g was n e u t r a l i z e d w ith

c o n c e n tr a te d h y d r o c h lo r ic a c i d , th e n was e x t r a c t e d w ith 15 cc* o f e th e r *

The e t h e r e x t r a c t was w ashed w ith 10 c c . o f w a te r ,

th e s o lv e n t rem oved h y e v a p o r a tio n , f i n a l l y u n d e r vacuum*

The

r e d d is h o i l was d is s o lv e d w ith 5 cc* o f e t h a n o l , b o i l e d s e v e r a l m in u te s w ith a l i t t l e N o r ite u n t i l th e s o l u t i o n was a l i g h t y e llo w c o l o r , th e n was f l i t e r e d * 5 cc* o f f r e s h , h o t e t h a n o l .

and t h e N o r ite w ashed w ith

The com bined e th a n o l s o lu t io n s

w ere e v a p o ra te d s lo w ly a t room te m p e r a tu r e , g iv in g l i g h t brown r o s e t t e s , M .P. 104-119°C , y i e l d 0*23 g . (80 p e r c e n t b a s e d on XXXVII).

The c ru d e was r e c r y s t a l l i z e d fro m 2*5 c c . o f h o t

l i g r o i n , c o n ta in in g a few d ro p s o f benzene* c r y s t a l l i n e s o l i d g r a d u a lly p r e c i p i t a t e d o u t.

A l i g h t , g ra n u la r, A f te r s ta n d in g a t

room te m p e r a tu r e o v e r n ig h t, th e p ro d u c t was c e n tr if u g e d o f f , w ashed w ith 2 cc* o f l i g r o i n , d r ie d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum .

T his y ie ld e d alm o st q u a n t i t a t i v e l y , a l i g h t t a n ,

g r a n u la r s o l i d , M.P. 1 2 4 -6 °C •

Mixed m e ltin g p o in t o f t h i s

p r o d u c t w ith 2 ,3 - d ip h e n y l in d o le o b ta in e d b y th e Jap p -M u rray ( c f . p . 77) showed no d e p re s s io n *

A seco n d r e c r y s t a l l i z a t i o n

fro m g l a c i a l a c e t i c a c id gave w h ite c r y s t a l s , M.P. 125*2-126*0°C . The r e p o r t e d m e ltin g p o in t i s 123-4°C ( 4 9 ) . Anal*

C alcd* f o r

N, 5 .2 0 .

Pound:

N, 5.11*

77

2 , 5 - d ip h e n y l I n d o le (XXXVII) v i a th e Ja p p -M u rray method A m ix tu re o f 16 g . (0*076 m*) o f b e n z o in (M .P*132-4°C ), 24 g . (0 .2 6 m .) o f a n i l i n e , and 10 g . (0 .0 7 7 m .) o f a n i l i n e h y d r o c h lo r id e (M .P. 193-5°C) was r e f lu x e d u n d e r a f r a c t i o n a t i n g column su ch t h a t w a te r and a minimam o f a n i l i n e d i s t i l l e d o v e r . A f te r f o r t y - f i v e m in u te s , no more w a te r came o v e r and a t o t a l volume o f 10 c c . o f d i s t i l l a t e had b e e n c o l l e c t e d ( 2 .0 c c . o f w a te r m e a s u re d ).

The m ix tu re was c o o le d , a s o l u t i o n o f

26 c c . o f c o n c e n tr a te d h y d r o c h lo r ic a c id i n 75 c c . o f w a te r a d d e d ,th e n th e m ix tu re was e x t r a c t e d w ith 125 c c . o f e t h e r . The o rg a n ic e x t r a c t was th e n w ashed w ith a s o l u t i o n o f 20 c c . o f c o n c e n tr a te d h y d r o c h lo r ic a c id i n 80 c c . o f w a te r , 100 c c . o f w a te r , 50 c c . o f 5 p e r c e n t aqueous sodium b ic a r b o n a te , f i n a l l y w ith 150 c c . o f w a te r .

The e t h e r was d i s t i l l e d , and

l a s t t r a c e s w ere rem oved u n d e r vacuum .

A medium y e llo w o i l

was o b ta in e d w hich c o m p le te ly s o l i d i f i e d o v e r n ig h t to a l i g h t y e llo w s o l i d , M.P. 1 2 0 .5 - 1 2 4 .5°C*

The c ru d e p ro d u c t

was ground up and d r ie d u n d e r vacuum , y i e l d i n g 2 0 .0 g . (9 8 .5 p e r c e n t) o f a pow der.

