Nitrogen Derivatives of L-Ascorbic Acid - Advances in Chemistry (ACS

8 Nitrogen Derivatives of L-Ascorbic A c i d EL SAYED H. EL ASHRY

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Chemistry Department, Faculty of Science, Alexandria University, Alexandria, E g y p t

The nitrogen derivatives of L-ascorbic acid or its dehydro derivative, and the rationale for interest in these derivatives, are reviewed. In particular, the reactions of dehydro-L -ascorbic acid (DHA) with o-phenylenediamine or its substi tuted derivatives are surveyed as well as the reactions of D H A with hydrazines, which yield monohydrazones or bishydrazones. Further conversion of these initial deriva tives into a variety of nitrogen heterocyclic compounds is evaluated. The reactions of L-ascorbic acid with amino acids are also examined.

The role of L-ascorbic acid as a vitamin probably involves its participation in oxidation-reduction reactions. In those reactions dehydroL-ascorbic acid ( D H A ) is the first stable oxidation product; D H A is often the first product in the degradation of L-ascorbic acid. Because of its three adjacent carbonyl groups, D H A would be expected to undergo nucleophilic reactions with a number of functional groups, including amines. Nitrogen compounds arise in biological systems either from naturally occurring amino acids and proteins or from added chemotherapeutic agents such as sulfa drugs, isoniazide, and hydralazine; therefore, the study of the products of amine reactions with D H A is important. Moreover, L-ascorbic acid in foods is converted to D H A when it acts as an antioxidant. Thus, the survival of vitamin C during food processing depends in part on its involvement, and the involvement of D H A , in reactions with amines in foods, giving products mostly incapable of regenerating the vitamin. Nitrogen derivatives of L-ascorbic acid are important because they have been used extensively for the vitamin's determination (1) in the form of the bis(2,4-dinitrophenylhydrazone) of dehydro-L-ascorbic acid (1). In addition, because of the commercial availability of L-ascorbic acid with a relatively low price as well as the widespread use of hetero0065-2393/82/0200-0179$06.00/0 © 1982 American Chemical Society In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

180

ASCORBIC

ACID

cycles, L - a s c o r b i c a c i d c o u l d b e u s e d as a p r e c u r s o r i n t h e synthesis of a v a r i e t y of h e t e r o c y c l i c c o m p o u n d s w i t h o r w i t h o u t c a r b o h y d r a t e s u b stituents. Reaction

of DHA with o-Phenylene diamine

I n its o x i d i z e d f o r m , L - a s c o r b i c a c i d is m o r e r e a c t i v e t h a n a r e a l d o 2-uloses ( o s o n e s ) ; this greater r e a c i t v i t y is c a u s e d b y t h e c a r b o x y l i c


g r o u p adjacent t o t h e d i c a r b o n y l g r o u p s . B e c a u s e of these three a d j a c e n t f u n c t i o n a l g r o u p s , D H A reacts w i t h a m i n e s or o - p h e n y l e n e d i a m i n e t o y i e l d a v a r i e t y of p r o d u c t s ; t h e p r o d u c t is d e t e r m i n e d b y t h e m o l e c u l a r p r o p o r t i o n s of t h e reactant (2-7).

T h e product resulting from the con

d e n s a t i o n of o n e m o l a r e q u i v a l e n t of o - p h e n y l e n e d i a m i n e w i t h t h e C l a n d C 2 carbons reacted ( 5 ) w i t h p h e n y l h y d r a z i n e to give 2,2'-anhydro[ 2-hydroxy-3- (1-phenylhydrazono-L-f /ireo-2,3,4-trihydroxybutyl) quinoxal i n e ] (2) i n its h y d r a t e d f o r m .

T h e s t r u c t u r e of 2 w a s b a s e d o n t h e

f o r m a t i o n of its d i a c e t a t e

upon acetylation.

