SYNTHESIS OF TETEÎAZOLES AS POTENTIAL ANTIMETABOLITES BY JAMES M. MCMANUS A THESIS S u b m itte d t o th e S c h o o l o f G r a d u a te S t u d i e s o f M ic h ig a n S t a t e U n i v e r s i t y o f A g r i c u l t u r e and A p p lie d S c ie n c e i n p a r t i a l f u l f i l l m e n t o f t h e r e q u ir e m e n ts f o r th e d e g re e o f DOCTm OF PHILOSOPHY D e p a rtm e n t o f C h a m is try 1958 ProQuest Number: 10008558 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10008558 Published by ProQuest LLC (2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346 A(3CN0mJSI)GMENT The w r i t e r w is h e s t o e x p r e s s h i s a p p r e c i a t i o n t o D o c to r R o b e r t M* H e r b s t f o r h i s m o st h e l p f u l c o u n s e l and g u id a n c e d u r in g t h e c o u r s e o f t h i s work* A p p r e c i a t i o n i s a l s o e x te n d e d t o t h e W h ite L a b o r a t o r i e s w hose F e llo w s h ip P ro g ra m p r o v id e d p e r s o n a l f i n a n c i a l a s s i s t a n c e d u r i n g t h e a c a d e m ic y e a r s 1 956-1958* ************** 11 SYNTHESIS OF TETRAZOIES AS POTENTIAL AIÎTIMETABOLITES BY JAMES M. MCMANUS AN ABSTEIACT S u b m itte d t o t h e S c h o o l o f G ra d u a te S t u d i e s o f M ic h ig a n S t a t e U n i v e r s i t y o f A g r i c u l t u r e an d A p p lie d S c ie n c e i n p a r t i a l f u l f i l l m e n t o f t h e r e q u ir e m e n ts f o r th e d e g re e o f DOCTOR OF PHILOSOPHY D e p a rtm e n t o f C h e m istry 195 8 A p proved ABSTEIACT I n many i n s t a n c e s th e s u c c e s s o f c h e m o th e ra p y i n th e tr e a t m e n t o f b o t h i n f e c t i o u s and non i n f e c t i o u s d i s e a s e s d e p en d s u p o n an a n ta g o n is m b e tw e e n t h e c h e m o th e r a p e u tic a g e n t u se d an d a m e t a b o l i t e o f t h e p a r a s i t i c o rg a n is m o r f o r e i g n s u b s ta n c e i n th e p a t i e n t ’ s sy stem * One o f t h e d i r e c t m e th o d s o f a n ta g o n is m i n v o lv e s c o m p e t i t i v e i n h i b i t i o n o f an enzym e o r t i s s u e r e c ^ t o r a s s o c i a t e d w i t h a m e t a b o l i t e by a s t r u c t u r a l l y r e l a t e d a n ta g o n is t* The re s e m b la n c e o f th e a n t a g o n i s t t o t h e m e t a b o l i t e may b e th r o u g h a g e n e r a l o v e r a l l s h a p e o f th e m o le c u le o r th e s i m i l a r i t y may b e m ore r e f i n e d an d r e q u i r e t h e p r e s e n c e o f one o r m ore f u n c t i o n a l g ro u p s p r o p e r ly sp aced w ith in th e s tr u c tu r e * B e c a u se o f t h e a c i d i c n a t u r e o f $ - m o n o s u b s titu te d t e t r a z o l e s (1 ,2 ,3 ) i t a p p e a r e d t h a t th e i n v e s t i g a t i o n o f su ch com pounds a s p o s s i b l e a n t i m e t a b o l i t e s f o r c e r t a i n p h y s i o l o g i c a l l y a c t i v e o a r b o x y lic a c i d s m ig h t p ro v e f r u i t f u l . A c c o r d in g ly , th e t e t r a z o l e a n a lo g u e s ( I ) o f g l y c i n e , D ,I , - a l a n i n e , - a l a n i n e , D ,L - p h e n y la la n in e and D ,L - tr y p to p h a n e h a v e b e e n p re p a re d * I E-ÜH-CN.H iv T h ra o d i f f e r e n t r o u t e s h a v e b e e n d e v e lo p e d f o r t h e s y n t h e s i s o f t h e s e 5- a m i n o a l k y l t e t r a z o l e s : 1 . fro m o ^ - h a l o a c y l h a l i d e s b y way o f th e N - b e n z y l- o C - h a lo a m id e s , 2 . from a c y l am ino a c i d s b y way o f t h e i r n i t rile s , 3* from a n a p p r o p r i a t e l y a l k y l a t e d e t h y l a c e ta m id o c y a n o a c e ta t e . The pK v a l u e s o f a l l t h e 5 - a m in o a lk y lt e t r a z o l e s , e x c e p tin g th e t r y p t o p h a n e a n a lo g u e , h a v e b e e n d e te r m in e d p o t e n t i o m e t r i c a l l y an d shown t o b e a n a lo g o u s to th o s e o f t h e c o r r e s p o n d i n g am ino a c i d s . The t h r e e is o m e r ic 5 - n i t r o p h e n y l t e t r a z o l e s a n d ( 2 ’- h y d r o x y - A ’- n i t r o p h e n y l ) t e t r a z o l e h a v e b e e n p r e p a r e d from th e c o r r e s p o n d in g benzoni t r i l e s . R e d u c tio n o f th e 5 - n i t r o p h e n y l t e t r a z o l e s r e s u l t e d i n t h e f o i m a t i o n o f t h e c o r r e s p o n d in g 5 - a m i n o p h e n y lte tr a z o l e s w h ic h i n c l u d e d t h e a n a lo g u e s ( I I ) o f p a r a - aml no b e n z o ic a c i d , m e ta - a m in o b e n z o ic a c id a n d p a r a - a m i n o s a l i c y l l c a c i d . CN^H II The t h r e e is o m e r ic 5 - p y r i d y l t e t r a z o l e s ( I I I ) an d 2 , 6 - d i ( 5 ’- t e t r a z o l y l ) p y r i d i n e h a v e b e en p r e p a r e d a s a n a lo g u e s o f t h e c o r r e s p o n d i n g p y r i d i n e c a r b o x y l i c a c i d s b y t h e i n t e r a c t i o n o f t h e c y a n o p y r ld in e w ith sodium a z i d e an d g l a c i a l a c e t i c a c id * ■GN^H N' III V R e d u c tio n o f th e $ - p y r i d y l t e t r a z o l e s h a s l e d t o t h e s y n t h e s i s o f th e c o r r e s p o n d i n g 5 - p i p e r i d y l t e t r a z o l e s . A g ro u p o f s i x s u b s t i t u t e d p h e n o x y a c e t o n i t r i l e s h a s b e e n p r e p a r e d fro m t h e c o r r e s p o n d i n g ji i e n o l s an d c h l o r o a o e t o n i t r i l e . By I n t e r a c t i o n w i t h h y d ra z o i c a c id t h e s e w e re c o n v e r te d i n t o s u b s t i t u t e d 5 -p h e n o x y m e t h y l t e t r a z o l e s (IV ) i n c l u d i n g t h e t e t r a z o l e a n a lo g u e s o f 2 ,4 -D and IV 2 ,4 .,5 -T . S e v e r a l 5 - p h e n o x y m e th y lte tr a z o le s h a v e b een p r e p a r e d b y an a l t e r n a t e m ethod t h a t in v o lv e d i n t e r a c t i o n o f s u b s t i t u t e d p h e n o ls w i t h l - b e n z y l - 5 - c h l o r o m e t h y l t e t r a z o l e and s u b s e q u e n t c a t a l y t i c d é b e n z y la ti o n o f th e r e s u l t i n g l - b e n z y l - 5 - p h e n o x y m e t h y l t e t r a z o l e s . The t e t r a z o l e a n a lo g u e o f 3 - i n d o l e a c e t i c a c id h a s a l s o b e e n p r e p a r e d by th e i n t e r a c t i o n o f 3 - i n d o l y l a c e to n i t r H e w ith alum inum a z i de. The i n t e r a c t i o n o f 3 , 4 , 5 - t r ime th o x y b e n z o n i t r l i e w ith sodium a z i d e and g l a c i a l a c e t i c a c i d h a s l e d t o th e f o r m a ti o n o f 5 - ( 3 * ,4 * ,5 * trim e th o x y p h e n y l)te tra z o le . A l k y l a t i o n o f t h i s compound w ith d i - a l k y lam i n o a l k y l h a l i d e s was u s e d to p r e p a r e t h r e e 2 - ( d i a l k y l ami n o a l k y l ) ■ 5 - ( 3 ’ >4*f5 ^ - tr ir a e th o x y p h e n y l) t e t r a z o l e s w h ic h h a v e b e en c h a r a c t e r i z e d a s th e h y d ro c h lo rid e s . Vi R e f e r e n c e s C ite d 1* E . O l i v e r i - M a n a d a la , G a zz , c h im . i t a l . , ^ C .A ., 2 , 884 ( 1 9 1 5 ) . 2. J . M ih in a and R . H e r b s t , J . O rg . C hem ., 1 5 . 1082 (1950) 3. R . H e r b s t an d K . W ils o n , J . O rg , C hem ., 2 2 . 1142 (1 9 5 7 ) . v ii II, 175 (1914) ; TABLE OF CONTENTS Page INTRODUCTION...................................................................................................... 1 3 HISTORICAL.............................................................................................................................. PART I, TETRAZOLE ANALOGUES OF AMINO A C ID S ............................................ 5 D is c u s s io n E x p e r im e n ta l ...................................................... 18 T he P r é p a r â t ! on o f 5 - A m in o m e th y lte tr a z o lo ( G ly c in e A n a lo g u e) ............................................. Schem e A 18 •••• N - B e n z y l- o c - o h lo r o a c e ta m id e .......... . . . . . . l-B e n z y l-^ -o h lo rc m e th y lte tra z o le . . . . . . . . 1 -B e n z y l - 5 - p h t h a l im i d o m e t h y l t e t r a z o l e . . . . . . l- B e n z y l- 5 - a m ln o m e th y lt e t r a z o l e h y d ro c h lo rid e ............................ 5 - A m in o m e th y lte tr a z o le ............................................. Schem e B l8 18 19 19 20 ...................................................... 21 P h th a lim ld o a c e to n ltrile .............................. 5 - (P h th a llm id c m e th y l)te tra z o le ........................... 5-A m inom ethyl t e t r a z o l e D e riv a tiv e s l8 21 21 22 . . . . . . . 23 5 - A c e t y l a m i n o m e t h y l t e t r a z o l e ............................... 5 - B e n z o y la m in o m e th y lte tr a z o le . . . . . . . . . N -P h e n y l-N ’ - ( 5 - t e t r a z o l y l m e t h y l ) u r e a 23 23 The P r e p a r a t i o n o f 5 - o6-A m inoethy 1 t e t r a z o l e ( A la n in e A n a lo g u e ) .............. Scheme A 23 24 ............................................................... N -B e n z y l- -b ro m o p ro p io n a m ide . . . . . . . . . . N - B e n z y l- ^ ^ - p h th a lim id o p r o p io n a m id e . . . . . . . l- B e n z y l- 5 - ( c < * - p h th a l im i do e t h y l ) t e t r a z o l e . . 1-B e n z y l- 5 - (« ^ -a m in o e th y 1 ) t e t r a z o l e h y d ro c h lo rid e ...... 24 24 24 25 26 Pag© 5 -o 6 - .A m ln o e th y ltQ tra z o le 26 Schem e B 2? P h th a ly l a la n in e e c - P h th a lim id o p r o p lo n a m ld e .............. o ^ -P h th a llin ld o p ro p lo n ltrlle . . . . . . . . . . . . . 5 - o ^ - P h th a llm ld o e th y l t e t r a z o l e ........................ 5* eC-Ami n o e th y l t e t r a z o l e ................ 27 27 , 28 28 29 D e riv a tiv e s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5 - oC. - A c e t y l a i n i n o e t h y l t e t r a z o l e . . . . . . . . . . . . . 5. e ( .- B e n z o y la m in o e th y lte tr a z o le . . . . . . . . . . . . N -P h e n y l-N *- ( 0 6 - 5 - t e t r a z o l y l e t h y l ) u r e a . . . . . 30 30 30 The P r e p a r a t i o n o f 5 - ( / ^ - A m i n o e t h y l ) t e t r a z o l e ( - A la n in e A n a lo g u e ) ............................................... 31 Scheme A 31 P h th a ly l ^ - a la n in e .............. /3 - P h th a l 1 m ld o p ro p lo n y 1 c h l o r i d e . . . . . . . . . . N - B e n z y l- /3 - p h th a lim ld o p r o p l o n a m ld e . . . . . . . . l-B e n z y l-5 --p h th a lim ld o e th y lte tra z o le . . . . 1 - B e n z y l- 5 - ( - a m ln o e th y l) t e t r a z o l e h y d ro c h l o r i d e . ...................... . . . . . . . . . . . . . 5 - / 8 -A m ino a t h y l t e t r a z o l e h y d r o c h l o r i d e . . . . . 31 31 32 32 Scheme B 33 33 ................................................................................34 5 - /3 -P h th a lim lc b e th y lt e t r a z o le . . . . . . . . . . . . . 5 - / 3 -A m ln o e th y l t e t r a z o l e h y d ro c h l o r i d e . . . . . 5 - /3 -A m ln o e th y lte tra z o le . . . . . . . . . . . . . . . D e riv a tiv e s 34 35 35 36 5 - ( /8 -A c e ty la m in o e th y l)te tra z o le . . . . . . . . . . . 5 - ( /3 - B e n z o y la m in o e th y l) t e t r a z o l e . . . . . . . . . N -P h e n y l-N - 5 - te tr a z o ly le th y l )u rea . . . . . 36 36 36 T he P r e p a r a t i o n o f 5 -(< ? ^ -A m in o p h e n y le th y l)t e t r a z o l e ( P h e n y la la n in e A n a lo g u e ) . . . . . . . . . . . . . . 37 Scheme B ............ 06 - P h t h a l i m l d o - /3 - p h e n y lp r o p io n y l c h lo rid e o c - P h t h a lim l d o - ^ - p h e n y l p r o p lo n a m i d e . . . . . . . ix 37 37 38 Page < » ^ - P h th a liin id o -/^ -p h e n y lp ro p io a itrllo . . . . . . 5 -(o ^ -P h t h a l l mi do - /6 - p h e n y l e t h y 1 ) te tra z o le 5 - ( 06- A m i n o - / 3 - p h e n y l e t i i y l ) t e t r a z o l e . . . . . . . 38 39 Schem e C . . . . . . . . . . . . . . . . . . . . . . . . . . 40 E t h y l oc. - a c e ta m id o - o 6 -c y a n o - /3 - p h e n y l p r o p i o n a t e ..................«......................................................... E t h y l oc - a o e t a m i d o - = 6 - ( 5 - t e t r a z o l y l ) /3 - p h e n y I t e t r a z o l e . . . . . . 06-A c e ta m ld o -o C - ( 5 - t e t r a z o l y l ) - / ^ - p h e n y l p ro p lo n ic a c id ........... 5 - - A . e e ta m id o -/3 - p h e n y le th y l) te tra z o le • • • 5 - ( oC -A m in o -/g - p h e n y l e t h y l ) t e t r a z o l e D e riv a tiv e s .............................. 40 40 41 42 42 « . . . ............................ 43 5 - (o 6 -A c e ta m id o --p h e n y le th y l)te tra z o le . . . 5 - ( oC -B en zo y la m in o - - p h e n y le t h y l ) te tra z o le ... N -P h e n y l-N * - (oC - ( 5 - t e t r a z o l y l ) - /9 - p h e n y l­ e th y l) u re a ......................... . . . . . . . . . . 43 The P r e p a r a t i o n o f 5 - (o 6 -A m ln o -/9 - ( 3 ’- i n d o l y l ) e t h y l ) t e t r a z o l e (T ry p to p h a n e A n a lo g u e ) . . . . . . Scheme 0 ................ 43 43 44 44 E t h y l oL- a c e t a m i d o - o 6 - c y a n o - / 3 - ( 3 - i n d o l y l ) p ro p io n a te ........... E t h y l o6 - a c e t a mid o - oC- ( 5 - t e t r a z o l y l ) - / 3 ( 3 ’- i n d o l y l ) p r o p i o n a t e .............. oC- A cetam id o -o C - ( 5 * -1 e t r a z o l y l ) - / 3 ( 3 - i u d o l y l ) p r o p i o n i c a c i d ................ 5 - {©<: -Ac e ta m i d o -/3 - ( 3 * -in d o l y l ) e t h y l ­ te tra z o le ............................ 5 - ( oC-A m ino- /3 - (3 ’- i n d o l y l ) e t h y l ) te tra z o le ................................................................... The D e te r m in a tio n o f t h e A p p a re n t pK V a lu e s o f Some 5 -A m ln o a lk y l t e t r a z o l e s ............................ II. 38 44 45 46 46 47 47 TETEIAZOLE analogues of a c t iv e AMINOBENZOIC ACID DERIVATIVES.................................................................................................... 49 D is c u s s io n ....• • 49 ........ 53 E x p e r im e n ta l ......................... I Page T he P r e p a r a t i o n o f N l t r o p h e n y l t e t r a z o l e s 53 5 - ( 2 ’- N i t r o p h e n y l ) t e t r a z o l e .............. 5 - ( 3 ^ -N ltro p h e n y l)te tra z o le . . . . . . . . . . . . (a ) P r e p a r a t i o n fro m a B en zen e S o l u t i o n o f H y d ra z o ic A c id (b ) P r e p a r a t i o n fro m Sodium A z id e a n d G l a c i a l A c e t i c A c id . . . . . . . . . 5 - ( 4 * -N ltro p h e n y l)te tra z o le . . . . . . . . . . . . . (a ) P r e p a r a t i o n frc m a B en zen e S o l u t i o n o f H y d ra z o ic A c id . . . . . . . (b ) P r e p a r a t i o n frc m Sodium A z id e a n d G l a c i a l A c e tic A c id . . . . . . . . . . 5 - ( 2 ’- H y d ro x y - 4 ’- n l t r o p h e n y l ) t e t r a z o l e . . . . 53 54 54 54 55 56 The P r e p a r a t i o n o f A m in o p h e n y lte tr a z o le s . . . . . . . 56 5 - ( 3 ’- A m i n o p h e n y l) t e tr a z o le . . . . . . . . . . . . .......................... 5 - ( 4 ’- A m in o p h e n y l) t e tr a z o l e (a ) R e d u c tio n U s in g T in an d H y d ro c h l o r i c A c id ..................... (b ) R e d u c tio n U sin g P la tin u m O x id e and H y d ro g e n 5 - ( 2 ’- H y d ro x y - 4 ’- a m i n o p h e n y l ) t e t r a z o l e . . . . 56 57 D e r i v a t i v e s ..................................... 57 58 58 59 5 - ( 2 ’-A c e ty la m in o p h e n y l) t e t r a z o l e . . . . . . . 5 - ( 3 ’- A c e t y l a m i n o p h e n y l ) t e t r a z o l e . . . . . . . . . 5 - (4 ’-A c e t y l am inophe n y l) t e t r a z o l e . . . . . . . . 5 - ( 2 ’-H y d ro x y -4 ’- a c e ty la m in o p h e n y l) te tra z o le . . . . . . . . . . . . . . . . . . . . . . . . . . III. 53 53 59 60 6o 6l TETRAZOLE ANALOGUES OF NICOTINIC ACID AND OTHER PYRIDINE CARBOXYLIG A C ID S ................................................................... 62 D is c u s s io n 62 E x p e r im e n ta l .............................. The P r e p a r a t i o n o f 5 - P y r i d y l t e t r a z o l e s . . . 6? ...... 67 5 - { 2 ’- P y r i d y l ) t e t r a z o l e * ............................ 5 - ( 3 ’- P y r i d y l ) t e t r a z o l e 5 - ( 4 ’- P y r i d y l ) t e t r a z o l e . . . . . . . . . . . . . . . . . . . 2 , 6 - D i ( 5 ’- t e t r a z o l y l ) p y r l d i n o . . . . . . . . . . . . . 67 67 68 68 xl Page T he ... ... 69 ............. 5 -(2 * -P ip e rid y l)te tra z o le 5- ( 3 * - P i p e r i d y l ) t e t r a z o l e .............. ..................... 5- ( 4 » -P i p e r i d y l ) t e t r a z o l e .................. 69 70 70 P re p a ra tio n o f A c e ty lp ip e rid y lte tra z o le s . . . . 71 5 - ( 2 ’- N - A c e t y l p i p e r i d y l ) t e t r a z o l e . . . . . . . . . . 5 - ( 3 ’- N - A c e t y l p i p e r i d y l ) t e t r a z o l e . . . . . . . 5 - ( 4 ’- N - A o e t y l p i p e r i d y l ) t e t r a z o l e . . . . . . . 71 72 73 TETRAZOLE ANALOGUES OF PLANT A U X IN S............................................ 74 D is c u s s io n 74 The IV . P re p a ra tio n o f 5 -P ip e r id y lte tra z o le s . .......... E x p e r im e n ta l The P r e p a r a t i o n o f P h e n o x y a c e to n i t r i l e s 80 ........ 80 P h e n o x y a c e to n itrile .......... ...... . .... 2 -C h lo ro p h e n o x y a c e to n itrile . . . . . . . . . . . . . . 4 -C h lo rc p h e n o x y a c e to n itrile 2 , 4 -D i c h i o r ophenoxyac e t o n i t r i l e ............ 2 . 4 . 5 -T ric h lo ro p h e n o x y a c e to n itrile ............ 2 .4 .6 -T ric h lo ro p h e n o x y a c e to n itrile . . . . . . . . . . 80 80 8l 8l 82 82 Ity d ro ly s is of P h e n o x y a c e to n itr ile s . . . . . . . . . . . . 83 P h e n o x y a c e tic a c i d ................................................. 2 ,4 - P i c h l o r o p h e n o x y a c e t i c a c i d ..................... 2 , 4 , 5 - T r ic h lo r o p h e n o x y a c e t ic a c i d .................... 83 83 84 The P r e p a r a t i o n o f P h e n o x y m e th y lte tr a z o l e s . . . . . . . 84 5 - ( P h e n o x y m e th y l) te tr a z o le ..................... 5 - ( 2 ’- C h lo r o p h e n o x y m e t h y l ) te t r a z o le .. 85 5 - ( 4 ’-G h lo ro p h e n o x y m e th y l) t e t r a z o l e . . . . . . . . . 5 - (2 ’ ,4 ’-D ic h lo ro p h e n o x y m e th y l) t e t r a z o l e . . . . 5 - ( 2 * , 4 ’ ,5 ’- T r i c h l o r o p h en o x y m eth y l) te tra z o le ....................... 5 - ( 2 * ,4 * ,6 * - T r i c h lo ro p h e n o x y m e th y l)te tra z o le ................ T he P r e p a r a t i o n o f 1 -B e n z y l-5 -p h e n o x y m e th y lte tra z o le s l- B e n z y l - 5 - p h e n o x y m e t h y lte t r a z o l e .............. l - B e n z y l - 5 - ( 2 ’ , 4 ’- d ic h lo r o p h e n o x y m e th y l) te tra z o le ................................. x ii 84 85 86 87 87 88 88 88 Page l - B e n z y l - 5 - (2 ’ , 4 *, 5 ’- t r i c h l o r o p h e n o x y m e th y l)te tra z o le • • • • # • « • • • • • • * • • • • • • • • • • • • • 1 - B e n z y l- 5 - ( 2 ’ ,4 * ,6 * - t r i c h i o ro p h e n o z y me t h y l ) t e t r a z o l e ........... D e b e n z y la tlo n o f 1-B e n z y l- 5 -p h e n o x y m e th y lte tra z o le s 5 - ( P h e n o x y m e th y l) te tr a z o le 5 - (2 *,4 • , 5 ’- T r ic h lo r o p h e n o x y m e th y l) te tra z o le ........... 7. 89 89 90 90 90 A tte m p te d D é b e n z y la tio n o f l - B e n z y l - 5 - ( 2 ’ , 4 ’d ic h lo ro p b e n o x y m e th y l)te tra z o le . . . . . . . . . . . . . . . . 91 A tte m p te d D é b e n z y la tio n o f 1-B e n z y l - 5 - ( 2 ’ , 4 ’ , 6 tric h lo ro p h e n o x y m e th y l)te tra z o le . . . . . . . . . . . . . . . 91 T he P r e p a r a t i o n o f I n d o l y m e t h y l t e t r a z o l e . . . . . . . 92 5 - ( 3 ’- I n d o l y l m e t h y l ) t e t r a z o l e . . . . . . . . . . 92 DISDBSTITÜTED TETRAZOLES AS ANALOGUES OF ACTIVE BASIC E S T E R S ................................... 94 D is c u s s io n 94 E x p e r im e n ta l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3 . 4 . 5 -T rim e th o x y b e n z a m id e .................. 3 .4 .5 - T r l m e t h o x y b e n z o n l t r i l e . . . . . . . . . . . . 5 - ( 3 ’ , 4 * , 5 ’-T rIm e th o x y p h e n y l) t e t r a z o l e . . . . 2 - ( D le th y la m l n o e th y l ) - 5 - ( 3 *, 4 *, 5 t r l m e th o x y p h e n y l)te tra z o le . . . . . . . . . . . . . . 2 - (3 • - D ie th y la m ln o p r opy 1 ) - 5 - ( 3 * , 4 * , 5 * trlm e th o x y p h e n y l)te tra z o le ........... 2 - ( 3 ’-D lm e th y la m in o p l o p y l ) - 5 - ( 3 * , 4 * , 5 ’................ trim e th o x y ^ e n y l)te tr a z o le 98 98 98 99 100 100 SUMMARY......................................................... 102 APPENDIX I ....................................................................................................... 104 LITERATURE C IT E D ......................................................................................... 112 x lll LIST OF TABLES TABLE I# Page A p p a re n t pK V a lu e s o f Some 5 - A m i n o a l k y l t e t r a z o l e s a n d C o rre s p o n d in g Amino A c id s i n A queous S o l u t i o n a t 2 5 °C .............................................................................................................. x iv 17 INTRODUCTION I n many I n s t a n c e s th e s u c c e s s o f c h e m o th e ra p y i n t h e t r e a t m e n t o f b o th i n f e c t i o u s a n d n o n i n f e c t i o u s d i s e a s e s d e p e n d s upon an a n ta g o n is m b e tw e e n th e c h e m o th e r a p e u tic a g e n t u s e d an d a m e t a b o l i t e o f th e p a r a s i t i c o rg a n is m o r f o r e i g n s u b s ta n c e s i n t h e p a t i e n t ' s s y s te m . S in c e s y n t h e s i s and u t i l i z a t i o n o f m e t a b o l i t e s o r m e ta b o l ic p r o d u c t s a r e e s s e n t i a l t o t h e m a in te n a n c e and p r o d u c t i o n o f l i v i n g c e l l s , an y i n t e r f e r e n c e w ith t h e s e p r o c e s s e s w o u ld r e s u l t i n th e d e a t h o f t h e o r g a n is m . One o f t h e d i r e c t m e th o d s o f a n ta g o n is m in v o l v e s c o m p e t i t i v e i n ­ h i b i t i o n o f an enzym e o r t i s s u e r e c e p t o r a s s o c i a t e d w ith a m e t a b o l i t e by a s t r u c t u r a l l y r e l a t e d a n t a g o n i s t . The re s e m b la n c e o f th e a n t a g o n i s t t o t h e m e t a b o l i t e may b e th ro u g h a g e n e r a l o v e r a l l s h a p e o f t h e m o le c u le o r th e s i m i l a r i t y may b e m ore r e f i n e d a n d r e q u i r e t h e p r e s e n c e o f one o r m ore f u n c t i o n a l g r o u p s p r o p e r l y s p a c e d w i t h i n t h e s tru c tu re . T h e se f u n c t i o n a l g r o u p s a r e b e l i e v e d t o b e c a p a b le o f a s s o c i a t i n g w i t h t h e p r o s t h e t i c o r r e a c t i v e g ro u p o f th e enzyme n o r m a lly a v a i l a b l e f o r th e m e t a b o l i t e . One o f th e m o st o u t s t a n d i n g a n d w e ll known e x a m p le s o f s t r u c t u r a l a n ta g o n is m a p p l i e d i n c h e m o th e ra p y i s t h a t shown f o r b a c t e r i a l p a r a a m in o b e n z o ic a c i d by p a r a - a m in o b e n z e n e s u lfo n a m id e . I t is s u g g e s te d t h a t th e i n h i b i t i o n o f th e u t i l i z a t i o n o f p a r a - a m in o b e n z o ic a c i d i n b a c t e r ia p re v e n ts i t s in c o rp o ra tio n in to f b lic a c id , a v i t a l l y needed com p o n en t f o r g ro w th a n d r e p r o d u c t i o n . 2 B e c a u s e o f t h e a c i d i c n a t u r e o f 5 - n io n o s u b s titu te d t e t r a z o l e s ( 1 ,2 ,3 ) i t a p p e a r e d t h a t t h e i n v e s t i g a t i o n o f su c h com pounds a s p o s s ib le a n tim e ta b o lite s f o r c e r ta in p h y s io lo g ic a lly a c tiv e c a rb o x y lic a c i d s m ig h t p ro v e f r u i t f u l * T h is i s t h e f i r s t r e p o r t e d i n s t a n c e vdiere 5 - m o n o s u b s t i t u t e d t e t r a z o l e s h a v e b e e n p r e p a r e d a s a n a lo g u e s o f b i o ­ l o g i c a l l y a c tiv e c a rb o x y lic a c id s . A c c o r d i n g ly , th e p r e s e n t woik i n v o l v e s t h e s y n t h e s i s o f t e t r a z o l e s m o d e le d a f t e r v a r i o u s c l a s s e s o f m e ta b o lic a n d p h y s i o l o g i c a l l y a c t i v e a c i d s a n d d e r i v a t i v e s i n v h ic h t h e c a r b o x y l g ro u p i s r e p l a c e d by a t e t r a z o l y l g ro u p s u b s ti t u t e d in th e 5 p o s it io n . c la rity F o r c o n v e n ie n c e and th e d i s c u s s i o n and e x p e r im e n t a l a r e d i v i d e d i n t o th e c l a s s e s o f c a r b o x y l i c a c i d s u s e d a s m o d e ls f o r th e t e t r a z o l e s y n th e s e s a s fo llo w s : P a rt 1. T e t r a z o l e A n a lo g u e s o f Amino A c id s . P a rt I I . T e t r a z o l e A n a lo g u e s o f A c tiv e Ami nob e n z o ic A c id D e riv a tiv e s . P a r t I I I . T e t r a z o l e A n a lo g u e s o f N i c o t i n i c A c id an d O th e r P y r i d i n e C a r b o x y lic A c id s . P a r t IV . T e t r a z o l e A n a lo g u e s o f P l a n t A u x in s . P a rt Di s u b s t i t u t e d T e t r a z o l e s a s A n a lo g u e s o f A c t iv e B a s ic V. E s te rs . HISTORICAL M o n o s u b s titu te d t e t r a z o l e s w i t h th e s u b s t i t u e n t i n th e 5 p o s i t i o n h a v e b e e n p r e p a r e d fro m n i t r i l e s b y a v a r i e t y o f p r o c e d u r e s . T he c o n ­ v e r s i o n o f a r y l c y a n id e s t o 5 - a r y l t e t r a z o l e s b y way o f th e im ln o e t h e r s , a m id ra z o n e s a n d im ide a z i d e s i n a s t e p w is e m an n er was d e v e lo p e d b y P i n n e r (4 ) a n d may b e i l l u s t r a t e d s c h e m a t i c a l l y a s fo llo w s : ArCN G^HcOH ---------------- A r—C HCl ^NoHo A r-C ^ 'H C l ^N H >^^2^5 N ;^ 4 '^NH*HC1 NaNOn ------------------- /N o A r-C ^ A r-G -------- N—H II I I t h a s a l s o b e e n shown t h a t 5 - a r y l t e t r a z o l e s may b e p r e p a r e d i n a c o n v e n ie n t m anner and i n e x c e l l e n t y i e l d s th r o u g h t h e r e a c t i o n o f a r y l c y a n id e s w i t h e q u i v a l e n t am o u n ts o f sodium a z id e an d g l a c i a l a c e t i c a c i d i n r e f l u x i n g n o rm a l b u t y l a l c o h o l ( 3 ) . 