One r e c r y s t a l l i z a t i o n from

50 c c . o f e th a n o l gave a w h ite , c r y s t a l l i n e s o l i d , M .P. 1 2 4 .0 1 2 6 .5 °C , y i e l d 1 5 .1 g . (74 p e r c e n t ) .

R e p ea ted r e c r y s t a l l i z a t i o n s

o f t h i s from g l a c i a l a c e t i c a c id gave w h ite c r y s t a l s , M.P. 1 2 6 .0 - 1 2 6 .5°C .

78 A lp h a -( o - c a r b o x y a n llin o ) - a c e tic a e ld

COOH S ^ / ’-NHCHgCOOH

A s o l u t i o n o f 435 g . ( 4 .1 m .) o f anhydrous sodium c a rb o n a te i n 2 l i t e r s o f w a te r was made up i n a f i v e l i t e r , th r e e - n e c k e d , ro u n d -b o tto m ed f l a s k e q u ip p e d w ith a l i q u i d - s e a l e d s t i r r e r and a co n d en ser*

A n t h r a n i l i c a c id (375 g * , 2 .7 4 m.) was added

g r a d u a l ly w ith s t i r r i n g u n t i l c o m p le te ly d i s s o lv e d .

To t h i s ,

a s o l u t i o n o f 258 g* (2 .7 4 m .) o f c h l o r a c e t i c a c id (C .P .) in 750 c c . o f w a te r was added w ith s t i r r i n g a t a r a t e s u f f i c i e n t to p r e v e n t e x c e s s iv e fo a m in g .

The m ix tu re was h e a te d two h o u rs

ov er a ste am b a th w ith s t i r r i n g , th e n 75 g* o f N o rite was added, th e m ix tu re h e a te d f i f t e e n m in u tes m ore.

The h o t s o l u t i o n was

f i l t e r e d , a c i d i f i e d w ith c o n c e n tr a te d h y d r o c h lo r ic a c id * y e llo w s o l i d p ro d u c t s e p a r a te d q u ic k ly *

The

A fte r s ta n d in g i n th e

r e f r i g e r a t o r o v e r n ig h t, th e c ru d e p ro d u c t was f i l t e r e d o f f , t r i t u r a t e d w ith 2 l i t e r s o f w a te r , f i n a l l y w ashed w ith w a te r u n t i l th e s o l i d m e lte d a t 205-217°C •

The cru d e p ro d u c t was a

y e llo w pow der, y i e l d 320 g . (60 p e r c e n t ) . n e x t s t e p w ith o u t f u r t h e r p u r i f i c a t i o n . i s c a . 215°C (50)*

T h is was u s e d i n th e The r e p o r t e d m e ltin g

79 N - a c e ty 1 - a lp h a - ( o - c a r b o x y a n llin o ) - a c e tic a c id

#s^ ~ C O O H ^ v j»-NCE2C00H coch3 To a s o l u t i o n o f 25 g . o f sodium h y d ro x id e i n 250 c c . o f w a te r , 50 g . (0 .2 6 m .) o f a l p h a - ( o - c e r b o x y a n i l i n o ) - a c e t i c a c id was added and s t i r r e d u n t i l c o m p le te ly d i s s o l v e d .

A c e tic

a n h y d rid e (50 c c .) was added a l l a t once w ith o u t c o o lin g , and th e m ix tu re was s t i r r e d f o r tw e n ty m in u te s .

A seco n d p o r t i o n o f

a c e t i c a n h y d rid e (50 c c . ) was added end s t i r r e d tw en ty m in u tes more w ith o u t c o o lin g .

To co m p lete th e r e a c t i o n , th e m ix tu re

was h e a te d o v e r th e ste a m b a t h f o r te n m in u te s .

The h o t s o l u t i o n

was made d e f i n i t e l y a c i d i c w ith c o n c e n tr a te d h y d r o c h lo r ic a c i d , c o o le d , s e t I n th e r e f r i g e r a t o r o v e r n ig h t.

The cru d e p ro d u c t

was f i l t e r e d , washed q u ic k ly w ith 100 c c . o f w a te r , d r ie d a t room te m p e r a tu r e , f i n a l l y u n d e r vacuum.