(3)

s t r u c t u r e of 2 w a s r e v i s e d ( 8 - 1 0 )

M o r e recently, the

to the acyclic form

3

3-[(l-phenyl-

R' = Ac

hydrazono) -L-fTireo-2,3,4-trihydroxybutyl] -2-quinoxalinone

(4,

where

R = P h ) . T h o s e reactions h a v e b e e n e x t e n d e d u s i n g a v a r i e t y of a r y l h y d r a z i n e s a n d a r o y l h y d r a z i n e s (9,11) as w e l l as s e m i c a r b a z i d e a n d t h i o s e m i c a r b a z i d e (12) i n s t e a d of p h e n y l h y d r a z i n e . T h e s t r u c t u r e of 4 w a s b a s e d o n spectroscopic studies (mass a n d I R s p e c t r a ) as w e l l as p e r i o d a t e o x i d a t i o n studies (10,13).

Periodate oxidation afforded the correspond

i n g a l d e h y d e s w h o s e structures w e r e c o n f i r m e d t o b e 3 - ( l - s u b s t i t u t e d hydrazono)glyoxal-l-yl]-2-quinoxalinones

(6) r a t h e r t h a n 5, as w a s ex

p e c t e d f r o m t h e c y c l i c structures. T h e s e a l d e h y d e s p r o v i d e a s i m p l e route

to glyoxalylquinoxalinone derivatives

(6),

w h i c h are potential

p r e c u r s o r s t o other h e t e r o c y c l i c c o m p o u n d s s u c h as 7-12. 7-12

are monosubstituted glyoxal monohydrazones,

Compounds

w h i c h w o u l d be

difficult t o o b t a i n i f w e s t a r t e d w i t h t h e p o s s i b l e , b u t u n k n o w n , p r e -

In Ascorbic Acid: Chemistry, Metabolism, and Uses; Seib, P., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

8.

181

Nitrogen Derivatives of L-Ascorbic Acid

E L ASHRY


H

cursor, 3 - ( g l y o x a l - l - y l ) - 2 - q u i n o x a l i n o n e , hydrazines.

a n d a l l o w e d i t t o react

T h e only possible monohydrazone

upon such direct

d e n s a t i o n is the h y d r a z o n e o n the C 2 c a r b o n y l .

R e a c t i o n of

6

with con with

c a r b o e t h o x y m e t h y l i d e n e t r i p h e n y l p h o s p h o r a n e gave 13, w h i c h w a s s u c cessfully c y c l i z e d to 14. T h i s r e a c t i o n ( 6 to 14) monohydrazones

of 1 , 2 - d i c a r b o n y l c o m p o u n d s ,

w a s a p p l i e d to other

i n d i c a t i n g its use as a

g e n e r a l m e t h o d for p y r i d a z i n o n e s synthesis.



182

T h e f o r m a t i o n of 1-phenylflavazole

ASCORBIC

ACID

f r o m r e d u c i n g sugars n o t

sub

s t i t u t e d o n 0 2 a n d 0 3 is a g e n e r a l r e a c t i o n

(14-18),

t h r o u g h the f o r m a t i o n of

group

moiety

attached

flavazole

to

an arylhydrazono

a quinoxaline.

synthesis c o u l d b e

w h i c h proceeds

o n C 3 of a

This prerequisite

sugar

intermediate

4, w h i c h o n t r e a t m e n t w i t h a l k a l i

3-(L-threo-glycerol- 1-yl)-1-arylflavazole

(15)

(5,9).

The

in

gave

rearrange

ment proceeds i n 1 h i n b o i l i n g , dilute, aqueous sodium hydroxide, but fission

of the p o l y h y d r o x y a l k y l c h a i n o c c u r s i n m o r e c o n c e n t r a t e d

line solution.

O n t h e other h a n d , d i s s o l u t i o n of 4 i n a l k a l i ,

alka

followed

i m m e d i a t e l y b y a c i d i f i c a t i o n , regenerates t h e s t a r t i n g m a t e r i a l . F o r m a t i o n of

flavazoles

f r o m L - a s c o r b i c a c i d is a n i n e x p e n s i v e a n d s i m p l e r o u t e

to flavazoles o t h e r w i s e o b t a i n e d f r o m L - g a l a c t o s e or L - t a l o s e . of these

flavazoles

were studied ( 9 ) ;

Reactions

d e r i v a t i v e s s u c h as 16-18

can be

prepared.

