Fase 1 (pre activa):

V

LX X

\ /

AcNH

3)Ac.O /A cO H^

(AcDkCH

L X X I

V

AcNH

L X X II

i

HCO

,6)Me^S0. f

^FeSpyNRnH

V

X

V "

L X X IV

NO,

V

L X X III

SCHEME 13

E x p e r im e n ta l. -

M a t e r i a l s . - T h e h y d ro c h lo ric a c id used w as A n a la R g ra d e . T h e 4 -d im e th y la m in o b e n z a ld e h y d e w as p u rc h a s e d and w as A n a la R g ra d e . T rim e th o x y b e n z a ld e h y d e w as p u rc h a s e d fr o m A ld r ic h C h e m ic a l C o . and r e c r y s ta llis e d th re e tim e s fr o m eth an o l b e fo re u s e .

4 -D im e th y la m in o a c e to p h e n o n e w as p re p a re d b y m é th y la tio n of 4 -a m in o a c e to p h e n o n e u sin g the m eth o d S u zu k i and N a g a w a

(1 4 5 ). D ip h e n y lc y c lo p ro p e n o n e w as bought f r o m K o c h -L ig h t and used w ith o u t fu r th e r p u rific a tio n .

A s a m p le of 2 ,4 -b is (d im e th y la m in o )b e n z a ld e h y d e w as p re p a re d by th e ro u te o u tlin e d in S ch em e 13. 2, 4 -D in itro to lu e n e w as f ir s t c o n v e rte d to 2 -n itr o -4 -a c e ty la m in o to lu e n e b y the

m eth o d of H ille r s et a l (14 6 ). T h e a m id e w as th e n c o n v e rte d to 2 , 4 -d ia m in o b e n z a ld e h y d e b y th e m eth o d of R ic c i (1 4 7 ) and fin a lly N -m e th y la te d u s in g d im e th y l su lp h ate to g ive th e re q u ire d com pound, A t stage 3) (S ch em e 13) no so lid p re c ip ita te w as o b tain ed on

n e u tra lis a tio n as found b y R ic c i (147) but th is n e u tra lis e d re a c tio n m ix tu r e on e x tra c tio n w ith m e th y le n e c h lo rid e y ie ld e d a sticky re d liq u id w h ic h w a s d is s o lv e d in a m in im u m am o u n t o f b o ilin g

m e th y le n e c h lo rid e and r e fr ig e r a te d . A f t e r 24 h o u rs a y e llo w - w h ite s o lid w a s p re c ip ita te d . T h is p ro v e d to be the re q u ire d com pound and w a s s u b seq u en tly r e c r y s ta llis e d fr o m aqueous m e th a n o l.

S tage 6) (S chem e 13) w as c a r r ie d out as fo llo w s :-

2, 4 -d ia m in o b e n z a ld e h y d e ( 1 .3 6 g) w as s tir r e d u n d e r re flu x w ith a s o lu tio n of an h y d ro u s sodium c a rb o n a te (30 g) in w a te r (80 m l) .

89

T o th is w as added d im e th y l sulphate (30 g) d r op w is e o v e r 45 m in u te s . T h e s o lu tio n w as th e n re flu x e d a f u r th e r 15 m in u te s , a llo w e d to co o l and e x tra c te d w ith c h lo ro fo rm (2 x 30 m l) . T h e c h lo ro fo rm e x tra c ts w e re w a s h e d , d rie d and e v a p o ra te d to g ive the d e s ire d p ro d u c t ( 1 ,3 5 g, 7 0 % ), T h is can be p u r ifie d by d is tilla tio n (B . P ^^ = 1 9 0 °C ) o r b y c h ro m a to g ra p h y s im ila r to th a t d e s c rib e d b e lo w . R e a c tio n b e tw e e n 1, 3 -b is (d im e th y la m in o )b e n z e n e and a p h o s p h o ry l c h lo r id e /d im e th y lfo r m a m id e s o lu tio n ,- 1, 3 -B is (d im e th y la m in o )b e n z e n e w as p re p a re d fr o m 1, 3 - d ia m in o b e n ze n e by the m e th o d of T o r f and K h r o m o v -B o r is o v (14 8 ). T h is w as re a c te d w ith p h o s p h o ry l c h lo r id e /d im e th y lfo r m a m id e u n d e r tw o sets of e x p e rim e n ta l co n d itio n s le a d in g to the th re e p ro d u c ts , B D M A B , B D M A I and B D A D F B .