The c ru d e p ro d u c t was

a w h ite c r y s t a l l i n e pow der, y i e l d 5 0 .0 g . (82 p e r c e n t ) , M.P. 208-210°C .

T h is was u s e d i n th e n e x t s t e p w ith o u t f u r t h e r

p u rific a tio n .

The r e p o r t e d m e ltin g p o in t i s c a . 214°C ( 1 0 ) .

80

1 , 3 - d l a c e t v l ln d o x v l

OCOCH„ ^

N iocH„

The same p ro c e d u re was u s e d a s i n th e s y n th e s is o f V II (c f* p . 3 1 ) , u s in g th e same w e ig h t q u a n t i t i e s o f a l l r e a c ta n t s * The cru d e p r o d u c t was a medium brown s o l i d , y i e l d 3 7 ,5 g* (88 p e r c e n t ) , M*P. 61-74°C*

The r e p o r te d m e ltin g p o i n t i s

82°C ( 8 ) . R ep eated N o r ite tr e a tm e n t and e th a n o l r e c r y s t a l l i z a t i o n s d id n o t im prove th e p u r i t y o f t h i s m a te r ia l*

81

1 - a c e t y l ln d o x y l

6 och, The same p ro c e d u re was u s e d aa i n th e a y n th e a ia o f IX (c f* p . 3 2 ) , u s in g th e same w eig h t p r o p o r tio n s (37*5 g . o f c ru d e 1 , 3 - d i a c e t y l in d o x y l, e t c . ) o f a l l r e a c t a n t s .

The c ru d e

p ro d u c t was a l i g h t brown pow der, y i e l d 20 g . (66 p e r c e n t ) , M .P. 132—141°C .

A ttem p ts t o p u r i f y b y N o r ite tr e a tm e n ts and

e th a n o l r e c r y s t a l l i z a t i o n s d id n o t p ro d u c e any s i g n i f i c a n t changes i n c o lo r o r m e ltin g p o in t r a n g e . p o in t i s 136°C ( 5 1 ) .

The r e p o r te d m e ltin g

82 D im e th y l a s t e r o f a ljfa a -(o -c a rb o x y a n llin o ) - a c e tic

a c id

^^-C O O C H g nhch2 cooch3

A m ix tu re o f 14 g . (0*09 m .) o f m eth y l a n t h r a n i l a t e , 10*2 g* (0*09 m.) o f m e th y l e h l o r o a c e t a t e , and 5 g« (0 .0 4 7 m») o f sodium c a r b o n a te (an h y d ro u s) was h e a te d t e n h o u rs o v er an o i l b a t h a t 140°C .

The v o l a t i l e com ponents w ere d i s t i l l e d u n d e r

vacuum (25 mm.) o v e r an o i l b a t h a t 140°C .

The o i l re m a in in g

was w ashed b y d e e a n ta tlo n w ith tw o-100 c c . p o r t i o n s o f w a te r , th e n t r i t u r a t e d w ith a s o l u t i o n o f 7 .5 c c . o f c o n c e n tr a te d h y d r o c h lo r ic a c id i n 2 2 .5 c c . o f w a te r , f i n a l l y was washed w ith 20 c c . o f w a te r .

The s o l i d c ru d e e s t e r was f i l t e r e d , d r i e d a t

room te m p e r a tu r e , f i n a l l y u n d e r vacuum.

T h is y ie ld e d 1 2 .5 g .

(60 p e r c e n t) o f c ru d e y e llo w p r o d u c t, M .P. 8 0 -9 5 °C •

The c ru d e

was r e c r y s t a l l i s e d from a m e th a n o l-w a te r s o l u t i o n (26 c c . : 8 c c . ) , y i e l d i n g 9 .3 5 g . (45 p e r c e n t) o f l i g h t y e llo w s o l i d , M.P. 9 4 -7 °C . F o r u s e i n th e n e x t s t e p , t h e c ru d e p r o d u c t was p u r i f i e d by vacuum d i s t i l l a t i o n o f th e s o l i d (B .P . 160-225°C/4m m .) , th e n was r e c r y s t a l l i z e d from a b s o lu te m e th a n o l. p r o d u c t was a w h ite c r y s t a l l i n e s o l i d , M .P. 9 7 °C . m e ltin g p o in t i s 97°C ( 5 0 ) .