NHR'


8.

E L ASHRY

183


A f t e r the a c y c l i c s t r u c t u r e of 4 h a d b e e n a s s i g n e d , t h e b e h a v i o r of similar compounds,

w h i c h are p r e s u m a b l y i n c a p a b l e of e x i s t i n g i n a

c y c l i c f o r m [ s u c h as 19, w h i c h w a s p r e p a r e d b y t h e m e t h y l a t i o n of 4], w a s s t u d i e d .

P e r i o d a t e o x i d a t i o n of

19 g a v e the

(19)

corresponding

a l d e h y d e t h a t c o u l d b e c o n v e r t e d i n t o v a r i o u s other d e r i v a t i v e s . D u r i n g a c e t y l a t i o n w i t h b o i l i n g acetic a n h y d r i d e ( 8 , 9 ) , t h e a l d i t o l portions i n the molecules

4 a n d 19 d e h y d r a t e w i t h s i m u l t a n e o u s

c l o s u r e to g i v e p y r a z o l e s 23 a n d 21, r e s p e c t i v e l y .

ring

D e a c e t y l a t i o n of

23


a f f o r d e d 20, w h i c h c o u l d also b e o b t a i n e d f r o m 4 u s i n g h y d r o x y l a m i n e hydrochloride.

T h e structures of t h e p r o d u c t s

were confirmed b y

N M R , a n d mass spectra, a n d a m e c h a n i s m f o r t h e f o r m a t i o n of p y r a z o l e s w a s also suggested stituted

o-phenylenediamines

(9).

IR, such

A n extension of this w o r k u s i n g s u b

such

as

those w i t h

d i m e t h y l g r o u p s has also b e e n c o m p l e t e d

chloro,

methyl,

or

(8,20).

T h e r e a c t i o n of 2 m o l of o - p h e n y l e n e d i a m i n e

w i t h D H A was re

p o r t e d ( 2 ) to g i v e 26, w h i c h p r o d u c e d colorless crystals f r o m w a t e r a n d y e l l o w crystals f r o m e t h a n o l . gave the monoquinoxaline

T r e a t m e n t of 26 w i t h c o l d m i n e r a l a c i d

d e r i v a t i v e 24, w h i c h u p o n a c e t y l a t i o n g a v e

t h e d i a c e t a t e 25 a n d u p o n r e a c t i o n w i t h o - p h e n y l e n e d i a m i n e again.

gave

26

T r e a t m e n t of 24 w i t h a l k a l i g a v e the s o d i u m salt 27, w h i c h o n

a c i d i f i c a t i o n g a v e the y- a n d 8-lactones (24 a n d 29),

respectively, i n d i

c a t i n g t h a t the t w o n i t r o g e n atoms are p r e s e n t o n C 2 a n d C 3 . O n t h e o t h e r h a n d , H a s s e l q u i s t (21)

a s s i g n e d t h e structures 28 a n d 30 to t h e

colorless a n d y e l l o w crystals, r e s p e c t i v e l y , one of w h i c h w a s i n t o the d i - N - a c e t y l d e r i v a t i v e (31). p r o d u c t w a s r e p o r t e d to b e 32 (22). a c e t y l d e r i v a t i v e (33) 24.

converted

L a t e r , t h e s t r u c t u r e of t h e r e a c t i o n C o m p o u n d 32 g a v e t h e m o n o - N -

and, u p o n treatment w i t h hydrochloric acid, gave

F u r t h e r studies to c l a r i f y these structures are n o w u n d e r w a y i n o u r

laboratory.



30 31

R r= H R = Ac


8.