4 T he f o r m a ti o n o f e i t h e r 5 - a l k y l o r a r y l t e t r a z o l e s h a s b e e n r e ­ p o r t e d b y M ih in a a n d H e r b s t (2 ) t o p ro c e e d i n a s i n g l e s t e p fro m th e r e s p e c t i v e c y a n id e s b y h e a t i n g t h e n i t r i l e w ith a b e n z e n e s o l u t i o n o f h y d r a z o ic a c i d i n a s e a l e d t u b e . T h i s i s b e l i e v e d t o p r o c e e d th r o u g h t h e im ide a z i d e a s f o l l o w s : RON + HN^ R -G ^ •NH ». R -C -------- N-H II I M ore r e c e n t l y a v a r i e t y o f 5 - s u b s t i t u t e d t e t r a z o l e s h a v e b e e n p re p a r e d by r e a c t i o n o f th e cy an o compound w ith an e x c e s s o f alum inum a z i d e , g e n e r a t e d i n s i t u fro m alum inum ( d ilo r id e and sodium a z i d e i n re flu x in g te tra h y d ro fu ra n . (5) PART I TETRAZOLE ANALOGUES OF AMINO ACIDS D is c u s s io n N um erous e x a m p le s o f m e t a b o l i t e a n ta g o n is m h a v e b e e n r e p o r t e d f o r com pounds w h ic h a r e a n a lo g u e s o f n a t u r a l l y o c c u r r i n g o t-a m in o a c id s * One o f th e m o st th o r o u g h ly i n v e s t i g a t e d o f t h e s e am ino a c i d s i s p h e n y la la n in e ( I ) . V a r io u s c h a n g e s i n i t s m o le c u la r s t r u c t u r e h av e NH2 // \-r!H ^G H G 02H I b e e n show n t o tr a n s f o r m i t i n t o a n a n t a g o n i s t o f th e n a t u r a l l y o c c u r r ­ i n g p h e n y l a l a n i n e i n b a c t e r i a l g ro w th . Among t h e s e c h a n g e s s u f f i c i e n t t o r e v e r s e t h e n u t r i t i o n a l e f f e c t o f t h i s am ino a c i d a r e t h e i n t r o ­ d u c t i o n o f a n am ino g ro u p ( I I ) (6 ) o r a f l u o r o g ro u p ( I I I ) (7) p a r a t o t h e a l a n i n e m o ie ty i n th e b e n z e n o id p o r t i o n o f th e s t r u c t u r e . // // % I NVcHoCHCOpH NH2 I I I : R= F S u b s t i t u t i o n o f c e r t a i n h e t e r o c y c l i c r i n g s f o r th e p h e n y l g r o u p , s u c h a s 2 - p y r i d y l (IV ) 2 - p y r r y l (V II) ( 8 ) , 2 - t h i e n y l (V) ( 9 ) , 2 - f u r y l (V I) ( 1 0 ) , an d (1 1 ) h a s a l s o r e s u l t e d i n a n a lo g u e s w h ich h a v e a m2 V: R s IV : R s RGH2CHCO2H N V I I : R= V I: R= N' H • p e c i f l c a n ta g o n is m f o r p h e n y la la n in e * A n t i m e t a b o l i t e s f o r t r y p t o p h a n e , an e s s e n t i a l am ino a c id f o r m an, a r e fo u n d i n 5 - m e th y ltr y p to p h a n e (1 2 ) an d y ( 9 - in d o l e a c r y lic a c i d ( V I I I ) (1 3 ). .CH=CHC02H 1 I H v rii T h e se c h a n g e s n e c e s s a r y t o d e v e lo p a n t i m e t a b o l i t e a c t i v i t y a r e n o t r e s t r i c t e d t o any one p o r t i o n o f t h e am ino a c id s t r u c t u r e ; r e p la c e m e n t o f t h e o a r boxy g ro u p b y a s u l f o n i c a c i d r e s i d u e h a s l e d t o th e s y n t h e s i s o f a n a lo g u e s o f g l y c i n e , v a l i n e , a l a n i n e and l e u c i n e ( 1 4 ) . I n some c a s e s t h e s e am ino s u l f o n i c a c i d s h a v e shown s p e c i f i c i n h i b i t i o n o f t h e u s e o f th o s e am in o a c i d s o f w hich th e y w e re th e a n a lo g u e s a s m e a s u re d b y b a c t e r i a l g ro w th ( 1 4 ) . 7 I t a p p e a re d f r u i t f u l , t h e r e f o r e , i n v ie w o f t h i s e n c o u r a g in g e v i d e n c e , t o p r e p a r e a n a lo g u e s o f n a t u r a l l y o c c u r r i n g am ino a c i d s i n w h ic h a t e t r a z o l y l g ro u p was s u b s t i t u t e d f o r t h e c a rb o x y g ro u p a s t h e a c i d i c p o r t i o n o f th e am ino a c i d m o le c u le . F iv e d i f f e r e n t am ino a c i d a n a lo g u e s w e re p r e p a r e d : o f g l y c i n e , D ,L - a l a n i n e , try p to p h a n e . t h e a n a lo g u e s /3 -a Q .a n in e , D ,L - p h e n y la la n in e a n d D ,L - The s y n t h e s i s o f e a c h a m in o a lk y lt e t r a z o l e , w i t h t h e e x c e p t i o n o f t h e t r y p t o p h a n e a n a lo g u e , w as c a r r i e d o u t by two d i f f e r e n t m e th o d s , m aking i t p o s s i b l e t o c o r r o b o r a t e t h e s t r u c t u r e o f th e f i n a l p r o d u c t fro m one s e q u e n c e o f r e a c t i o n s b y a s e c o n d u n e q u iv o c a l s y n th e s is . O th e r a d v a n ta g e s o f u s in g c e r t a i n s p e c i f i c s y n t h e t i c m e th o d s w i l l b e m e n tio n e d i n t h e d i s c u s s i o n o f t h a t s p e c i f i c schem e o f p re p a ra tio n . The t h r e e g e n e r a l m e th o d s u s e d i n t h e p r e p a r a t i o n o f th e 5 -a m in o a l l Q ^ l t e t r a z o l e s a r e d e s i g n a t e d , f o r s i m p l i c i t y , schem es A, B a n d C a s fo llo w s : Scheme A T h is s e q u e n c e o f s te p w is e c o n v e r s io n s in v o lv e d th e i n i t i a l r e ­ a c t i o n o f an o c -h a lo a m id e . o c - h a lo a c y l h a l i d e w it h b e n z y la m in e fo rm in g th e N - b e n z y lS u b s e q u e n t c o n v e r s io n o f th e o o -h a lo a m id e w ith p h o s ­ p h o r u s p e n t a c h l o r i d e t o th e im in o c h l o r i d e f o llo w e d b y t r e a t m e n t w ith h y d r a z o ic a c i d g a v e r i s e t o a 1 -b e n z y 1 -5 - oc - h a l o a l k y 1 t e t r a z o l e . The h a l o a l k y l t e t r a z o l e w as th e n c a u s e d t o r e a c t w i t h p o ta s s iu m p h t h a l i m l de fo rm in g t h e l - b e n z y l - 5 - o o - p h t h a l i m i d o a l k y l t e t r a z o l e . irrita tin g B e c a u se o f th e e f f e c t s o f th e © c - h a l o a l k y l t e t r a z o l e s on t h e mucous a m em branes i t mas fo u n d m ore a d v a n ta g e o u s t o f i r s t foxm t h e ©c- p h th a lim id o a m id e fro m p o ta s s iu m p h th a l im id e a n d t h e © c -h a lo a m id e . The p r o d u c t w as t h e n t r e a t e d w i t h p h o s p h o ru s p e n t a c h l o r i d e a n d h y d r a z o ic a c id * T h e s e s e q u e n c e s o f r e a c t i o n s may b e r e p r e s e n t e d s c h e m a t i c a l l y a s fo llo w s : I 9 R"“CHC>*X -{- R—CHCNHCH2C^5 1 . P C li K R (0 0 )2 C ^ ^ R-CH-C- II 2 . HN, N. N "N N-CH-0 1 . PC I 2 . HN. or I 9 R-GHGNHCH2C^5 ZK (C0)2C6P4 --------------------- ^ T he p h t h a l y l r e s i d u e w as c o n v e n i e n t l y rem oved frc m t h e 1 -b e n z y l5 - o d - p h t h a l i m i d o a l k y l t e t r a z o l e by t r e a t m e n t w it h h y d ra z in e * The r e ­ s u l t i n g l - b e n z y l - 5 - o C - a m i n o a l k y l t e t r a z o l e w as i s o l a t e d a s th e h y d ro ­ c h lo rid e * T r e a tm e n t o f th e l - h e n z y l - 5 - o ^ -a m in o a llîy lt e t r a z o l e w it h h y d ro g e n i n t h e p r e s e n c e o f p a lla d iu m on c h a r c o a l e f f e c t e d d é b e n z y l a t i o n o f t h e compound* L i b e r a t i o n o f t h e 5 - ■ HCl R 1 CÆrO^CC-C-------- K-H ^ ^ R N .N I 11 I E i t h e r a s te p w is e h y d r o l y s i s o f th e f u n c tic a n a l g r o i n s o r a s i n g l e s t e p a c id h y d r o l y s i s g a v e r i s e t o d i e • c - a m in o a c i d a n a lo g u e . T h i s r o u t e t o 5 - ^ C - a m i n o a l k y l t e t r a z o l e s o f f e r s a minimum num ber o f s t e p s and m akes u s e o f i n t e r m e d i a t e com pounds common t o a n in o a c i d s y n th e s is . The s y n t h e s i s o f d ie i n d i v i d u a l am ino a c i d a n a lo g u e s i s i n t h e r e m a in in g p o r t i o n o f t h i s c o n s id e r e d d i s c u s s i o n ; m e n tio n i s made o f any n o te w o r th y d i f f e r e n c e s o r a n o m a lie s i n t h e r e a c t i o n se q u e n c e o r i n t h e i s o l a t i o n o f th e f i n a l p r o d u c t . 5-oC -Ami n o m e th y l t e t r a z o l e - The ^ y c i n e a n a lo g u e was c o n v e n ie n t ly p r e p a r e d by schem e A and schem e B. S in c e g l y c i n e I s n o t o p t i c a l l y a c t i v e th e p u r s u i t o f schem e B s t a r t i n g fro m th e am ino a c i d o f f e r e d no a d v a n ta g e o v e r s t a r t i n g fro m some m ore e a s i l y a v a i l a b l e i n t e r m e d i a t e . F o r t h i s r e a s o n th e s y n t h e s i s o f 5 - 06-a m in o m e th y lt e t r a z o l e by schem e B was i n i t i a t e d w ith p h t h a l i m i d o a c e t o n i t r i l o p r e p a r e d b y th e a l k y l a t i o n o f p o ta s s iu m p h th a lir a id e w ith c h l o r o a c e t o n i t r i l e . D .L - 5 - o C - A m in o e th y lte tr a z o le - The s y n t h e s i s o f th e t e t r a z o l e a n a lo g u e o f D ,L - a la n in e fro m o c -b ro m o p ro p io n y l b ro m id e was e f f e c t e d u s i n g schem e A and fro m D ,L - a la n i n e a c c o r d i n g to schem e B . I n t h e s y n t h e t i c r o u t e f o llo w in g schem e A d i f f i c u l t i e s e x p e r ie n c e d 13 i n h a n d l i n g th e lo w m e l t i n g , mucous membrane i r r i t a t i n g o C - c h lo r o m e th y lte tra z o le i n th e g l y c i n e a n a lo g u e s y n t h e s i s p ro m p ted t h e c o n ­ v e r s i o n o f t h e N -b e n z y l-o C -b ro m o p ro p io n a m id e i n t o t h e N -benzyl-e> C p h th a lim ld o p r o p io n a m id e and t h i s s u b s e q u e n tly I n to l - b e n z y l- 5 - o O p h th a lim id o e th y lte tra z o le , Im lo a lk y lte tra z o le . t h e r e b y a w i d in g th e f c r m a tio n o f t h e ©c- The r e m a in in g r e a c t i o n s i n t h i s s e r i e s w ere c a r r i e d o u t w i t h o u t f u r t h e r d e p a r t u r e fro m th e s e q u e n c e a s p r e v i o u s l y d i s c u s s e d . 5-yS - A m in o e t h y l t e t r a z o i e - The a n a lo g u e o f - a l a n i n e was sy n ­ t h e s i z e d f o ll o w i n g t h e p r o c e d u r e s o f schem e A an d scheme B . D u rin g p r e p a r a t i o n o f th e p r o d u c t b y schem e A, t h e r e a c t i o n o f N - b e n z y l- ^ - b r o m o p r o p io n a m id e w ith p o ta s s iu m p h th a li m i d e was fo u n d to r e s u l t i n d e h y d r o h a lo g e n a ti on o f th e /9 - h a lo a m id e . The n e c e s s a r y a d a p t a t i o n In t h a t p o r t i o n o f t h e s y n t h e s i s t o c o m p e n sa te f o r t h i s d i f f i c u l t y c o n s i s t e d i n t r e a t i n g th e a c i d c h l o r i d e o f p h th a ly l-y < 3 a l a n i n e w i t h b e n z y l ami ne to form N -b e n z y l-y g - p h t h a l im i d o p ro p i onam l de . The s u b s e q u e n t r e a c t i o n s in v o lv e d i n schem e A w ere f o l l o w e d w i th o u t f u r t h e r changes. S y n t h e s i s o f t h e f i n a l p r o d u c t f o llo w in g schem e B was c a r r i e d o u t s ta rtin g fro m / 3 - p h t h a l i m i d o p r o p i o n i t r i l e , o b ta in e d by th e c y a n o - e t h y l a t i o n o f p h th a lim id e w ith a c r y l o n i t r i l e . T he r e m a in d e r o f th e s y n t h e s i s was e f f e c t e d u s i n g t h e s te p w is e c o n v e r s io n s p r e v i o u s l y d i s ­ cu ssed fo r th is i^ n th e tic ro u te . C o m p a riso n o f t h e f i n a l p r o d u c ts from e a c h schem e o f p r e p a r a t i o n f o r t h e g l y c i n e , D ,L - a la n in e , and - a l a n i n e a n a lo g u e s was made by m e l t i n g p o i n t an d m ix tu r e m e lt in g p o i n t . u T he a n a lo g u e s th u s f a r m e n tio n e d w e re s o l i t i l e i n w a te r , a q u e o u s a c i d s an d a q u e o u s a l k a l i e s and e x h i b i t e d h ig h m a ltin g p o i n t s a cc o m p a n ie d by d e c o m p o s itio n * The a m i n o a l k y l t e t r a z o l e s a r e i n s o l u b l e i n a c e t o n e , e t h a n o l an d n o n - p o l a r s o l v e n t s . U s in g m eth o d s a p p l i c a b l e t o t h e c h a r a c t e r i z a t i o n o f am ino a c i d s , th e a c e t y l , b e n z o y l and p h e n y lu r e a d e r i v a t i v e s w e re p r e p a r e d . 5-oC-Ami n o p h en y l e t h y l t e t r a z o l e - Schem es B an d C w e re u s e d a s t h e s y n t h e t i c r o u t e s f o r th e p r e p a r a t i o n o f t h e p h e i y l a l a n i n e a n a lo g u e . T he i n t e r m e d i a t e p r o d u c t, e t h y l o 6 - a c e ta m id o - o C - ( 5 “ t e t r a z o l y l ) - p h e n y l p r o p l o n a t e , o b t a in e d b y f o llo w in g schem e C, was s u b j e c t e d t o b o th s te p w is e d e g r a d a t i o n a n d s i n g l e s t e p a c i d h y d r o l y s i s . NHCOCH' NHCOCH' H^O -N-H N HOgC N^ -CO' H^O NHCOCH' NH. (CH^C0)20 C^^5CH20HC' N, N-H I N C^^CH^CH—C- N-H I N N. N 15 S i m i l a r p r o d u c t s p r e p a r e d b y schem e B o r schem e C w ere shown to b e i d e n t i c a l b y m e l t i n g p o i n t a n d m ix tu r e m e ltin g p o i n t d e te r m in a tio n s * T he D ,L - p h e n y la la n ln e a n a lo g u e w h ic h p o s s e s s e d a h ig h m e ltin g p o i n t a c c o m p a n ie d b y d e c o m p o s itio n w as s o l u b l e i n a q u e o u s a c i d s and a q u e o u s a l k a l i e s and in s o lu b le i n e th a n o l an d n o n - p o l a r s o lv e n t s * I t was s o l u b l e i n h o t w a t e r a n d c r y s t a l l i z e d a s t h e s o l u t i o n was c o o le d * The a c e t y l , b e n z o y l and p h e n y lu r e a d e r i v a t i v e s w e re u s e d to c h a r a c t e r i z e t h e 5- o C - a m in o p h e n y le th y l te tr a z o le * 5 - ( o6 - A m i n o * - i n d o l y l ) e t h y l ) t e t r a z o l e - Scheme C was t h e o n ly s y n t h e t i c r o u t e u s e d f o r th e p r e p a r a t i o n o f th e tr y p t o p h a n e a n a lo g u e * The p r o d u c t fo rm ed fro m th e r e a c t i o n o f e t h y l o C -a ce ta r a id o o C - c y a n o - ^ - ( 3- i n d o l y l ) p r o p i o n a t e w ith alum inum a z i d e was d e g ra d e d t o th e t r y p t o p h a n e a n a lo g u e i n a s te p w is e m an n er u s i n g sodium h y d r o x id e a s r e p r e s e n t e d s c h e m a t i c a l l y below * NHGOGH3 NHGOCH C H ^C -C - CS.2p“0 CoH 2^5 NHCOCH, C H oC H -C -------- N -H II I H 20 N -H 16 I n a n a tte m p t t o f u r t h e r s u b s t a n t i a t e th e s i m i l a r i t y o f 5 a l k y l a m i n o t e t r a z o l e s t o 5 - -a m in o e th y l)te tra z o le m e th y l t e t r a z o l e > 5 -(o c -a m in o - ^ - p h e n y l e t h y l ) t e t r a z o l e . > 5 -a m in o ­ T h is o r d e r p a r a l l e l s t h a t i n t h e am ino a c i d s e r i e s w ith o u t e x c e p tio n * E x a m in a tio n o f th e pK^ v a l u e s show s a s i m i l a r p a r a l l e l o r d e r i n t h e b a s i c i t y o f t h e a n in o g ro u p o f th e ami no a l k y l t e t r a z o l e s a s com pared t o t h e am ino g ro u p o f t h e am ino a c i d s . ( y 3 - a m in o e th y l) t e t r a z o l e T he v a lu e s d e c re a se in th e c r d e r: > 5-(•=<'-a m i no e t h y l ) t e t r a z o l e 5- ^ 5 -a m in o - m e th y lte tra z o le y 5 - (^ - a m in o -^ -p h e n o th y l) te tr a z o le * T h e s e r e s u l t s a r e sum m arized i n T a b le I and t h e d a ta a r e c o l l e c t e d i n A p p e n d ix I* 17 TABLE I APPARENT pK VALUES OF SOME 5-AI.ILNQALOLTETRAZOLES AND CORRESPONDING AMINO ACIDS IN AQUEOUS SOLUTION AT 25®C, T e tra z o le Amino A c id ^ A n alo g u e pK^ 8 .5 4 G ly c in e 2 .3 4 9 .6 0 2 .6 3 8 .7 7 D ,L -A la n in e 2 .3 4 9 .6 9 5 - fè -A m in o e th y l 3 .9 9 9 .5 8 /3 - A la n in e 3 .6 0 1 0 .1 9 5- 1 .9 3 8 ,1 8 D ,L - H ie n y la la n in e 1 .8 3 9 .1 3 pK i pK^ 5-Aminome t h y l 2 .6 2 5 - oC -A m inoethyl -A m ino—/3 p h e n y le th y l pK v a l u e s f o r t h e am in o a c i d s w e re o b t a i n e d fro m r e f e r e n c e ( 2 8 ) . 1 2 E s c p e rlm e n ta l ' The P r e p a r a t i o n o f 5 - A m in o m e th y lte tr a z o le (G ly c in e A n a lo g u e ) Scheme A, (a ) N—B e n z y l - oc- c h lo r o a c e ta m i de * C h lo ro a c e ty lc h lo rid e (1 0 0 g . , 0 .8 8 m o le ) w as s lo w ly a d d e d t o l 8 8 , 5 g* ( 1 .7 6 m o le s) o f b e n z y la m in e d i s s o l v e d i n 1 l i t e r o f b e n z e n e . A f t e r t h e a d d i t i o n was c o m p le te t h e m ix tu r e w as s t i r r e d o v e r n i ^ t . The r e a c t i o n m ix tu r e was t h e n f i l t e r e d , th e s o l i d s u sp e n d e d i n w a t e r and a g a in f i l t e r e d . The b e n z e n e s o l u t i o n was c o n c e n t r a t e d to a sm a U volum e, c h i l l e d and filte re d . T h is s o l i d w as co m b in ed w i t h th e w a t e r i n s o l u b l e m a t e r i a l an d th e com bined p r o d u c t r e c r y s t a l i i z e d fro m b e n z e n e . (6 6 ^ o f th e o r y ) T h i s g a v e 106 g . o f N - b e n z y l- o C - c h lo r o a c ta m id e , m .p . 92-93*5*^0, T h i s compound i s r e p o r t e d by J a c o b s an d H e i d e l b e r g e r (15) t o h a v e a m e ltin g p o i n t o f 9 3 .5 - 9 4 * 5 ^ 0 . (b) l- B e n z y l - 5 - c h l o r o i a e t h y l t e t r a z o l e . To 9 8 .6 g . (0 .5 4 3 m o le) o f N -b e n z y l c h lo r o a c e ta m id e su sp e n d e d i n 1 l i t e r o f b e n z e n e was a d d ed i n p o r t i o n s 113 g . (0*543 m o le ) o f p h o s p h o ru s p e n t a c h l o r i d e . The m ix tu r e w as a llo w e d t o s t i r a t room te m p e r a tu r e f o r s i x h o u r s a f t e r w h ic h i t ^ M ic r o a n a ly s e s by M ic ro -T e c h L a b o r a t o r i e s , S k o k ie , I l l i n o i s . 2 M e ltin g p o i n t s w e re ta k e n i n o p en c s p i l l a r y c o rre c te d * tu b e s a n d a r e un ­ 19 w as c o n c e n t r a t e d t o a volum e o f 500 m l. u n d e r r e d u c e d p r e s s u r e . t h e c o n c e n t r a t e d s o l u t i o n 3 8 .1 g . (0 .8 8 5 m o le) o f h y d r a z o ic a c i d i n 300 m l, o f x y le n e was a d d e d w ith c o o l i n g . to To A f t e r a llo w in g th e m ix tu r e s t i r o v e r n i g h t a t room t e m p e r a t u r e i t was h e a te d to r e f l u x tem p­ e r a t u r e u n t i l h y d ro g e n c h l o r i d e e v o l u t i o n c e a s e d . R em oval o f th e s o l v e n t u n d e r vacuum l e f t a t h i c k s y ru p to w h ic h w as a d d e d 500 g . o f i c e and w a t e r . F i l t e r i n g g a v e a brow n s o l i d w hich was f u r t h e r p u r i f i e d by r e c r y s t a l l i z a t i o n fro m a n i s o p r o p y l s ü .c o h o l-n o rm a l h e p ta n e m ix tu r e . The p r o d u c t w eig h ed 5 5 .2 g . (495^ o f t h e o r y ) and m e lte d a t 6 6 - 6 ? . 5 ° 0 . T h i s com pound i s d e s c r i b e d by H a r v i l l , H e r b s t an d S c h r e i n e r ( l 6 ) , who r e p o r t e d t h e m e l t i n g p o i n t as 67-68® C . (c ) l - B e n z y l - 5 - p h t h a l i m i dome t h y l t e t r a z o l e . A m ix tu r e o f 21 g . ( 0 .1 m o le ) o f l - b e n z y l - 5 - c h l o r o m e t h y l t e t r a z o l e a n d 21 g . ( 0 .1 1 4 m o le) o f p o ta s s iu m p h th a lim id e was r e f l u x e d t o g e t h e r i n 250 m l. o f d r y x y le n e f o r fiv e h o u rs. filtra te 2 6 .4 g . c o o le d . The h o t s o l u t i o n was f i l t e r e d w ith s u c t i o n and th e The p r e c i p i t a t e , w h ic h was f i l t e r e d an d d r i e d , w eig h ed (8 3 ^ o f t h e o r y ) . The p r o d u c t w as f u r t h e r p u r i f i e d by r e c r y s t a l l i o z a t i o n fro m t o l u e n e , m .p . 1 3 2 -1 3 3 0 . A n a ly s is , Found; (d ) C a lc u la te d fo r C, 6 3 .9 4 ; H, 4 .1 0 ; N , 2 1 .9 3 . C, 6 4 .0 7 ; H , 4 . 2 3 ; N, 2 2 .1 6 . 1 -B e n zy l-5 -e u ain o m e t h y l t e t r a z o l e H y d r o c h lo r i d e . To 1 0 .6 g . (0 .0 3 3 m o le ) o f l - b e n z y l - 5 - p h t h a l im i dome t h y l t e t r a z o le s u sp e n d e d i n 120 m l. o f a b s o l u t e e t h a n o l was ad d ed 33 m l. o f a o n e m o la r s o l u t i o n o f h y d r a z i n e h y d r a t e i n e t h a n o l (0 .0 3 3 m o le ) and t h e r e s u l t i n g m ix tu r e r e f l u x e d w ith c o n tin u e d s t i r r i n g f o r t h r e e h o u r s . The m ix tu r e was t h e n 20 e v a p o r a te d t o d r y n e s s and t r e a t e d w ith 75 m l. o f a 2N h y d r o c h l o r i c a c i d f o r te n m in u te s a t 50°G . filtra te The r e s u l t i n g s u s p e n s io n was f i l t e r e d an d t h e e v a p o r a te d to d r y n e s s . R o c r y s t a l l i z a t i o n o f th e r e s i d u a l s o l i d fro m a n i s o p r o p y l a l c o h o l w a t e r m ix tu r e g a v e 4 .0 g . (5 3 ^ o f th e o r y ) o f t h e p r o d u c t , m .p . 2 2 8 - 229^0 . A n a ly s is . N, 3 1 .0 4 . (e ) C a l c u l a t e d f o r C^H^^CIN^: Found: C, 4 8 . l l ; H, 5 .2 5 ; 0 1 , 1 5 .7 1 ; N, 3 1 . 1 6 . 5-Aminome t h y l t e t r a z o l e . d ro c h lo rid e C, 4 7 .9 0 ; H, 5 .3 6 ; C l, 1 5 .7 1 ; 1 -B e n z y l-5 -a m i n o m e th y l t e t r a z o l e h y ­ (1 0 .5 g . , 0 ,0 4 7 m ole) was d i s s o l v e d i n a m ix tu r e o f 2 0 0 m l. o f a b s o l u t e e t h a n o l and 30 m l. o f w a t e r . A f t e r a d d i t i o n o f 2 .5 g . o f 5% p a lla d iu m on c h a r c o a l t h e m ix tu r e was Ë iak e n i n a h y d ro g e n a tm o s p h e re a t a i i n i t i a l p r e s s u r e o f 47 p . s . i , and h e a te d t o m a i n t a i n a te m p e r a t u r e o f 60^C , A f t e r t w e n t y - f o u r h o u r s tb a c a t a l y s t was rem oved by f i l t r a t i o n a n d th e f i l t r a t e e v a p o r a te d to d r y n e s s i n v a c u o . T h is g a v e 6 . 2 g . (9 7 ^ o f th e o r y ) o f th e c r u d e am ine h y d r o c h l o r i d e . The c ru d e 5 -suninom©t h y l t e t r a z o l e h y d r o c h l o r id e ( 6 ,1 g . , 0 .0 4 5 m o le) was d i s s o l v e d i n 100 m l. o f a b s o l u t e e t h a n o l to w h ich was th e n a d d e d 3 .5 6 g . (0 .0 4 5 m ole) o f p y r i d i n e . On a llo w in g th e s o l u t i o n to s t a n d i n a n i c e c h e s t o v e r n i ^ t t h e r e was d e p o s i t e d 3 . 8 g . c ry s ta llin e s o lid . ( 85^ o f th e o r y ) o f a T h e p r o d u c t was f u r t h e r p u r i f i e d b y d i s s o l v i n g i t i n a s m a ll am ount o f w a te r a n d a d d in g enough a b s o l u t e e t h a n o l t o g iv e a 95^ e th a n o l s o lu tio n . T h i s s o l u t i o n was a llo w e d t o s t a n d i n an i c e c h e s t o v e r n i g h t a llo w in g th e p u r e p r o d u c t to s e p a r a t e , m .p . 267*^0., w ith decompo s i t i on. 21 A n a ly s is . Found: C a lc u la te d f o r G, 2 4 .2 4 ; H, 5 .0 9 ; N, 7 0 .6 8 . C, 2 4 .4 9 ; H, 5 .1 7 ; N, 7 0 .5 5 . Schem e B. (a ) P h th a lim ld o a c e to n itrile . P o ta s s iu m p h th a lim id e (1 1 0 .4 g . , 0 .6 m ole) w as a d d ed to 4 5 0 m l. o f d i s t i l l e d dim e t h y l foim am i de c o n t a i n i n g 4 0 .8 g . ( 0 .5 4 m o le) o f c h l o r o a c e t o n i t r i l e . s o l u t i o n was s t i r r e d The r e s u l t i n g w in e c o lo r e d a t room t e m p e r a t u r e f o r one h o u r a n d th e n a t s te a m h a t h t e m p e r a t u r e f o r tw o h o u r s . T he r e s u l t i n g m ix tu r e was t r a n s f e r r e d t o a t h r e e l i t e r b e a k e r a n d 600 m l. o f c h lo ro fo r m a d d e d f o llo w e d by 1 5 0 0 m l, o f w a t e r . The o r g a n i c l a y e r was s e p a r a t e d an d t h e a q u e o u s p o r t i o n w ashed w ith a n a d d i t i o n a l 300 m l. o f c h lo r o f c r m . The two o r g a n ic l a y e r s w e re t h e n co m b in ed , w ashed w i t h 300 m l. o f 0 . 2 N sodium h y d r o x id e s o l u t i o n and t h e n w it h 300 m l. o f w a t e r . E v a p o r a tio n o f t h e c h lo r o f o r m a f t e r d r y in g th e s o l u t i o n w it h so d iu m s u l f a t e , g a v e a s o lid re s id u e . R e c r y s t a l l i z a t i o n o f th e p r o d u c t g a v e 7 0 ,8 g , ( 6 3 .5 ^ o f th e o r y ) o f a c o l o r l e s s c r y s t a l l i n e m a t e r i a l m e lt in g a t 1 2 7 .5 - 1 2 8 .5 ^ 0 . A n a ly s is , C a lc u la te d f o r N, 1 5 .0 5 . Found: N, 1 5 .3 2 . T h is compound i s r e p o r t e d b y S onn a n d F a lk e n h e im (17) t o m e lt a t ia ;-i 2 5 °c. (b) 5 - (P h th a lim ld o m e th y l)te tra z o le . To 4 6 .5 g . (0 .2 5 m o le) o f p h t h a l i m i d o a c e t o n i t r i l e and 50 g . o f sodLura a z i d e s u sp e n d e d i n 100 m l. o f d iy t e t r a h y d r o f u r a n was a d d ed 35 g . (0 ,2 6 m o le ) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 300 m l, o f t h e same s o l v e n t . The m ix tu r e was th e n h e a t e d a t r e f l u x te m p e r a t u r e f o r t w e n t y - f o u r h o u r s 22 w i t h c o n tin u o u s s t i r r i n g . A t t h e end o f t h i s tim e th e t e t r a h y d r o f u r a n w as d i s t i l l e d o u t o f th e r e a c t i o n m ix tu r e an d w a te r a d d e d a t su c h a r a t a t h a t t h e volum e re m a in e d c o n s t a n t . The r e s u l t i n g r e s i d u a l s u s ­ p e n s io n w as c o o le d an d t h e s o l i d f i l t e r e d . The s o l i d was i n t u r n s u s ­ p e n d e d i n 450 ml# c f w a te r to w h ic h w as th e n a d d e d 50 m l. o f c o n c e n ­ t r a t e d h y d ro c h lo ric a c i d . T h e r e s u l t i n g m ix tu r e was s t i r r e d h c u r a t rocm te m p e r a t u r e , f i l t e r e d a n d th e p r o d u c t w e ig h e d 5 0 .6 g . d e c o B ç io s itio n . s o lid d rie d . fb r one The c ru d e ( 8 8 .5 ^ o f t h e o r y ) , m .p . 2 3 3 .5 -2 3 5 * ^ 0 ., wiUi R e c r y s t a l l i z a t i o n fro m a m ix tu r e o f e t h y l a c e t a t e - e t h a n o l r a i s e d t h e m e l t i n g p o i n t to 2 3 4 -2 3 5 * ^0 ., wi ih d e c o m p o s itio n . A n a ly s is . Found: C a lc u la te d f o r 5 2 .4 0 ; H, 3 .0 8 ; N, 3 0 .5 6 . C, 5 2 .4 4 ; H, 2 .9 8 ; N, 3 0 .7 6 . (c ) 5-Ami n o m e th y l t e t r a z o l e , A s u s p e n s io n o f 4 5 .8 g . ( 0 .2 m ole) o f 5 - ( p h t h a l i m i d o m e t h y l ) t e t r a z o l e i n 300 m l. o f a b s o l u t e e t h a n o l w as t r e a t e d w ith 200 m l. o f a one m o la r s o l u t i o n o f h y d r a z in e h y d r a te i n e t h a n o l a n d t h e r e s u l t i n g m ix tu r e s t i r r e d a t r e f l u x te m p e r a tu r e f o r th re e h o u rs . filte re d . The m ix tu r e was t h e n c o o le d i n a n i c e - b o x o v e r n ig h t and T he s o l i d was su sp e n d e d i n 4 5 0 m l. o f a 2N h y d r o c h l o r i c a c i d f o r f i f t e e n m in u te s a t 5 0 -5 5 ^C. The r e s u l t i n g p r e c i p i t a t e was f i l t e r e d . The f i l t r a t e was e v a p o r a te d to d r y n e s s In v a c u o l e a v i n g 2 3 .6 g . o f t h e c ru d e 5 -a m in o m e th y lte tra z o le h y d ro c h lo r id e . T h i s r e s i d u e was d i s s o l v e d i n a b s o l u t e e t h a n o l , t r e a t e d w ith 2 3 .7 g . ( 0 .3 m ole) o f p y r i d i n e an d c h ille d to -5 ^ 0 . fo r t h i r t y - s i x h o u rs. T he c o l o r l e s s , c r y s t a l l i n e s o l i d w h ic h fo rm ed was f i l t e r e d , w ashed w ith a l c o h o l a n d d r i e d , g i v i n g 1 4 .6 g . ( 7 3 .7 ^ o f th e o r y ) o f 5 - e m i n o m e t h y l t e t r a z o l e , m .p . 2 6 8 . 5 *^0 . , w ith 23 d e c o m p o s itio n . OB page T h i s p r o d u c t w as i d e n t i c a l w ith th e m a t e r i a l d e s c r i b e d 2Gk o b t a i n e d b y f o ll o w i n g Scheme A. D e riv a tiv e s 5 -A c e ty la m in o m e th y lte tra z o le . One and f i v e - t e n t h s gram s (0 .0 1 5 m o le ) o f 5 -am i nome t h y l t e t r a z o l e was a d d e d to 10 m l, o f g l a c i a l a c e t i c a c i d c o n t a i n i n g 1 .5 3 g . (0 .0 1 5 m o le) o f a c e t i c a n h y d rid e an d t h e m ix­ t u r e r e f l u x e d f o r tw o h o u r s . T he s o lv e n t w as rem oved u n d e r vacuum and t h e r e s i d u e r e c r y s t a l l i z e d fro m amyl a c e t a t e , m*p. 1 5 9 * 5 - l6 l^ C . A n a ly s is . Found: C a l c u l a t e d f o r CyE^N^O: C, 3 4 .0 4 ; H, 4 .9 9 ; N, 4 9 .6 3 . C, 3 4 .1 5 ; H, 4 .9 4 ; N, 4 9 .5 9 . 5 - B e n z o y la m in o m e th y lte tr a z o le . To 15 m l. o f w a t e r c o n ta i n in g 1 .0 g . o f sodium h y d r o x id e w as a d d ed 0 .9 9 g . me t h y l t e t r a z o l e . ( 0 .0 1 m ole) o f 5 -a m in o - When a c o m p le te s o l u t i o n h a d b e e n a t t a i n e d 1 .4 g . (0*01 m o le ) o f b e n z o y l c h l o r i d e was a d d ed an d t i e m ix tu r e sh a k e n f o r one h o u r. T he r e s u l t i n g s o l u t i o n w as th e n n e u t r a l i z e d w ith d i l u t e h y d r o c h l o r i c a c i d a n d a d j u s t e d t o a pH o f 4 - 5 . T h e p r e c i p i t a t e w h ic h fo rm e d was f i l t e r e d an d r e c r y s t a l l i z e d fro m w a t e r , m .p . 2 2 9 .5 - 2 3 0 ^ 0 ., w ith d e< x > m position. A n a ly s is . Found: C a l c u l a t e d f o r C ^^N ^O ; C, 5 3 .2 0 ; H, 4 * 4 7 ; N, 3 4 * 4 7 . C, 5 3 .3 7 ; H, 4 .4 5 ; N, 3 4 .3 0 . N -P heny 1 - N ( 5 - 1 e t r a z o l y l m e t h y l )u r e a . One gram (O .O l m ole) o f 5 -am i nome t h y l t e t r a z o l e was d i s s o l v e d i n 12 m l. o f IN p o ta s s iu m h y ­ d r o x id e s o l u t i o n to w h ic h m s t h e n a d d e d 15 m l. o f w a t e r . One and s i x - t e n t h s g ra m s o f p h e i y l i s o c y a n a t e was th e n ad d ed a n d th e m ix tu r e sh a k e n 24 f o r one h o u r . T h e s o l u t i o n was f i l t e r e d a n d t h e f i l t r a t e a c i d i f i e d t o piH o f 4 -5 w i t h d i l u t e h y d r o c h l o r i c a c i d . & T he p r e c i p i t a t e w hich fo rm ed w as f i l t e r e d and r e c r y s t a l l i z e d fro m w a te r , m .p . 