(a) P h o s p h o ry l c h lo rid e (2 6 g) w as added d ro p w is e and w ith s t ir r in g to d im e th y lfo rm a m id e (2 2 g) b e lo w 1 5 ° C . T o th is s tir r e d so lu tio n w as added 1, 3 -b is (d im e th y la m in o )b e n z e n e (8 g) d ro p w is e w ith th e te m p e ra tu re b eing k e p t b e lo w 2 5 ° C . T h e re s u lta n t

so lu tio n w as th e n s tir r e d fo r 2 h o u rs a t 6 5 - 7 0 ° C , c o o led and

p o u re d onto ic e / w a te r (5 0 0 m l) . T h is w as b a s id ifie d (p H 1 0 — >11) by adding so d iu m h y d ro x id e so lu tio n (3 0 g N a O H in 70 m l of w a te r) d ro p w is e w ith v ig o ro u s s t ir r in g . T h e m ix tu r e w as h e a te d on a s te a m b ath fo r 10 m in u te s , co o led and e x tra c te d w ith c h lo ro fo rm (3 X 100 m l) . T h e o rg a n ic e x tra c ts w e re w ash ed w ith w a te r (2 X 50 m l) , d rie d o v e r C a C l^ and e v a p o ra te d to g ive

2, 4 -b is (d im e th y la m in o )-3 , 5 -d ifo rm y lb e n z a ld e h y d e (B D A D F B ), T h is w as r e c r y s ta llis e d fr o m a h e x a n e /e th y l a c e ta te m ix tu re to y ie ld y e llo w n e e d le s ( m .p . = 1 1 7 -1 1 9 ^ 0 , m /e = 24 8), T h e n . m . r . s p e c tru m , ta k e n in C D C l^ , showed th e fo llo w in g peaks (in te g ra l v a lu e s in b ra c k e ts ) r e la tiv e to T M S - 3 .3 3 (1 2 ), 8. 1 3 (1 ), 9 . 3 3 (1 ), 9 . 7 5 3 (2 ).

A n a ly s is - c a lc u la te d 6 2 ,8 4 % C , 6 .4 0 % H , 1 1 .2 8 % N found 6 2 .5 7 % G, 6 .5 8 % H , 11. 14 % N .

(b) P h o s p h o ry l c h lo rid e (7 . 65 g) w as added d ro p w is e w ith good s tir r in g to a m ix tu r e of 1, 3 -b is (d im e th y la m in o )b e n z e n e ( 8 .2 g) and d im e th y lfo rm a m id e (1 4 . 6 g) w ith th e te m p e r a tu r e b eing k e p t b e lo w 1 0 °C . T h e te m p e ra tu re of the s tir r e d m ix tu r e w as a llo w e d to r is e to ro o m te m p e ra tu re o v e r 2 h o u rs and s tir r e d a fu r th e r ^ h o u r. It w as th e n added to ic e /w a t e r (400 m l) and b a s id ifie d (p H 10 — >11) b y adding so d iu m h y d ro x id e s o lu tio n (10 g N a O H in 25 m l of w a te r) d ro p w is e and w ith v ig o ro u s s t ir r in g . T h e

re s u ltin g s o lu tio n w as h e a te d on a s te a m b ath f o r 10 m in u te s , cooled and e x tra c te d w ith c h lo ro fo rm (3 x 75 m l) . T h e o rg a n ic e x tra c ts w e re w a s h e d , d rie d o v e r G a C l^ and e v a p o ra te d to g ive a s tic k y liq u id . T h is w as d is s o lv e d in a lit t le c h lo ro fo rm and a b s o rb e d onto a 1 m e tr e a lu m in a c h ro m a to g ra p h y c o lu m n p re p a re d in p e tro le u m . E lu tio n w ith p e tro le u m s p ir it /e t h e r

(5 0 :5 0 ) gave f ir s t u n re a c te d s ta rtin g m a t e r ia l and th e n 2 , 4 - b i s - (d im e th y la m in o )b e n z a ld e h y d e (B D M A B ) as a y e llo w b an d . A y e llo w band of 2 , 4 -b is (d im e th y la m in o )is o p h th a la ld e h y d e (B D M A I)

91

o r by e lu tio n w ith a m o r e p o la r s o lv e n t.