185


E L ASHRY

DHA Monobydrazones L-£ftreo-2,3-Hexodiulosono-l,4-lactone

2-(phenylhydrazone)

(38,

R = P h ) , w a s first p r e p a r e d ( 2 3 ) b y r e a c t i n g 34 w i t h t h e s o d i u m d e r i v a t i v e of d i e t h y l m a l o n a t e t o g i v e 35. H y d r o l y s i s of t h e a d d u c t 35 g a v e 36, w h i c h u p o n t r e a t m e n t w i t h a l c o h o l i c a l k a l i a f f o r d e d 37. R e a c t i o n of 37 w i t h b e n z e n e d i a z o n i u m c h l o r i d e g a v e 38 ( R = P h ) , w h i c h w a s c o n v e n i e n t l y p r e p a r e d (24) b y r e a c t i o n of D H A w i t h N - a c e t y l - N - p h e n y l -


h y d r a z i n e i n t h e p r e s e n c e of i o d i n e .

Controlled reaction

(25,26)

substituted phenylhydrazine w i t h D H A gave the corresponding hydrazones

of

mono-

(38), a l t h o u g h t h e p h e n y l d e r i v a t i v e w a s n o t i s o l a t e d b y

this m e t h o d .

X - r a y c r y s t a l l o g r a p h y c o n f i r m e d t h e s t r u c t u r e (37) o f t h e

corresponding p-bromo derivative. COOEt

COC1

I

—OAc

CH—COOEt

X

C=0 -OAc

34

COOEt 36

35

38 37

39

R' = H R' = COR

A c e t y l a t i o n a n d b e n z o y l a t i o n of 38 c a u s e d a s i m u l t a n e o u s d e h y d r a t i o n w i t h t h e f o r m a t i o n of a n o p t i c a l l y i n a c t i v e olefinic c o m p o u n d

(40),

p r o b a b l y t h r o u g h t h e f o r m a t i o n of t h e d i a c y l a t e d d e r i v a t i v e ( 3 9 ) ; t h e structures w e r e c o n f i r m e d

(24) b y spectroscopic

methods.

40 c a n also b e p r e p a r e d f r o m t h e c o r r e s p o n d i n g D - a n a l o g u e

Compound (28,29).

T h e r e a c t i o n of 38 w i t h v a r i o u s h y d r a z i n e s gave t h e c o r r e s p o n d i n g mixed

bishydrazones

heterocycles

(25,26).

(42),

which

could

T h e bishydrazones

be

rearranged

into

c o u l d not be isolated


other with

186

ASCORBIC

ACID

—OH ^ = 0

—OH

R'OH C 2

0

N—NHR R'HN—N


40

41 42

N—NHR R = R' R ^ R '

m e t h y l h y d r a z i n e , a n d a p y r a z o l e d e r i v a t i v e (43) w a s d i r e c t l y o b t a i n e d T h e r e a c t i o n of 40 w i t h m e t h y l h y d r a z i n e w a s m o r e c o m p l i

(30,31).

c a t e d , a f f o r d i n g a p r o d u c t w h o s e e l e m e n t a l analysis a n d s p e c t r a l d a t a i n d i c a t e that 2 m o l of m e t h y l h y d r a z i n e w a s c o n s u m e d

i n the reaction

to g i v e 45 ( S c h e m e 1 ) . T h e s t r u c t u r e 45 a n d n o t 44 w a s a s s i g n e d o n the basis of x-ray c r y s t a l l o g r a p h y (32).

Spectroscopic

methods

agreed

w i t h b o t h structures. Me

43 DHA

Bishydrazones T r e a t m e n t of D H A or 38 w i t h t h e c o r r e s p o n d i n g

afforded t h e b i s ( a r y l h y d r a z o n e )

(41)

(33-40).

arylhydrazine

Similarly, aroylhydra-

zines a n d s e m i c a r b a z i d e c o n d e n s e d r e a d i l y w i t h D H A t o g i v e t h e c o r r e sponding

bishydrazone

(41,42)

a n d bis(semicarbazone)

(43,44).

A

series of d e r i v a t i v e s r e l a t e d t o s u l f a d r u g s (45) w a s p r e p a r e d b y t h e r e a c t i o n of D H A w i t h h y d r a z i n e s h a v i n g s u c h moieties. T h e bishydrazones

a r e n o w k n o w n t o b e i n t h e 1,4-lactone f o r m ,

s h o w i n g that n o o p e n i n g of t h e lactone r i n g i n D H A o c c u r r e d d u r i n g the reaction.