1 9 4 .5 - 1 9 5 ° C ., w ith d e c o m p o s ! tio n . A n a ly s is . Found: C a lc u la te d f o r C, 4 9 .5 3 ; H, 4 .6 2 ; N, 3 8 .5 2 . 0 , 4 9 .6 0 ; H , 4 .8 1 ; N, 3 8 . 5 3 . The P r e p a r a t i o n o f 5 - o C - A m in o e th y lte tr a z o le ( A la n in e A n alo g u e) Schem e A . (a ) N -B e n z y l-c 4 -b ro m o p ro p io n a m id e . One h u n d re d gram s o f =»o- b ro m o p ro p io n y l b ro m id e (0 .4 6 3 m o le ) was a d d ed to 9 9 .1 g . o f b e n z y la m in e d i s s o l v e d i n one l i t e r o f d iy b e n z e n e o v e r a p e r i o d o f t h i r t y m in u te s a n d th e r e s u l t i n g m ix tu r e a llo w e d to s t i r cv © m ig h t . The m ix tu r e w as th e n f i l t e r e d , t h e s o l i d w ash ed w i th w a te r a n d th e f i l t r a t e co n ce n ­ t r a t e d a n d c o o le d . s o l i d w h ic h The r e s i d u e from th e w a te r w ash and th e c r y s t a l l i z e d from t h e b e n z e n e c o n c e n t r a t e w e re com bined and r e c r y s t a l l i z e d s e v e r a l tim e s fro m b e n z e n e to g i v e 5 8 .1 g . ( 5 1 .8 ^ o f t h e o r y ) o f p r o d u c t , m .p . 9 1 .5 - 9 2 .5 ° C . K u s h n e r and c o -w o rk e rs (1 8 ) r e p o r t a m e l t i n g p o i n t o f 93»5-9A »5 C ., f o r t h i s com pound. A n a ly s is . C a l c u l a t e d f o r C^^H^^BrNO: B r, 3 3 .0 1 ; N, 5 .7 9 . F ou n d : B r , 3 3 .1 0 ; N, 5 .9 9 . (b ) N -B e n z y l- o C -p h th a lim i d o p ro p i onami d e . Tw enty two an d tw o - 25 t e n t h s g ram s ( 0 .1 2 m o le ) o f p o ta s s iu m p h th a l im id e was a d d e d to 24*2 g . ( 0 .1 m o le ) o f N -b e n z y l-o C -b ro n o p ro p i onamid© d i s s o l v e d i n 75 m l. o f dim e t h y l f o r mami de a n d t h e m ix tu r e h e a t e d on a s te a m b a th f o r o n e h o u r w ith c o n tin u e d s t i r r i n g . The m ix tu r e was th e n t r a n s f e r r e d t o a 500 m l. b e a k e r , 100 m l. o f c h lo r o f o r m w as a d d e d an d th e r e s u l t i n g m ix tu r e t r e a t e d w ith 250 m l. o f w a t e r . The o r g a n i c l a y e r w as s e p a r a t e d a i d th e a q u e o u s l a y e r w ashed w ith 50 m l. o f c h lo r o f o r m . The o r g a n ic l a y e r was c om bined w ith t h e c h l o r o f o m w a sh , t r e a t e d f i r s t w ith 50 m l. o f a 0.2N so d iu m h y d r o x id e s o l u t i o n and t h e n w ith 50 m l. o f w a te r a n d th e n e v a p o r a te d i n a s tr e a m o f d iy a i r . t o g iv e 2 3 .4 g . The r e s i d u e v h ic h re ra a in e d was d r i e d a t 7 0 ^ 0 ., ( 7 6 .0 ^ o f th e o r y ) o f p r o d u c t , m .p . 1 3 0 -1 3 8°C . c r y s t a l l i z a t i o n fro m t o l u e n e g a v e 1 8 .0 g . m e l t i n g a t 140-141*^0. A n a ly s is . Found: (c ) R e­ (5 8 .5 ^ o f th e o r y ) o f p r o d u c t The a n a l y t i c a l sam p le m e lte d a t 141-142*^0. C a lc u la te d f o r 7 0 .1 2 ; H, 5 .2 3 ; N, 9 .0 9 . C, 7 0 .1 3 ; H , 5 .3 4 ; N, 9 . 2 3 . 1 - B e n z y l- 5 - ( oC - p h t h a l i m i doe t h y l ) t e t r a z o l e . S ix an d t w o - t e n t h s gram s ( 0 .0 2 m o le) o f N - b e n z y l- oC- p h t h a l i mid opr o p i onami d e su sp e n d e d i n 1 0 0 m l. o f d ry b e n z e n e was t r e a t e d w ith 4 .1 6 g . ed p h o ^ h o ru s p e n ta c h lo ri d e . s o l u t i o n becauB c l e a r . ( 0 .0 2 m o le) o f pow der­ A f t e r a few m in u te s o f s t i r r i n g t h e A f t e r tvro h o u r s o f c o n tin u e d s t i r r i n g 2 .7 8 g . (0 .0 6 5 m o le) o f h y d r a z o ic a c i d d i s s o l v e d i n 20 m l. o f d ry b e n z e n e was added. A f t e r a s h o r t tim e a c o l o r l e s s p r e c i p i t a t e s t a r t e d t o Ib rm . S t i r r i n g w as c o n tin u e d f o r two h o u r s a t room te m p e r a tu r e and f o r two h o u r s a t r e f l u x te m p e r a t u r e . The f l a s k was th e n c o o le d u n t i l th e t e m p e r a t u r e o f th e s o l u t i o n was 5 ^ 0 . , and th e p r e c i p i t a t e was f i l t e r e d . 26 T he s o l i d , a f t e r w a sh in g w i t h w a t e r an d d l y i n g , am ounted to 5 . 9 g . ( 8 8 *1^ o f t h e o r y ) , m .p . 1 4 7 *^0 . The a n a l y t i c a l sa m p le w as r e c r y s t a l l i z e d fro m t o l u e n e , m .p . 1 4 5 • 7- 1 4 6 . 7 *^0 . A n a ly s is . Found: (d ) C a lc u la te d f o r 6 4 . 8 5 ; H, 4 .5 4 ; N, 2 1 .0 1 . G, 6 4 .9 5 ; H , 4 .5 4 ; N, 2 0 .9 2 . l - B e n z y l - 5 - - a m i n o e t h y l ) t e t r a z o l e H y d r o c h lo r id e . F i v e an d t h r e e - t e n t h s gram s (O .O I6 m ole) o f l - b e n z y l - 5 - ( « ^ - p h t h a l i m i doe t h y l ) t e t r a z o l e was r e f l u x e d w i t h 16 m l. o f a one m o la r s o l u t i o n o f h y d r a z in e h y d ra te i n a b s o lu te e th a n o l, to v h ic h h a d b e e n a d d ed 50 m l. o f a b s o l u t e e t h a n o l , f o r a p e r i o d o f t h r e e h o u r s w ith c o n tin u e d s t i r r i n g . t h e m ix tu r e h a d b e e n e v a p o r a te d t o d r y n e s s A fte r v acu o th e r e s i d u e w as d i g e s t e d w ith 40 ml* o f 2N h y d r o c h lo r ic a c id f o r 10-15 m in u te s a t 40- 50*^C. T he p r e c i p i t a t e w h ich re m a in e d was f i l t e r e d and t h e f i l t r a t e e v a p o r a te d to d r y n e s s . The c ru d e p r o d u c t, 3 .5 g . , w as r e c r y s t a l l i z e d s e v e r a l tim e s fro m i s o p r o p y l a l c o h o l to g iv e 2 .3 g . (6 0 . 5^ o f th e o r y ) o f p u re p r o d u c t , m .p . 184- 1 8 4 . 5 *^0 . A n a ly s is . 1 4 .7 9 ; N, 2 9 . 2 2 . (e ) C a l c u l a t e d f o r C^ qH^^CIN^: Found: C, 5 0 .1 0 ; H, 5 .8 9 ; C l, G, 5 0 .0 4 ; H, 5 . 8 9 ; C l, 1 4 .9 2 ; N, 2 9 .1 6 . 5- 06- A m i n o e t h y l t e t r a z o l e . F i v e - t e n t h s g ram s (0 .0 0 2 1 m o le) o f l - b e n z y l - 5- (0 6 - a m i n o e t h y l ) t e t r a z o l e was d i s s o l v e d i n a m ix tu r e o f 10 m l. o f w a te r and 65 m l. o f a b s o l u t e e t h a n o l and t h e m ix tu r e s h a k e n w i t h 0 .5 g . o f p a lla d iu m o n c h a r c o a l i n a h y d ro g e n a tm o s p h e re a t an i n i t i a l p re s s u re o f 40 p . s . i . a n d te m p e r a t u r e o f 50-55*^0. A f t e r tw e n ty - f o u r h o u r s t h e c a t a l y s t was f i l t e r e d and th e f i l t r a t e e v a p o r a te d to d r y n e s s . The r e s i d u e v h ic h re m a in e d w as d i s s o l v e d i n 5 m l. o f h o t e th a n o l an d 27 t r e a t e d w ith . 0 .5 ml* o f p y r i d i n e . C o o lin g o v e r n i g h t i n a n i c e - b o x r e ­ s u l t e d i n t h e f c r m a t i o n o f a o o l o r l e s s p r e c i p i t a t e w hich w as f i l t e r e d a n d w ashed w i t h a b s o l u t e e t h a n o l . T he p r o d u c t am o u n ted t o 110 m g ., m .p . 2 6 7 - 2 6 8 ^ 0 ., w ith d e c o m p o s itio n , A m ix tu r e m e l t i n g p o i n t w ith an a n a l y t i c a l sa m p le o f 5 -o C -a m in o e t h y l t e t r a z o l e p r e p a r e d a c c o r d in g t o Scheme B, p a g e 29» showed no d e p re s s io n . Schem e B (a ) P h th a ly l a la n in e . F i f t y t l i r e e a n d f o u r - t e n t h s g ram s ( 0 .6 m o le) o f a l a n i n e was m ix e d w ith 8 8 .9 g# ( 0 .6 m o le) o f p h t h a l I c a n h y d r id e and th e m ix tu r e h e a t e d i n an o i l b a th f o r one h o u r a t l6o-170*^C. m e lt w as c o o le d and r e c r y s t a l l i z e d from w a te r to g i v e 1 3 0 .1 g . T he (98*75^ o f th e o r y ) o f t h e p r o d u c t , m .p . 158-159*^0. A m e l t i n g p o i n t o f l 6 0 - l 6 2 ° C . , i s r e p o r t e d f o r t h i s compound b y G a b rie l (1 9 ). (b ) oC - P h t h a l im l d o p ro p i on ami d e . To a s t i r r e d s u s p e n s io n o f 6 8 ,5 g . ( 0 .3 3 4 m ole) o f p h t h a l y l a l a n i n e i n 500 m l. o f d r y b e n ze n e w as a d d e d 6 1 .3 6 . ( 0 .5 2 m ole) o f t h i o n y l c h l o r i d e . T he m ix tu r e was th e n h e a te d on a s te a m b a t h w i t h c o n tin u e d s t i r r i n g u n t i l a c l e a r s o l u t i o n fo rm e d . The y e llo w s o l u t i o n w h ic h r e s u l t e d a f t e r two h o u r s o f h e a t i n g w as th e n c o o le d t o 1 5 ^ 0 ., a n d ammonia g a s s lo w ly b u b b le d i n t o th e s o l u t i o n u n t i l a p r e ­ c i p i t a t e c e a s e d to fo rm . The s o l i d p r e c i p i t a t e was f i l t e r e d , d r i e d and su sp en d ed in a l i t e r o f w a te r . g a v e 4 6 .5 g . F i l t r a t i o n and d r y in g o f t h e s o l i d ( 64^ o f th e o r y ) o f t h e d e s i r e d p r o d u c t, m .p . 2 0 9 - 2 1 0 ^0 , 28 No f u r t h e r p u r i f i c a t i o n was c a r r i e d o u t . T h i s com pound i s r e p o r t e d b y R adde (20) t o h a v e a m e ltin g p o i n t o f 211-212*^0. (c ) -P h th a lim id o p ro p io n itrile . F o r t y f o u r and f i v e - t e n t h s g ram s (0 .2 0 4 m o le) o f <56- p h t h a l i m i d o p r o p i onami de was r e f l u x e d w i t h 200 m l. o f p y r i d i n e a n d 120 m l. o f b e n z e n e s u lf o n y l c h l o r i d e f o r te n m in u te s . T he r e a c t i o n m ix tu r e was t h e n c o o le d a n d p o u r e d i n t o i c e an d w a t e r . A f t e r s t a n d i n g f o r tw e n ty m in u te s th e s o l i d p r e c i p i t a t e was f i l t e r e d and d r i e d a n d am ounted to 4 0 .9 g . (1 0 0 $ o f t h e o r y ) , m .p . 129-130*^0. R e c r y s t a l l i z a t i o n fro m m e th a n o l g a v e a c o l o r l e s s c r y s t a l l i n e s o l i d , m .p . 1 3 6 - 1 3 8 *^0 . T h is m a t e r i a l i s r e p o r t e d by R adde (20) t o m e l t a t 1 3 9 -1 4 0 % . (d ) 5 -o d -P h th a lim ld o e th y lte tra z o le . o C - p h th a lim i d o p ro p i o n i t r i l e To 4 9 .3 g . (O.2 4 6 m o le) o f and 4 8 g . (0 .7 3 8 m ole ) o f sodium a z i d e s u s p e n d e d i n 100 m l. o f d ry t e t r a h y d r o f u r a n was a d d ed 3 2 .7 g . (0 .2 4 6 m o le ) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 300 m l. o f d r y te tra h y d ro fu ra n . T he r e s u l t i n g m ix tu r e was r e f l u x e d w ith c o n tin u e d s t i r r i n g f o r tw e n ty - f o u r h o u r s . A t th e end o f t h i s tim e t h e t e t r a h y d r o ­ f u r a n was d i s t i l l e d fro m th e r e a c t i o n m ix tu r e an d w a te r a d d e d a t s u c h a r a t e t h a t th e w lu m e re m a in e d th e sam e. filte re d , The r e s u l t i n g s u s p e n s io n was th e s o l i d r e s u s p e n d e d i n 400 m l. o f w a te r a n d t r e a t e d w i t h 50 m l. of c o n c e n t r a t e d h y d r o c h l o r i c a c i d . A f t e r s t i r r i n g a t room tem p­ e r a t u r e f o r o n e h o u r t h e s o l i d was f i l t e r e d and d r i e d t o g i v e 5 4 .3 g . ( 9 0 . 7$ o f th e o r y ) o f p r o d u c t , m .p . 229-231*^0. A p o r t i o n o f th e p r o d u c t was r e c r y s t a l l i z e d fro m a q u e o u s e t h a n o l , m .p . 23 0 -2 3 1 * ^0 ., w ith de comp- 29 o s i t i on. A n a ly s is . Found: C a lc u la te d f o r C, 5 4 -3 2 ; H, 3 .7 3 ; N, 2 8 .8 0 . C, 5 4 .2 9 ; H, 3 .7 5 ; N, 2 8 . 7 8 . (c ) 5- -Ami no e t h y l t e t r a z o l e . To 3 7 .1 g . (0 .1 5 3 m ole) o f 5-f>(:- p h t h a l i m i d o e t h y l t e t r a z o l e s u sp e n d e d i n 400 m l. o f a b s o l u t e e t h a n o l w as a d d e d 153 m l. o f a o n e m o la r e t h a n o l s o l u t i o n o f h y d ra z in e an d th e r e ­ s u l t i n g m ix tu r e s t i r r e d u n d e r c o n tin u e d r e f l u x f o r t h r e e h o u r s . A t th e e n d o f t h i s tim e t h e m ix tu r e was e v a p o r a te d to d r y n e s s and th e r e s i d u e t r e a t e d w i t h 400 m l. of 55°C . 2N h y d r o c h l o r i c a c i d f o r f i f t e e n m in u te s a t T he r e s u l t i n g s u s p e n s io n w as f i l t e r e d an d th e f i l t r a t e , i n tu rn , e v a p o r a te d t o d r y n e s s . The c ru d e h y d r o c h l o r i d e , 2 0 .0 g . , w as d i s s o l v e d i n 100 m l. o f a b ­ s o l u t e e t h a n o l a n d t r e a t e d w ith 18 g . of p y r i d i n e . A f t e r t h e m ix tu r e h a d re m a in e d i n an i c e box f o r t h i r t y - s i x h o u r s i t was f i l t e r e d . d r i e d s o l i d am ounted t o 7 . 2 g . The ( 4 0 .4 $ o f t h e o r y ) , m .p . 260- 2 6 2 % . , w i th de comp o s i t i o n . The p r o d u c t was p u r i f i e d by d i s s o l v i n g i t i n a minimum am ount o f w a t e r and r e p r e c i p i t a t i n g i t b y t h e a d d i t i o n o f s u f f i c i e n t a b s o l u t e e t h a n o l to m ake a 90$ a l c o h o l s o l u t i o n , m .p . 2 7 2 - 2 7 3 % ., w ith decom pos i t i on. A n a ly s is . Found: C a lc u la te d f o r C, 3 1 .7 9 ; H, 6 .1 0 ; N, 6 2 .0 9 . C, 3 1 .8 5 ; H, 6 .2 4 ; N, 6 1 . 9I . 30 D e riv a tiv e s 5 - o < S - A c e ty la m iiio e th y lte tr a z o le . One an d t h i r t e e n - h u n d r e d t h s g ra m s ( 0 .0 1 m o le ) o f 5 -o C -am i noe t h y l t e t r a z o l e a n d 1 .0 2 g . (O .O l m o le) o f a c e t i c a n h y d r id e w e re r e f lu x e d f o r o n e h o u r i n 10 m l. o f g l a c i a l a c e t i c a c id . The e x c e s s a c e t i c a c i d w as rem oved i n a vacuum and t h e s o l i d r e s i d u e r e c r y s t a l l i z e d fro m amyl a c e t a t e , m .p . 1 4 5 - 1 4 5 .5 % . A n a ly s is . Found: C a l c u l a t e d f o r C ^^N ^O : C, 3 8 .7 0 ; H, 5 .8 5 ; N , 4 5 .1 4 . G, 3 8 .6 9 ; H, 5 .7 1 ; N, 4 5 .1 3 . 5 - o ^ -B e n z o y lam in o e t h y l t e t r a z o l e » am ino e t h y l t e t r a z o l © To 1 .1 3 g . ( 0 .0 1 m ole) o f 5 -o C - d i s s o l v e d i n 20 m l. o f i m t e r c o n t a i n i n g 0 .9 g . o f so d iu m h y d r o x id e w as a d d e d 1 . 4 g . ( 0 .0 1 m ole) o f b e n z o y l c h l o r i d e . T he r e s u l t i n g m ix tu r e w as sh ak en s e v e r a l tim e s o v e r a p e r i o d o f one h o u r. The s o l u t i o n was th e n f i l t e r e d an d th e f i l t r a t e a c i d i f i e d t o a pH o f 4 -5 w ith d i l u t e h y d r o c h l o r i c a c i d . f i l t e r e d a n d r e c r y s t a l l i z e d fro m w a t e r . The s o l i d w h ic h fb im ed was The p r o d u c t m e lte d a t 1 7 6 - 1 7 7 % . , t h e n s o l i d i f i e d an d r e m e lte d a t 1 9 9 -2 0 0 % . A n a ly s is . Found: C a l c u l a t e d f o r C^ qH^^N^O; C, 5 5 .2 9 ; H, 5 .1 1 ; N, 3 2 .2 4 . C, 5 5 .4 9 ; H, 5 .0 9 ; N, 3 2 .4 3 . N -P h e n y l-N (o 4 - 5 - te tr a z o ly le th y l) u r e a . One an d t h i r t e e n - h u n d r e d ­ t h s g ram s ( 0 .0 1 m o le) o f 5 - « C - a m i n o e t h y l t e t r a z o l e was d i s s o l v e d i n 12 m l. o f a IN p o ta s s iu m h y d ro x id e s o l u t i o n to w h ic h was th e n added 18 m l. of w a t e r . One an d t w o - t e n t h s g ram s o f p h e n y l i s o c y a n a t e w as a d d ed an d th e m i x t u r e sh ak e n s e v e r a l tim e s o v e r a p e r io d o f two h o u r s . A fte r t h i s tim e t h e s o l u t i o n w as f i l t e r e d an d th e f i l t r a t e a c i d i f i e d t o pH 4 31 w ith d i l u t e h y d ro c h lo ric a c i d . The p r e c i p i t a t e w h ich fo rm ed w as f i l t e r e d a n d r e c r y s t a l l i z e d fro m w a te r , m .p . 1 8 4 - 1 8 5 % ., w ith decomp­ o s itio n . A n a ly s is . Found: C a lc u la te d f o r C, 5 1 .7 1 ; H, 5 .2 1 ; N, 3 6 .2 0 . G, 5 1 .8 8 ; H, 5 .3 5 ; N, 3 6 .2 2 . T he P r e p a r a t i o n o f 5 - (/8-A m i no e t h y l ) t e t r a z o l e ( - A l a n i n e A n a lo g u e ) Scheme A. (a ) P h th a ly l f t - a l a n i ne. A m ix tu r e o f 3 5 .6 g . ( 0 .4 m ole) o f / 3 - a l a n i n e and 5 9 .3 g . ( 0 .4 m ole) o f p h t h a l i c a n h y d rid e was f u s e d a t 1 8 0 % . f o r a p e r i o d o f t h i r t y m in u te s . c o n t e n t s o f the g a v e 8 0 .0 g . A t th e end o f t h i s tim e th e f l a s k w e re rem oved an d r e c r y s t a l l ! z e d fro m w a t e r . T h is ( 9 1 .4 $ o f th e o r y ) o f th e p r o d u c t m e ltin g a t 1 4 9 -1 5 0 % . T h is compound was r e p o r t e d by G a b r i e l (1 9 ) to m e lt a t 1 5 0 - 1 5 1 % . (b) ^ -P h th a lim id o p r o p io n y l C h lo rid e . To 3 9 .1 g . (0 .1 7 9 m ole) o f p h t h a l y l - y Q - a l a n i ne s u sp e n d e d i n 500 m l. o f d r y b e n z e n e was a d d e d 3 5 .4 g . ( 0 .3 m o le) o f t h i o n y l c h l o r i d e . T h e r e s u l t i n g m ix tu r e w as h e a t e d j u s t u n d e r r e f l u x te m p e r a t u r e w ith c o n tin u e d s t i r r i n g f c r t h r e e h o u rs. A f t e r t h i s tim e th e s o l u t i o n was c o n c e n t r a t e d i n a vacuum u n t i l th e e x c e s s t h i o n y l c h l o r i d e an d a l l t h e b e n ze n e had b e e n rem o v ed . T r i t u r a t i o n o f t h e r e s i d u e w ith p e tr o le u m e t h e r g a v e a c o l o r l e s s c r y s ­ t a l l i n e m a t e r i a l w h ic h w as f i l t e r e d and d r i e d . 3 8 .6 g . The a c i d c h lo rl(d e w e ig h e d ( 9 0 .9 $ o f t h e o r y ) , m .p . 1 0 5 - 1 0 6 .5 % . T h i s c o rp o u n d i s r e p o r t e d b y G a b r ie l (21) t o m e lt a t 1 0 7 -1 0 8 % , 32 (c ) N -B en2y l - / 3 - p h th a lI m id o p r o p io n a m id e . To 34*9 g . (0 .3 2 6 m ole) o f b e n z y la m in e i n 500 m l. o f d r y b e n z e n e was ad d ed 3 8 .6 g . ( O .I 63 m ole) o f / 3 - p h t h a l i m i d o p ro p i o n y l c h l o r i d e i n s m a ll p o r t i o n s o v e r a p e r i o d o f tw e n ty m in u te s * T he r e a c t i o n m ix tu r e was k e p t a t room te m p e r a tu r e b y m ean s o f a n i c e - w a t e r b a t h . A f t e r a llo w in g t h e m ix tu r e to s t i r o v e r ­ n i g h t t h e p r e c i p i t a t e was f i l t e r e d , w a t e r f o r tvjo h o u r s . d r i e d an d d i g e s t e d w ith 750 m l. o f F i l t e r i n g an d d r y in g a g a in g a v e 5 0 .9 g . (q u a n tita tiv e y i e l d ) o f t h e p r o d u c t , m .p . 194- 1 9 7 % . R e c r y s t a l l i z a t i o n from a b s o l u t e e t h a n o l g a v e 4 1 .0 g . ( 8 1 .7 $ o f th e o r y ) o f p u r e p r o d u c t m e ltin g a t 198- 1 9 9 . 5 % . ; th e a n a l y t i c a l sam p le m e lte d a t 198- 1 9 8 . 5 % . A n a ly s is . F ound: (d ) C a lc u la te d f o r C, 7 0 .1 2 ; H , 5 .2 3 ; N , 9 .0 9 . C, 6 9 .9 8 ; H, 5 .0 3 ; N , 9 . I 6 . 1 -B en g y 1 - 5 - / 3 - P h t h a l i m i d o e t h y l t e t r a z o l e . To 3 5 .1 g . (0 . I I 4 m o le ) o f N - b e n z y l - - p h t h a l i m i d o p r o p i o n a r a i de s u sp e n d e d i n 500 m l. o f d ry b e n z e n e w as a d d e d 2 3 .8 g . ( 0 . I I 4 m o le) o f p h o s p h o ru s p e n t a c h l o r i d e . m ix tu r e was s t i r r e d a t 6 0 % . f o r a p e r io d o f two h o u rs d u r in g w h ich tim e t h e s o l u t i o n becam e h om ogeneou s. t h e n a d d ed I 4 . 8 g . benzene. To t h e s l i g h t l y y e llo w s o l u t i o n was ( 0 .3 4 4 m ole) o f h y d r a z o ic a c i d i n 106 m l. o f d ry The s o l u t i o n was s t i r r e d f o r two h o u r s a t room t e m p e r a t u r e , f o llo w e d by tw o h o u r s a t r e f l u x te m p e r a t u r e . w as c o o le d an d f i l t e r e d . The r e s u l t i n g s u s p e n s io n A f t e r d r y in g th e r e s i d u e i t was d i g e s t e d i n w a te r and a g a in f i l t e r e d an d d r i e d t o g iv e 2 2 .8 g . c ru d e p r o d u c t , m .p . in h a l f i t s The ( 6 0 , 0$ o f th e o r y ) o f 1 5 3 .5 - 1 5 7 % . The b e n z e n e f i l t r a t e was c o n c e n t r a t e d v o lu m e , c o o le d an d f i l t e r e d . The d r i e d p r e c i p i t a t e am ounted 33 t o 5 .1 g . ( 1 3 .4 $ o f t h e o r y ) , m .p . 1 4 8 .5 - 1 5 3 % . R e c r y s t a l l i z a t i o n o f th e co m b in ed s o l i d s fro m t o l u e n e g av e 2 5 .5 g . ( 6 7 . ^ o f th e o r y ) o f p r o d u c t , m .p . 156. 5- 1 5 8 % , T he a n a l y t i c a l sa m p le m e lte d a t 1 5 9 - 1 5 9 .5 % . A n a ly s is . Found: C a lc u la te d fo r C, 6 4 .8 5 ; H , 4 .5 4 ; N, 2 1 .0 1 . 0 , 6 5 .0 3 ; H , 4 .3 3 ; N , 2 1 .1 9 . (e ) l-B e n z y l-5 -( - a m in o e th y l) t e t r a z o l e H y d r o c h lo r id e . To 20*5 g . ( 0 .0 6 2 m ole) o f l - b e n z y l - 5 - / 9 - p h t h a l i m i doe t h y l t e t r a z o l e I n 250 m l. o f e t h a n o l was a d d e d 62 m l. o f a o n e m o la r e t h a n o l s o l u t i o n o f h y d r a z i n e . T he m ix tu r e was s t i r r e d u n d e r r e f l u x f o r t h r e e h o u rs a n d th e n e v a p o r a te d to d iy n e s s . The r e s i d u e vœas th e n t r e a t e d w ith 200 m l. o f 2K h y d ro ­ c h l o r i c a c i d a t 50- 5 5 % . f o r te n m in u te s f o llo w e d b y f i l t r a t i o n . E v a p o r a t i o n o f th e f i l t r a t e gave 1 1 .1 g . (7 4 .8 $ o f t h e o r y ) o f th e c r u d e , c o l o r l e s s p r o d u c t m e l t i n g a t 126- 1 2 9 % . R e c r y s t a l l i z a t i o n fro m a m ix tu r e o f w a te r and i s o p r o p y l a lc o h o l r a i s e d t h e m e l t i n g p o i n t to 1 3 8 . 5- 1 3 9 . 5 % . A n a ly s is . N, 2 9 . 2 2 . (f) C a l c u l a t e d f o r Cg^gS^^GlN^: F ound: 5- C, 5 0 .1 0 ; H, 5 .8 9 ; C l, 1 4 .7 9 ; G, 4 9 .8 8 ; H, 6 .0 0 ; C l, 1 4 .9 8 ; N, 2 8 ,9 7 . - Ami n o e t h y l t e t r a z o le H ydro c h l o r i d e . Four and e ig h t- t e n t h s gram s (0 .0 2 m ole) o f l - b e n z y l - 5- - a m i noe th y I t e t r a z o l e h y d ro ­ c h l o r i d e was d i s s o l v e d i n a m ix tu r e o f 100 m l. o f a b s o l u t e e th a n o l and 15 m l. o f w a t e r . A f t e r a d d i t i o n o f 1 .2 g . o f 5$ p a lla d iu m on c h a r c o a l t h e m ix tu r e was sh ak e n i n a n a tm o s p h e re o f h y d ro g e n a t 50- 6 0 % . , a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . th e n f i l t e r e d and th e f i l t r a t e f o r tw e n ty - f o u r h o u r s . The m ix tu r e was e v a p o r a te d t o d r y n e s s ; t h e r e s i d u e w as 34 r e c r y s t a l l i z e d fro m e t h a n o l - e t h e r , a n d g a v e 1 .1 g . ( 3 6 .8 $ o f th e o r y ) o f p r o d u c t , m .p . 1 2 7 .5 - 1 2 8 .8 % . A n a ly s is . N, 4 6 . 8 2 . C a l c u l a t e d f o r C^H^GIN^: Found: G, 2 4 .0 9 ; H, 5 .3 9 ; C l, 2 3 .7 0 ; C, 2 4 .0 9 ; and 2 4 .2 4 ; H, 5 .5 4 an d 5 .4 5 ; C l, 2 3 .5 1 ; N, 4 6 . 6 9 . Schem e B (a ) 5 - /3 -P h th a lim id o e th y lt e tr a z o l e . /S -p h th a lim id o p ro p io n itrile To 50 g . (0 .2 5 m ole) o f (2 2 ) a n d 50 g . o f sodium a z i d e su sp e n d e d i n 100 m l. o f d ry t e t r a h y d r o f u r a n was a d d ed 35 g . ( 0 .2 6 m ole) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d in 300 m l. o f d r y t e t r a h y d r o f u r a n . The r e ­ s u l t i n g m ix tu r e was r e f l u x e d f o r t w e n t y - f o u r h o u rs w i th c o n tin u e d s tirrin g . A t t h e end o f t h i s tim e t h e t e t r a h y d r o f u r a n was d i s t i l l e d fro m th e m ix tu r e a n d w a te r a d d e d a t s u c h a r a t e t h a t t h e TOlume o f th e c o n t e n t s o f th e f l a s k re m a in e d t h e sam e . T he r e s u l t i n g s u s p e n s io n w as f i l t e r e d a n d t h e s o l i d r e s u sp e n d e d i n 450 m l. o f w a te r a n d t r e a t e d w ith 50 m l. o f c o n c e n t r a t e d h y d r o c h lo r i c a c i d . A f t e r one h o u r o f s t i r r i n g t h i s was f i l t e r e d a n d t h e s o l i d d r i e d t o g i v e 5 7 .3 g . ( 9 4 .2 $ o f th e o r y ) o o f c r u d e p r o d u c t , m .p . 2 4 0 -2 4 4 .5 G ., w i th d e c o m p o s itio n . R e c r y s t a l l i z a t i o n from a m ix tu r e o f e t h a n o l and e t h y l a c e tia te r a i s e d t h e m e ltin g p o i n t to 2 4 9 . 5 - 2 5 0 . 5 % . , w ith d é c o m p o s itio n . A n a ly s is . Found: C a lc u la te d f o r C H N 0 ; ■ix 7 5 2 C, 54* 3 2 ; H, 3 * 7 3 ; N , 2 8 . 8 0 . C, 5 4 .3 3 ; H , 3 .9 3 ; N, 2 8 .9 9 . T h is compound i s r e p o r t e d by B e h r in g e r and K ohl (5) t o m e lt a t o 241 G. 35 (b ) 5 * / 3 - A m i n o e t h y l t e t r a a o l e H ydro c h lo r id e » To 24*3 g . ( 0 .1 m o le ) o f 5 - / ^ - p b t h a l i m i d o © t h . y l t e t r a z o l e s u s p e n d e d i n 360 m l. o f a b s o l u t e e t b a n o l was ad d ed 100 m l. o f a one m o la r s o l u t i o n o f h y d r a z in e h y d r a t e i n e t h a n o l an d th e r e s u l t i n g m ix tu r e r e f l u x e d w ith c o n tin u e d s t i r r i n g f o r th re e h o u rs. T he s o l v e n t w as rem oved i n a vacuum and t h e d ry r e s i d u e t r e a t e d w i t h 225 m l. o f 2N h y d r o c h l o r i c a c id a t 50-55*^0* f o r a p e r i o d o f te n m i n u t e s . T he r e s u l t i n g m ix tu r e w as f i l t e r e d and t h e f i l t r a t e e v a p o r a te d t o d r y n e s s o n a stea m b a th i n a j e t o f d r y a i r . The r e s i d u e , 13*3 g* (8 9 * 3 ^ o f t h e o r y ) , was r e c r y s t a l l i z e d fro m e t h a i o l , m .p . 1 3 0 132 °0 . The m e l t i n g p o i n t f o r t h i s compound i s r e p o r t e d a s 1 2 8 -1 2 9 °C . by A in s w o rth (2 3 ) and 1 3 2 ^ 0 . by B e h r in g e r an d K o h l ( 5 ) . (c ) 5 - /3 -A m in o e th y lte tra z o le . A s o l u t i o n o f 7*45 g* (0 .0 5 m ole) o f 5 - - a m i n o e t h y l t e t r a z o l e h ydro c h l o r i d e was d i s s o l v e d i n 65 m l. o f w a t e r t o w h ich was th e n a d d ed 6 . 1 g , o x id e * The r e s u l t i n g m ix tu r e was p r o t e c t e d frcm l i g h t an d a llo w e d t o s t i r f o r tw e n ty -e ig h t h o u rs . filtra te (0*0264 m ole) o f pow dered s i l v e r The s u s p e n s i o n w as f i l t e r e d and t h e was s a t u r a t e d w ith h y d ro g e n s u l f i d e . The r e s u l t i n g b la c k p r e c i p i t a t e o f s i l v e r s u l f i d e w as rem oved by f i l t r a t i o n and t h e f i l t r a t e , a f t e r tr e a t m e n t w ith N o r i t e , was e v a p o r a te d to a s m a ll v o lu m e . T ri­ t u r a t i o n w i t h a c e to n e g a v e a c o l o r l e s s p r e c i p i t a t e id iic h was f u r t h e r p u r i f i e d by d i s s o l v i n g i n a s m a ll amount o f w a t e r f b llo w e d b y p r e c i p ­ i t a t i o n w i t h a c e to n e * The p u re p r o d u c t w e ig h e d 3 .0 g . a n d m e lte d a t 2 2 3 - 2 2 4 , w ith d e c o m p o s itio n * (5 8 * 3 ^ o f th e o r y ) 36 A n a ly s is , Found: C a lc u la te d f o r ; C, 3 1 ,8 5 ; H, 6 ,2 4 ; N, 6 1 ,9 1 , C, 3 2 ,1 1 ; H, 6 ,3 2 ; N, 6 2 ,0 2 , D e riv a tiv e s 5 - ( /3 - A c e t y l a m i n o e t t i y l ) t e t r a z o l e * One a n d t h i r t e e n - h u n d r e d t h s g ram s (O .O l m ole) o f 5 - ( / ^ - a m i n o e t h y l ) t e t r a z o l e w as ad d ed t o 10 m l. o f g la c ia l a c e tic a c id c o n t a i n i n g 1 .0 2 g . an d th e m ix tu r e re f l u x e d f o r one h o u r . (O .O l m ole) o f a c e t i c a n h y d rid e R em oval o f t h e s o l v e n t i n a vacuum l e f t a s o l i d r e s i d u e w hich w as r e c r y s t a l l i z e d from aiqyl a c e t a t e , m .p . 2 0 2 -2 0 3 '^C. A n a ly s is . Found: C a lc u la te d fo r G, 3 8 .7 0 ; H, 5 * 8 5 ; N, 45*14* G, 3 8 .8 1 ; H, 6 .0 6 ; N, 4 5 .2 8 . 5 - ( /6 -B e n z o y la m i no e t h y l ) t e t r a z o l e . One a n d t h i r t e e n - h u n d r e d t h s g ra m s (O .O l m o le s ) o f 5 - ( / 3 - a m i n o e t h y l ) t e t r a z o l e w as a d d e d t o 20 m l. o f w a te r c o n ta in in g 0 .8 g . ( 0 .0 1 m ole) o f so d iu m h y d r o x id e . To th e r e s u l t i n g s o l u t i o n w as t h e n a d d ed 1 . 