2, 4 -b is (d im e th y la m in o )b e n z a ld e h y d e , - y ie ld = 3 ,3 g (3 5 % ), m /e = 192 T h e n . m . r . s p e c tru m , ta k e n in C D C l^ , showed the fo llo w in g p eaks (in te g r a l v a lu e s in b ra c k e ts ) r e la tiv e to T M S - 2 ,8 5 J (6 ), 3 .0 0 3 (6 ), 6 .0 5 3 d o u b let (1 ), 6 ,2 5 3 q u a rte t (1 ), 7 .6 0 3 do u b let (1) and 9 .9 3 ( l ) .

\

A n a ly s is - c a lc u la te d 6 8 .7 2 % G , 8. 39 % H , 14. 67 % N found 6 8 .9 3 % G , 8 .3 3 % H , 1 4 .7 3 % N

N o te . - B D M A B is b e s t s to re d at O^G sin ce it w as found to u n d e rg o slow d e c o m p o s itio n a t ro o m te m p e r a tu r e . B e fo re p re p a rin g the s ta n d a rd B D M A B so lu tio n s u sed in the p y r r o le te s ts the B D M A B can be d is tille d o r m o re c o n v e n ie n tly d is s o lv e d in b o ilin g

p e tro le u m s p ir it (4 0 - 6 0 ^ G ), th is so lu tio n b ein g f ilt e r e d h o t. It w as found th a t the im p u r ity p ro d u c e d in d e c o m p o s itio n w as in s o lu b le in th is s o lv e n t. E v a p o ra tio n of th e p e tro le u m g iv e s the B D M A B w h ic h can be used in th e te s ts ,

2, 4 -B is (d im e th y la m in o )is o p h th a la ld e h y d e . - y ie ld = 2. 5 g( 25% ), m /e = 2 2 0 , m .p . = 1 2 3 - 125°G (fr o m h e x a n e -e th y l a c e ta te m ix tu r e ).

T h e n . m . r . s p e c tru m , ta k e n in G D G l^ , showed the fo llo w in g p eaks (in te g r a l v a lu e s in b ra c k e ts ) r e la tiv e to T M S - 3 .1 5 3 (6 ),

3 . 3 0 3 (6 ), 6 .4 5

3

3

3

A n a ly s is - c a lc u la te d 6 5 ,4 3 % G , 7 .3 2 % H , 1 2 .7 1 % N found 6 5 .0 1 % G , 7 .0 8 %

H,

A tte m p te d s y n th e s is o f 2, 4 -b is (d im e th y la m in o )a c e to p h e n o n e (B D M A A ). -

1, 3 -B is (d im e th y la m in o )b e n z e n e w as p re p a re d by the m eth o d re p o rte d p re v io u s ly (148) and v a rio u s a tte m p ts at a c y la tio n of th is com pound w e re m ade: -

(a) a c y la tio n w as a tte m p te d u s in g the m e th o d of B o u rn e e t a l (149) w ith th e fo llo w in g q u a n titie s : 1, 3 -b is (d im e th y la m in o )b e n z e n e (1 . 64 g), a c e tic a c id (0 . 9 g) and tr iflu o r o a c e tic a n h y d rid e ( 4 ,2 g). T h e m a s s s p e c tru m and the n . m . r . s p e c tru m of th e re s u ltin g p ro d u c t in d ic a te d th a t th is w as e s s e n tia lly a ll u n re a c te d s ta rtin g m a t e r ia l.

(b) th e above e x p e rim e n t w as c a r r ie d out in an ic e /w a t e r b ath but a g a in no re a c tio n to o k p la c e .

(c) the a b o ve re a c tio n m ix tu r e w as h e a te d in a w a te r bath at 5 5 -6 0 C fo r 9 h o u rs . T h e m a s s s p e c tru m and n . m . r . s p e c tru m of th e p ro d u c t show ed it to be a m ix tu r e of th e tr iflu o r o a c e ty l

com pound and s ta rtin g m a t e r ia l.

(d) u n d e r th e e x p e rim e n ta l c o n d itio n s in (c) b u t w ith o n ly 0 .5 g of t r iflu o r o a c e tic a n h y d rid e th e o n ly p ro d u c ts w e re a re d u c e d y ie ld of the t r iflu o r o a c e ty l com pound and s ta rtin g m a t e r ia l.

(e) w ith a c e tic a n h y d rid e in p la c e of tr iflu o r o a c e tic a n h y d rid e and w ith th e re a c tio n m ix tu r e b e in g h e a te d in a w a te r