H o w e v e r , a t o n e t i m e (38) t h e 1,5-lactone w a s t h e p r e

f e r r e d f o r m , since t h e I R s p e c t r a of t h e b i s h y d r a z o n e s b o n y l lactone

b a n d at a f r e q u e n c y

lower

showed

a car

than that expected for a


8.

E L ASHRY

Nitrogen Derivatives of L-Ascorbic Acid CH OAc 2

n

c= H

187

0 }

^

H

MeHN—N

\ Ar 0

CH OAc 2


COOH AcO MeHN—N

N—NHAr

I

N—NHMc

N-NHAr

COOH

C — C

AcO

MeHN—N

I

N—NHAr

Me I

N N—NHAr

Scheme 1.


188

ASCORBIC

ACID

1,4-lactone. T h e o b s e r v e d l o w f r e q u e n c y is p r o b a b l y c a u s e d b y h y d r o g e n b o n d i n g of t h e l a c t o n e c a r b o n y l w i t h t h e i m i n o p r o t o n of the h y d r a z o n e r e s i d u e o n C 2 , as s h o w n b y N M R s p e c t r o s c o p y . T h e same l o w f r e q u e n c y b a n d also a p p e a r e d i n the s p e c t r a of t h e b i s ( a r y l h y d r a z o n e s ) of analogues

(42,46)

s u c h as t h e p h e n y l a n a l o g u e

of

DHA

other

[4-phenyl-

b u t a n o - l , 4 - l a c t o n e 2 , 3 - b i s ( p h e n y l h y d r a z o n e ) ] , w h i c h c a n n o t f o r m a 1,5l a c t o n e . F i n a l l y , t h e l a c t o n e r i n g size w a s also d e d u c e d f r o m its c h e m i c a l reactions

(24).


A n o t h e r c o n t r o v e r s i a l aspect of

the

bishydrazone

structure

con

cerns t h e h y d r a z o n e residues. T h e b i s h y d r a z o n e w a s p r o p o s e d to h a v e the s t r u c t u r e 4 6 , w h i c h m u t a r o t a t e s i n s o l u t i o n to 4 7

(47).

M o r e re

c e n t l y , o n the basis of a c o m p a r a t i v e s t u d y of the s p e c t r o s c o p i c p r o p e r ties of

the b i s ( p h e n y l h y d r a z o n e )

bishydrazone

was

assigned

the

w i t h some related compounds, structure

phenylhydrazino-L-f/ireo-hex-2-enone-l,4-lactone this latter s t r u c t u r e w a s i n c o n s i s t e n t w i t h its

the

2,3-dideoxy-3-phenylazo-21

3

(48)

(48).

However,

C N M R spectra


(49).

8.

Nitrogen Derivatives of L-Ascorbic

E L ASHRY

Reactions of the Rearrangement

Bishydrazones into

Pyrazolediones.

1,4-lactone 2 , 3 - b i s ( p h e n y l h y d r a z o n e )

L -threo - 2,3 - H e x o d i u l o s o n o -

rearranged to l-phenyl-4-phenylazo-

3- ( L - f / i r e o - g l y c e r o l - l - y l ) - p y r a z o l i n e - 5 - o n e (49) w a s a c i d i f i e d w i t h acetic a c i d ( 5 0 ) . to other bis ( a r y l h y d r a z o n e s ) (49)

(51).

w h e n its s o l u t i o n i n a l k a l i

T h e reaction was further extended T h e s t r u c t u r e of the p h e n y l a n a l o g u e

w a s e s t a b l i s h e d b y o x i d a t i o n to the k n o w n

phenylazopyrazolin-5-one


189

Acid

3-carboxy-l-phenyl-4-

L a t e r , o n t h e basis of N M R d a t a

(50).