4 6* (O .O l m ole) o f b e n z o y l c h l o r i d e an d th e m ix tu r e shak en f o r o n e h o u r . T he s o l u t i o n was th e n n e u t r a l i z e d w ith d i l u t e h y d r o c h l o r i c a c i d an d a d j u s t e d to a pH o f 4 -5 * 'Hie r e s u l t i n g p r e c i p i t a t e w as f i l t e r e d and r e c r y s t a l l i z e d tw ic e from o w a t e r , m .p . 2 0 0 .5 - 2 0 1 .0 C . , w ith d e c c r a p o s itio n . T h i s compound i s r e p o r t e d by A in s w o rth (23) to m e lt a t 206^C . A n a ly s is . Found: C a lc u la te d fo r 0 H N 0: 10 11 5 0 , 55*29; H, 5 .1 1 ; N, 3 2 .2 4 * C, 5 5 .1 3 ; H , 5 .1 6 ; N, 3 2 .2 7 . N -P h e n y l-N * -(/3 -5 -te tra z o ly le th y l)u re a . One and t h i r t e e n - h u n d r e d t h s g ra m s (O .O l m ole) o f 5 - ( / ^ - a m i n o e t h y l ) t e t r a z o l e was d i s s o l v e d i n 12 m l. 37 o f IN p o ta s s iu m h y d ro x id e s o l u t i o n to w h ic h was t h e n a d d ed 18 m l. o f w a te r. To t h e r e s u l t i n g s o l u t i o n w as ad d ed 1 .2 g . o f p h e n y l i s o c y a n a t e a n d t h e m ix tu r e sh a k e n f o r one h o u r . T he s u s p e n s i o n was f i l t e r e d an d t h e f i l t r a t e a c i d i f i e d to a pH o f 4—5 w i th d i l u t e h y d r o c h l o r i c a c id * The p r e c i p i t a t e w h ic h form ed w as f i l t e r e d an d r e c r y s t a l l i z e d from a q u e o u s a l c o h o l , m *p. 1 9 9 - 1 9 9 .5 ^ 0 ., w ith d e c o m p o s itio n . A n a ly s is . Found: C a lc u la te d f o r G, 5 1 .7 1 ; H, 5 .2 1 ; N, 3 6 .2 0 . G, 5 1 .9 3 ; H, 5 .4 3 ; N, 3 6 .3 3 . The P r e p a r a t i o n o f 5 - -A m in o p h e n y le th y l) t e t r a z o l e ( P h e n y la l a n in e A n a lo g u e) Scheme B (a ) o C - P h th a lim id o - /6 - p h e n y l p r o p io n y l C h l o r i d e . (25 g . , 0 .1 5 2 m o le ) , was f u s e d w ith 2 2 .4 g . D ,L - P h e n y la la n in e (0 .1 5 2 m o le) o f p h t h a l i c a n h y d r id e a t 1 4 5 -1 5 0 °C . f o r a p e r i o d o f t h i r t y m i n u t e s . m e l t was p o u re d i n t o i c e an d w a te r w ith s t i r r i n g d e r i v a t i v e f i l t e r e d an d d r i e d t o g i v e 4 3 .5 g . The r e s u l t i n g a n d th e s o l i d p h th a lim ld o ( 9 7 .4 ^ o f th e o r y ) o f p r o d u c t , m .p . 1 7 4 -1 7 6 ^ 0 . W ith o u t f u r t h e r p u r i f i c a t i o n t h e c ru d e a c id w as a d d e d t o 500 m l. o f d r y b e n z e n e c o n t a i n i n g 3 1 .0 g* (0 .1 4 9 m o le ) o f f i n e l y g r o u n d p h o s p h o ru s p e n t a c h l o r i d e a n d t h e r e s u l t i n g m ix tu r e h e a te d t o 5 0 -5 5 ^ 0 . on a ste a m h a t h w ith c o n tin u e d s t i r r i n g f o r one h o u r. A f t e r t h i s tim e t h e s o l v e n t a n d p h o s p h o ru s o x y c h lo r id e w e re rem o v ed i n a vacuum and th e r e s i d u e t r i t u r a t e d w ith p e tr o le u m e t h e r . and d r ie d . T he s o l i d w hich fo rm ed was f i l t e r e d The y i e l d o f a c i d c h l o r i d e was 4 3 .9 g . (96.5% o f t h e o r y ) . 38 m.p# 134—136 0. S h e e h a n and F r a n k (2 4 ) r e p o r t e d th e a c i d t o m e lt a t 1 7 7 .5 - 1 7 9 ° C ., a n d t h e a c i d c h l o r i d e t o m e lt a t 124- 1 2 6 ^ 0 . (b ) 06 - P h t h a l i m i d o - / 3 - p h e n y lp r o p i onami d e . p h e n y lp r o p io n y l c h l o r i d e o t-P h th a lim id o -^ - (10 g . , 0 .0 3 m ole) was a d d e d a l l a t o n ce t o 50 m l. o f a c o ld ammonium h y d r o x id e s o l u t i o n an d s t i r r e d w ith c o n tin u e d c o o lin g f o r t h i r t y m in u te s . The a m id e , v;hich s e p a r a t e d a s a s o l i d was f i l t e r e d and d r i e d a t 70 C. g i v i n g 9*0 g . p r o d u c t , m .p . 2 3 1 -2 3 3 ^ 0 . ( 96% o f th e o r y ) o f c ru d e The p r o d u c t was n o t p u r i f i e d f u r t h e r b u t u s e d i n th e c ru d e s t a t e . The p u re a m id e i s r ^ o r t e d to m e l t a t 2 3 6 - 2 3 7 b y P e t e r s o n a n d Wieman ( 2 5 ) . (c ) 0 6 -P h th a lim id o -/3 -p h e n y lp ro p io n itrile . To 1 9 .5 m l. o f b e n z e n e - s u l f o n y l c h l o r i d e and 3 2 .6 ml* o f p y r i d i n e was a d d ed 9 .0 g . ( 0 .0 3 2 m o le) o f o C -p h th a lim id o -/S -p h e n y lp ro p io n a m id @ and t h e r e s u l t i n g m ix tu r e r e ­ f l u x e d f o r t e n m in u te s . i n t o i c e and w a t e r . The m ix tu r e was a llo w e d to c o o l an d was p o u re d T he p r e c i p i t a t e w h ic h fo rm ed w as f i l t e r e d and d r i e d . T he p r o d u c t w e ig h e d 8 .1 g . , m .p . 1 2 7 - 1 3 0 ^ 0 ., an d w as n o t f u r t h e r p u r i f i e d f o r u s e i n th e n e x t r e a c t i o n . T h is com pound, p r e p a r e d i n e x a c t l y th e same m a n n e r, i s r e p o r t e d by o N io n a n n a n d P e t e r s o n (25) t o m e lt a t 1 34-135 C. v h en p u r e . (d) 5 - («2,- P h t h a l i m i d o - / ^ - p h e n y l e t h y l ) t e t r a z o l e . ( 0 .0 3 0 5 m o le) o f 06 - p m o le ) 4 .4 g . of so d iu m (0 .0 3 3 a z id e m o le ) h th a lim ld w as of o - added an h y d ïD U S -p h e n y lp ro p io 75 m l. o f a lu m in u m dry n itr To 8 .1 g . i le and 6 .5 g . te tra h y d ro flira n c h lo rid e . ( 0 .1 c o n ta in in g The r e s u l t i n g 39 m ix tu r e w as s t i r r e d u n d e r r e f l u x f o r a p e r i o d o f t w e n ty - f o u r h o u r s . T he t e t r a h y d r o f h r a n was t h e n d i s t i l l e d o u t o f th e r e a c t i o n m ix tu r e and w a t e r a d d ed a t s u c h a r a t e t h a t t h e volum e o f t h e m ix tu r e re m a in e d co n ­ s ta n t. The s o l i d m a t e r i a l w as t h e n f i l t e r e d o f f , r e s u s p e n d e d i n 175 m l. o f w a t e r an d t r e a t e d w i t h 20 m l. o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d . The m ix tu r e was f i l t e r e d an d t h e s o l i d p r o d u c t w ashed w i t h w a te r and d rie d . The y i e l d o f t e t r a z o l e was 9*2 g . (94.5% o f t h e o r y ) , m .p . 2 1 2 - 2 1 3 °C . R e c r y s t a l l i z a t i o n frc m e t h y l a c e t a t e r a i s e d t h e m e l t i n g p o i n t to o 2 1 2 .5 -2 1 3 C ., w ith s l i g h t d e c o m p o s itio n . A n a ly s is . Found: C a lc u la te d fo r C, 6 3 .9 4 ; H , 4 .1 0 ; N, 2 1 .9 4 # C, 6 3 .9 7 ; H, 4 .3 9 ; N , 2 2 .1 9 . (e ) 5 - ( o 6 - A m i n o - / 3 - .p h e n y l e t h y l ) t e t r a z o l e . m ole) o f 5 F iv e gram s ( 0 .0 1 6 2 - - p h t h a l i m i d o - ^ - p h e n y l e t h y l ) t e t r a z o l e was a d d ed to l 6 . 2 m l. o f a one m o la r e t h a n o l i c s o l u t i o n o f h y d r a z in e fo llo w e d b y t r e a t m e n t w ith 50 m l. o f a b s o l u t e e t h a n o l . The r e s u l t i n g m ix tu r e was r e f l u x e d f o r two h o u r s , a llo w e d t o c o o l an d t h e n e v a p o r a te d to d r y n e s s . The r e s i d u e was t r e a t e d w i t h 40 m l. o f 2N h y d r o c h lo r ic a c i d an d warmed f b r t e n m in u te s a t 5 0 -5 5 ^ 0 . The m ix tu r e was th e n f i l t e r e d an d t h e f i l t r a t e n e u t r a l i z e d to a pH o f 5 . The r e s ’o l t i n g p r e c i p i t a t e was f i l t e r e d , w ashed w ith c o ld w a te r and d r i e d . The y i e l d o f p r o d u c t was 2 .5 g . (81.5% o f t h e o r y ) , m .p . 271-272*^0., w ith d e c o m p o s itio n . M ix tu re m e ltin g p o i n t s w ith a n a n a l y t i c a l sa m p le o f 5 -(« C -a m in o ^ - p h e n y l e t h y l ) t e t r a z o l e p r e p a r e d b y a n a l t e r n a t e m e th o d , showed no d e p re s s io n . 40 Schem e C. (a ) E t h y l o d - a c e ta m ld o - o 6 - c y a n o - /3 - p h e n y lp r o p io n a t e * a o lu tio n o f 4 .6 g . w as a d d e d 3 4 .0 g . To a (0*2 m o le) o f so d iu m i n 100 m l. o f a b s o l u t e e t h a n o l ( 0 .2 m ole) o f e t h y l ac e ta m i d o cy an o ac e t a t e . ^ s u l t i n g s o l u t i o n w as h e a t e d an d s t i r r e d w h ile 26.6 g . The r e ­ (0 .2 1 5 m o le) o f b e n z y l c h l o r i d e was a d d e d o v e r a p e r i o d o f f i f t e e n m in u te s . Re f l u x i n g a n d s t i r r i n g w e re c o n tin u e d f o r two h o u rs a f t e r W iich th e m ix tu r e was c o o le d an d p o u re d on t o 500 g , o f i c e and w a t e r . The s^T up v h ic h r e ­ s u l t e d w as s e p a r a t e d by d é c a n t a t i o n o f t h e w a te r and d i s s o l v e d i n b e n z e n e - c y c lo h e x a n e m i x t u r e . a D ry in g by a z e o t r o p i c d i s t i l l a t i o n f o llo w e d by c o o lin g and s c r a t c h i n g g a v e a l i g h t t a n p r e c i p i t a t e w h ic h was f i l t e r ­ e d an d d r i e d . The y i e l d o f c ru d e p r o d u c t was 3 1 .4 6« (59.6% o f t h e o r y ) , m .p . 1 2 9 .5 -1 3 0 ^ 0 . R e c r y s t a l l i z a t i o n from a q u e o u s a l c o h o l r a i s e d t h e m e ltin g p o i n t t o 130 - I 3 i ° c . The compound i s r e p o r t e d b y A lb e r ts o n and T u l l a r (26) to m e lt a t 134°C . (b ) E t h y l o d -a c e ta m id o - « 6 - ( 5 - t e t r a z o l y l ) - / 3 - p h e n y lp r o p i o n a te a n d 5 - (<*i - A m in o - /3 - p h e n y le th y l) t e t r a z o l e . To 6 7 .8 g . (0 .2 5 6 m ole) o f e t h y l «6- a c e ta m id o - o C - c y a n o - y S - p h e n y lp r o p io n a te a n d 4 9 .9 g . m o le ) o f so d iu m a z i d e was added 3 4 .1 g . (0 .7 6 8 (0 .2 5 6 m o le ) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 550 m l. o f d r y t e t r a h y d r o f u r a n . r e s u l t i n g m ix tu r e was r e f l u x e d w i t h c o n tin u e d s t i r r i n g ^ Win t h r op L a b o r a t o r i e s The f o r tw e n t y - f o u r 41 h o u rs * A t t h e e n d o f t h i s tim e t h e t e t r a h y d r o f h r a n was d i s t i l l e d o u t o f t h e r e a c t i o n m ix tu r e an d w a t e r a d d e d a t s u c h a r a t e t h a t th e volum e r e m a in e d c o n s t a n t . T he s u e nde d alum inum s a l t w as f i l t e r e d an d d r ie d * The f i l t r a t e w as made a c i d t o C ongo r e d a n d c o o le d o v e r n i g h t . The p r e c i p i t a t e v h ic h f o m e d was f i l t e r e d an d d r i e d t o g i v e 8 .0 g . o f c ru d e p r o d u c t . R e c r y s t a l l i z a t i o n fro m a q u e o u s a l c o h o l g a v e th e p u re e t h y l * » ^ - a c e t a m id o - t> 6 - ( 5 - te t r a z o y l ) - /3 - p h e n y lp r o p i o n a t e , m.p* 1 4 7 .5 U 8 .5 ° C . A n a ly s is * C a lc u la te d f o r C H N O : 1 4 17 5 3 G, 5 5 .4 1 ; H , 5 .4 0 ; N , 2 3 .0 9 . Found: C, 5 5 .4 3 ; H, 5 .6 5 ; N, 2 3 .0 9 . T he d r i e d alum inum s a l t was r e f l u x e d w i t h 450 m l. o f c o n c e n t r a t e d h y d r o c h l o r i c a c id f o r t h r e e h o u rs and th e m ix tu r e e v a p o r a te d a lm o s t t o d ry n e ss. The r e s i d u e w as ta k e n iq> in 250 m l. o f 95% e t h a n o l an d t r e a t ­ e d w i t h 30 gram s o f p y r i d i n e . C o o lin g o f t h e m ix tu r e o v e r n i g h t i n an i c e - h o x r e s u l t e d i n t h e f o r m a tio n o f a c r y s t a l l i n e p r e c i p i t a t e o f 5 - (o d -a m in o -/3 -p h e n y le th y l)te tra z o le * The y i e l d a f t e r f i l t e r i n g and d i y i n g w as 25*9 g .» m .p . 2 6 1 .5 - 2 6 3 ° G ., w ith d e c o m p o s itio n . R e- o c r y s t a l l i z a t i o n fro m w a te r r a i s e d t h e m e ltin g p o i n t t o 2 7 0 * 5 -2 7 1 * 5 C . , w i t h d é c o m p o s itio n * A n a ly s is . F ound: C a l c u l a t e d f o r C ^H ^N ^: C, 5 7 .1 2 ; H, 5 .8 6 ; N, 3 7 .0 2 * C, 5 6 * 8 5 ; H. 5 .9 5 ; N, 3 7 .2 4 . (c ) «a^-A cetam i d o - o C - ( 5 - t e t r a z o l y l ) - / 3 - p h e n y l p r o p i o n i c a c id * One a n d f i v e - t e n t h s gram s (0*005 m o le) o f e t h y l c < .-a c e ta m id o -o 6 -{ 5 t e t r a z o l y l ) - / 3 - p h e n y l p r o p i o n a t e was added to l 6 m l. o f w a te r c o n t a i n i n g 0 . 8 g . o f sodium h y d r o x id e an d t h e m ix tu r e r e f l u x e d f o r a p e r i o d o f o n e h o u r. T he r e s u l t i n g s o l u t i o n w as f i l t e r e d and th e f i l t r a t e a c i d i f i e d 42 w i t h d i l u t e h y d r o c h l o r i c a c i d t o a pH o f 2 - 3 . S c ra tc h in g i n i t i a t e d t h e fo n a a tiO Q o f a c o l o r l e s s c r y s t a l l i n e p r e c i p i t a t e # A f t e r a llo w in g t h e m ix tu r e t o s t a n d o v e r n i g h t in an i c e - b o x t h e s o l i d was f i l t e r e d a n d a i r d r ie d # The p r o d u c t m e lte d a t a p p r o x im a te ly 110^C* w ith d e­ c o m p o s i tio n , r e s o l i d i f i e d a n d m e lte d a g a i n a t 2 2 4 -2 2 5 ^ 0 . The compound was p u r i f i e d b y d i s s o l v i n g i t i n t e t r a h y d r o f u r a n , d e c o l o r i z i n g t h e s o l u t i o n w i t h N o r i t e a n d r e p r e c i p i t a t i n g w ith p e tr o le u m e t h e r # A n a ly s is . 2 5 .4 5 . (d ) Found: C a lc u la te d f o r C, 5 2 .3 6 ; H, 4 .7 6 ; N, C, 5 2 .6 8 ; H, 5 .0 0 ; N, 2 5 .5 5 . 5 - ( o C -A c e ta m id o -^ -p h e n y le th y l)te tra z o le # T w enty m i l l i g r a m s o f o C - a c e t a m i d o - o c - ( 5 - t e t r a z o l y l ) - / 3 - p h e n y l p r o p i o n i c a c i d was h e a te d a t 170*^0.; a f t e r r e c r y s t a l l i z a t i o n from w a te r i t m e lte d a t 2 2 6 ^0 . A m ix tu r e m e l t i n g p o i n t w i t h t h e p r o d u c t fo rm ed b y t h e a c é t y l a t i o n o f 5 - ( ^ - Q J o i n o - ^ - p h e n y l e t h y l ) t e t r a z o l e , p a g e 43 , showed no d e p r e s s i o n . (e ) 5 -(o o -A m ino-/3 - p h e n y l e t h y l ) t e t r a z o l e . Two g ra m s (0 .0 0 6 6 m ole) o f e t h y l o 6 - a c e t a m i d o - o 6 - ( 5 - t e t r a z o l y l ) - / 3 - p h e n y l p r o p i o n a t e was r e f l u x e d i n 25 m l. o f c o n c e n t r a t e d h y d r o c h lo r i c a c id f o r two h o u r s . A t t h e en d o f t h i s tim e t h e pH o f th e s o l u t i o n was a d j u s t e d t o a p p r o x im a te ly 5 w ith ammonium h y d r o x id e a t w hich p o i n t a p r œ l p i t a t e s t a r t e d t o fo rm ; a t a pH o f 6 th e p r e c i p i t a t i o n w as c o m p le te . w e ig h e d , 1 .2 g . (96% o f t h e o r y ) . F i l t e r e d an d d r i e d , t h e s o l i d The m a t e r i a l was r e c r y s t a l l i z e d frcm w a t e r t o g iv e Q .9 g . (72% of t h e o r y ) , o f p u re p r o d u c t , m .p . 2 7 6 -2 7 7 ° C ., w ith d e c o m p o s itio n . A m ix tu r e m e ltin g p o i n t w i t h a n a n a l y t i c a l sam p le o f 5 -( o ^ -u m in o - 43 - p h e n y l e t h y l ) t e t r a z o l e p r ^ a r e d by a d i f f e r e n t m e th o d showed no d e p re s s io n . D e riv a tiv e s 5 -(o C -A c e ta m id o -/3 -p h e n y le th y l)te tra z o le . To 2 0 m l. o f g l a c i a l a c e t i c a c i d w as a d d ed I .8 9 g . ( 0 .0 1 m ole) o f 5 - (ex^ - a m in o - / 3 - p h e n y l e t h y l ) t e t r a 2X)le and 1 . 1 g . o f a c e t i c a n h y d r id e an d th e m ix tu r e r e f l u x e d f o r one h o u r* and w a t e r . The s o l u t i o n w as c o o le d a n d p o u re d on t o 50 g . o f i c e T he r e s u l t i n g s o l i d w as f i l t e r e d and r e c r y s t a l l i z e d from a q u e o u s e t h a n o l to g iv e 1 .7 5 g . o f a c e t y l d e r i v a t i v e , m .p . 2 2 4 .5 - 2 2 5 .5 ^ 0 , A n a ly s is . Found: C a lc u la te d fo r C, 5 7 .1 3 ; H , 5 .6 ? ; N, 3 0 .2 9 . C, 5 7 .1 7 ; H, 5 .7 9 ; N, 3 0 .1 5 . 5 - ( 06-B e n z o y la m in o - / 3 - p h e n y l e t h y l ) t e t r a z o l e . To 0 .9 4 g . (0 .0 0 5 m o le ) o f 5 - ( c C - a m i n o - - p h e n y l e t h y l ) t e t r a z o l e d i s s o l v e d i n 10 m l. o f w a te r c o n t a i n i n g 0 .4 5 g . o f sodium h y d ro x id e was ad d ed 0 .7 g . (0 .0 0 5 m o le ) of benzoyl c h lo rid e . A f t e r s h a k in g th e m ix tu r e s e v e r a l tim e s o v e r a p e r i o d o f two h o u r s th e m ix tu r e was f i l t e r e d and t h e f i l t r a t e a c i d i f i e d w ith d i l u t e h y d r o c h lo r ic a c i d to a pH o f 4 - 5 . The p r e c i p ­ i t a t e w h ich form ed w as r e c r y s t a l l i z e d s e v e r a l tim e s from a q u e o u s o e t h a n o l , m .p . 2 3 4 -2 3 5 G ., w ith d e c o m p o s itio n . A n a ly s is . Found: C a l c u l a t e d f o r C H N O; I d 15 5 C, 6 5 .5 1 ; H, 5 .1 5 ; N, 2 3 .8 8 . 0 , 6 5 .5 2 ; H , 5 .0 0 ; N, 2 3 .9 7 . N -P h e n y l-N *- (o^ - ( 5 - t e t r a z o l y l ) - -p h e n y le th y l )u r e a . One a n d n i n e - t e n t h s g ra m s ( 0 .0 1 m ole) o f 5 - ( o C - a m i n o - / ^ - p h e n y le t h y l) t e t r a z o l e was d i s s o l v e d i n 12 m l. o f a IN p o ta s s iu m h y d r o x id e s o l u t i o n and th e n 44 d i l u t e d w i t h 18 ml* o f w a t e r . One a n d t w o - t e n t h s g ra m s o f p h e n y l i s o c y a n a t e w as a d d e d t o t h e s o l u t i o n and th e m ix tu r e s h a k e n s e v e r a l tim e s o v e r a p e r i o d o f tw o h o u r s . f i l t e r e d and t h e f i l t r a t e c h lo r ic a c id . T h e r e s u l t i n g m ix tu r e w as t h e n a c i d i f i e d to a pH o f 4 -5 w ith d i l u t e h y d ro ­ The p r e c i p i t a t e was f i l t e r e d and r e c r y s t a l l i z e d fro m a q u e o u s e t h a n o l , m ,p , 1 8 8 ,5 - 1 8 9 ,5 ^ 0 ,, w ith d e c o m p o s itio n . A n a ly s is . Found: C a l c u l a t e d f o r C ,H N .O : 1 6 16 D C, 6 2 .4 0 ; H , 5 .2 4 ; N, 2 7 .4 2 . C, 6 2 .3 2 ; H, 5 .2 3 ; N, 2 7 .2 6 . T he P r e p a r a t i o n o f 5 - ( - A m i n o - (3 ' - i n d o l y l ) e t h y l ) t e t r a z o l e (T ry p to p h a n e A n alo g u e) Scheme C (a ) E th y l -a c e ta m id o -o c -c y a n o -/3 -(3 -in d o ly l)p ro p io n a te . In a o n e l i t e r t h r e e n e c k e d f l a s k f i t t e d w i t h a m e c h a n ic a l s t i r e r , r e f l u x c o n d e n s e r a n d n i t r o g e n i n l e t was p la c e d 5 .1 g , o f d r y p o w d ered sodium h y d r o x id e a n d 400 m l. o f d ry t o l u e n e . 9 0 - 9 5 ° C ., and a m ix tu r e o f 75 g . 7 3 .3 g . T he te m p e r a tu r e w as r a i s e d t o ( 0 ,4 3 2 m ole) o f g ra m in e (2 7 ) a n d (0 .4 3 2 m o le ) o f e t h y l a c e ta m i do c y a n o a c e ta te w as a d d ed o v e r a p e r i o d o f tw e n ty m i n u t e s . A f t e r t h e a d d i t i o n was c o m p le te t h e r e a c t i o n s t a r t e d and d im e th y la m in e commenced t o b e l i b e r a t e d . The t a a p e r a t u r e w as r a i s e d t o t h e r e f l u x p o i n t an d h e l d a t t h i s p o i n t f o r tw e lv e h o u r s d u r i n g w h ic h tim e s t i r r i n g an d n i t r o g e n p e r f u s i o n w e re c o n tin u e d . T he r e a c t i o n m ix tu r e w as f i l t e r e d w h ile s t i l l warm an d t h e s o l i d a i r d rie d . S u s p e n s io n o f t h e d r i e d s o l i d i n w a t e r fo llo w e d by f i l ­ t r a t i o n an d d r y in g a t 5 0 ^ 0 ., g a v e 7 6 ,4 g . ( 5 9 . ^ o f th e o r y ) o f th e 45 p r o d u c t , nup« 193-195*^0. R e c r y a t a l l l z a t l o n from a q u e o u s e t h a n o l o r n o rm a l b u t y l a l c o h o l r a i s e d t h e m e l t i n g p o i n t t o 1 9 5 * 5 -1 9 7 ^0 * T h i s compound i s r e p o r t e d b y A l b e r ts o n an d T u l l a r (26) t o m e l t a t 1 9 6 -1 9 8 ° C . E t h y l eC - a c e t M i l d o - gb- ( 5 - t e t r a z o l y l ) - (b ) - ( 3 * -ln d o ly l) p r o p io n a te . To 19*5 g* (0 . 3 m o le) o f so d iu m a z i d e i n 50 m l. o f d r y t e t r a h y d r o f u r a n w as a d d ed 1 3 .3 g* ( 0 .1 m ole) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 200 m l. o f th e same s o l v e n t . T he r e s u l t i n g m ix tu r e was h e a te d t o r e f l u x te m p e r a t u r e w ith c o n tin u e d s t i r r i n g f o r one h o u r. A f t e r a llo w ­ in g th e m ix tu r e t o c o o l to room te n g a e ra tu re 29*9 g* ( 0 .1 m ole) o f e t h y l o 6 - a c e t a m l d o - a C - c y a n o - - ( 3 - l n d o l y 1 ) p r o p l o n a t e was a d d e d an d r e f l u x i n g a n d s t i r r i n g c o n tin u e d f o r a n a d d i t i o n a l tw e n t y - f o u r h o u r s . A t th e en d o f t h i s tim e 150 m l. o f w a t e r w as ad d ed t o t h e r e a c t i o n m ix tu r e f o llo w e d o b y c o o lin g w i t h a n i c e - w a t e r b a th t o 5 C . To th e c o o le d m ix tu r e w as a d d e d 50 m l. o f c o n c e n t r a t e d h y d r o c h lo r ic a c i d o v e r a p e r i o d o f tw e n ty m in u te s . T h e c o n t e n t s o f t h e f l a s k w e re th e n p o u re d i n t o 300 m l. o f e t h e r a n d th e o r g a n i c l a y e r s e p a r a t e d . The a q u e o u s l a y e r was w ashed w i t h 100 m l. o f a m ix tu r e o f e q u a l v o lim e s o f e t h e r an d t e t r a h y d r o f h r a n , t h e o r g a n i c l a y e r s c c c ib in e d , w ashed w ith 100 m l. o f w a t e r an d d r i e d o v e r sod iu m s u l f a t e . R em oval o f th e o r g a n i c s o l v e n t i n v acu o l e f t a s o l i d r e s i d u e W iich w as d i s s o l v e d in 500 m l. o f b o i l i n g c h lo r o f o r m . Upon c o o lin g i n an i c e - w a t e r b a t h t h e r e was d e p o s i t e d a c r y s t a l l i n e p r e c i p i t a t e w hich was f i l t e r e d a n d d r ie d * C o n c e n t r a t i o n o f t h e m o th e r l i q u o r y i e l d e d a n a d d itio n a l b a tc h o f p ro d u c t. C o m b in a tio n o f t h e s o l i d s g a v e 1 1 .1 g ra m s (32.5% o f t h e o r y ) , o f th e d e s i r e d p r o d u c t , m .p . l 7 8 - l 8 l ^ C . 46 R e c r y s t a l l i z a t i o n fro m c h lo r o f o r m r a i s e d t h e m e l t i n g p o i n t t o 1 8 3 . 5- 1 8 5 w ith s l i g h t d e c a m p o s itio n . A n a ly s is . Found: C a lc u la te d f o r C, 5 6 .1 3 ; H, 5*30; N , 2 4 .5 5 * C , 5 6 .0 0 ; H, 5* 2 9 ; N , 2 4 .5 4 * (c ) -A c e t ami d o - 06- ( 5 * - te t r a z o l y l ) - /&- ( 3 - i n d o l y l ) p r o p io n i c a c i d . S ix and e i g h t - t e n t h s gram s ( 0 .0 2 m ole) o f e t h y l o c -a c e ta m id o -o C -(5 t e t r a z o l y l ) - ( 3 - l n d o l y 1 ) p r o p i o n a t e an d 3*2 g . (0 .0 8 m o le) o f sodium h y d r o x id e w e re h e a t e d i n 32 m l. o f w a t e r a t r e f l u x t e n t e r a t u r e f o r f o u r h o u rs. The r e s u l t i n g s o l u t i o n w as t r e a t e d w ith N o r i t e , f i l t e r e d an d a c i d i f i e d w i t h 8 ,4 m l. o f c o n c e n t r a t e d h y d r o c h lo r ic a c i d ( 0 .1 0 m o le ) . C o n tin u e d c o o l i n g and s c r a t c h i n g c a u s e d th e f o r m a tio n o f a c r y s t a l l i n e p re c ip ita te . A f t e r a llo w in g t h e m ix tu r e to re m a in o v e r n i g h t i n a n i c e ­ b o x t h e s o l i d w as f i l t e r e d an d w ashed w ith a s m a ll am ount o f c o l d w a t e r . o D ry in g gave 4*0 g . (64% o f th e o r y ) o f th e p r o d u c t, m .p . 1 4 6 -1 5 0 0 . , w ith d e c o m p o s itio n . R e c r y s t a l l i z a t i o n from w a te r r a i s e d t h e m e ltin g p o i n t to 1 5 3 - 1 5 5 ^ 0 ., w i t h d e c o m p o s itio n . A n a ly s is . T he p r o d u c t c r y s t a l l i z e d a s a d i h y d r a t e . C a l c u l a t e d f o r C ^ ^ ^ ^ ^ 0 ^ .2 H ^ 0 : N, 2 3 * 9 9 . Found: N, 24*15 an d 2 3 . 8 9 . C a lc u la te d f o r C H : 1 4 14 ® 3 (d) N, 2 6 .7 4 . Found: N, 2 6 .6 5 * 5 -(o c -A c e ta n iid o -/5 -(3 * -iu d o ly l)e th y l)te tra z o le . S ev en and f o u r - t e n t h s g ra m s ( 0 .0 2 4 m ole) o f « s d -a c e ts s n id o - o c -(5 * - t e t r a z o l y l ) - / 3 ( 3 - i n d o l y l ) p r o p i o n i c a c i d was h e a t e d a t r e f l u x t e n t e r a t u r e in 200 m l. o f w a te r f o r two and a h a l f h o u r s . The r e s u l t i n g s o l u t i o n was th e n t r e a t e d w ith N o r i t e a n d f i l t e r e d w h i le h o t . C o o lin g o f th e f i l t r a t e 47 c a u s e d t h e f o r m a t i o n o f a p r e c i p i t a t e w h ich vthen f i l t e r e d and d r i e d am o u n ted t o 5 . 8 g . ( 91. 4% o f t h e o r y ) , m .p . 2 2 0 . 5- 2 2 1 . 5 *^0 . , w ith decomp­ o s itio n . R e c r y s t a l l i z a t i o n fro m w a te r r a i s e d th e m e ltin g p o i n t t o 2 2 3 2 2 3 .5 ^ 0 ., w ith d e c c m p o s itio n . A n a ly s is . Found: (e ) C a lc u la te d f o r G, 5 7 .7 6 ; H, 5 .2 2 ; N, 3 1 .1 0 . C, 5 7 .8 7 ; H, 5 .2 6 ; N, 3 1 .1 8 . 5- (oc -Ami no - /8 - ( 3 *- j ndo l y l ) e t h y l ) t e t r a zo l e . One an d t h r e e - t e n t h s g ram s (0 .0 0 5 m o le ) o f 5 - ( ^ - a c e t a m i d o - ^ - ( 3 * - i n d o l y l ) e t h y l ) t e t r a z o l e was d i s s o l v e d i n 16 m l. o f w a t e r c o n t a i n i n g 1 . 3 g . o f sodium h y d r o x id e a n d th e s o l u t i o n r e f l u x e d f o r tw e lv e h o u r s . W ith o u t a llo w ­ in g th e s o l u t i o n t o c o o l to any e x t e n t 2 .7 m l. o f c o n c e n t r a t e d h y d ro ­ c h l o r i c a c i d was a d d e d a l l a t once and th e pH a d j u s t e d t o 5 wL t h d i l u t e ammonium h y d r o x id e s o l u t i o n . C o o lin g and s c r a t c h i n g c a u s e d t h e f o r m a ti o n o f a c r y s t a l l i n e p r e c i p i t a t e w h ich was f i l t e r e d and d r i e d . w e ig h e d 0 . 8 g . The p r o d u c t (70% o f t h e o r y ) , m .p . 246-249*^0., w ith d e c o m p o s itio n . R e c r y s t a l l i z a t i o n from w a te r r a i s e d th e m e ltin g p o i n t t o 2 6 8 .5 - 2 6 9 ^ 0 ., w i t h d e c o m p o s itio n . A n a ly s is . Found: C a l c u l a t e d f o r C^^H^ C, 5 7 .8 8 ; H, 5 .3 0 ; N, 3 6 . 8 2 . C, 5 7 .8 3 ; H , 5 .4 7 ; N, 3 6 .9 2 . The D e te r m in a t io n o f t h e A p p a re n t pK V a lu e s o f Some 5 -A m in o a lk y lt e t r a z o l e s The a p p a r e n t pK v a l u e s o f t h e 5 - a r a i n o a l k y l t e t r a z o l e s w ere d e te r m in e d b y t i t r a t i o n o f w eig h ed s a m p le s i n a q u e o u s s o l u t i o n w ith s ta n d a r d so d iu m h y d r o x id e and h y d r o c h l o r i c a c i d s o l u t i o n s . T he w eig h ed sa m p le s w ere 48 t r a n s f e r r e d t o a t h r e e n e c k e d , 250 m l. f l a s k and d i s s o l v e d i n 1 0 0 -1 2 5 m l. o f w a t e r . a t 25 dr 1 °G . T he s o l u t i o n was t h e n t i t r a t e d i n a th e r m o s ta te d b a t h The pH was d e te r m in e d a f t e r e a c h a d d i t i o n o f t i t r a n t w i t h a Beckman pH M e te r , M odel H -2 . From t h e s e d a t a th e r e g i o n o f h a l f n e u t r a l i z a t i o n was p l o t t e d on a l a r g e s c a l e a n d t h e b e s t s t r a i g h t l i n e d ra w n . The pH a t t h e m id - p o in t o f t h i s l i n e was d e te rm in e d fro m t h e p l o t a n d a s s i g n e d th e v a lu e o f t h e pK o f t h e f u n c t i o n a l g ro u p b e in g t i t r a t e d . T he t i t r a t i o n c u r v e s i n e a c h i n s t a n c e e x h i b i t e d t h e form n o rm a lly o b t a i n e d f o r a n am ino a c i d . C o m p a riso n o f th e and pK^ v a lu e s o f th e am ino a c i d s a n d th e t e t r a z o l e a n a lo g u e s a r e p r e s e n t e d i n T a b le I . The d a ta f o r th e p o t e n t i o m e t r i e t i t r a t i o n s a r e r e c o r d e d i n A p p en d ix I . PART I I TETRAZOLE ANALOG-UES OF ACTIVE AMINOBENZOIC A C ID D ERIVA TIVES D is c u s s i o n D u rin g r e c e n t y e a r s two a ra in o b e n z o ic a c id d e r i v a t i v e s h a v e b e en p ro m in e n t i n c h e m o th e ra p y * P a r a - a m in o b e n z o ic a c i d i t s e l f p l a y s a u n iq u e r o l e i n m e ta b o lis m a s a p o r t i o n o f f o l i c a c i d ( I ) , an e s s e n tia l m a te r i a l f o r th e s y n t h e s i s o f n u c l e i c a c i d s . y C O m C E ( CHg ) gCOgH C02H E v id e n c e t h a t c e r t a i n d ru g s s t r u c t u r a l l y r e l a t e d t o p a r a - ami opb e n z o ic a c i d c o u ld i n h i b i t i t s i n c o r p o r a t i o n i n t o f o l i c a c id (2 9 ) r e ­ s u l t e d fro m th e a p p l i c a t i o n o f t h e a n t i m e t a b o l i t e c o n c e p t in chemo­ t h e r a p y a s a m eans o f c o m b a tin g b a c t e r i a l in v a s i o n o f th e b o d y . T h o se d r u g s v h ic h have b e e n m o st e f f e c t i v e i n i n t e r f e r i n g w ith th e u t i l i z a t i o n o f p a r a ami no b e n z o l c a c i d l^ v e b e e n shown to b e r e l a t e d to s u lfa n ila m id e (II) (3 0 ). One o f th e b e s t b a c t e r i o s t a t i c d r u g s t o r e s u l t fro m e x t e n s i v e i n v e s t i g a t i c n s i s s u lfa th ia z o le (III) (3 1 )» lA iich i s m o st w id e ly u s e d i n th e t h e r a p y o f s ta p h y l o c c o c c a l an d pneumo­ coccal in fe c tio n s . 