The p u re The r e p o r t e d

83>

M e th y l l n d o x y l a t e

=o

'O H

-H C 0 0 C H b

— COOCHg H

A s u s p e n s io n o f 17*8 g . (0 .3 3 m.) o f sodium m e th y la te i n 110 o c . o f d ry x y le n e was p r e p a r e d as p r e v io u s ly d e s c r ib e d .

A

s o l u t i o n o f 7 3 .5 g* (0*33 m .) o f p u re d im e th y l e s t e r o f a l p h a ( o - c a r to x y a n ilin o ) - a c e t i c a c id i n 310 c c . o f d r y , h o t x y le n e was added a l l a t o n c e .

The m ix tu re was s t i r r e d v ig o r o u s ly a t

room te m p e ra tu re f o r f o r t y m in u te s , th e n was h e a te d o v e r a steam b a t h f o r f o r t y m in u te s .

The c o ld m ix tu re was p o u red s lo w ly

w ith s t i r r i n g i n t o 500 c c . o f i c e - c o l d w a te r .

The aqueous la y e r

was s e p a r a t e d , th e n th e o rg a n ic la y e r was e x t r a c t e d tw ic e w ith 250 c c . p o r tio n s o f w a te r .

The com bined aqueous e x t r a c t s w ere

a c i d i f i e d w ith g l a c i a l a c e t i c a c i d , th e n c o o le d i n th e r e f r i g e r a t o r one hour*

The c ru d e s o l i d was f i l t e r e d , w ashed q u ic k ly w ith

500 c c . o f 5 p e r c e n t aqueous sodium b i c a r b o n a t e , f i n a l l y w ith 500 c c . o f w a te r .

The Im pure p ro d u c t was d r ie d a t room te m p e r a tu r e ,

f i n a l l y u n d e r vacuum , y i e l d i n g 4 7 .3 g . (75 p e r c e n t) o f a g re y p o w d er, M .P. 157-161°C .

A sam ple (0 .3 2 g . ) o f c ru d e was r e c r y s t a l ­

l i z e d fro m 1 .5 c c . o f a b s o lu te e t h a n o l , w ashed w ith 1 c c . of f r e s h a l c o h o l.

T h is y ie ld e d 0 .2 5 g* (59 p e r c e n t) o f l i g h t g re e n

c r y s t a l s , M .P. 166-7 °C • (5 2 )*

The r e p o r t e d m e ltin g p o in t i s 1 5 5 -7 °C

SUMMARY

1*

1-a c e t y l - 2 - s u b s t i t u t e d In d o x y ls w ere p re p a re d by

r i n g c l o s u r e o f d e r i v a t i v e s o f N - a c e ty l- a lp h a - ( o - c a r b o x y a n ilin o ) a c e t i c a c id u n d er P e r k in c o n d i tio n s , fo llo w e d b y s e l e c t i v e h y d ro ly s is . 2*

A p p lic a tio n o f th e Dieckmann r e a c t i o n to d e r i v a t i v e s

o f th e n e u t r a l e s t e r s o f a lp h a - ( o - c a r b o x y a n ilin o ) - a c e t i c a c id y ie ld e d 2 ,2 * - d i s u b s t i t u t e d - 3 , 3 ’ - d i k e t o - d i i n d o l i n y l - 2 , 2 ’ d e r i v a ­ tiv e s . 3.

By th e R efo rm atsk y r e a c t i o n , 1- a c e t y l - 2 - s u b s t i t u t e d

in d o x y ls w ere c o n v e rte d t o 2 -su b s t i t u t e d - 3 - i n d o l e a c e t i c a c id d e riv a tiv e s .

The p ro d u c ts w ere compared w ith th o s e o b ta in e d

by c a r b o n - a lk y 1a t io n o f M annich b a s e s d e r iv e d fro m 2 - s u b s t i t u t e d in d o le s . 4.

By means o f th e G rig n a rd r e a c t i o n , 1- a c e t y l - 2 - s u b s t i ­

t u t e d in d o x y ls w ere c o n v e rte d to 2 , 3 - d i s u b s t i t u t e d i n d o l e s .

84

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um m

op

H P T O M 0RI71RSITT nWIVlRSTTY HEIGHTS