50 HG II N III The s e c o n d d e r i v a t i v e o f a in in o b e n z o ic a c i d , im p o r ta n t f o r i t s tu b e rc u lo s ta tic a c tiv ity ( 3 2 ) , i s 2 - h y d r o x y - ^ - a m in o b e n z o ic a c i d commonly r e f e r r e d to a s p a r a - a m in o s a lic y lic a c id . I n v ie w o f t h e s i m i l a r i t y o f 5- m o n o s u b s tit u te d t e t r a z o l e s to c a r b o x y l i c a c i d s , th e s y n t h e s i s o f t e t r a z o l e s r e l a t e d t o p a r a - a m in o b e n zo io a c i d and 2 -h y d r o x y -4 -a n iin o b e n z o ic a c i d was u n d e r ta k e n . T he r e s p e c t i v e n i t r o p h e n y l t e t r a z o l e s w e re r e a d i l y s y n th e s iz e d from s u b s t i t u t e d b e n z o n itrile s . R e d u c tio n o f t h e n i t r o p h e n y l t e t r a z o l e s l e d t o t h e d e s i r e d a m in o p h e n y lte tra z o le s . A c c o r d in g ly , $ - ( 4 '- a m i n o p h e n y l ) t e t r a z o l e (IV ) w as o b t a i n e d i n good y i e l d s th r o u g h th e r e d u c t i o n o f 5 - ( 4 * - n i t r o p h e n y l ) t e t r a z o l e u s in g tin and h y d r o c h lo r i c a c i d . IV 51 5 " ( 3 ’—A m in o p h e n y l)t e t r a z o l e , a l s o p r e p a r e d f o r e v a l u a t i o n a s an a n t i ­ m e t a b o l i t e f o r p a r a —a m in o b e n z o lc a c i d , was s y n t h e s i z e d fro m th e c o r r e s ­ p o n d in g n i t r o compound u s in g e i t h e r z in c and h y d r o c h l o r i c a c id o r h y d ro g e n a n d p la tin u m o x id e c a t a l y s t a s r e d u c in g a g e n t s . 5 * ( 2 ’-H y d ro x y - 4 *—a m in o p h e n y l) te tr a 2 5 o le , t h e a n a lo g u e o f p a r a - a m i n o s a l i c y l i c a c i d , was p r e p a r e d frcan 5 - ( 2 ’- h y d r o x y - 4 ’- n i t r o p h e n y l ) t e t r a z o l e b y r e d u c t i o n w i t h h y d ro g e n and p la tin u m o x id e . T he h i g h m e ltin g a m i n o p h e n y l t e t r a z o l e s , w h ic h c o u ld b e r e a d i l y r e c r y s t a l l i z e d frcm w a te r o r a q u eo u s e t h a n o l , p o s s e s s a m p h o te ric c h a r a c t e r ; th e y a r e r e a d i l y s o l u b l e i n b o th a q u eo u s a c i d s and a q u e o u s a lk a lie s . The a c e t y l d e r i v a t i v e s , u s e d t o c h a r a c t e r i z e th e a m in o p h e n y l­ t e t r a z o l e s , w e re p r e p a r e d by r e f l u x i n g ttie r e s p e c t i v e a m in e s w ith g l a c i a l a c e t i c a c i d c o n t a i n i n g a n e q u i v a l e n t am ount o f a c e t i c a n h y d r id e . T h e n i t r o p h e n y l t e t r a z o l e s u s e d a s i n t e r m e d i a t e s f o r t h e a m in o p h e n y lte tra z o le s y n th e s e s w ere p r e p a r e d from th e c o r r e s p o n d in g n i t r o - b e n z o n i t r i l e s a c c o r d in g t o t h e p r o c e d u r e s o f H e r b s t and W ils o n (3 ) by h e a t i n g t h e a r y l c y a n id e s w ith so d iu m a z i d e an d g l a c i a l a c e t i c a c i d i n n o rm a l b u t y l a l c o h o l a t r e f l u x te m p e r a tu r e f o r s e v e r a l d a y s . W ith t h e e x c e p tio n o f 2 - h y d r o x y - 4 - n i t r o b e n z o n i t r i l e th e n i t r o b e n z o n i t r i l e s w ere c o m m e rc ia lly a v a i l a b l e . 2-H yd r o x y - 4 - n i t r o b e n z o n i t r i l e w as s y n t h e s i z e d by a s e r i e s o f r e a c t i o n s s t a r t i n g w i t h p h e n y l a c e t i c a c i d (3 3 ) w h ic h may be i l l u s t r a t e d s c h e m a t i c a l l y a s f o ll o w s : fj V \ fu m in g // O2 N-V HNO^ \ \VnH2C0^ \\ ^VgH2C0^ ■—/ HCl --------C H ^H 52 0 —1\ n -b u t y l V- n itrite 5 1 . KOE C— 2* HCl - ’- A m i n o p h e n y l) t e tr a z o le , 5 - ( 3 ’- a m i n o p h e n y l ) t e t r a z o l e an d t h e i r d e r i v a t i v e s , a s w e ll a s 5 - ( 2 * - h y d r o x y - 4 * - a m in o p h e n y l) te tr a z o le w e re s u b m itte d f o r p h a rm a c o lo g ie a l s c r e e n i n g . E x p e r im e n ta l The P r e p a r a t i o n o f N i t r o p h e n y l t e t r a z o l e s 5 * (2 * * N itro p h e n y l)te tra z o le # 0 .1 7 m o le ) , 1 6 .2 g . O r th o - n i t r o b e n z o n i t r i 1 e (25 g . , ( 0 .2 5 m o le) o f sodium a z i d e a n d 15 g . (0 .2 5 m ole) o f g l a c i a l a c e t i c a c i d w e re a d d ed t o 100 m l. o f n o rm a l b u t y l a l c o h o l an d th e m ix tu r e r e f l u x e d f o r f o u r d a y s . A t th e end o f t h i s tim e an a d d i t i o n a l 5 g* o f sodium a z id e an d 10 g , o f g l a c i a l a c e t i c a c i d w ere a d d e d an d th e h e a t i n g c o n tin u e d f o r a n a d d i t i o n a l two d a y s . The co n ­ t e n t s o f t h e f l a s k w ere t h e n t r a n s f e r r e d to a l a r g e r f l a s k , 200 m l. o f w a t e r a d d ed an d th e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c o h o l h a d b e e n re m o v e d . The s o l u t i o n w as f i l t e r e d , and th e f i l t r a t e t r e a t e d w ith c o n c e n t r a t e d h y d r o c h l o r i c u n t i l a p r e c i p i t a t e no l o n g e r fo rm e d . The s o l i d w as f i l t e r e d and d r i e d ; th e y i e l d o f c ru d e p r o d u c t was 1 2 .2 g . (37*6% o f t h e o r y ) . R e c r y s t a l l i z a t i o n from w a t e r g a v e a c o l o r l e s s c r y s t a l l i n e p ro d u c t ( n e e d le s ) m e l t i n g a t 1 5 9 # 5 - l6 l° C . A n a ly s is . Found: C a lc u la te d f o r C , 43*99; H, 2 .6 4 ; N, 3 6 . 6 4 * C, 44 * 1 3 ; H, 2 . 8 4 ; N, 36.3 7 * 5 - ( 3 * -N itro p h e n y l)te tra z o le . (a ) P r e p a r a t i o n from a B enzene S o l u t i o n o f H y d ra z o ic A c id . n itro b e n z o n itrile M e ta - ( 1 5 .6 g . , O .IO 6 m ole) was a d d ed t o 50 m l. o f x y le n e c o n t a i n i n g 6 . 8 g . o f h y d r a z o i c a c i d an d th e m ix tu r e s e a l e d i n a P y r e x c o m b u s tio n tu b e w hich in t u r n was h e a t e d f o r 125 h o u rs a t 1 4 0 -1 4 5 ^ 0 . A t th e en d o f t h i s tim e t h e tu b e w as c o o le d and o p e n ed , a n d th e c o n t e n t s 54 w a sh e d o u t w i t h a s m a ll am ount o f b e n z e n e . C h i l l i n g o f th e b e n z e n e — x y le n e m ix tu r e g a v e a c r y s t a l l i n e m a t e r i a l w h ic h was f i l t e r e d an d d r ie d # R e c r y s t a l l i z a t i o n o f t h e p r o d u c t from w a t e r , u s in g N o r i t e t o d e c o l o r i z e t h e s o l u t i o n , g a v e 8 ,6 g# (3 9 * 0 ^ o f th e o r y ) o f a c r y s t a l l i n e s o l i d m e ltin g a t 1 5 0 .5 -1 5 1 # 5 ^ C . A n a ly s is . Found: C a lc u la te d f o r C, 4 3 * 9 9 ; H, 2 .6 4 ; N, 3 6 . 6 4 * C, 44*19; H, 2 .6 8 ; N, 3 6 .9 3 * T h i s ccanpound i s r e p o r t e d by L o s s e n (34) to m e lt a t 145 C. (b ) P r e p a r a t i o n fro m Sodium A z id e an d G l a c i a l A c e tic A c id . M eta - n i t r o b e n z o n i t r i l e , ( 3 2 .5 g . , 0 .2 5 m o le ) , 22 g . o f sodium a z i d e an d 20 g . o f g l a c i a l a c e t i c a c i d w ere h e a t e d a t r e f l u x te m p e r a tu r e n o rm a l b u t y l a l c o h o l f o r f o u r d a y s . i n 100 m l. o f A t t h e en d o f t h i s tim e an a d d i t i o n ­ a l 5 g* o f so d iu m a z id e and 10 g . o f g l a c i a l a c e t i c a c i d w e re a d d e d and th e r e f l u x i n g c o n tin u e d f o r two m o re d a y s . The r e a c t i o n m ix tu r e w as th e n p o u re d i n t o a l a r g e r f l a s k , 300 m l. o f w a t e r a d d e d and th e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c o h o l h a d been rem o v ed . C o o lin g o f t h e a q u e o u s , r e s i d u a l s o l u t i o n c a u s e d th e s e p a r a t i o n o f a pal© y e llo w s o l i d w h ic h i ^ e n f i l t e r e d a n d r e c r y s t a l l i z e d fro m w a te r , u s in g N o rit© to rem ove t h e c o l o r , g a v e 4 1 * ^ g . (87.5% o f th e o r y ) o f t h e p a l e , y e llo w p r o d u c t ( n e e d l e s ) , m .p . 1 5 0 .5 - 1 5 1 .5 °G. A m ix tu r e m e l t i n g p o in t w i t h t h e p r o d u c t fo rm ed fro m th e s e a l e d t u b e r e a c t i o n o f m e ta - n i t r o b e n z o n i t r i l e and h y d ra z o ic a c id showed no d e p re s s io n . 5 -(4 * -N itro p h e n y l)te tra z o le (a ) P r e p a r a t i o n from a B enzene S o l u t i o n o f H y d ra z o ic A c id . P a ra - 55 n i tro b © n z o n i t r i l e { 1 5 .6 g . , 0 .1 0 6 m ole) was a d d e d t o 50 m l. o f x y le n e c o n ta in in g 6 .8 g . (0 .1 5 8 m o le ) o f h y d r a z o ic a c i d and th e m ix tu r e s e a l e d i n a P y r e x c o m b u s tio n t u b e . a t 1 4 0 -1 4 5 ^ 0 . f o r 125 h o u r s . The tu b e and i t s c o n t e n t s w e re t h e n h e a te d A f t e r t h i s tim e th e tu b e w as a llo w e d t o c o o l , o p e n e d and th e c o n t e n t s w ash ed o u t w i t h a s m a ll am ount o f b e n z e n e . The s o l i d m a t e r i a l w as f i l t e r e d a n d r e c r y s t a l l i z e d from a b s o l u t e e t h a n o l u n t i l t h e c o l o r l e s s , c r y s t a l l i n e p r o d u c t m e lte d a t 2 1 8 . 5- 2 1 9 *^0 . T he c ru d e y i e l d am ounted t o l 6 , 6 g . (77% o f t h e o r y ) . A n a ly s is . Found: C a l c u l a t e d f o r CyH^N^O^: C, 4 3 .9 9 ; H , 2 .6 4 ; N , 3 6 . 6 4 . C, 4 4 .1 5 ; H, 2 .7 0 ; N, 3 6 .7 4 . T h is compound i s r e p o r t e d by P in n e r (35) t o m e lt a t 2 1 9 ^ 0 . (b) P r e p a r a t i o n from Sodium A z id e and G l a c i a l A c e tic A c id . n itro b e n z o n itrile P a ra - (3 2 .5 g .» 0 .2 5 m o le ), 22 g . o f sodium a z i d e a n d 20 g , o f g l a c i a l a c e t i c a c i d w e re a d d e d to 100 m l. o f n o rm al b u t y l a l c o h o l an d t h e m ix tu r e h e a t e d a t r e f l u x te m p e r a tu r e f o r f o u r d a y s . A t th e end o f t h i s tim e a n a d d i t i o n a l 5 g . o f sodium a z i d e an d 1 0 g . o f g l a c i a l a c e t i c a c i d w e re a d d e d and th e h e a t i n g c o n tin u e d f o r two more d a y s . The r e a c t i o n m ix tu r e w as t h e n t r a n s f e r r e d t o a l a r g e r f l a s k , 300 m l. o f w a t e r a d d e d a n d t h e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c o h o l h ad b e e n re m o v e d . On c o o lin g th e c l e a r s o l u t i o n a y e llo w p r e c i p i t a t e fo rm ed w h ich w as f i l t e r e d an d d r i e d . The s o l i d was th e n d i s s o l v e d i n a minimum am ount o f h o t w a te r and t r e a t e d w ith c o n c e n t r a t e d h y d r o c h l o r i c a c i d u n t i l t h e s o l u t i o n w as a c i d t o Congo r e d p a p e r . D u rin g t h e a c i d i f i c a t i o n a p r e ­ c i p i t a t e fo im e d w h ic h , a f t e r c o o l i n g , was f i l t e r e d and d r i e d . T h is c ru d e p r o d u c t am ounted to 3 7 .0 g . (77.8% o f t h e o r y ) , and c o u ld b e f u r t h e r p u r i f i e d by r e c r y s t a l l i z a t i o n fro m w a t e r , m .p . 2 1 8 . 5- 2 1 9°C, 56 A m ix tu r e m e l t i n g p o i n t d e t e r m i n a t i o n w i th th e p r o d u c t from t h e r e a c t i o n o f p a r a - n i t r o b e n z o n i t r i l e an d h y d r a z o ic a c i d in a s e a l e d tu b e show ed no d e p r e s s i o n . 5 - (2 *-H y d ro x y -4 * - n i t r o ï h e n y l ) t e t r a z o l e . n itrile (33) 2 - H y d r o x y - 4 - n itr o b e n z o - ( 4 1 .0 g . , 0 .2 5 m o le ) , 22 g ♦ o f so d iu m a z i d e an d 20 g . o f g l a c i a l a c e t i c a c id w e re h e a t e d a t r e f l u x te m p e r a t u r e i n 100 m l. o f n o rm a l b u t y l a l c o h o l f o r s i x d a y s . A t th e end o f t h i s tim e th e r e a c t i o n m ix tu r e w as t r a n s f e r r e d t o a l a r g e r f l a s k , 300 m l. o f w a te r a d d e d and d i s t i l l e d u n t i l 250 m l. o f d i s t i l l a t e h a d b e e n c o l l e c t e d . On c o o l i n g a s o l i d c r y s t a l l i z e d fro m th e r e s i d u a l s o l u t i o n ; th e s o l i d w as f i l t e r e d and r e c r y s t a l l i z e d tw ic e fro m w a te r t o g i v e 5 3 .5 g . (86.6% o f th e o ry ) o f p u re p ro d u c t. A n a l y t i c a l d a ta i n d i c a t e s t h a t t h i s w as th e sodium s a l t o f th e c o r r e s p o n d in g t e t r a z o l e . A n a ly s is . C a l c u l a t e d f o r G ^^N ^O ^N a: N, 3 0 .5 7 . Found: N, 3 0 .3 7 an d 3 0 . 1 4 . The so d iu m s a l t w as c o n v e r te d q u a n t i t a t i v e l y i n t o t h e f r e e t e t r a z o l e b y t r e a t i n g a h o t a q u e o u s s o l u t i o n o f th e sodiim i s a l t w ith c o n c e n t r a t e d h y d r o c h l o r i c a c id u n t i l i t w as a c i d t o Congo r e d p a p e r . The m ix tu r e was t h e n c o o le d , f i l t e r e d an d t h e p r o d u c t r e c r y s t a l l i z e d from e th a n o l , m .p . 283- 2 8 3 . 5 ^0 . , w ith d e c o m p o s itio n . A n a ly s is . Found: C a l c u l a t e d f o r C ^^N ^O ^: C, 4 0 .7 2 ; C, 4 0 .5 9 ; H, 2 .4 3 ; N, 3 3 .8 1 . H, 2 .8 2 ; N , ,3 3 ^ 7 2 , The P r e p a r a t i o n o f A m in o p h e n y lte tr a z o le s 5 - ( 3 * - A m in o p h e n y l) t e tr a z o le . C o n c e n tr a te d h y d r o c h l o r ic a c id 57 (85 m l .) w as a d d e d t o a m ix tu r e o f 1 7 .2 g . (0 .0 9 m o le) o f 5 - ( 3 * - n i t r o - p h e n y l) t e t r a z o l e and 35 g . o f g r a n u l a r t i n c o n ta i n e d i n a 300 m l . , t h r e e n e c k e d fla s k . The r e a c t i o n s t a r t e d a lm o s t im m e d ia te ly and c o o lin g w as n e c e ssa ry . A fte r s t i r r i n g th e r e a c t i o n m ix tu r e f o r a n a d d i t i o n a l f i f t e e n m in u te s th e c l e a r s o l u t i o n was d e c a n te d fro m t h e u n r e a c te d t i n v d iich w as t h e n w ashed w ith a s m a ll am ount o f w a t e r . The w a s h in g s w ere com bined w i t h t h e d e c a n te d a c i d s o l u t i o n and th e r e s u l t i n g m ade b a s i c w i t h cone a i t r a t e d ammonium h y d r o x id e . s o lu tio n T he t i n h y d r o x id e w as f i l t e r e d an d th e f i l t r a t e made a c i d w i t h g l a c i a l a c e t i c a c i d u n t i l a p r e c i p i t a t e no l o n g e r fo rm ed on th e a d d i t i o n o f m ore a c i d . The c r u d e 5 - ( 3 * - u m i n o p h e n y l ) t e t r a z o l e was f i l t e r e d and d r i e d g i v i n g 1 1 .5 g . (79.5% o f th e o r y ) o f a c o l o r l e s s c r y s t a l l i n e s o l i d w h ich may b e f u r t h e r p u r i f i e d b y r e c r y s t a l l i z a t i o n from w a te r , m .p . 1 9 9 -2 0 0 ^ 0 . A n a ly s is . Found: C a lc u la te d f o r C ^^N ^i C, 5 2 .1 7 ; H , 4 .3 8 ; N, 4 3 .4 6 . C , 5 2 .1 2 ; H, 4 .4 9 ; N , 4 3 .1 1 . 5 - ( 4 *- Ami n opheny 1 ) t e t r a z o l e (a ) te tra z o le necked a c id . R e d u c tio n U sin g T in an d H y d ro c h lo ric A c id . 5 - ( 4 '- N i t r o p h e n y l ) - (1 7 .2 g . , 0 .0 9 m o le) and 35 g . o f g r a n u l a r t i n i n a 300 m l. tw o f l a s k w ere t r e a t e d w ith 75 m l. o f c o n c e n t r a t e d h y d r o c h l o r i c C o o lin g was n e c e s s a r y o nce t h e r e a c t i o n s t a r t e d . IVhen th e r e a c t i o n h a d s u b s i d e d , th e c l e a r h o t s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l f i f t e e n m in u te s an d th e n d e c a n te d fro m th e u n r e a c t e d t i n . The t i n was w ashed w i t h a s m a ll am ount o f w a te r an d th e w a sh in g s com bined w ith t h e h y d ro c h lo ric a c id s o lu tio n . The a c id s o l u t i o n was made s t r o n g l y b a s i c w i t h c o n c e n t r a t e d ammonium h y d r o x id e , th e s ta n n o u s h y d ro x id e f i l t e r e d 58 a n d w a sh e d w ith d i l u t e ammonium h y d r o x id e and th e b a s i c s o l u t i o n n e u t r a l i z e d w ith g l a c i a l a c e t i c a c id u n t i l a p r e c i p i t a t e no lo n g e r form ed* F i l t r a t i o n a n d d r y in g o f th e s o l i d g a v e 1 2 .7 g . (87.5% o f th e o r y ) o f th e c r u d e p r o d u c t , w h ic h may b e f u r t h e r p u r i f i e d by r e c r y s t a l l i z a t i o n fro m e t h a n o l - w a t e r m ix tu r e , m .p . 2 6 7 ^ 0 ., w ith d e c o m p o s itio n . A m ix tu r e m e l t i n g p o i n t w i t h th e p r o d u c t from th e c a t a l y t i c r e ­ d u c t i o n o f th e c o r r e s p o n d in g n i t r o compound show ed n o d e p r e s s i o n i n t h e d e c o m p o s itio n p o i n t . (b ) R e d u c tio n U s in g P la tin u m O xide an d H y d ro g e n . te tra z o le 5 - ( 4 ’- N i t r o p h e n y l ) - ( 7 .3 g . , 0 .0 3 8 2 mole)^ s u sp e n d e d i n 150 m l. o f g l a c i a l a c e t i c a c i d ,w a s s h a k e n w ith 150 mg. o f p la tin u m o x id e i n a h y d ro g e n a tm o s p h e re a t a n i n i t i a l p r e s s u r e o f 4 8 .5 p . s . i . A t th e end o f tw e n ty - f o u r h o u r s t h e t h e o r e t i c a l am ount o f h y d ro g e n h a d b e e n ta k e n up and th e c h i l l e d s u s p e n s io n o f c a t a l y s t a n d a w h ite s o l i d was f i l t e r e d w ith s u c t i o n . T h e s o l i d s w e re t r e a t e d w ith h o t e t h a n o l , t h e p la tin u m f i l t e r e d an d th e a l c o h o l rem oved i n a vacuum . o ff The s o l i d r e s i d u e w as r e c r y s t a l l i z e d frc m e t h a n o l - w a t e r m i x tu r e , u s in g No r i t e t o d e c o l o r i z e th e s o l u t i o n , g i v i n g 5 .0 g . (8 l.5 % o f th e o r y ) o f 5 - ( 4 '- a m i n o p h e n y l ) t e t r a z o l e a s c o l o r l e s s n e e d l e s m e l t i n g w ith d e c o r c p o s itio n a t 2 6 7 ^ 0 . A n a ly s is . Found: C a l c u l a t e d f o r C^H^N^: C, 5 2 .1 7 ; H , 4 . 3 8 ; N , 4 3 . 4 6 . C, 5 1 .9 3 ; H, 4 .3 4 ; N, 4 3 .2 9 . 5 - ( 2 *- H y d r o x y - 4 '- a m i n o p h e n y l ) t e t r a z o l e . o f 5 - ( 2 '- h y d r o x y - 4 ' - n i t r o p h e n y l ) t e t r a z o l e The h y d r a te d sodium s a l t (2 4 .7 g . , 0 .1 0 m o le) was s u s p e n d e d i n 1 5 0 m l. o f w a te r w it h 250 mg. o f p la tin u m o x id e and 59 h y d r o g e n a te d a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . A f te r tw e n ty -fo u r h o u r s th e r e a c t i o n was c c m p le te and t h e c a t a l y s t w as f i l t e r e d o f f . The f i l t r a t e w as h e a t e d w ith a s m a ll am ount o f a sodium h y d ro s u l f i t e s o l u t i o n to rem ove a n y t r a c e s o f o ra n g e c o l o r . w i t h N o r i t e and f i l t r a t i o n . T h is w as f o llo w e d by t r e a t m e n t C o n c e n tr a te d h y d r o c h lo r ic a c i d w as th e n a d d e d t o t h e c o o le d f i l t r a t e u n t i l a p r e c i p i t a t e no l o n g e r fo rm e d . F i l t e r i n g and d r y in g g a v e a c o l o r l e s s , c r y s t a l l i n e s o l i d w h ich am ounted t o 1 3 .0 g . (73.5% o f t h e o r y ) , m .p . 2 6 l- 2 6 2 ^ C ., w ith d e c o m p o s itio n . F u r t h e r r e c r y s t a l l i z a t i o n from, w a te r d id n o t c h an g e th e d e c o m p o s itio n p o in t. A n a ly s is . Found! C a l c u l a t e d f o r C^H^N^O: C, 4 7 .4 5 ; H, 3 .9 9 ; N, 3 9 .5 5 . C, 4 7 .3 2 ; H , 4 .1 7 ; N, 3 9 .7 2 . D e riv a tiv e s 5 - ( 2 '- A c e t y l a m i n o p h e n y l ) t e t r a z o l e . 5 - ( 2 *-N i tro p h e n y l ) t e t r a z o l e ( 7 .7 g . , 0 .0 4 0 m o le) was m ixed w ith 15*7 g . o f t i n a n d t h e m ix tu r e t r e a t e d w ith 35 m l. o f c o n c e n t r a t e d h y d r o c h lo r ic a c i d ; c o o lin g was n e c e s s a r y once th e r e a c t i o n s t a r t e d . IWhen th e r e a c t i o n h a d s u b s id e d th e c l e a r s o l u t i o n w as d e c a n te d fro m t h e u n r e a c te d t i n . T he t i n was w ashed w ith a s m a l l am ount o f w a te r a n d t h e w a sh in g s com bined w ith t h e h y d r o c h lo r ic a c i d s o l u t i o n . The a c id s o l u t i o n was made s t r o r g l y b a s i c w i t h ammonium h y d r o x id e and th e t i n h y d ro x id e f i l t e r e d . The e x c e s s ammonium h y d r o x id e was n e u t r a l i z e d w ith g l a c i a l a c e t i c a c i d and t h e s o l u t i o n a d j u s t e d t o a pH o f 5 . C o n tin u e d c o o li n g d id n o t p r e c i p i t a t e th e a m i n o p h e n y l t e t r a z o l e . The s l i g h t l y a c id s o l u t i o n w as t h e n e v a p o r a te d to d iy n e s s and th e 60 r e s i d u e r e f l u z e d w i t h 4 .0 8 g , m l. o f g l a c i a l a c e t i c a c i d . p o u re d i n t o i c e a n d w a t e r . s o lid . (O.0 4 0 m o le) o f a c e t i c a n h y d r id e i n 25 A f t e r tw o h o u r s th e m ix tu r e w as c o o le d an d T h is p r o v id e d th e c ru d e p r o d u c t a s a brow n R e c r y s t a l l i z a t i o n frcan w a te r , u s i n g N o rl t e t o d e c o l o r i z e t h e s o l u t i o n , g a v e th e p u r e p r o d u c t a s a c o l o r l e s s s o l i d , m ,p , 1 7 6 -1 7 7 ^ 0 , A n a ly s is . Found: C a l c u l a t e d f o r C ^^N ^O : C, 5 3 .1 9 ; H, 4 . 4 6 ; N, 3 4 * 4 7 . C, 5 2 .8 7 ; H, 4 .4 4 ; N, 3 4 .3 7 . 5 -(3 * -A c e ty la m in o p h e n y l)te tra z o le , 5 - ( 3 ^-Amin o p h e n y l) t e t r a z o le (7 .0 g , , 0 ,0 4 3 5 m o le) w as r e f l u x e d w i t h 5 .0 g , o f a c e t i c a n h y d r id e i n 30 m l. o f g l a c i a l a c e t i c a c id f o r tw o h o u r s . A t th e end o f t h i s tim e th e m ix tu r e w as p o u re d i n t o 50 m l. o f i c e and w a te r an d t h e s o lid f i l t e r e d . N o rite to R e c r y s t a l l i z a t i o n o f th e p r o d u c t from w a t e r , u s in g d e c o l o r i z e th e s o l u t i o n , g a v e 5 .7 g . (65?» o f th e o r y ) o f t h e a c e t y l d e r i v a t i v e a s a c o l o r l e s s c r y s t a l l i n e s o l i d m e ltin g w ith decomp­ o s i t i o n a t 254-255*^0. A n a ly s is , F ound; C a l c u l a t e d f o r C ^^N ^O : C, 5 3 .1 9 ; H, 4 . 4 6 ; N, 3 4 .4 7 . 0 , 5 3 .2 2 ; H, 4 .5 ^ ; N, 3 4 .5 0 , 5 - ( 4 *-Ace t y l a m i n o p h e n y l ) t e t r a z o l e , 5 - ( 4 * - A m in o p h e n y l) te tr a z o le (10 g , , 0 ,0 6 2 m o le) w as r e f l u r e d w ith 7 .0 g . o f a c e t i c a n h y d rid e i n 30 m l, o f g l a c i a l a c e t i c a c id f o r a p e r i o d o f two h o u r s . The m ix tu r e was t h e n p o u re d i n t o 50 m l. o f i c e an d w a te r and th e s o l i d m a t e r i a l f i l t e r ­ ed. The d r i e d c ru d e p r o d u c t am ounted to 1 2 .5 g . w as f u r t h e r r e c r y s t a l l i z e d w ith d i f f i c u l t y (999^ o f t h e o r y ) an d from g l a c i a l a c e t i c a c i d g i v i n g a c o l o r l e s s pow der m e lt in g w ith d e c o m p o s itio n a t 2 7 8 C. 61 A n a ly s is . F ound: C a l c u l a t e d f o r C ^^N ^O : G, 5 3 .1 9 ; H, 4 .4 6 ; N, 3 4 .4 7 . C , 5 3 .0 9 ; H, 4 .6 8 ; N , 3 4 .2 7 . 5 - (2 *-Hydroxy«-4 * - a c e ty la m ln o p I ie n y l) t e t r a z o l e . a m in o p h e n y l)te tra z o le 5 - ( 2 * -H y d ro x y -4 ’- ( 2 .6 6 g . , 0 .0 1 5 m o le) w as h e a t e d w ith 1 ,5 g . o f a c e t i c a n h y d r id e i n 15 m l. o f g l a c i a l a c e t i c a c i d a t r e f l u x tem p­ e r a t u r e f o r tw o h o u r s . T he s o l u t i o n w as t h e n p o u re d i n t o 50 m l. o f o i c e a n d w a t e r , t h e s o l i d f i l t e r e d an d oven d r i e d a t 7 0 C. T h is g a v e 3 .2 g , ( 9 7 .5 ^ o f th e o r y ) o f a cream c o l o r e d m a t e r i a l m e ltin g w ith d e c o m p o s itio n a t 2 7 7 .5 ^ 0 . w h ich i t i s F u r t h e r r e c r y s t a l l i z a t i o n fro m w a t e r , i n d i f f i c u l t y s o lu b le , gave a c o l o r l e s s , c r y s t a l l i n e p ro d u c t ( n e e d l e s ) , m .p . 281-282*^0., w ith d e c o m p o s iti cn. A n a ly s is . Found: C a lc u la te d fo r C ^ ^ ^ O ^ î C, 4 9 .1 5 ; H, 4 .3 1 ; N, 3 2 .0 6 . 0 , 4 9 .3 1 ; H, 4 * 1 4 ; N, 3 1 .9 5 . PART I I I TETRAZOLE ANALOGUES OF NICOTINIG ACID AND OTHER PYRIDINE CARB02TLIC ACIDS D is c u s s i o n One o f t h e f i r s t i n s t a n c e s o f v ita m in a n ta g o n is m was t h a t o b s e r v e d i n th e c a s e o f p y r i d i n e - 3 - s u lf o n a m id e ( I ) (3 6 ) f o r n i a c i n (II) an d n ia c in a m id e ( I I I ) . I: 3 -A c e t y l p y r i d i n e R% S 0 ; ^ 2 II: R= CO2H III : R= CONH2 (37) and t h ia z o le - 5 - c a r b o x a m id e (IV ) ( 3 8 ) h a v e a l s o b e e n r e p o r t e d t o e x h i b i t n i c o t i n i c a c i d a n ta g o n is m . .CONE' N. IV N ia c in i s im p o r t a n t i n b o th a n im a l an d b a c t e r i a l m e ta b o lis m and e x i s t s a s a p o r t i o n o f coenzym e I enzym es i n b i o l o g i c a l o x i d a t i o n s . (V) and coenzym e I I , b o th e s s e n t i a l 63 mcom . + Nh 6- HÇ0H HGOH ^ HCOH I H90H HÇ 1 H9 H^C-0—ÏM3-P-0-CH^ ^ _o'% d'o 1 y ' ^ H The p o s s i b i l i t y t h a t 3 - ( 5 ’- t e t r a z o l y l ) p y r i d i n e (V I) m ig h t a c t a s VI a n i c o t i n i c a c i d a n t a g o n i s t p ro irp te d i t s s y n th e s is , a s w e ll a s t h a t o f th e two o t h e r p o s i t i o n a l is o m e r s , th e 2 - an d 4 - ( 5 ’- t e t r a z o l y l ) p y r i d i n e s . T he p r o c e d u r e f o r t h e s y n t h e s i s was t h a t em ployed by H e r b s t and W ilso n (3 ) f o r th e p r e p a r a t i o n o f 5 - a r y l t e t r a z o l e s a n d c o n s i s t e d o f h e a t i n g t h e r e s p e c t i v e c y a n o p y r id in e s w i t h so d iu m a z id e and g l a c i a l a c e t i c a c i d i n r e f l u x i n g n o rm a l b u t y l a l c o h o l . A lth o u g h th e m eth o d r e q u i r e s c o n tin u o u s h e a t i n g a t r e f l u x te m p e r a t u r e f o r s i x d a y s , th e y i e l d s w e re , i n e v e r y c a s e , o v e r 90^ o f t h e o r y . I t was fo u n d i n 64 s e v e r a l r u n s t h a t r e d u c i n g th e h e a t i n g p e r i o d to t h r e e o r f o u r d a y s d id n o t lo w e r th e y i e l d s to a n y e x te n t* I n a l l th e p r e p a r a t i o n s o f t h e p y r l d y l t e t r a z o l e s , r e p la c e m e n t o f th e b u t y l a l c o h o l s o l v e n t b y w a te r , d u r in g t h e w o rk in g up o f t h e r e a c t i o n m i x t u r e , r e s u l t e d i n a c l e a r s o l u t i o n o f th e so d iu m s a l t o f th e t e t r a z o l e . A c i d i f i c a t i o n o f t h i s s o l u t i o n w ith c o n c e n tr a te d h y d r o c h l o r i c a c i d fo llo w e d by c o o lin g a n d f i l t r a t i o n , p r o v id e d t h e c o r r e s p o n d in g p y r i d y l t e t r a z o l e i n a r e l a t i v e l y p u re s t a t e * F u rth e r p u r i f i c a t i o n was c a r r i e d o u t by r e c r y s t a l l i z a t i o n from w a t e r , in w h ic h th e t e t r a z o l e s w e re m o d e r a te ly s o l u b l e when h o t and i n s o l u b l e when c o ld * A l l th e p y r l d y l t e t r a z o l e s w ere s o l i d s w hich e x h i b i t e d d e c o m p o s itio n a t t h e i r m e ltin g p o i n t s . They d i s p l a y e d t y p i c a l a m p h o te ric c h a r a c t e r b e in g s o l u b l e i n b o t h a q u e o u s a c i d s and a l k a l i e s and p o s s e s s e d a n is o e le c tric p o i n t a t a pH o f a b o u t 5* T h e ir s o l u b i l i t i e s in w a te r , a l t h o u g h c o n s i d e r a b l y l e s s th a n t h a t o f th e p y r i d i n e e a r b o x y l i c a c i d s , f o llo w e d t h e same o r d e r a s t h a t o b s e r v e d in th e e a r b o x y l i c a c id s e r i e s . I . e . , 2 - is o m e r > 3 - is o m e r > 4 - is o m e r . The p y r l d y l t e t r a z o l e s w ere shown to u n d e rg o n o rm a l r e d u c t i o n i n g l a c i a l a c e t i c a c id u s in g h y d ro g e n an d a p la tin u m o x id e c a t a l y s t to t h e re s p e c tiv e p ip e r id y lte tr a z o le s . S in c e t h e r e d u c t i o n o f t h e p y r i d i n e r i n g to a pi p e r i d y l s t r u c t u r e w as a c c o m p a n ie d by th e fo r m a tio n o f a m ore b a s i c s e c o n d a ry am ino g ro u p , t h e p h y s i c a l c h a r a c t e r i s t i c s o f th e p i p e r i d y l t e t r a z o l e s d i f f e r e d m a rk e d ly fro m th o s e o f th e s t a r t i n g p y r l d y l t e t r a z o l e s . I n a d d i t i o n to b e h a v in g a s a m p h o te r ic s u b s ta n c e s th e p i p e r i d y l t e t r a z o l e s h a d h i g h e r 65 d e c o m p o s itio n p o i n t s a n d a n i n c r e a s e d w a t e r - s o l u b i l i t y . P u r i f i c a t i o n o f t h e t h r e e is o m e r ic p i p e r i d y l t e t r a z o l e s was a c c o m p lis h e d b y d i s s o l v i n g th e m a t e r i a l i n a minimum am ount o f w a te r$ t r e a t i n g w ith N o r i t e and a f t e r f i l t e r i n g , p r e c i p i t a t i n g w ith a c e t o n e . T he a c e t y l d e r i v a t i v e s o f th e p i p e r i d y l t e t r a z o l e s w e re p r e p a r e d c o n v e n i e n t l y and i n m o d e r a te ly good y i e l d s b y r o f l u x i n g them i n g l a c i a l a c e t i c a c i d c o n t a i n i n g a n e q u i v a l e n t am ount o f a c e t i c a n h y d r id e . T h e a c e ' l l p i p e r i d y l t e t r a z o l e s w e re a l s o p r e p a r e d w ith o u t i s o l a t i o n o f t h e i n t e r m e d i a t e p i p e r i d y l t e t r a z o l e b y r e d u c t i o n o f th e r e s p e c t i v e p y r ld y lte tr a z o le s in g la c i a l a c e tic a c id , f i l t r a t i o n o f th e re a c tio n m ix tu r e fro m th e c a t a l y s t a n d s u b s e q u e n t r e f l u a i n g o f t h e f i l t r a t e w ith th e r e q u i r e d am o u n t o f a c e t i c a n h y d r id e . The a c e ty I p i p e r i d y l t e t r a z o l e s , w h ic h c o u ld b e p u r i f i e d b y r e c r y s t a l l i z a t i o n fro m w a t e r o r i s o p r o p y l a l c o h o l , e x h i b i t e d m o d e r a te ly h ig h m e ltin g p o i n t s . B e c a u se o f i t s p o s s i b l e a n ta g o n is m to w a rd 2 , 6 - p y r i d i n e d i e a r b o x y l i c a c i d , a m a t e r i a l in v o lv e d i n s p o r e f o r m a t i o n , 2 , 6 - d i ( 5 * - t e t r a z o l y l ) — p y rid in e ( T i l l ) w as a l s o p r e p a r e d . H -N -N-H — O' II V T in 66 T he s y n t h e s i s w as c a r r i e d o u t u n d e r t h e c o n d i t i o n s s u g g e s te d f o r th e p y r l d y l t e t r a z o l e s . A lth o u g h t h e r e a c t i o n m ix tu r e o f th e 2 , 6 - d i - o y a n o p y r id in e , g l a c i a l a c e t i c a c i d and so d iu m a z i d e i n b u t y l a l c o h o l show ed no a p p a r e n t c h an g e i n p h y s i c a l a p p e a ra n c e a f t e r one day o f r e f l u x i n g , t h e r e a c t i o n p e r i o d was e x te n d e d f o r f o u r d a y s . A c i d i f i c a t i o n o f th e c l e a r a q u eo u s s o l u t i o n a f t e r th e b u t y l a l c o h o l h a d b e e n d i s p l a c e d b y w a te r , g a v e a c o p io u s p r e c i p i t a t e o f th e c o r r e s ­ p o n d in g 2 , 6 - d i ( 5 ’- t e t r a z o l y l ) p y r i d i n e in a q u a n t i t a t i v e y i e l d . A tte m p ts t o p u r i f y th e p r o d u c t b y r e c r y s t a l l i z a t i o n fro m v a r i o u s s o l v e n t s was n o t a p p l i c a b l e to a v e ry l a r g e q u a n t i t y and t h e m eth o d o f d i s s o l v i n g t h e p r o d u c t in b a s e fo llo w e d b y t r e a t m e n t w ith No r i t e and r e a c i d i f i c a t i o n p r o v id e d p u r i f i c a t i o n o f th e c ru d e p r o d u c t . C o m p ariso n o f th e d e c c m p o s itio n p o i n t s o f sam p les p u r i f i e d i n t h i s m an n er w ith t h a t o f th e a n a l y t i c a l sam p le w h ich was r e c r y s t a l l i z e d fro m a l a r g e volum e o f w a te r show s no a p p r e c i a b l e d i f f e r e n c e . The d i t e t r a z o l y l p y r i d i n e , a lth o u g h i n s o l u b l e in m o st s o l v e n t s , d i s s o l v e s i n s t r o n g a c i d s and a q u e o u s a l k a l i e s . I t m e l t s w ith sp o n ­ ta n e o u s d e c o m p o s itio n w h ic h e x p e l I s th e m a t e r i a l o u t o f t h e to p o f th e c a p illa r y tu b e . The p y r l d y l - , p ip e rid y l- and a c e t y l p i p e r i d y l t e t r a z o l e s w ere s u b ­ m i t t e d f o r s c r e e n i n g a lo n g w ith th e 2 , 6 - d i ( 5 ’- t e t r a z o l y l ) p y r i d i n e . Experimental T he P r e p a r a t i o n o f 5 - P y r i d y l t e t r a z o l e s 5 - ( 2 * -P y rid y l)te tra z o le . 20 g . 2 - C y a n o p y rid in e (26 g . , 0 .2 5 m o le ), ( 0 .3 3 m o le) o f g l a c i a l a c e t i c a c id and 22 g . ( 0 .3 3 m ole) o f sodium a z i d e w e re a d d e d t o 100 m l. o f n o rm al b u t y l a l c o h o l and th e m ix tu r e h e a t e d a t r e f l u x te m p e r a tu r e f o r a p e r io d o f f o u r d a y s . At t h i s tim e a n a d d i t i o n a l 5 g . o f so d iu m a z i d e an d 10 g . o f g l a c i a l a c e t i c a c i d w ere ad d ed and th e h e a t i n g c o n tin u e d f o r tw o m ore d a y s . The c o n t e n t s o f t h e f l a s k w ere t r a n s f e r r e d t o a 500 m l. f l a s k , 300 m l. o f w a te r w as a d d ed a n d th e m ix tu r e d i s t i l l e d u n t i l 300 m l. o f d i s t i l l a t e had c o lle c te d . The r e s i d u a l s o l u t i o n w as th e n t r e a t e d w ith c o n cen ­ t r a t e d h y d r o c h l o r i c a c i d u n t i l a p r e c i p i t a t e n o lo n g e r fo rm e d . The s o l i d was f i l t e r e d , r e c r y s t a l l i z e d from w a te r and f i n a l l y o v e n d r i e d a t 70*^0. t o g i v e 3 3 .4 g . (919^ o f th e o r y ) o f a c o l o r l e s s c r y s t a l l i n e s o l i d m e l t i n g a t 2 1 1 -2 1 1 .5°C . A n a ly s is . Found: C a l c u l a t e d f o r C^H^N^: C, 4 9 .1 6 ; H, 3 .6 7 ; N , 4 7 .8 1 . 5 -(3 * -P y rid y l) t e t r a z o l e . g. C, 4 8 .9 8 ; H, 3 .4 3 ; N, 4 7 .6 0 . 3 -0 y ano p y r i d i n e (26 g . , 0 .2 5 m o le ) , 22 (0 .3 3 m ole) o f so d iu m a z i d e and 20 g . (0 .3 3 m o le) o f g l a c i a l a c e t i c a c i d w ere h e a t e d i n 100 m l. o f n o rm a l b u t y l a lc o h o l a t r e f l u x te m p e r a tu r e f o r a p e rio d o f fo u r d a y s. A t th e end o f t h i s tim e a n a d d i t i o n a l 5 g . o f so d iu m a z id e and 10 g . o f g l a c i a l a c e t i c a c id w e re a d d ed and th e r e f l u x i n g c o n tin u e d f o r two a d d i t i o n a l d a y s . The r e a c t i on m ix tu r e was th e n t r a n s f e r r e d t o a 500 m l. f l a s k , 300 m l. o f w a t e r ad d ed and th e m ix tu r e d i s t i l l e d u n t i l 300 m l. o f d i s t i l l a t e h a d b e e n c o l l e c t e d . 68 C o n c e n tr a te d h y d r o c h l o r i c a c id w as a d d ed t o th e r e s i d u a l aq u eo u s s o l u t i o n u n t i l a p r e c i p i t a t e no l o n g e r fo rm e d . The s o l i d was f i l t e r e d , r e c r y s t a l l i z e d fro m w a te r a n d d r i e d g i v i n g 3 3 .3 g . (9 0 .5 ^ o f th e o r y ) o f a c o l o r l e s s c r y s t a l l i n e s o l i d m e lti n g a t 234-235*^0. A n a ly s is . Found; C a l c u l a t e d f o r C^H^N^: 4 7 .6 0 . G, 4 9 .1 7 ; H, 3 .4 2 ; N, 4 7 .6 6 . 5 - ( 4 * - P y r id y l) t e t r a z o l e . 22 g . C, 4 8 . 9 8 ; H , 3 .4 3 ; N, 4 -C y a n o p y rid in e (26 g . , 0 .2 5 m o le ) , { 0 .3 3 m ole) o f sod iu m a z i d e and 20 g . (0 .3 3 m ole o f g l a c i a l a c e t i c a c i d w e re a d d e d to 100 m l. o f n o rm al b u t y l a l c c h o l an d th e m ix tu r e h e a t e d t o r e f l u x te m p e r a tu r e f o r a p e r io d o f f o u r d a y s . th is tim e a n a d d i t i o n a l 5 g . o f sodium a z id e and 10 g . o f g l a c i a l a c e t i c a c i d w ere T he A f te r a d d e d an d th e h e a t i n g c o n tin u e d f o r t w m ore d a y s . c o n t e n t s o f th e f l a s k w ere th e n t r a n s f e r r e d t o a 500 m l. f l a s k , 300 m l. o f w a t e r ad d ed and th e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c o h o l h a d b een re m o v e d . The r e s i d u a l a q u eo u s s o l u t i o n was th e n t r e a t e d w ith c o n c e n t r a t e d h y d r o c h l o r i c a c i d u n t i l a p r e c i p i t a t e no l o n g e r fo rm ed on th e a d d i t i o n o f m ore a c i d . The s o l i d w as f i l t e r e d , 3 4 .3 g. r e c r y s t a l l i z e d from w a te r and d r i e d g iv in g ( 9 3 . 2^ o f th e o r y ) o f p u re p r o d u c t, m .p . 253- 254*^0 . , w ith d e­ com posi t i o n . A n a ly s is * Found: C a lc u la te d f o r C N : 0 5 5 C, 4 8 . 9 8 ; H, 3 .4 3 ; N, 4 7 .6 0 . G, 4 9 .1 9 ; H, 3 .5 7 ; N, 4 7 .3 3 . 2 . 6 - P l ( 5 ’- t e t r a z o l y l ) p y r id in e ♦ 0 .2 1 3 m o le ) , 3 8 ,2 g . 2 , 6 -D i cya n o p y r id in e (2 7 .5 g .» (0 .5 8 6 m o le ) o f so d iu m a z id e and 38 m l. o f g l a c i a l a c e t i c a c id w e re a d d e d to 100 m l. o f n o rm al b u t y l a l c o h o l and t h e 69 m ix tu r e r e f l u x e d f o r two d a y s . A t th e end o f t h i s tim e an a d d i t i o n a l 10 g . o f s o d iu m a z i d e and 20 m l. o f g l a c i a l a c e t i c a c i d w ere a d d ed and th e r e f l u x i n g c o n tin u e d f o r a n a d d i t i o n a l two d a y s . The c o n t e n t s o f th e f l a s k w e re t h e n t r a n s f e r r e d t o a l a r g e r f l a s k , 300 m l. o f w a te r a d d e d and th e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c c h o l had b e e n rem oved. C o n c e n tr a te d h y d r o c h l o r i c a c i d was a d d e d to th e a q u e o u s r e s i d u a l s o l u t i o n u n t i l a p r e c i p i t a t e no l o n g e r fo rm ed on th e a d d i t i o n o f m ore a c i d . s o l i d w as f i l t e r e d g iv in g 4 5 .6 g , ( 9 9 .5 ^ o f th e o r y ) The of a c o lo rle s s c r y s t a l l i n e m a t e r i a l w h ic h decom posed a t 287°C . The c ru d e p r o d u c t was f u r t h e r p u r i f i e d by d i s s o l v i n g i n a q u e o u s b a s e a n d r e p r e c i p i t a t i n g w ith a c i d . The a n a l y t i c a l sam p le was r e - c r y s t a l l i z e d fro m w a t e r , i n "which th e p r o d u c t i s v e r y s l i g h t l y s o l u b l e , m .p . 290*^C., w i t h d e c o m p o s itio n . A n a ly s is . Found: C a lc u la te d fo r C ^^N ^: G, 39*07; H, 2 .3 4 ; N , 58.59* C, 39*15; H, 2 .5 7 ; N , 5 8 .6 0 . T he P r e p a r a t i o n o f 5 -P i p e r i d y l t e t r a z o l e s 5 - ( 2 '- P i p e r i d y l ) t e t r a z o l e . 5 - ( 2 '- P y r i d y l ) t e t r a z o l e (1 1 .0 g . , 0 .0 7 5 m o le ) w as s u s p e n d e d in 150 n il. o f g l a c i a l a c e t i c a c id and h y d r o g e n a te d i n a h y d ro g e n a tm o s p h e re o v e r 250 mg. o f p la tin u m o x id e c a t a l y s t a t a n i n i t i a l p r e s s u r e o f 50 p . s . l . ; t h e r e a c t i o n was com­ p l e t e i n tw e n ty - f o u r h o u r s . The c a t a l y s t was f i l t e r e d fro m th e s o l u t i o n an d t h e f i l t r a t e c o n c e n t r a t e d t o a s m a ll v o lu m e. The a d d i t i o n o f e t h e r c a u s e d th e p r e c i p i t a t i o n o f a c o l o r l e s s s o l i d w h ich was f u r t h e r p u r i f i e d b y d i s s o l v i n g i n w a t e r , t r e a t i n g w ith N o r i t e a n d p r e c i p i t a t i n g w ith a c e to n e . T h is g a v e 1 0 .5 g . (91.5% o f th e o r y ) o f p u re p r o d u c t . 70 m .p . 287- 2 8 7 . 2 ^ 0 . , w ith d e c o m p o s itio n . A n a ly s is . Found: C a lc u la te d f o r C, 4 7 .0 5 ; H, 7 .2 4 ; N, 4 5 .7 2 . C, 4 7 .0 3 ; H, 7 .1 2 ; N, 4 5 .9 8 . 5 - ( 3 ’- P i p e r i d y l ) t e t r a z o l e . 5 - ( 3 ’- P y r l d y l ) t e t r a z o l e ( 1 1 .7 g . , 0 .0 7 9 5 m o le) was s u s p e n d e d i n 150 m l. o f g l a c i a l a c e t i c a c id and h y ­ d r o g e n a te d o v e r 300 mg. o f p la tin u m o x id e c a t a l y s t i n a h y d ro g e n a t ­ m o s p h e re a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . A f t e r tw e n ty - f o u r h o u r s th e r e a c t i o n was c o m p le te a n d t h e c a t a l y s t was rem oved b y f i l t r a t i o n . The f i l t r a t e was c o n c e n t r a t e d to a s m a ll volum e an d e t h e r ad d ed t o p r e c i p i t a t e th e p r o d u c t . T h is g av e 1 2 . 2 g , (99.7% o f th e o iy ) o f t h e c ru d e p ro d u c t. The p r o d u c t was f u r t h e r p u r i f i e d by d i s s o l v i n g i n a minumum am ount o f w a te r and c o o lin g . The p r e c i p i t a t e w h ich was fo rm e d was f i l t e r e d a n d u s e d a s th e a n a l y t i c a l s a m p le , th e r e m a in d e r o f th e p r o d u c t was p r e c i p i t a t e d fro m th e a q u e o u s f i l t r a t e b y th e a d d i t i o n o f a c e t o n e . The c o l o r l e s s c r y s t a l l i n e p ro d u c t A n a ly s is . Found: m e lte d C a lc u la te d f o r w ith d e c o m p o s itio n a t C, 4 7 .0 5 ; H, 7 .2 4 ; N, 4 5 .7 2 . C, 4 7 .1 0 ; H , 7 .3 1 ; N, 4 5 .6 6 . 5 - ( 4 ’- P i p e r i d y l ) t e t r a z o l e . 5 - ( 4 ’- P y r i d y l ) t e t r a z o l e (1 4 .7 g . , 0 . 1 m a le ) was s u s p e n d e d in 200 m l. o f g l a c i a l a c e t i c a c id an d sh a k e n w i t h 400 mg. o f p la tin u m o x id e c a t a l y s t in a h y d ro g e n a tm o s p h e re a t a n i n i t i a l p r e s s u r e o f 50 p . s . l . m ix tu r e was f i l t e r e d . A f t e r tw e n t y - f o u r h o u r s t h e r e a c t i o n C o n c e n tr a tio n o f th e f i l t r a t e fo llo w e d by th e a d d i t i o n o f e t h e r g a v e a s o l i d p r e c i p i t a t e w h ic h w as f u r t h e r p u r i f i e d b y d i s s o l v i n g i n a minimum am ount o f w a te r , t r e a t i n g w ith N o r i t e , an d 296-297*^0. 71 r e p r e c i p i t a t i n g by th e a d d i t i o n o f a c e to n e t o g iv e 1 3 ,2 g . {86. t h e o r y ) o f c r u d e p r o d u c t. of T he p r o d u c t c r y s t a l l i z e d from w a te r a s c o l o r l e s s c u b ic c r y s t a l s , w h ic h d id n o t decom pose a t 370°C. b u t showed s h r i n k i n g and b ro w n in g a t 2 3 7 ^ 0 , A n a ly s is , Found: C a lc u la te d fo r C. 4 7 ,0 5 ; H, 7 .2 4 ; N, 4 5 .7 2 , 0 , 4 6 ,9 7 ; H, 7 .2 2 ; N, 4 6 .0 3 . T he P r e p a r a t i o n o f A c e t y l p i p e r i d y l t e t r a z o l e s (a ) 5 - (2 * - N - A c e t y l p i p e r i d y l ) t e t r a z o l e , (10 g , , 0 ,0 6 6 m ole) w as r e f l u x e d w i t h 6 ,7 g . 5 - ( 2 '- P i p e r i d y l ) t e t r a z o l e (0 ,0 6 6 m ole) o f a c e t i c a n h y d r id e i n 30 m l, o f g l a c i a l a c e t i c a c id f o r a p e r io d o f two h o u r s . T h e s o l v e n t was th e n rem oved in a vacuum and th e r e s i d u e r e c r y s t a l l i z e d fro m w a t e r , d e c o l o r i z i n g w i t h N o r i t e , t o g iv e 6 ,0 g , (46.6% o f th e o r y ) o f th e c o l o r l e s s c r y s t a l l i n e p r o d u c t w h ich m e lte d a t 1 3 5 .4 - 1 3 6 ,5 ^ 0 . A n a ly s is . Found: C a l c u l a t e d f o r GgH^^N^O; C, 4 9 .2 2 ; H, 6 .7 1 ; N, 3 5 .8 8 , C, 4 9 .1 4 ; H, 6 .6 4 ; N, 3 5 .6 1 , (b) 5 - ( 2 '- P y r i d y l ) t e t r a z o l e (2 2 .5 g . , 0 ,1 5 m ole) w as su sp e n d e d i n 150 m l. o f g l a c i a l a c e t i c a c i d an d s h a k e n w ith 150 mg. o f p la tin u m o x id e c a t a l y s t i n a h y d ro g e n a tm o s p h e re a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . A f t e r th e t h e o r e t i c a l am ount o f h y d ro g e n h a d b e e n ta k e n up t h e c a t a l y s t was rem oved by f i l t r a t i o n . d i r e c t l y w ith l 6 , 3 g , The f i l t r a t e was t r e a t e d ( 0 , l 6 m ole) o f a c e t i c a n h y d rid e a n d t h e m ix tu r e r e f l u x e d f o r two h o u r s . E v a p o r a tio n o f th e s o l v e n t l e f t 2 4 .6 g , ( 8 4 , 0% o f th e o r y ) o f th e c ru d e p r o d u c t w h ich was p u r i f i e d by r e c r j ^ t a l l i z a t i o n f r a n w a t e r , d e c o l o r i z i n g th e s o l u t i o n w ith N o r i t e , m .p . 1 3 5 .5- 1 3 6 . 5 °C . 72 A m ix tu r e m e l t i n g p o i n t d e t e r m in a tio n w i t h th e p r o d u c t fo rm ed fro m th e r e a c t i o n o f a c e t i c a n h y d rid e an d 5“ ( 2 ' —p i p e r i d y l ) t e t r a z o l e show ed DO d e p r e s s i o n , 5 - ( 3 ’- N - A c e t y l p i p e r i d y l ) t e t r a z o l e (a ) 5 - ( 3 ’- P i p e r i d y l ) t e t r a z o l e ( 9 .0 g , , 0 ,0 5 9 m ole) w as r e f l u x e d f o r two h o u r s i n 30 m l. o f g l a c i a l a c e t i c a c i d c o n t a i n i n g 6 ,0 g , (0 ,0 5 9 m ole) o f a c e t i c a n h y d r id e . At th e end o f t h i s tim e t h e s o l v e n t was rem o v ed in a vacuum and th e r e s i d u e r e c r y s t a l l i z e d from is o p r o p y l a l c o h o l g i v i n g 5 .6 g . o f t h e o r y ) o f th e c o l o r l e s s c r y s t a l l i n e a c e t y l d e r i v a t i v e w hich m e lte d a t 1 7 0 -1 7 1 °G , A n a ly s is , Found: (h) C a l c u l a t e d f o r C ^^^N ^O ; C, 4 9 .2 2 ; H, 6 ,7 1 ; N, 3 5 .8 8 , G, 4 9 .4 5 ; H, 6 ,7 4 ; N, 3 6 .0 6 . 5 - ( 3 ’- p y r l d y l ) t e t r a z o l e (2 2 ,5 g . , 0 ,1 5 m ole) w as su sp e n d e d i n 125 m l, o f g l a c i a l a c e t i c a c id an d sh a k e n w ith 150 mg, o f p la tin u m o x id e c a t a l y s t in a h y d ro g e n a tm o s p h e re a t an i n i t i a l p r e s s u r e o f 50 p .s .i. A f t e r tw e n t y - f o u r h o u rs th e r e a c t i o n was c o m p le te a n d th e c a t a l y s t w as f i l t e r e d from th e r e a c t i o n m ix tu r e . S ix t e e n an d t h r e e - t e n t h s gram s ( 0 « l6 m ole) o f a c e t i c a n h y d r id e was th e n a d d e d t o t h e filtra te and t h e s o l u t i o n r e f l u x e d f o r two h o u r s . A t t h e en d o f t h i s tim e th e s o l v e n t w as rem o v ed in a vacuum and t h e r e s i d u e r e c r y s t a l l i z e d from i s o p r o p y l a l c o h o l to g iv e th e a c e t y l d e r i v a t i v e , ra ,p . 1 6 9 - 1 7 0 ,5 °G, A s e c o n d r e c r y s t a l l i z e t i o n r a i s e d t h e m e ltin g p o i n t to 1 7 0 ,5 -1 7 1 G.> an d g a v e 1 5 ,5 g . (53% o f th e o r y ) o f th e d e s i r e d p r o d u c t . A m ix tu r e m e ltin g p o i n t w ith 5 - ( 3 ’- a c e t y l p i p e r i d y l ) t e t r a z o l e , fo rm ed from th e r e a c t i o n o f a c e t i c a n h y d r id e and 5 - ( 3 ’- p i p e r i d y l ) - 73 t e t r a z o l e , show ed n o d e p r e s s i o n . (4 *-N-Ac 0 t y l p i p e r i d y l ) t e t r a z o l e (a ) { 1 2 .2 g . , 0 .0 8 m o le ) was r e f l u x e d w i t h 8 .2 g . 5 - ( 4 ’- P i p e r i d y l ) t e t r a z o l e ( 0 .0 8 m o le) o f a c e t i c a n h y d r id e i n 30 m l. o f g l a c i a l a c e t i c a c id f o r tw o h o u r s . The s o l v e n t w as t h e n rem oved i n a vacuum an d th e r e s i d u e r e c r y s t a l l i z e d from i s o p r o p y l a l c o h o l g i v i n g 9*2 g . ( 5 ^ o f th e o r y ) o f a c o l o r l e s s c r y ­ s ta llin e p r o d u c t m e l t i n g a t 156.5-157*5*^0. A n a ly s is . Found: C a lc u la te d fo r C ^ ^ ^ O : C, 4 9 .2 2 ; H, 6 .7 1 ; N , 3 5 * 8 8 . C, 4 9 * 2 5 ; H, 6 .8 4 ; N, 3 5 .8 1 . (b ) 5 - ( 4 ’- P y r i d y l) t e t r a z o l e (2 2 .5 g . > 0 .1 5 m ole) was s u sp e n d e d w ith 200 mg. o f p la tin u m o x id e c a t a l y s t In 125 m l. o f g l a c i a l a c e t i c a c i d and s h a k e n in an a tm o s p h e re o f h y d ro g e n a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . A f t e r t w e n t y - f o u r h o u rs th e r e a c t i o n was c o m p le te and t h e c a t a l y s t w as f i l t e r e d fro m th e r e a c t i o n m ix tu r e . S i x t e e n and t h r e e - t e n t h s g ra m s ( 0 . l 6 m ole) o f a c e t i c a n h y d rid e was a d d e d t o th e f i l t r a t e an d th e s o l u t i o n r e f l u x e d f o r two h o u r s . A f t e r t h i s tim e th e s o l v e n t was rem oved i n a vacuum and th e r e s i d u e r e c r y s t a l l i z e d fro m i s o p r o p y l a l c o h o l g iv in g 1 9 .7 g . (67.4% o f th e o r y ) o f th e p r o d u c t w h ich m e lte d a t 1 5 6 -1 5 7 °C . A m ix tu r e n e l t i n g p o i n t d e t e r m i n a t i o n w ith th e p r o d u c t from th e r e a c t i o n o f a c e t i c a n h y d r id e and 5 - ( 4 ’ - p i p e r i d y l ) t e t r a z o l e showed no d e p re s s io n . PART IV TETRAZOLE ANALOGUES OF PLANT AUXINS D is c u s s i o n I s o l a t i o n and i d e n t i f i c a t i o n o f in d o le - 3 - a c e tic a c id (I) a s a n a t u r a l g ro w th horm one i n p l a n t s i n i t i a t e d a s e a r c h f o r o t h e r su b ­ s t a n c e s w h ic h c o u ld e l i c i t t h i s ty p e o f a c t i v i t y . Among th o s e s y n t h e t i c m a t e r i a l s w h ic h w e re shown t o s t i m u l a t e g ro w th w as a g ro u p o f c h l o r i n ­ a t e d c h e m ic a l coimpounds d e r i v e d fro m p h e n o x y a c e tic a c id * V a ry in g d e­ g r e e s o f a c t i v i t y w ere d e m o n s tr a te d d e p en d in g on th e num ber a n d p o s i t i o n o f th e c h l o r i n e atom s In t h e b e n z e n o id p o r t i o n o f th e s t r u c t u r e . Of t h e p h e n o z y a c e tlc a c id d e r i v a t i v e s s t u d i e d , 2 ,A - d ic h lo r o p h e n o 2y a c e t i c a c id (2 ,4 -D ) ( I I ) and 2 , 4 , 5 - t r i c h l o r o p h e n o x y a c e t i c a c i d ( 2 , 4 , 5 -T ) w ere shown t o b e t h e m o st a c t i v e . (39) II K o e p f li a n d h i s c o -w o rk e rs ( 4 0 ) , i n a n a tte m p t t o c o r r e l a t e m o le c u la r s t r u c t u r e w ith a u x in a c t i v i t y , p o s t u l a t e d some o f t h e minimum s t r u c t u r a l r e q u ir e r a e n t s a s u b s ta n c e s h o u ld p o s s e s s in o r d e r to e l i c i t g ro w th s t i m u l a t i o n i n p l a n t s . T h e se i n c lu d e d : 75 a. a r i n g s y s ta n a s n u c le u s b. a d o u b le b o n d in t h i s r i n g 0» a s i d e c h a in d* a c a r b o x y l g ro u p on th e s id e c h a in a t l e a s t one c a rb o n r e ­ moved fro m t h e r i n g e* a p a r t i c u l a r s p a c e r e l a t i o n s h i p b etw een t h e r i n g and t h e c a r b o x y l g ro u p The r e q u ir e m e n t t h a t t h e r e b e a c a r b o ^ l g ro u p on th e s i d e c h a in f i n d s e x c e p tio n i n t h a t th e c o r r e s p o n d in g a ld e h y d e s , n i t r i l e s , e s te rs a n d am id es a l s o show, t o a c e r t a i n d e g r e e , h o rm o n a l a c t i v i t y * Ex­ c e p t i o n t o t h e e a r b o x y lic a c i d r u l e h a s a l s o b e e n shown b y a c t i v e c h e m ic a l com pounds i n w h ic h th e e a r b o x y l i c a c id g ro u p i s r e p l a c e d by a s u l f o n i c a c id m o ie ty ( I I I ) o r a n i t r o g ro u p (IV ) (4 1 )# 2NO2 III IV B e c a u se o f t h e a c i d i c c h a r a c t e r o f m o n o s u b s ti tu te d t e t r a z o l e s w i t h a s u b s t i t u t e n t i n th e 5 p o s i t i o n i t a p p e a re d o f i n t e r e s t i n t h i s s tu d y t o i n c o r p o r a t e th e t e t r a z o l e n u c le u s i n t o th e c h e m ic a l s t r u c t u r e o f a n a c t i v e p l a n t a u x in i n p l a c e o f th e c a r b o x y l g r o u p . I t was a n t i c i p a t e d t h a t th e a n a lo g u e c o u ld d i s p l a y s e v e r a l t y p e s 76 o f p h y s io lo g ic a l b e h a v io r; i t c o u ld p e rfo rm s i m i l a r t o a p l a n t horm one a n d s t i m u l a t e g ro w th , i t c o u ld p o s s e s s a c t i v i t y a s a p l a n t g ro w th i n ­ h i b i t o r , e i t h e r by p r e v e n tin g g ro w th th ro u g h a n ta g o n is m o f th e s p e c i f i c horm one o f w h ic h i t i s t h e a n a lo g u e o r b y i n h i b i t i o n o f t h e n a t u r a l p l a n t h o rm o n e s, o r t h e t e t r a z o l e c o u ld b e t o t a l l y i n a c t i v e in e i t h e r fa c ilita tin g o r i n h i b i t i n g p l a n t g r o w th . The e a r b o x y l i c a c i d a n a lo g u e s s y n t h e s i z e d f o r t h i s s tu d y w ere th o s e o f i n d o l e - 3 - a c e t i c a c id an d v a r i o u s l y s u b s t i t u t e d p h e n o x y a c e tic a c id s * The s y n t h e s i s o f 5 - ( 3 * - i n d o l y l m e t h y l ) t e t r a z o l e (v) was c a r r i e d o u t i n 8 8^ y i e l d s by th e r e a c t i o n o f 3 - i n d o l y l a c e t o n i t r i l e w ith alum inum a z i d e by a d a p t a t i o n o f th e p r o c e d u r e s o f B e h r in g e r an d K ohl (5). -N-H II I H The s u b s t i t u t e d p h e n o x y m e t h y lte t r a z o le s w ere s y n th e s iz e d b y two g e n e ra l p ro c e d u re s. ria te ly The f i r s t in v o lv e d th e r e a c t i o n o f th e a p p ro p ­ s u b s t i t u t e d p h e n o x y a c e t o n i t r i l e w ith sodium a z id e and a c e t i c a c i d i n r e f l u x i n g n o rm al b u t y l a l c o h o l f o llo w i n g t h e p r o c e d u r e o f H e r b s t and W ilso n ( 3 ) . T h is was a p p l i c a b l e to t h e s y n t h e s i s o f th e 2 , 4 - d i c h l o r o - , 2 , 4 , 5 - t r i c h l o r o - and u n s u b s t i t u t e d p h e n o x y m e t h y lt e t r a z o le s . 77 A tto n ip te d f o r m a t i o n o f th e c o r r e s p o n d in g m e th y l)te tra z o le tr ic h lo r o p h e n o z y - (V I) b y th e u s e o f t h e s e c o n d i t i o n s r e s u l t e d i n a d e e p b ro w n c o l o r a t i o n o f th e r e a c t i o n m ix tu r e due t o e x t e n s i v e d e c o m p o s itio n * ,01 01- N-H 01 VI H ie r e a c t i o n o f th e 2 - c h l o r o - , 4 - c h lo r O " and 2 , 4 , 6 - t r i c h l o r o p h e n o x y a c e to n I t r i l e s w ith alum inum a z id e i n r e f lu x i n g t e t r a h y d r o f u r a n , u s in g a n a d a p t a t i o n o f th e p r o c e d u r e o f B e h r in g e r a n d K o h l, r e s u l t e d i n v e r y good y i e l d s o f th e c o r r e s p o n d in g t e t r a z o l e s . T he a l t e r n a t e m ethod u s e d f o r t h e f o r m a ti o n o f th e p h en o x y m e t h y l t e t r a z o l e s in v o lv e d t h e a l k y l a t i o n o f t h e a p p r o p r i a t e l y sub­ s t i t u t e d p h e n o l w ith l - b e n z y l - 5 - c h l o r o m e t h y l t e t r a z o l e ( l 6 ) fo llo w e d b y re m o v a l o f th e b e n z y l g ro u p w i t h h y d ro g e n and p a lla d iu m on c h a r c o a l a s i l l u s t r a t e d s c h e m a t i c a l l y b e lo w ; + OCHo—C CIGH^-G % Pd/C ÎÏ-H N 4- N-CH2C6H5 78 I n s e v e r a l i n s t a n c e s , nam ely in t h e c a s e s o f th e 2 , 4 - d i c h l o r o a n d 2 , 4 , 6 —t r i c h l o i x ) — is c s n e r s , d é b e n z y l a t io n w as a c c o m p a n ied b y de— h a l o g é n a t i o n an d p o s s i b l y r e d u c t i o n m aking i d e n t i f i c a t i o n and c o m p a riso n w ith t h e com pounds p r e p a r e d b y th e a l t e r n a t e r o u t e d i f f i c u l t . Com­ p a r i s o n s w h e re m ade, w sre done by m e ltin g p o in t and m ix tu r e m e ltin g p o in ts . A lth o u g h d e r i v a t i v e s o f th e s u b s t i t u t e d p h e n o x y m e th y l t e t r a z o l e s w e re n o t p r e p a r e d , t h e 5—( 3 * - i n d o l y l m e t h y l ) t e t r a z o l e was c h a r a c t e r i z e d a s a m o n o p ic r a te . A l l t h e 3 - m o n o s u b s titu te d t e t r a z o l e s p r e p a r e d in t h i s g ro u p w ere s o l i d s e x h i b i t i n g m o d e r a te ly h i g h t o h ig h m e l tin g p o i n t s . a c i d i c s u b s t a n c e s r e a d i l y s o l u b l e i n aq u eo u s a l k a l i e s . A l l w ere 5 - (Phenoxy­ m e th y l) t e t r a z o l e a n d 5 - ( 3 ^ - i n d o l y l m e t h y l ) t e t r a z o l e , in a d d i t i o n t o b e in g r e c r y s t a l l i z a b l e from w a te r , w ere s o l u b l e in a c e to n e and e t h a n o l . T he c h l o r i n a t e d p h e n o x y m e th y lte t r a z o le s , a l th o u g h i n s o l u b l e i n c o ld w a te r a n d v e ry s l i g h t l y s o l u b l e i n h o t w a te r , c o u ld b e r e c r y s t a l l i z e d fro m e t h a n o l , a q u e o u s e th a n o l o r t o l u e n e . The n i t r i l e s u s e d a s in te im e d i a t e s f o r th e p h en o x y m eth y l t e t r a z o l e s y n t h e s e s w e re p r e p a r e d fro m th e p h e n o ls , c h l o r o a c e t o n i t r i l e and p o ta s s iu m c a r b o n a te i n r e f l u x i n g a c e t o n e . T h is m eth o d o f p r e p a r a t i c n o f f e r e d a d i s t i n c t a d v a n ta g e o v e r th o s e w h ic h in v o lv e d s y n t h e s i s o f th e n i t r i l e , e i t h e r fro m th e a c i d b y way o f th e a c i d c h l o r i d e and am ide o r from p h e n o x y m e th y l c h l o r i d e a n d sodium c y a n id e (4 2 ) ; b o th o f t h e s e l a t t e r m e th o d s in v o lv e a s e r i e s o f s te p w is e c o n v e r s io n s s t a r t i n g from th e p h e n o l. 79 S u b s t a n t i a t i o n o f th e i d e n t i t y o f th e p h e n o x y a c e t o n i t r i l e s was made by c o m p a r is o n w i t h p h y s i c a l c o n s t a n t s in th e l i t e r a t u r e , e le m e n ta l a n a ly s is , p h e n o x y a c e tic a c i d s . and i n some c a s e s h y d r o l y s i s t o th e c o rr e s p o n d in g 80 E x p é r im e n ta l The P r e p a r a t i o n o f P h e n o x y a ce to n i t r i l e s Phenoxyacet o n i t r i l e . p h e n o l, 1 8 .7 g . A m ix tu r e o f 2 3 .5 g . (0 .2 5 m ole) o f (0 .2 5 m ole) o f c h lo r o a c e t o n i t r l i e and 3 4 .5 g . (0 ,2 5 m o le) o f p o ta s s iu m c a r b o n a t e in 75 m l. o f d r y a c e to n e was h e a te d a t r e f l u x te m p e ra tu re f o r e ig h t h o u rs . 200 m l. o f w a t e r c o n t a i n i n g 10 g . e x tr a c te d w ith e th e r . The m ix tu r e was t h e n p o u re d i n t o (0 .2 5 m o le) o f so d iu m h y d ro x id e and The e t h e r l a y e r was s e p a r a t e d , d r i e d o v e r so d iu m s u l f a t e and t h e e t h e r rem oved In a vacuum . A re d d is h o i l (3 4 .5 g . ) w h ic h re m a in e d when d i s t i l l e d g a v e 2 7 .2 g . (8 2 ^ o f th e o r y ) o f a c l e a r o i l y H q u l d b o i l i n g a t 7 3 -7 6 ^ 0 . a t 1 mm. T h is p r o d u c t was p r e v io u s l y d e s c r ib e d b y P o w e ll and Adams (43) who r e p o r t e d b . p . 1 3 2 ^ 0 . a t 30 mm. 2 -C h lo ro p h e n o x y a c e to n itrile . o f 2 - c h l o r o p h e n o l , 1 8 .7 g . 3 4 .5 g . A m ix tu r e o f 3 2 .0 g . (0 .2 5 m ole) (0 .2 5 m ole) o f c h l o r o a c e t o n i t r i l e and (0 .2 5 m o le ) o f p o ta s s iu m c a r b o n a te i n 8o m l. o f d ry a c e to n e was h e a t e d a t r e f l u x te m p e r a tu r e w i t h c o n tin u e d s t i r r i n g f o r tw e n ty h o u rs. A f t e r t h i s tim e th e m ix tu r e was p o u re d i n t o 200 m l. o f w a te r c o n t a i n i n g 10 g . e th e r. (0 .2 5 m ole) o f sodium h y d ro x id e and e x t r a c t e d w ith On e v a p o r a t i o n o f th e d r i e d e t h e r l a y e r t h e r e re m a in e d 3 8 .7 g . o f a d a rk o i l . On d i s t i l l a t i o n t h e r e was o b ta in e d a f o r e r u n and a n a f t e r r u n , 1 0 2 -1 0 7 ^ 0 . a t 1 mm. and 1 0 9 -H 4 ° C . a t 1 mm., w h ich t o g e t h e r a m o u n ted to 1 2 .5 g . The m id d le f r a c t i o n w hich d i s t i l l e d a t 1 0 7 -1 0 9 a t 1 mm. am ounted t o 1 8 .3 g . ( 4 3 . ^ o f t h e o r y ) an d was r e d i s t i l l e d to o b t a i n an a n a l y t i c a l s a m p le , b . p . 1 0 9 ^0 * a t 1 mm. ai A n a ly s is . C a l c u l a t e d f o r CgH^ClNO; C l, 2 1 .1 6 ; N, 8 . 3 6 . Found; C l, 2 1 .0 7 ; N, 8 .1 0 . 4 -O h lo ro p h e n o x y a c e to n itrile . a d d e d 3 2 .0 g . To 100 m l. o f d ry a c e to n e w ere ( 0 .2 $ m o le) o f 4 - c h l o r o p h e n o l , 1 8 .7 g . c h lo r o a c e t o n i t r i l e an d 34# 5 g . (0 .2 $ m o le) o f ( 0 .2 $ m ole) o f p o ta s s iu m c a r b o n a te and t h e r e s u l t i n g m ix tu r e r e f lu x e d f o r e i g h t e e n h o u r s . The m ix tu r e w as t h e n p o u r e d i n t o 1$0 m l. o f w a t e r c o n t a i n i n g 1 0 g . (0 .2 $ m ole) o f so d iu m h y d r o x id e a n d e x t r a c t e d w i t h e t h e r . s e p a ra te d , vacuum . T he e t h e r l a y e r w as d r i e d o v e r sodium s u l f a t e an d th e e t h e r rem o v ed i n a The r e s i d u e c o n s i s t e d o f a d a rk r e d o i l w h ich s o l i d i f i e d on s t a n d i n g , 39*0 g . (933^ o f t h e o r y ) . R e c r y s t a l l i z a t i o n from p e tro le u m e t h e r g a v e a c o l o r l e s s c r y s t a l l i n e p ro d u c t m e l tin g a t 4 6 . $ - 4 7 #5 ^G. A n a ly s is . C a l c u l a t e d f o r C ^^C IN O : C l, 2 1 .1 6 ; N, 8 . 3 6 . F ou n d : C l, 2 1 .1 7 ; W, 8 .1 7 . 2 . 4 - P ic h lo r o p h e n o x y a c e to n i t r i l e . o f 2 , 4 - d i c h l o r o p h e n o l, I 8 .7 g . 34#6 g . A m ix tu r e o f 40 g . (0 .2 $ m ole) (0 .2 $ m o le) o f c h lo r o a c e to n i t r i l e and (0 .2 $ m o le ) o f p o ta s s iu m c a r b o n a te i n 60 m l. o f d ry a c e to n e WELS r e f l u x e d f o r tw e n ty h o u r s . The p in k c o l o r e d m ix tu r e was t h e n p o u re d i n t o 200 m l. o f w a t e r c o n t a i n i n g 10 g . ( 0 .2 $ m ole) o f sodium h y d r o x id e a n d t h e m ix tu r e e x t r a c t e d w i t h e t h e r . The e t h e r a l l a y e r was s e p a r a t e d , d r i e d w ith sodium s u l f a t e and th e s o l v e n t rem oved i n a vacuum . The r e s i d u e c o n s i s t e d o f 43*1 S# ( 8 $ .2 ^ o f th e o r y ) o f a d i r t y , w h ite s o l i d w h ic h m e lte d a t 4 $ -4 6 .$ ® C . R e c r y s t a l l i z a t i o n from p e tr o le u m e t h e r r a i s e d t h e m e ltin g p o i n t t o 4 8 . $ - 49 ^ 0 . , A n a ly s is , C a l c u l a t e d f o r C ^^C lgl^O ; (c o lo rle s s n e e d le s ). C, 4 7 # $ $ ; H , 2 ,5 0 ; C l, 3 5 * 1 0 ; 82 N, 6 .9 3 . Found; C, 4 7 .5 7 ; H, 2 .5 1 ; C l, 3 5 .2 4 ; N, 6 . 8 i , T h is p ro d u c t h a s been p re v io u s ly r e p o r te d by B e rb e r, e t . a l , (42) a s m e l t i n g a t 4 4 -4 6 ^0 * 2 . 4 . 5 - T r i c h l o r oph enozy a ce to n i t r i l e . m o le ) o f 2 ,4 » 5 - t r i e h l o r o p h e n o l , l8 * 7 g . a n d 3 4 .5 g . A m ix tu r e o f 4 9 .4 g . (0 .2 5 m ole) o f c h l o r o a c e t o n i t r i l e (0 .2 5 m ole) o f p o ta s s iu m c a r b o n a te i n 75 m l. o f d ry a c e to n e w as r e f l u x e d f o r t w e n t y - f o u r h o u r s . 200 m l. o f w a t e r c o n t a i n i n g 10 g . e x t r a c t e d w ith e t h e r . The m ix tu r e was t h e n p o u re d i n t o (0 .2 5 m o le ) o f so d iu m h y d ro x id e a n d The e t h e r l a y e r w as s e p a r a t e d , d r i e d o v e r sodium s u l f a t e an d t h e s o l v e n t rem oved i n a vacuum . 5 2 .8 g . 8 6 -9 0 ^ 0 . (0 .2 5 The r e s i d u e c o n s i s t e d o f (8S.23& o f th e o r y ) o f a cream c o l o r e d s o l i d w h ic h m e lte d a t R e c ry s t a l l i z a t i on frc m p e tro le u m e t h e r r a i s e d t h e m e ltin g p o i n t t o 9 1 .5 - 9 2 .5 ^ 0 . A n a ly s is . N, 5 .9 2 . C a lc u la te d f o r C ^ ^ C l^ O : F ound: C, 4 0 .6 3 ; H, 1 .7 1 ; 0 1 , 4 4 .9 8 ; C, 4 0 .8 8 ; H, 1 .9 6 ; C l, 4 4 .8 3 ; N, 5 .7 9 . 2 .4 .6 - T r ic h lo r o p h e n o x y a c e to n itr ile . m o le ) o f 2 , 4 , 6 - t r i c h l o r o p h e n o l , 1 8 .7 g . n i t r i l e an d 3 4 .5 g . A m ix tu r e o f 4 9 .4 g . (0 .2 5 (0 .2 5 m ole) o f c h l o r o a c e t o - (0 .2 5 m ole) o f p o ta s s iu m c a r b o n a te w ere r e f l u x e d t o g e t h e r i n 75 m l. o f d ry a c e to n e f o r e i g h t h o u r s . The m ix tu r e was th e n p o u re d i n t o 200 m l. o f w a te r c o n t a i n i n g 10 g . o f so d iu m h y d ro x id e and e x tr a c te d w ith e t h e r . sod iu m s u l f a t e The e t h e r l a y e r was s e p a r a t e d , d r i e d o v e r and t h e s o l v e n t rem oved i n a vacuum . c o n s i s t e d o f 5 8 .0 g . ( 9 8 .5 ^ o f th e o r y ) s o l i d m e ltin g a t 1 0 1 -1 0 2 °C . m e ltin g p o i n t t o 102- 1 0 3 ^0 . The r e s i d u a l p r o d u c t o f a c o lo rle s s c r y s ta llin e 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 r a i s e d t h e 83 T h i s p r o d u c t was r e p o r t e d b y D r a in , P e a k an d W h itm o n t (44) t o m e lt a t 103^0. A n a ly s is . N, 5 .9 2 . C a l c u l a t e d f o r C g H ^C l^O ; Found: C, 4 0 .6 3 ; H, 1 .7 1 ; C l , 4 4 .9 8 ; C, 4 0 .6 3 ; H, 1 .6 3 ; C l, 4 4 .8 7 ; N, 5 .6 8 . H y d r o ly s is o f Phe noxya ce t o n i t r i l e s P h e n o x y a c e tic a c i d . F iv e and t h r e e - t e n t h s gram s ( 0 .0 4 m ole) o f p h e n o x y a c e t o n i t r i l e was a d d e d t o 100 m l. o f a 25^ sodium h y d ro x id e s o l u t i o n and th e m ix tu r e r e f l u x e d f o r tw e lv e h o u r s . A t th e en d o f t h i s tim e th e s o l u t i o n was a c i d i f i e d w ith d i l u t e h y d r o c h l o r ic a c i d . The p r e c i p i t a t e w h ich fo rm e d was f i l t e r e d an d d r i e d ; i t w e ig h e d 4 . 9 g . ( 8 0 . 53S o f t h e o r y ) , m .p . 9 8 -9 9 ° C ., a f t e r r e c r y s t a l l i z a t i o n from iv a te r . S a b e n j e f f a n d D w o rkow itach (45) r e p o r t e d a m e ltin g p o i n t o f 9 7 ^ 0 . f o r t h i s com pound. 2 .4 - D ic h lo r o p h e n o x y a c e tic a c i d . F iv e gram s (0 .0 2 5 m ole) o f 2 , 4 - d ic h lo r o p h e n o x y a c e t o n i t r i l e w as ad d ed t o 50 m l. o f a 253^ s o l u t i o n o f so d iu m h y d r o x id e and t h e r e s u l t i n g m ix tu r e r e f l u x e d f o r tw e lv e h o u rs. The p r e c i p i t a t e w hich fo rm ed on c o o lin g th e r e a c t i o n m ix tu r e w as f i l t e r e d a n d d i s s o l v e d i n 200 m l. o f h o t w a t e r . A c id ific a tio n o f t h i s s o l u t i o n w i t h d i l u t e h y d r o c h l o r i c a c id g a v e a c o l o r l e s s c r y s t a l l i n e p r e c i p i t a t e w h ic h w hen f i l t e r e d an d d r i e d m e lte d a t 1 3 7 -1 3 8 .5 ^ 0 . R e- c r y s t a l l i z a t i o n o f t h e p r o d u c t frcm w a te r r a i s e d th e m e ltin g p o i n t t o 1 3 8 .5 -1 3 9 ° C . T h is com pound w as p r e v i o u s l y r e p o r t e d t o m e lt a t 138 G ., b y P o r k o rn y (4 6 ) . 84 2 ,4 .5 - T r i o h l o r o p h e n o x y a o e t i o a c i d . F o u r a n d s e v e n - t e n t h s g ra m s { 0 .0 2 m o le ) o f 2 , 4 * 5 - t r i c h l o r o p h e n o x y a c e t o n i t r i l e was a d d ed t o 6o m l, o f a 25^ sod iu m h y d r o x id e s o l u t i o n a n d th e m ix tu r e r e f l u x e d f o r tw e lv e h o u rs. A t t h e end o f t h i s tim e t h e s o l u t i o n was c o o le d an d t h e p r e ­ c ip ita te f ilte r e d . The s o l i d was d i s s o l v e d i n h o t w a te r ; a s m a ll am ount o f i n s o l u b l e m a t e r i a l w as ro n o v e d by f i l t r a t i o n . A c id ific a tio n o f t h e f i l t r a t e w i t h d i l u t e h y d r o c h lo r ic a c id g a v e a c o l o r l e s s p r e ­ c ip ita te . F i l t r a t i o n an d d ry in g g a v e 4 , 3 g . ( 8 4 , 55^ o f th e o r y ) o f 2 , 4 , 5 - t r i c h l o r o p h e n o x y a c e t i c a c i d , m .p . 1 5 0 .5 - 1 5 2 ° C ., a f t e r r e c r y ­ s t a l l i z a t i o n from b e n z e n e . T h is compound was p r e v i o u s l y d e s c r ib e d b y P o rk o rn y (4 6 ) who r e p o r t e d t h e m e ltin g p o i n t a s 1 5 3 ^0 , T he P r e p a r a t i o n o f P h e n o x y m e th y l t e t r a z o l e s 5 - (P h en o x y m e th y l ) t e t r a z o l e . o f p h en o x y a c e to n i t r i l e , 11 g . A m ix tu r e o f 1 6 .3 g . (0 .1 2 5 m ole) ( O .I 65 m ole) o f sodium a z id e and 10 g . (0 ,1 6 5 m o le) o f g l a c i a l a c e t i c a c i d i n 60 m l. o f n o rm a l b u t y l a l c o h o l w as b o i l e d u n d e r r e f l u x f o r f o u r d a y s . Sodium a z i d e ( 2 ,5 g . ) and 5 g . o f g l a c i a l a c e t i c a c id w e re t h e n a d d ed and th e h e a t i n g c o n tin u e d f o r an a d d i t i o n a l tw o d a y s . A t t h e end o f t h i s tim e th e c o n t e n t s o f th e f l a s k w e re t r a n s f e r r e d t o a l a r g e r c o n t a i n e r , 200 m l. o f w a te r a d d ed an d th e m ix tu r e d i s t i l l e d u n t i l a l l th e a l c o h o l h ad b e e n rem o v ed . A c i d i f i c a t i o n o f t h e r e s i d u a l aq u eo u s s o l u t i o n w ith d i l u t e s u l f u r i c a c i d g a v e a c o l o r l e s s p r e c i p i t a t e , w h ich when f i l t e r e d and d r i e d w e ig h e d 2 2 .1 g . ( q u a n t i t a t i v e y i e l d ) . R e c r y s t a l l i z a t i o n fro m w a te r gave c o l o r l e s s c r y s t a l s m e ltin g a t Ô5 127.5-129®C. A n a ly s is . Found: C a lc u la te d f o r C, 5 4 .5 4 ; H, 4 .5 8 ; N, 3 1 .8 0 . C, 5 4 .5 0 ; H , 4 .6 5 ; N , 3 1 .9 3 . 5 - (2 *-Q ]iloroptLenoxynieth,yl) t e t r a z o l e . To a s u s p e n s ! cn o f l 6 . 7 g . ( 0 .1 m o le) o f 2 - c h l o r o p h e n o x y a c e t o n i t r i l e an d 19*5 g . ( 0 .3 m ole) o f sodium a z i d e i n 50 m l* o f d ry t e t r a h y d r o f u r a n m s a d d e d 13*3 g . ( O .l m o le ) o f a n h y d ro u s alum inum c h l o r i d e i n l6 0 m l. o f th e sam e s o l ­ v e n t. The r e s u l t i n g m ix tu r e w as r e f l u x e d w i t h c o n tin u e d s t i r r i n g f o r tw e n ty -fo u r h o u rs . A t t h e end o f t h i s tim e th e o r g a n ic s o l v e n t was d i s t i l l e d and w a t e r a d d e d a t s u c h a r a t e t h a t th e volum e re m a in e d c o n s ta n t. A f t e r th e s o l i d w h ic h s e p a r a t e d h ad b e e n f i l t e r e d , i t was s u s p e n d e d i n 250 m l. o f w a t e r , t r e a t e d w i t h 30 m l. o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d a n d th e r e s u l t i n g m ix tu r e s t i r r e d a t rocm te m p e r a tu r e fo r one h o u r. F i l t e r i n g and d r y in g o f t h e p r e c i p i t a t e gave 18*8 g* ( 8 9 , 5^ o f th e o r y ) o f th e p r o d u c t m e ltin g a t 1 3 1 - 1 3 5 ^ 0 .; t h i s was f u r t h e r p u r i f i e d by r e c r y s t a l l i z a t i o n from a n a l c o h o l - w a t e r m ix tu r e , n u p . 1 3 4 - 1 3 5 .5 ° 0 . The a n a l y t i c a l sam p le was r e c r y s t a l l i z e d fro m t o l u e n e , m .p . 1 3 4 .5 -1 3 5 .5 ^ 0 * A n a ly s is . N, 2 6 . 6 0 . C a l c u l a t e d f o r C ^^C IN ^O : Found: C, 4 5 .6 2 ; H , 3 .3 5 ; C l, I 6 . 8 3 ; C, 4 5 .9 2 ; H, 3 .6 3 ; 0 1 , l 6 . 9 4 ; N, 2 6 .5 8 . 5 - ( 4 * -C h lo ro p h e n o x 3rm e th y l) t e t r a z o l e . To a s u s p e n s io n o f l 6 . 7 g . ( 0 .1 m o le ) o f 4 - G h lo r o p h e n o x y a o e t o n i t r i l e and 1 9 .5 g . ( 0 .3 m ole) o f sodium a z i d e i n 50 ml* o f d ry t e t r a h y d r o f u r a n was ad d ed 1 3 .3 g . ( 0 .1 m o le) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 160 m l. o f d ry te tra h y d ro fu ra n . The m ix tu r e w as r e f l u x e d w ith c o n tin u e d s t i r r i n g 86 f o r tw e n ty —f o u r h o u rs* A t th e en d o f t h i s tim e t h e t e t r a h y d r o f u r a n was d i s t i l l e d from th e r e a c t i o n m ix tu r e and w a t e r g r a d u a l l y a d d ed a t su ch a r a t e t h a t t h e volum e re m a in e d c o n s ta n t* a r a t e d was f i l t e r e d , A f t e r th e s o l i d t h a t s e p ­ i t was s u s p e n d e d i n 225 ml* o f w a t e r , t r e a t e d w ith 30 m l. o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d a n d th e r e s u l t i n g m ix tu r e s t i r r e d a t room te m p e r a t u r e f o r one h o u r . F i l t e r i n g and d r y in g o f th e s o l i d g a v e 2 0 .6 g . o f t h e c ru d e p r o d u c t . (9S^ o f th e o r y ) T h is w as r e c r y s t a l l i z e d frcm an a l c o h o l - w a t e r m ix tu r e to g iv e 13*9 g . (66^ o f th e o r y ) o f p u re p r o d u c t , m .p . l 6 5 - l 6 6 ° C . A n a ly s is * N, 2 6 . 6 0 . C a l c u l a t e d f o r C^HyClN^O; F ound: 0 , 4 5 .6 2 ; H, 3 .3 5 ; C l, 16 . 8 3 ; G, /^5.72; H, 3 .6 3 ; C l, 1 6 .7 8 ; N, 2 6 . 4 8 . 5 -( 2 * .^ ,^ -D ic h lo ro p h e n o x y m e th y l) t e t r a z o l e . A m ix tu r e o f 2 5 .2 g . (0 .1 2 5 m ole) o f 2 , 4 - d i c h l o r o p h e n o x y a c e t o n i t r i l e , U g . ( O .I 65 m ole) o f so d iu m a z i d e and 10 g . o f g l a c i a l a c e t i c a c id i n 60 m l. o f n o rm a l b u t y l a l c o h o l w as r e f l u x e d f o r f o u r d a y s . A t th e end o f t h i s tim e a n a d d i t i o n a l 2 .5 g . o f sodium a z id e and 5 g . o f g l a c i a l a c e t i c a c i d w e re a d d ed an d th e h e a t i n g c o n tin u e d f o r tw o m ore d a y s . The c o n t e n t s o f th e r e a c t i o n f l a s k w e re t h e n t r a n s f e r r e d to a 500 m l. ro u n d b o tto m f l a s k , 200 m l. o f w a te r a d d ed and t h e m ix tu r e d i s t i l l e d u n t i l a l l t h e a l c o h o l h a d b e e n re m o v e d . w ith N o r ite , The r e s i d u a l a q u e o u s s o l u t i o n was t r e a t e d f i l t e r e d a n d a c i d i f i e d w ith c o n c e n t r a te d h y d r o c h lo r ic a c i d u n t i l a p r e c i p i t a t e no l o n g e r form ed* and d r i e d ; i t w e ig h e d 2 5 .6 g . The s o l i d w as f i l t e r e d ( 8 3 , 7^ o f t h e o r y ) . R e c r y s t a l l i z a t i o n fro m t o l u e n e g av e c o l o r l e s s n e e d l e s m e l t i n g a t 1 2 4 .5 - 1 2 5 .5 ° C . 87 A n a ly s is . C a l c u l a t e d f o r C ^^C l^ N ^O : C l, 2 8 .9 4 ; N, 2 2 .8 6 . Found: C, 3 9 * 2 1 ; H , 2 .4 7 ; C, 3 9 .4 0 ; H, 2 .5 9 ; 0 1 , 2 9 .0 4 ; N, 2 2 .9 6 . 5 - ( 2 * .4 * .5 * -T ric h lo ro p h e n o x y m e th y l)te tra z o le . 2 9 .6 g . A m ix tu r e o f (0 .1 2 5 m o le ) o f 2 , 4 ^ 5 - t r i c h l o r o p h e n o x y a c e t o n i t r i l e , 11 g . ( 0 .1 6 5 m ole) o f sodium a z i d e a n d 10 g* ( O .I 65 m ole) o f g l a c i a l a c e t i c a c i d i n 60 m l. o f n o rm a l b u t y l a l c o h o l was b o i l e d u n d e r r e f l u x f o r fo u r d ay s. An a d d i t i o n a l 2 .5 g . o f sodium a z i d e an d 5 g . o f g l a c i a l a c e t i c a c id w e re a d d e d a n d t h e h e a t i n g c o n tin u e d f o r tw o m o re d a y s . T he e n t i r e c o n t e n t s o f th e f l a s k w ere t r a n s f e r r e d t o a l a r g e r f l a s k , 200 m l. o f w a t e r a d d e d and t h e m ix tu r e d i s t i l l e d u n t i l a b o u t 175 m l. o f d i s t i l l a t e had been c o lle c te d . The h o t r e s i d u a l s o l u t i o n w as t r e a t e d w ith N o r i t e , f i l t e r e d an d a c i d i f i e d w i t h c o n c e n t r a t e d h y d ro ­ c h l o r i c a c i d u n t i l a p r e c i p i t a t e no l o n g e r fo rm e d . The s o l i d was f i l t e r e d an d d r i e d g iv i n g 2 5 .4 g . (7 3 ^ o f th e o r y ) o f c ru d e p r o d u c t , n u p . 1 5 5 -1 6 2 ° 0 . R e c r y s t a l l i z a t i o n frcm to lu e n e g a v e a c o l o r l e s s c r y s t a l l i n e p r o d u c t ( p l a t e s ) w h ich m e lte d a t 1 6 3 .5 -1 6 5 ^ 0 . A n a ly s is . C a l c u l a t e d f o r CgH^Gl^N^O: 0 1 , 3 8 . 0 6 ; N, 2 0 . 0 5 . Found; C, 3 4 .3 7 ; H, I . 8 O; C , 3 4 .7 4 ; H, 1 .7 7 ; 0 1 , 3 8 . 2 8 ; N, 2 0 .1 1 . 5- ( 2 * .4 * .6 * -T ri c h io r o p h e n o x y m e t h y l) te t r a z o l e . 5 .8 g. A s u s p e n s io n o f (0 .0 2 4 6 m o le) o f 2 , 4 , 6 - t r i c h l o r o p h e n o x y a c e t o n i t r i l e a n d 4 . 8 g . ( 0 .0 7 4 m ole) o f sodium a z id e i n 30 m l. o f d ry t e t r a h y d r o f u r a n was t r e a t e d w ith 2 .9 8 g . (0 .0 2 5 m o le) o f a n h y d ro u s alum inum c h l o r i d e d i s s o l v e d i n 60 m l. o f d ry t e t r a h y d r o f u r a n . w ith c o n tin u e d s t i r r i n g f o r tw e n ty h o u r s . The m ix tu r e was r e f l u x e d A t th e end o f t h i s tim e t h e o r g a n i c s o l v e n t was d i s t i l l e d a n d w a te r g r a d u a l l y ad d ed a t su c h a 88 r a t e t h a t t h e volum e re m a in e d c o n s t a n t . A f t e r th e s o l i d udiich p r e ­ c i p i t a t e d h a d b e e n f i l t e r e d i t w as s u s p e n d e d i n 150 m l. o f w a t e r , 20 m l. o f c o n c e n t r a t e d h y d r o c h lo r ic a c i d was a d d e d an d t h e m i x t u r e s t i i r e d a t room t e m p e r a t u r e f o r o n e h o u r. The s o l i d was f i l t e r e d an d d r i e d a t 7 0 ®C., g i v i n g 6 .6 g . o f th e o r y ) o f c r u d e p r o d u c t , m .p . 1 5 9 -1 6 1^ 0 . (96.55^ The p r o d u c t was r e - c r y s t a l l i z e d fro m to l u e n e a n d t h e n from e t h a n o l , n u p . l 6 4 - l 6 5 ^C. A n a ly s is . C a l c u l a t e d f o r C g H ^ C l^ ^ : 3 8 . 0 6 ; N , 2 0 .0 5 * Found: 0 , 34*37; H, 1 .8 0 ; C l, C, 34*62; H, 2 .0 6 ; C l, 37*90; N , 2 0 .0 2 . T he P r e p a r a t i o n o f 1 - B e n z y l- 5-phenozym e t h y l t e t r a z o l e s . l-B e n z y l-5 -P h e n o x y m e th y lte tra z o le . A m ix tu r e o f 8 .3 g . (O.0 4 m o le) o f l - b e n z y l - 5 - c h l o r o m e t h y l t e t r a z o l e ( I 6 ) , 4*7 g* (0 .0 5 m ole) o f p h e n o l and 2*7 g* ( 0 .0 5 m ole) o f so d iu m m e tiiy la te i n 75 m l. o f ab ­ s o l u t e m e th a n o l w as b o i l e d u n d e r r e f l u x f o r t e n h o u rs w ith c o n tin u e d s tirrin g . The e n t i r e c o n t e n t s o f th e f l a s k was t h a i p o u re d i n t o 150 m l. o f w a t e r a n d th e s o l i d p r e c i p i t a t e f i l t e r e d . R e c ry s ta lliz a tio n fro m a q u e o u s m e th a n o l g a v e 3*8 g . ( 3 5 * ^ o f t h e o r y ) o f th e d e s i r e d p r o d u c t m e ltin g a t 6 6 .5 - 6 7 ^ 0 . A n a ly s is . Found: C a lc u la te d f o r C ^ ^ ^ N ^ O ; C, 6 7 * 6 5 ; H, 5*30; N, 2 1 .0 4 , C, 6 7 * 4 0 ; H , 5 * 3 6 ; N, 2 1 .0 8 . l - B e n z y l - 5 - ( 2 *.4 * - d i c h l o r o p h e n o x y m e t h y l ) t e t r a z o l e . A m ix tu r e o f 8 .3 g* (0 .0 4 m ole) o f l - b e n z y l - 5 - c h l o r o m e t h y l t e t r a z o l e , 8 .1 5 g* (0 .0 5 m o le) o f 2 , 4 - d i c h l o r opheno 1 a n d 2 .7 g* (0 .0 5 m ole) o f so d iu m m e th y la te w as r e f l u x e d i n 75 m l. o f a b s o l u t e m e th a n o l w ith c o n tin u e d s t i r r i n g fo r s ix te e n h o u rs. A t th e end o f t h i s tim e t h e c o n t e n t s o f t h e f l a s k 89 w e re a d d e d t o 150 m l. o f w a t e r a n d t h e p r e c i p i t a t e w hich fo im ed f i l t e r e d and d r i e d to g i v e 1 2 .4 g . 9 5 -9 7 ^ 0 . (9 2 . 5^ o f th e o r y ) o f c ru d e p r o d u c t , R e c r y s t a l l i z a t i o n fro m m e t h a i o l g a v e 8 . 6 g . ( 6 4 . 29^ o f th e o r y ) o f p u re p r o d u c t , m .p . 1 0 7 .5 -1 0 8 ° C . A n a ly s is . C a lc u la te d f o r 2 1 .1 6 ; N , 1 6 .7 2 . Found: C, 5 3 .7 5 ; H , 3 .6 1 ; 0 1 , C, 5 3 .8 3 ; H , 3 .9 0 ; C l, 2 1 .0 4 ; N , 1 6 .7 6 . l - B e n z y l - 5 - ( 2 * . 4 * . 5 * - tr ic h lo r o p h e n o z y m e th y l) t e t r a z o l e . A m ix tu r e o f 6 .9 3 g . ( 0 .0 3 3 m ole) o f l - b e n z y l - 5- c h l o r o m e t h y l t e t r a z o l e , 8 .1 5 g . ( 0 .0 4 1 6 m o le) o f 2 , 4 , 5 - t r i c h l o r o p h e n o l and 2 .2 4 g . (O.0 4 1 6 m ole) o f so d iu m m e th y la te was r e f l u x e d in 75 m l. o f a b s o l u t e m e th a n o l w ith co n ­ tin u e d s t i r r i n g fo r seven h o u rs. p o u re d i n t o 1 5 0 m l. o f w a t e r . g i v i n g 1 0 .6 g . T he r e s u l t i n g m ix tu r e was c o o le d a n d The p r e c i p i t a t e was f i l t e r e d an d d r i e d (8 6 . 29G o f th e o r y ) o f c ru d e p r o d u c t, m .p . 1 0 1 , 5- 1 0 5 °G. R e c r y s t a l l i z a t i o n fro m m e th a n o l g a v e 6 . 4 g . (52gG o f th e o r y ) o f t h e c o l o r l e s s , c r y s t a l l i n e p r o d u c t m e ltin g a t 1 1 3 . 5- 1 1 4 . 5^ 0 . A n a ly s is , 2 8 .7 8 ; N, 15. 1 6 . C a lc u la te d f o r C ^ ^ ^ C l ^ ^ : Found: G, 4 8 .7 4 ; H, 3 .0 0 ; C l, C, 4 8 . 6 I ; H , 3 .1 2 ; C l, 2 8 .7 1 ; N, 1 5 .3 1 . l - B e n g y l - 5 - ( 2 * .4 * . 6 * - t r i c h l o r o p h e n o x y m e t h y l ) t e t r a z o l e . o f 6 .9 3 g . A m ix tu r e (0 .0 3 3 m o le ) o f 1 - b e n z y l - 5- c h l o r o m e t h y l t e t r a z o l e , 8 .1 5 g . (0 .0 4 1 6 m o le) o f 2 , 4 , 6- t r i c h l o r o p h e n o l and 2 . 2 g . (O.0 4 1 6 m ole) o f so d iu m m e th y la te w as r e f l u x e d i n 75 m l. o f a b s o l u t e m e th a n o l w ith c o n tin u e d s t i r r i n g f o r tw e n ty h o u r s . The c o n t e n t s o f t h e f l a s k w e re th e n p o u re d i n t o 150 m l. o f w a te r and t h e p r e c i p i t a t e w h ich fo rm ed o f i l t e r e d , a n d d r i e d , 1 2 .3 g . ( q u a n t i t a t i v e y i e l d ) , iru p . 1 0 9 -1 1 1 C. c r y s t a l l i z a t i o n fro m m e th a n o l g av e 9 .1 g . (7 4 .0 ^ o f th e o r y ) o f t h e R e- 90 c o l o r l e s s c r y s t a l l i n e p r o d u c t m e l t i n g a t 1 1 2 -1 1 3 ^ 0 , A n a ly s is . 2 8 .7 8 ; N , 1 5 .1 6 . C a lc u la te d f o r Found: C, 4 8 .7 4 ; H, 3 .0 0 ; C l, C, 4 8 .7 5 ; H, 3 .0 1 ; C l , 2 8 .9 2 ; N, 1 4 .9 8 . B e b e n z y la t i on o f l- B e n z y l- 5 - p h e n o z y m e th y lte t r a z o l e s 5—(P h e n o z y m e tb y l) t e t r a z o l e . Two an d s e v e n - t e n t h s gram s ( 0 .0 1 m ole) o f 1—b e n z y l—5 " p h e n o 3 q n iie th y lte tr a z o le was s h a k e n w ith 1 g . o f 55^ p a lla d iu m on c h a r c o a l i n 100 m l. o f a b s o l u t e e t h a n o l i n a h y d ro g e n a tm o s p h e re a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . f o r tw e lv e h o u r s . c a t a l y s t w as t h e n f i l t e r e d a n d th e s o l v e n t ra n o v e d i n a vacuum . T he The r e s i d u e v h ic h re m a in e d was t r e a t e d w ith d i l u t e b a s e and f i l t e r e d . From t h e a l k a l i i n s o l u b l e s o l i d 1 .3 g . w as r e c o v e r e d . (499^) o f s t a r t i n g m a t e r i a l On 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 w ith d i l u t e h y d r o c h l o r i c a c i d a p r e c i p i t a t e fo rm ed w h ic h w hen f i l t e r e d an d d r i e d g a v e 400 mg. (43.49^ o f th e o r y ) o f th e c ru d e p r o d u c t, m .p . 125 -1 2 7 ^0 * R e c ry s t a l l i z a t i o n o f th e p r o d u c t from w a te r r a i s e d th e m e l t i n g p o i n t t o 1 2 7 .5 - 1 2 8 .5 ®C. A m i x t u r e m e ltin g p o i n t w ith a sam p le o f th e same compound p r e ­ p a r e d fro m th e c o r r e s p o n d in g n i t r i l e , sodium a z i d e and g l a c i a l a c e t i c a c i d , showed no d e p r e s s i o n . 5 - ( 2 * . 4 * . 5 * - T r ic h lo r o p h e n o x y m e t h y l ) te t r a z o l e . One a n d e i g h t - t e n t h s g ra m s (0 .0 0 5 m ole) o f l - b e n z y l - 5 - ( 2 * ,4 % 5 * - tr ic h l o r o p h e n o x y m e t h y l ) t e t r a z o l e and 1 g . o f 5 ^ p a lla d iu m on c h a r c o a l w ere s u s p e n d e d i n 75 m l. o f a b s o l u t e e t h a n o l an d s h a k e n in an a tm o s p h e re o f h y d ro g e n a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . f o r tw e lv e h o u r s . The c a t a l y s t w as th e n f i l t e r e d an d w ash ed w ith warm e t h a n o l ; t h e w a s h in g s w e re 91 co m b in e d w ith , th e f i l t r a t e . R em oval o f th e s o lv e n t i n a vacuum l e f t a r e s i d u e w h ic h when r e c r y s t a l l i z e d from t o l u e n e g a v e 0 ,8 5 g . t h e o r y ) o f p r o d u c t m e l t i n g a t 149 -1 5 5 ^0 * (6 l^ o f H ^ e a te d re c r y s ta lliz a tio n s fro m t o lu e n e r a i s e d th e m e ltin g p o i n t t o l6 0 -l6 2 ° C * The m i x t u r e m e ltin g p o in t ( l 6 2 . 5 - l 6 4 ° 0 . ) , w ith a n a n a l y t i c a l sa m p le o f th e same p r o d u c t , m .p . l 6 3 . 5 - l 6 5 ° C . , fo rm e d fro m t h e r e a c t i o n o f th e co i r e s p e n d in g n l t r i l e w ith so d iu m a z id e a n d a c e t i c a c i d i n r e f l u x i n g b u t a n o l , was n o t m a rk e d ly d e p r e s s e d . A tte m p te d d é b e n z y la tio n o f 1 - B e n z y l- 5 - ( 2 * .4 '- d ic h lo r o p h e n o x y m e th y l) t e t r a z o l e One a n d s e v e n - t e n t h s g ram s (0 .0 0 5 m ole) o f l - b e n z y l - 5 - (2 * ,4 * d i e h l o r o p h e n o x y m e t h y l ) t e t r a z o l e a n d 1 g . o f 59& p a lla d iu m on c h a r c o a l w e re s h a k e n i n an a tm o s p h e re o f h y d ro g e n a t a n i n i t i a l p r e s s u r e o f 50 p . s . i . w h ile s u s p e n d e d i n 100 m l. o f a b s o l u t e e t h a n o l . A f t e r tw e lv e h o u r s t h e c a t a l y s t was f i l t e r e d and w ashed w i t h warm e t h a n o l . com bined f i l t r a t e The a n d w a s h in g s w e re e v a p o r a te d i n a vacuum an d t h e r e s i d u e r e c r y s t a l l i z e d from t o l u e n e s e v e r a l t i m e s , m .p . 1 0 1 -1 0 2 ^ 0 . A tte m p te d d é b e n z y la tio n o f l - B e n z y l - 5 - (2 * . 4 \ 6 ' - t r i c h l o r o p h e n o x y m eth y l) t e t r a z o l e T h re e a n d s e v e n - t e n t h s gram s (0*01 m ole) o f l - b e n z y l - 5 - ( 2 * , 4 ’ , 5 ’t r i c h l o r o phenoxym e t h y l ) t e t r a z o l e and 1 g . o f 5^ p a lla d iu m on c h a r c o a l , s u s p e n d e d i n 100 m l. o f a b s o l u t e e t h a n o l , w ere sh a k e n i n an a tm o s p h e re o f h y d ro g e n a t an i n i t i a l p r e s s u r e o f 50 p . s . i . f o r te n h o u r s . The c a t a l y s t w as t h e n f i l t e r e d fro m t h e r e a c t i o n m ix tu re and w ash ed w i t h 92 wazm e th a n o l* The co m b in e d f i l t r a t e and w a s h in g s w e re e v a p o r a te d i n a vacuum a n d t h e r e s i d u e r e c r y s t a l l i z e d fro m to lu e n e * In s p ite o f r e ­ p e a t e d r e c r y s t a l l i z a t i o n s t h e s o l i d m e lte d o v e r a w ide r a n g e . p r o d u c t was th e n t r e a t e d w ith d i l u t e b a s e , a c id ifie d . The f i l t e r e d an d th e f i l t r a t e The p r e c i p i t a t e fb im e d was r e c r y s t a l l i z e d from t o l u e n e , m .p . 1 0 9 -H 2 ® 0 . The P r é p a r a t i on o f I n d o l y l m e t h y l t e t r a z o l e 5 -(3 * -In d o ly lm e th y l)te tra z o le . S e v e n and e i g h t - t e n t h s gram s ( 0 .1 2 m o le) o f so d iu m a z id e w as c a u s e d t o r e a c t w ith 5 .3 2 g* (0*04 m o le ) o f a n h y d ro u s alum inum c h l o r i d e In 120 m l. o f d ry r e f l u r i n g t e t r a h y d r o f u r a n f o r o n e h o u r. g. To t h e r e s u l t i n g m ix tu r e was a d d e d 5 .8 (0 .0 3 7 m o le) o f 3 - i n d o l y l a c e t o n i t r i l e an d t h e r e f l u x i n g c o n tin u e d w ith s t i r r i n g f o r a n a d d i t i o n a l tw e n t y - f o u r h o u r s . A f t e r t h i s tim e t h e t e t r a h y d r o f u r a n w as d i s t i l l e d from th e r e a c t i o n m ix tu r e an d w a te r a d d e d a t s u c h a r a t e t h a t th e volum e o f th e m ix tu r e re m a in e d c o n s t a n t . A f t e r a l l th e o r g a n i c s o l v e n t h a d b e e n rem o v ed th e s o l i d p r e c i p i t a t e w as f i l t e r e d , r e s u s p e n d e d i n 250 m l. o f w a t e r an d t r e a t e d w ith s u f f i c i e n t c o n c e n t r a t e d h y d r o c h lo r ic a c i d t o make t h e pH o f t h e s o l u t i o n 2 . A fte r t e n m in u te s t h e s o l i d m a t e r i a l w as f i l t e r e d and w ashed w ith a s m a ll am ount o f w a t e r . D ry in g g a v e 6 .5 g . (88.4% o f th e o r y ) o f t h e c ru d e p r o d u c t m e l t i n g a t 1 7 3 - 1 7 6 .5 ^ 0 ., w ith d e c c m p o s itio n . The p r o d u c t w as r e c r y s t a l l i z e d fro m e t h y l e n e d i c h l o r i d e and t h e n fro m w a te r t o g iv e 4 . 5 g . (61.2% o f th e o r y ) o f p u re p r o d u c t , m .p . 1 7 9 - 1 8 0 ^ 0 ., w ith deoom posi t i o n . A n a ly s is . C a l c u l a t e d f o r ®^o^9^5* ^ * 6 0 .2 9 ; H, 4 .5 5 ; N , 3 5 .1 6 . 93 Found: 6 0 .3 4 ; H , 4 . 7 5 ; N, 3 5 .0 0 . The m onopi c r a t e was p r e p a r e d i n a n d r e c r y s t a l l i z e d fro m w a te r , m .p . 1 3 1 -1 3 2 ° C . A n a ly s is . Found: C a lc u la te d f o r C , 4 5 .5 2 ; H , 3 .2 0 ; H , 2 5 .8 3 . HgO^: C, 4 4 .8 6 ; H, 2 .8 3 ; N, 2 6 ,1 6 . PART 7 DISUBSTITÜTED TETRAZOLES AS ANALOGUES OF ACTIVE BASIC ESTERS P i s c u s slo n R e c o g n i t i o n o f th e h y p o te n s iv e a c t i o n o r t h e b lo o d p r e s s u r e lo w e r in g a b i l i t y o f th e e x t r a c t s o f R a u w o lf ia s e r p e n t i n a r e s u l t e d i n a n e x t e n s i v e i n v e s t i g a t i o n i n t o th e c h e m i s tr y , p h a rm a c o lo g y and m e d ic in a l a s p e c ts o f th e R a u v o lfia a l k a l o i d s . H e s e r p in e ( I ) , one o f th e m o st im p o r ta n t a l k a l o i d s o f t h i s g r o u p , w h ic h w as f i r s t I s o l a t e d i n th e p u r e s t a t e i n 1 9 5 2 , by S c h l l t t l e r an d h i s c o - w o r k e r s ( 4 7 ) , h a s b e e n show n by p h a r m a c o lo g ic a l and c l i n i c a l i n v e s t i g a t e r s n o t o n ly t o b e o n e th o u s a n d tim e s a s p o t e n t a h y p o te n s iv e a g e n t a s th e c ru d e d r u g , b u t to h a v e th e u n iq u e p r o p e r ty o f p r o d u c in g a s t a t e o f q u ie s e n c e v h ic h h a s v a lu e i n t h e tr e a t m e n t o f m e n ta l i l l n e s s . F o llo w in g th e p r o p o s a l f o r th e s t r u c t u r e o f r e s e r p i n o by S c h l i t t l e r (4 8 ) a n d t h e c o n f ir m a tio n o f t h i s s t r u c t u r e b y an u n e q u iv o c a l s y n th e s is (4 9 )» an i n t e n s e s e a r c h to d e te r m in e th e a c t i v e p o r t i o n o f th e r e s e r p i n e m o le c u le showed t h a t r e p la c e m e n t o f t h e 3 ,4 » 5 - t r i ­ me th o z y b e n z o y l m o ie ty b y o t h e r a c i d g ro u p in g s e i t h e r lo w e re d o r d e s ­ tro y e d i t s p h y s io lo g ic a l a c t i v i t y (5 0 ). T h is s u g g e s te d t h a t th e p harm acodynam ic a c t i o n w as d u e , n o t t o th e p o r t i o n o f th e m o le c u le c o n ta in in g th e in d o l e r i n g , b u t t o th e r e m a in d e r o f th e s t r u c t u r e w hich i n c lu d e d th e tr im e th o x y b e n z o y l e s t e r g ro tq p in g ( 5 1 ) . I n an e f f o r t t o s u b s t a n t i a t e t h i s th e o r y W ein b eig and M i l l e r p r e p a r e d a s e r i e s o f d ia lk y l a m i n o a l k y l 3 , 4 , 5 - t r i m e t h o x y b e n z o a t e s , t h e 95 n o s 't a c t l y o o f w h ic h ./n a s d lc th y la m in o -iL -p p o p y l 5 ,4 # 5 ^ trin ie th o % y b o n z o a te (II) • pCH. OOH. iCH G H r.0 II I n e x p l o r i n g t h e a n a lo g y o f 5 H n o n o s u b s titu te d t e t r a z o l e s t o c a r b o x y l i c a c i d a i t w as a n t i c i p a t e d t h a t a l k y l a t i o n o f 5 -(3 * # 4 * # 5 * trim e th o x y p h e x q rl) t e t r a z o l e w o u ld l e a d t o a s t r u c t u r e s i m i l a r t o th o s e s y n t h e s i z e d b y W einberg* i n id iic h th e e s t e r g r o u p in g w o u ld b e r e p i a c e d by a d ls u b s titu te d te tra z o le * B e c a u s e o f t h e ta u to m e r ic e q u i l i b r i u m w h ic h e x i s t s i n 5-m onos u b s titu te d te tra z o le s * a l k y l a t i o n c o u ld an d d o e s l e a d to t h e f o r m a ti o n 96 o f tw o I s o m e r ic p r o d u c t s ( 5 2 ) : R— G - II V N-R I R— 0 = H I R *X ----------^ R »x I R— 0 N-R • II V I R— 0 = N I I P r e v i o u s i n v e s t i g a t i o n s c a r r i e d o u t o n t h e a l k y l a t i o n o f 5-mono— s u b s t i t u t e d t e t r a z o l e s w ith d i a l k y l a m i n o a l k y l h a l i d e s h a v e shown t h a t b y th e u s e o f s e l e c t i v e s o l v e n t s o n e c o u ld i s o l a t e th e p r e d o m in a tin g is o n e r* th e 2 *5- d i s u b s t i t u t e d p r o d u c t , f r e e fro m c o n ta m in a tio n b y t h e o t h e r is o m e r ( 5 3 ) . A l k y l a t i o n s o f t h e 5 - a r y l t e t r a z o l e s w e re c a r r i e d o u t u n d e r t h e c o n d i t i o n s s u g g e s te d by B lp e r n (5 3 ) and th e p r o d u c t i s o l a t e d i n s u c h a m a n n e r t h a t i t p r o v id e d o n ly t h e 2*5 - d i s u b s t i t u t e d t e t r a z o l e . The 2 - d i a l k y l a m i n o a l k y l - 5 - ( 3 *#4 * » 5 * -trim e th o x y p h e n y l ) t e t r a z o l e s ( I I I ) * id iic h w e re i n i t i a l l y i s o l a t e d a s o i l s * w e re r e a d i l y c o n v e r te d t o s t a b l e h y d r o c h l o r i d e s by b u b b lin g d ry h y d ro g e n c h l o r i d e g a s i n t o a n e t h e r a l s o lu tio n o f th e b ase * T he h y d ro c h l o r i d e s w e re u s e d t o c h a r a c t e r i z e t h e p r o d u c t s a n d w e re a l s o t h e fo rm m o st s u i t a b l e f o r p h a r m a c o lo g ic a l t e s t in g p u rp o se s. 97 CHoO GH^O CH^O III T he s t a r t i n g m a t e r i a l f o r t h i s s e r i e s o f p r é p a r a t i o n s , 5 - ( 3 * ,4 * * 5 * t r i r a o t h o z y p h o n y l ) t e t r a z o l e , was s y n t h e s i z e d i n th e f o ll o w i n g m an n er: 3 ,4 $ 5 - tr im e th o z y b e n z o ic a c i d was c o n v e r te d t o th e a c i d c h l o r i d e an d s u b s e q u e n t l y , b y r e a c t i o n w ith a c o n c e n t r a t e d ammonium h y d ro x id e i n t o t h e c o r r e s p o n d in g am ide i n good y ie l d s * v e r t e d to t h e n l t r i l e The a m id e , i n t u r n , was co n ­ a c c o r d in g t o t h e g e n e r a l p r o c e d u r e o f F a h re n b a c h (54) • The n i t r i l e was th e n c a u s e d to r e a c t w ith sodium a z id e and g l a c i a l a c e tic a c id i n r e f l u x i n g n o rm a l b u t y l a l c o h o l , f o llo w in g t h e m eth o d o f H e r b s t a n d W ilso n ( 5 ) , a n d y i e l d e d t h e c o r r e s p o n d in g a r y I t e t r a z o l e * E x p é r im e n ta l 5 -T rIm e th o x y b e n z a m ld e * T he a c id c h l o r i d e fo rm ed fro m t h e r e a c t i o n o f 94 g* ( 0 .4 4 m ole) o f 3 ,4 ,5 - t r i m e t h o x y b e n z o i c a c i d a n d 100 m l. o f t h i o n y l c h l o r i d e was a d d e d i n s m a ll p o r t i o n s t o 400 m l. o f c o n c e n t r a t e d ammonium h y d r o x id e a t O^C* A f t e r two h o u r s o f s t i r r i n g t h e m ix tu r e w as a llo w e d t o warm up t o room te m p e r a tu r e an d w as f i l t e r e d . The i n s o l u b l e p r o d u c t a f t e r d r y in g , am o u n ted t o 7 4 .5 g . (8 0 .3 ^ o f t h e o r y ) , m .p . 1 7 8 -1 8 0 °C . G aebe an d Su t e r (55) r e p o r t a m e ltin g p o i n t o f 1 7 6 -1 7 7 ° C ., f o r t h i s com pound. 3 . 4 . 5 - T r ime th o z y b e n z o n i tar i l e . T h i r t y t h r e e a n d f i v e - t e n t h s g ram s (0 * l6 8 m o le ) o f 3 , 4 * 5 - tr im e th o x y b e n z a m ide w as r e f l u x e d w ith 1 8 .4 g , ( 0 .0 9 7 m o le ) o f so d iu m m e t a b i s u l f i t e an d 5 9 .5 g . o f p h o s p h o ru s o x y c h l o r i d e f o r one h o u r . c a r e f u l l y o n to i c e . The w in e c o lo r e d s o l u t i o n was th e n p o u re d The g r e y s o l i d w h ic h fo rm ed was f i l t e r e d and d r i e d ; th e c r u d e y i e l d w as 2 9 .8 g . ( 9 1 .9 ^ o f t h e o r y ) , m .p . 9 3 - 9 4 .5 °C* H e f f t e r and C a p e llm a n n (56) r e p o r t t h i s compound t o m e lt a t 9 5 °G. 5 - ( 3 * . 4 * «5 *- T r lm e th o x y p h e n y l) t e t r a z o l e . n itrile 3*4* 5 -T rim e th o x y b e n z o - ( 2 9 .8 g . , 0 .1 5 4 m o le ) , 1 4 .9 5 g . ( 0 .2 3 m ole) o f so d iu m a z i d e an d 1 3 .8 g . ( 0 .2 3 m ole) o f g l a c i a l a c e t i c a c id w e re a d d e d to 100 m l. o f n o rm a l b u t y l a l c o h o l and th e m ix tu r e r e f l u x e d f o r f o u r d a y s . At t h e end o f t h i s tim e a n a d d i t i o n a l 5 g . o f sodium a z i d e a n d 10 g . o f g l a c i a l a c e t i c a c i d w ere a d d ed and th e h e a t i n g c o n tin u e d f o r two m ore d ay s. The c o n t e n t s o f th e f l a s k w ere th e n t r a n s f e r r e d t o a l a r g e r 99 f l a s k , 250 m l. o f w a t e r a d d e d an d t h e m ix tu r e d i s t i l l e d th e a l c o h o l h a d b e e n rem oved* u n til a l l The r e s i d u a l s o l u t i o n w as c o o le d a n d e n o u g h h y d r o c h l o r i c a c i d a d d e d t o c o m p le te ly p r e c i p i t a t e th e t e t r a z o l e * T he s o l i d w as f i l t e r e d and r e c r y s t a l l i z e d fro m a w a t e r - i s o p r o p y l a l c o h o l m i x t u r e , 3 3 .9 g . A n a ly s is . Found: ( 9 3 . ^ o f t h e o r y ) , m *p. 1 9 9 -2 0 0 ^ 0 . C a lc u la te d fo r 5 0 .8 4 ; H, 5 .1 2 ; N, 2 3 .7 2 . C, 5 1 .0 7 ; H , 5 .2 2 ; N, 2 3 .5 5 . 2- (D ie th y la m in o e t h y l ) - 5 - ( 3 '. 4 * . 5 H y d r o c h lo r id e . tr lm e th o x y p h e n y l) t e t r a z o l e 5 - ( 3 * » 4 * ,5 * - T r i m e th o x y p h e n y l) t e tr a z o l e ( 1 1 .8 g . , 0 .0 5 m o le ) a n d 8 .6 g* (0 .0 5 m ole) o f d i e th y l a m in o e th y l c h l o r i d e hydro c h l o r i d e w e re s u s p e n d e d i n ^ m l. o f a c e to n e t o w h ich w as t h e n a d d e d 8 .4 g . ( 0 .2 1 m o le) o f so d iu m h y d r o x id e i n 7 .5 m l. o f w a t e r . h e a t e d u n d e r r e f l u x w i t h c o n tin u e d s t i r r i n g T he m ix tu r e w as fo r th re e h o u rs. At th e end o f t h i s tim e 50 m l. o f w a t e r w as a d d e d , and t h e m i x t u r e e x t r a c t e d w ith b e n z e n e . d is tilla tic n The b e n z e n e l a y e r w as s e p a r a t e d , d r i e d by a z e o t r o p i c a n d th e s o l v e n t rem oved i n a vacuum . T he o i l y r e s id u e w h ic h re m a in e d was d i s s o l v e d i n 250 m l. o f c o ld e t h e r and d ry h y d ro g e n c h l o r i d e b u b b le d i n t o t h e s o l u t i o n u n t i l a p r e c i p i t a t e no l o n g e r fo rm e d . The s o l i d w as f i l t e r e d and d r i e d t o g i v e 1 5 .4 g . o f c r u d e p ro d u c t. ( 8 3 .2 ^ o f th e o r y ) R e c r y s t a l l i z a t i o n from i s o p r o p y l a l c o h o l g a v e t h e p u r e , c o l o r l e s s , c r y s t a l l i n e p r o d u c t m e ltin g a t 1 4 7 -1 4 8 0 . A n a ly s is . C a lc u la te d f o r C l, 9 .5 3 ; N, 1 8 .8 4 . Found: C, 5 1 .6 7 ; H , 7 .0 5 ; C, 5 1 .6 9 ; H, 6 .9 5 ; 0 1 , 9 .5 2 ; N, 1 9 .0 5 . 100 2- ( 3 * - D le t h y la m in o p ro p y l ) - 5 - ( 3 * « 4 * .5 *- t r l m e th o x y p h e n y l ) t e t r a z o l e H y d ro c h lo rid e . 5 - ( 3 * # 4 * * 5 ’- T r i m e t h o x y p h e n y l ) t e t r a z o l e (1 8 .0 g . , 0 .0 7 6 m o le ) a n d 14*5 g . ( 0 .0 7 8 m o le) o f 3—d i e th y lam ln o p ro p y l c h l o r i d e h y d r o c h l o r i d e w e re s u s p e n d e d i n 100 m l. o f a c e to n e t o w h ic h w as t h e n a d d e d 1 2 .6 g . ( 0 .3 2 m o le ) o f so d iu m h y d r o x id e i n 12 m l. o f w a t e r . m ix tu r e was r e f l u x e d w ith c o n t i n u e d s t i r r i n g fo r e ig h t h o u rs. The A fte r d i l u t i o n w i t h 80 m l. o f w a t e r t h e m ix tu r e w as e x t r a c t e d w ith b en zen e# T he b e n z e n e l a y e r w as t h e n s e p a r a t e d , d r i e d by a z e o t r o p i c d i s t i l l a t i o n and t h e s o l v e n t rem oved i n a vacuum . T he o i l y r e s i d u e w h ich r e n a l n e d w as d i s s o l v e d i n 300 m l. o f c o ld e t h e r and d r y h y d ro g e n c h l o r i d e b u b b le d i n t o th e s o l u t i o n u n t i l a p r e c i p i t a t e no l o n g e r fo im e d . T he s o l i d w as f i l t e r e d an d d r i e d ; t h i s g a v e 2 7 .1 g . t h e o r y ) o f c ru d e p r o d u c t, m .p . 1 5 0 -1 5 5 ^ 0 . p r o p y l a l c o h o l g a v e 2 1 .8 g . ( 9 2 .5 ^ o f R e c r y s t a l l i z a t i o n fro m i s o ­ (74.39^ o f th e o r y ) o f a c o l o r l e s s c r y s t a l l i n e p ro d u c t m e ltin g a t l6 0 -l6 l^ C . A n a ly s is . C a l c u l a t e d f o r C ^,^^gC lN ^O ^: 9 .1 9 ; N, 1 8 .1 5 . 2- F ound: C, 5 2 .9 2 ; H, 7 .3 1 ; C l, C, 5 2 .9 0 ; H , 7 .2 5 ; C l, 9 .4 1 ; N , 1 8 .3 1 . (3 '-D lm e th y la m in o p ro p y l) - 5 - (3 *. 4 *. 5 * - tr im e th o x y p h e n y l) t e t r a z o l e H y d ro c h lo rid e . 5 - ( 3 ’ , 4 * , 5 ^ - T r im © th o x y p h e n y l) te tr a z o le (1 8 .0 g . , 0 .0 7 6 m ole) an d 1 2 .0 g . (0 .0 7 6 m ole) o f 3 -d im e th y la m in o p r o p y l c h l o r i d e h y d r o c h l o r i d e w e re s u s p e n d e d i n l 60 m l. o f a c e to n e t o w h ich was t h e n a d d e d 1 2 .6 g . w a te r. ( 0 .3 2 m o le ) o f so d iu m h y d ro x id e d i s s o l v e d in 12 m l. o f The r e s u l t i n g m ix tu r e w as r e f l u x e d w ith c o n tin u e d s t i r r i n g fo r e ig h t h o u rs. A t t h e end o f t h i s tim e 80 m l. o f w a t e r was a d d e d Anr) t h e m i x t u r e e x t r a c t e d w ith b ^ i z e n e . The b e n ze n e l a y e r w as s e p - 101 a r a te d , d r i e d b y a z e o t r o p i c d i s t i l l a t i o n a n d t h e s o l v e n t rem oved i n a v acu u m . "Die o i l y r e s i d u e w h ich re m a in e d w as d i s s o l v e d i n 300 m l. o f c o ld e t h e r and d r y h y d ro g e n c h l o r i d e b u b b le d i n t o t h e s o l u t i o n u n t i l a p r e c i p i t a t e n o l o n g e r fo rm e d . The f i l t e r e d , d r i e d s o l i d am ounted t o 1 3 .6 g . (50.3% o f th e o r y ) a f t e r r e c r y s t a H i z a t i on from i s o p r o p y l a l c o h o l , m .p . 1 6 2 .5 -1 6 3 .5 ^ 0 * A n a ly s is . C a lc u la te d f o r C ^ ^ ^ G IN ^ O ^ : C l, 9 .9 1 ; N, 1 9 .5 7 . F ound : C, 5 0 .3 4 ; H, 6 .? 6 ; C, 5 0 .1 7 ; H, 6 .8 9 ; C l , 9 .9 8 ; N, 1 9 .3 7 . SUMMARY 1* T h r e e d i f f e r e n t r o u t e s f o r t h e s y n t h e s i s o f 5-a m in o a lk y 1 - t e t r a z o l e s have b e e n d e v e lo p e d t o p r e p a r e th e t e t r a z o l e a n a lo g u e s o f g l y c i n e , D ,L - a l a n l n e , phane. - a l a n i n e , D ,L - p h e n y la la n in e and D , l - t r y p t o ­ The a c e t y l , b e n z o y l a n d p h e n y lu r e a d e r i v a t i v e s o f th e 5 -n m in o - a l k y l t e t r a z o l e s h a v e b e e n p r e p a r e d and i n o n e i n s t a n c e t h e h y d ro ­ c h lo r id e h as been d e s c rib e d , 2. T he a p p a r e n t pK^ and v a l u e s o f t h e 5 - a m l n o a l k y l t e t r a z o l e s , w ith t h e e x c e p tio n o f th e tr y p t o p h a n e a n a lo g u e , h a v e b e e n d e te r m in e d and shown t o b e a n a lo g o u s t o th o s e o f th e c o r r e s p o n d in g am ino a c i d s , 3. S t a r t i n g fro m th e a p p r o p r i a t e l y s u b s t i t u t e d n ltr o b e n z o n i t r i l e s t h e t h r e e is o m e r ic 5 - n i t r o p h e n y l t e t r a z o l e s an d 5 - ( 2 * - h y d r o x y - 4 '- n i t r o p h e n y l) te tr a z o l e have b e en p re p a re d . 4. R e d u c tio n o f th e 5 - n i t r o p h e n y l t e t r a z o l e s u s in g tw o d i f f e r e n t m e th o d s h a s b e e n ;^ow n t o r e s u l t i n th e f o r m a ti o n o f th e c o r r e s p o n d in g 5- a m i n o p h e n y l t e t r a z o l e s w h ic h i n c l u d e d th e t e t r a z o l e a n a lo g u e s o f p a r a - a m ln o b e n z o ic a c i d , m e ta - a m in o b e n z o lc a c i d an d p a r a - a m i n o s a l i c y l i c a c id . The a c e t y l d e r i v a t i v e s o f a l l t h e a m in o p h e n y l t e t r a z o l e s h a v e b e e n p re p a re d . 5. The t h r e e is o m e r ic 5 - ( p y r i d y l ) t e t r a z o l e s , i n c l u d i n g th e t e t r a z o l e a n a lo g u e o f n i c o t i n i c c o r r e s p o n d i n g c y a n o p y r id in e s . a c i d , h av e b e e n p r e p a r e d from th e The p r e p a r a t i o n o f 2 , 6 - d i (5 * - t e t r a z o l y l ) - p y r i d i n e h a s a l s o b e e n d e s c r ib e d * 103 6. The 5—( p y r i d y l ) t e t r a z o l e s , on t r e a t m e n t w ith h y d ro g e n an d p la tin u m o x i d e , h a v e b e e n re d u c e d t o th e c o r r e s p o n d in g 5—( p i p e r i d y l ) te tra z o le s . 7. A g ro u p o f s i x s u b s t i t u t e d p h e n o x y a c e t e n i t r i l e s h a s b e e n p r e p a r e d ft"cm t h e c o r r e s p o n d in g p h e n o ls a n d c h lo r o a c e to n i t r i l e * The h y d r o l y s i s o f t h r e e o f t h e s e h a s b een show n t o l e a d t o t h e f o r m a tio n o f t h e c o r r e s p o n d in g p h e n o x y a c e tic a c i d . 8* A g ro u p o f s i x s u b s t i t u t e d 5 - p h e n o x y m e t h y l te t r a z o l e s , i n c l u d i n g t h e t e t r a z o l e a n a lo g u e s o f 2,4D and 2 ,4 * 5 T , h a s b e e n p r e p a r e d from t h e c o r r e s p o n d in g n l t r i l e . 9# A g ro u p o f f o u r l - b e n z y l - 5 - p h e n o x y m e t h y l t e t r a z o l e s h a s b e e n p re p a red . D é b e n z y la tio n in two c a s e s h a s b e e n shown t o l e a d t o th e f o r m a ti o n o f t h e s i m i l a r l y s u b s t i t u t e d 5 -p h e n o x y m e th y lte t r a z o l e . In t h e o t h e r two c a s e s d é b e n z y l a t i o n was acco m p an ied by de h a lo g é n a ti o n an d p o s s ib ly re d u c tio n . 10. The t e t r a z o l e a n a lo g u e o f 3 - i n d o l e a c e t i c a c i d , 5 - ( 3 '- I n d o l y l ) - te tr a z o le , h as been p re p a red . 11. The i n t e r a c t i o n o f 3*4»5 - t r i m e t h o x y b e n z o n i t r i l e w ith h y d r a - z o i c a c i d h a s l e d t o th e f o r m a ti o n o f 5 - ( 3 '* 4 * , 5 '- t r l m e t h o x y p h e n y l ) te tra z o le . A l k y l a t i o n o f t h i s compound w ith d la lk y la m in o a lk y l h a l i d e s h a s r e s u l t e d In t h e f o r m a tio n o f t h r e e 2 - (d i a l k y l a m in o a lk y l) - 5 - ( 3 ', 4 % 5 't r i m e t h o x y p h e n y l ) t e t r a z o l e s w h ich h a v e b e en c h a r a c t e r i z e d a s t h e h y d ro ­ c h lo rid e s . AETTODIX I POTENTIOMETRIG TITRATION DATA Compound 5-Ami n o m eth y I t e t r a zo 1 e 0 .3 1 8 4 g ./ 1 2 5 m l. aqueous s o lu tio n pH 5 .7 0 3 .6 5 3 .5 5 3 .4 7 3 .3 9 3 .3 5 3 .2 7 3 .2 1 3 .1 5 3 .1 1 3 .0 5 3 .0 0 2 .9 5 2 .9 2 2 .8 8 2 .8 3 2 .8 0 2 .7 6 2 .7 1 2 .6 3 2 .6 0 2 .5 6 2 .5 2 2 .4 9 2 .4 1 2 .3 8 2 .3 4 2 .3 0 2 .2 5 2 .2 0 2 .1 5 2 .1 2 2 .0 5 2 .0 0 1 .9 8 M l. o f A q. HCl 0 .1 0 1 7 5 K 0 .0 4 .0 5 .0 6 .0 7 .0 8 .0 9 .0 1 0 .1 1 1 .0 1 2 .0 1 3 .0 1 4 .0 1 5 .0 1 6 .0 1 7 .0 1 8 .0 1 9 .0 2 0 .0 2 1 .0 2 3 .0 2 4 .0 2 5 .0 2 6 .1 2 7 .0 2 9 .0 3 0 .0 3 1 .0 3 2 .0 3 3 .0 3 5 .0 3 6 .0 3 8 .0 4 0 .0 4 2 .0 4 4 .0 A p p a re n t pEi 2 .6 2 105 APPENDIX I (C ontinued) Compound 5 - (aC - A m i n o e t h y l ) t e t r a z o l e 0 .2 9 5 0 g ./ 1 2 5 m l. aqueous s o lu tio n pH 5 .6 o 3 .9 2 3 .6 0 3 .4 0 3 .1 0 3 .0 5 3 .0 0 2 .9 5 2 .9 0 2 .8 5 2 .8 0 2 .7 5 2 .7 0 2 .6 5 2 .6 2 2 .5 9 2 .5 5 2 .5 0 2 .4 5 2 .4 3 2 .4 0 2 .3 5 2 .3 3 2 .3 0 2 .2 7 2 .2 3 2 .1 3 2 .0 2 1 .9 5 1 .8 8 M l. o f Aq. HCl 0 .1 0 1 7 5 N 0 .0 2 .0 4 .0 6 .0 1 0 .0 1 1 .0 1 1 .5 1 2 .5 1 3 .5 1 4 .5 1 6 .0 1 7 .0 1 8 .0 1 9 .0 2 0 .0 2 1 .0 2 2 .0 2 3 .0 2 4 .0 2 5 .0 2 6 .0 2 7 .0 2 8 .0 2 9 .0 3 0 .0 3 2 .0 3 6 .0 4 0 .0 4 5 .0 5 0 .0 A p p a re n t 2 .6 3 106 APPENDIX I (Continued) Compound 5 - ( /^ - A m in o e th y l) t e t r a z o l e 0 .2 9 0 6 g ./lO O m l. aqueous s o lu tio n pH M l. o f Aq. HCl 0 .1 0 1 7 5 N 6 .5 2 5 .0 5 4 .8 5 4 .7 5 4 .6 0 4 .4 5 4 .3 5 4 .2 2 4 .1 5 4 .1 0 4 .0 7 4 .0 3 4 .0 0 3 .9 8 3 .9 2 3 .8 6 3 .8 0 3 .7 2 3 .6 6 3 .5 0 3 .4 3 3 .3 5 3 .2 4 3 .1 3 2 .8 0 2 .4 0 2 .2 8 2 .1 8 2 .0 5 1 .9 8 0 .0 2 .0 3 .0 4 .0 5 .0 7 .0 8 .0 1 0 .0 1 1 .0 1 2 .0 1 2 .5 1 3 .0 1 3 .5 1 4 .0 1 5 .0 1 6 .0 1 7 .0 1 8 .0 1 9 .0 2 1 .0 2 2 .0 2 3 .0 2 4 .0 2 5 .0 2 8 .0 3 3 .0 3 6 .0 3 9 .0 4 3 .0 5 0 .0 A p p a re n t pK, 3 .9 9 107 APPENDIX I (Continued) Compound 5 - ( cjC -Ami n o - /? - p h e n y le t h y l ) t e t r a z o l e .......... 0 .1 3 5 3 g ./lO O m l. aque o u s s o l a t i on pH 5 .2 0 3 .2 8 2 .9 0 2 .6 7 2 .5 2 2 .3 6 2 .3 0 2 .1 9 2 .1 4 2 .1 2 2 .1 0 2 .0 5 1 .9 8 1 .9 4 1 .9 0 1 .8 8 1 .8 3 1 .7 8 1 .7 2 1 .6 9 M l. o f A q. HCl 0 .1 0 1 7 5 N 0 .0 2 .0 4 .0 6 .0 8 .0 1 0 .5 1 2 .0 1 4 .5 1 6 .0 1 6 .5 1 7 .0 1 9 .0 2 2 .0 2 4 .0 2 5 .5 2 7 .0 3 0 .0 3 5 .0 4 0 .0 4 5 .0 A p p a re n t 1 .9 3 108 A P SnoIZ I (C ontinued) Compound fQ SrnAminomethyl t e t r a z o l e 0 ,3 0 2 2 g . / 1 2 5 m l. aqueous s o lu tio n 5 .7 5 7 .6 0 7 .9 5 8 ,1 0 8 .2 7 8 .3 8 8 .5 0 8 .6 3 8 .7 3 8 .8 5 8 .9 9 9 .0 5 9 .1 3 9 .2 0 9 .2 9 9 .3 4 9 .3 9 9 .4 5 9 .5 0 9 .5 8 9 .6 5 9 .8 5 9 .9 7 1 0 .1 3 1 0 .3 1 1 0 .5 1 1 0 .6 8 1 0 .8 4 1 0 .9 5 11 . U 1 1 .2 5 1 1 .4 5 M l. o f A q . NaCH 0 .0 9 6 8 8 N 0 .0 3 .0 6 .0 8 .0 1 0 .0 1 2 .0 1 4 .0 1 6 .0 1 8 .0 2 0 .0 2 2 .0 2 3 .0 2 4 .0 2 5 .0 2 6 .0 2 6 .5 2 7 .0 2 7 .5 2 8 .0 2 8 .5 2 9 .0 3 0 .0 3 0 .5 3 1 .0 3 1 .5 3 2 .0 3 2 .5 3 3 .0 3 3 .5 3 4 .5 3 6 .0 3 9 .0 A p p a re n t ^2 8 .5 4 109 SŒTÆÜIX I (C o n tin u e d ) Compound 5 - - Ami n o e t h y l ) t e t r a z o l e 0 .3 1 8 3 g . / 1 2 5 m l. aqueous s o lu tio n * pH 5 .8 0 7 .6 0 7 .9 5 8 .1 5 8 .3 0 8 .4 5 8 .5 5 8 .7 0 8 .8 2 8 .9 5 9 .0 8 9 .2 2 9 .4 0 9 .4 5 9 .5 0 9 .5 9 9 .6 5 9 .8 0 1 0 .0 9 1 0 .4 5 1 0 .8 4 1 1 .0 9 1 1 .3 0 1 1 .5 0 1 1 .6 5 1 1 .7 6 1 1 .8 6 Ml* o f Aq* NaOH 0 *09688 N 0 .0 2 .0 4 .0 6 .0 8*0 1 0 .0 1 2 .0 1 4 .0 1 6 .0 1 8 .0 2 0 .0 2 2 .0 2 4 .0 2 4 .5 2 5 .0 2 5 .5 2 6 .0 2 7 .0 2 8 .0 2 9 .0 3 0 .0 3 1 .0 3 3 .0 3 5 .0 3 8 .0 4 2 .0 4 6 .0 A p p a re n t 8 .7 7 110 APPENDIX I Gompotmd 5 » ( y ^ - > A m iiio e th y l) ta tr a z o le 0 #3106 g , / l 2 5 m l. a q u e o u s so lu tlO D . pE 6«65 8 .8 5 8 .9 5 9 .1 3 9 .2 0 9 .3 5 9 .4 0 9 .5 0 9 .6 5 9 .7 0 9 .8 5 9 .9 0 9 .9 9 1 0 .0 5 1 0 .1 5 1 0 .2 5 1 0 .3 9 1 0 .4 5 1 0 .5 0 1 0 .6 4 1 0 .7 9 1 0 .9 0 1 1 .0 2 1 1 .1 0 1 1 .2 1 1 1 .2 5 1 1 .3 5 1 1 .4 9 (C o n tin u e d ) M l. o f A q. NaOH 0 .0 9 6 8 8 N 0 .0 6 .0 7 .0 9 .0 1 0 .0 1 2 .0 1 3 .0 1 5 .0 1 7 .0 1 8 .0 2 0 .0 2 1 .0 2 2 .0 2 3 .0 2 4 .0 2 5 .0 2 6 .0 2 6 .5 2 7 .0 2 8 .0 2 9 .0 3 0 .0 3 1 .0 3 2 .0 3 3 .5 3 4 .5 3 6 .0 4 0 .0 A p p a re n t *2 9 .5 8 Ill APPENDIX I Compound (C o n tin u e d ) IH Ml. o f Aq« NaQS 0.09688 N 5 .2 7 7 .1 5 7 .5 0 7 .7 5 7 .9 5 8 .1 5 8 .2 8 8 .4 0 8 .4 5 8 .5 0 8 .6 0 8 .7 5 8 .8 5 8 .9 3 8 .9 7 9 .1 0 9 .3 0 9 .3 5 9 .5 5 9 .7 0 1 0 .0 0 1 0 .2 5 1 0 .4 0 1 0 .6 5 1 0 .8 5 1 1 .0 5 0 .0 1 .0 2 .0 3 .0 4 .0 5 .0 6 .0 6 .5 6 .7 7 .0 7 .5 8 .0 8 .3 8 .4 8 .5 8 .8 9 .0 9 .1 9 .3 9 .4 9 .6 9 .8 1 0 .0 1 0 .5 1 1 .0 1 2 .0 Apparent I«2 5- ( «C-Ami no» /3 -phenyle tfa y l-te tr a z o le 0 .1 7 9 6 g . / l 25 m l. aqueous aolubion 8.18 LITERATURE CITED !• 2 . O llv e r l- M a n a d a la , G azz. o h lm . i t a l . , 44* I I , 175 (1 9 1 4 ); C .A ., 884 ( 1 9 1 5 ) . 2. J . M ih in a and R . H e r b s t , J . O rg . C hem .. 1082 (1 9 5 0 ) . 3. R . H e r b s t a n d K . 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