(39),

t h e s t r u c t u r e of this g r o u p of c o m p o u n d s w a s f o r m u l a t e d as t h e h y d r a zones (51).

A c y l a t i o n of 51 a f f o r d e d t h e t r i - O - a c y l a t e d d e r i v a t i v e s

w h i l e p e r i o d a t e o x i d a t i o n of 51 gave 4- ( a r y l h y d r a z o n e )

(51),

3-formyl-l-aryl-4,5-pyrazoledione-

w h i c h c o u l d b e t r a n s f o r m e d i n t o a v a r i e t y of

(54),

derivatives ( 2 9 , 5 1 ) u p o n reaction w i t h amines, hydrazines, semicarbazide, or thiosemicarbazide.

T h e t h i o s e m i c a r b a z o n e s w e r e c y c l i z e d to t h e

t h i a d i a z o l e s , w h i c h are of c h e m i t h e r a p e u t i c interest

(52).

COOH Ph-N=N< 50

Ph

H

/ Ph—N

51

N

52

54

R=CHO

55

R = CH =N—NHR'

53


190

ASCORBIC

ACID

R e d u c t i o n of the p h e n y l a n a l o g u e 51 w i t h z i n c i n acetic a c i d i n e t h a n o l i c s o l u t i o n afforded s u b s t i t u t e d r u b i a z o n i c a c i d (56), was confirmed by I R a n d N M R spectroscopy (53).

whose structure

U p o n r e a c t i o n of 51

w i t h h y d r o g e n b r o m i d e i n acetic a c i d , the m a j o r p r o d u c t w a s a n d its structure w a s c o n f i r m e d (54) deoxy derivative

(52)

to be t h a t of 53.

was prepared

from

the

isolated

The monobromo-

bromodeoxy-L-ascorbic


acid.

0

OH

56

Treatment

of L-£hreo-2,3-hexodiulosono-l,4-lactone 2,3-bis ( s e m i c a r -

b a z o n e ) w i t h d i l u t e s o d i u m h y d r o x i d e s o l u t i o n afforded the s o d i u m salt of L-f7ireo-2,3-hexodiulosonic a c i d 2 , 3 - b i s ( s e m i c a r b a z o n e ) (43, 44), u p o n h e a t i n g y i e l d e d 57. (59)

on dissolution i n l i q u i d ammonia

and acidification w i t h

s u l f u r i c a c i d to p H 4, whereas a c i d i f i c a t i o n to p H 2 afforded

57

which

T h e bis ( s e m i c a r b a z o n e ) afforded the p y r a z o l e

58 59

R = R =

dilute

58.

H CONHo


8.

E L ASHRY

191


Conversion into Pyrazine Derivatives.

Pyrazine derivatives

are

examples of 1,2-diazines i n t h e c a r b o h y d r a t e series (24).

T h e derivative

w a s p r e p a r e d b y p a r t i a l t o s y l a t i o n of 41 to g i v e t h e

mono-p-toluene-

s u l f o n y l d e r i v a t i v e (60),

w h i c h u p o n treatment w i t h sodium iodide i n

acetone gave t h e b i c y c l i c d i a z i n e d e r i v a t i v e (62). t o l u e n e s u l f o n y l d e r i v a t i v e (61)

afforded,

those specified, t h e 6-deoxy-6-iodo 63.

H o w e v e r , the d i - p -

under conditions similar

to

T h e 6 - b r o m o d e o x y 64 w a s p r e

p a r e d (54) b y r e a c t i n g p h e n y l h y d r a z i n e w i t h

6-bromo-6-deoxy-L-ascorbic


acid. [-OR

PhHN—N 63

R = I,R' =

64

R = Br, R' =

Oxidation of Bishydrazones. (41)

N—NHPh Ts H

M i l d o x i d a t i o n of t h e b i s h y d r a z o n e s

w i t h cupric chloride yielded yellow bicyclic compounds

not t h e a n t i c i p a t e d triazoles (72). b o t h degradative a n d spectroscopic

(66)

(55-60) m e t h o d s .

m o n o p h e n y l h y d r a z i d e of m e s o x a l i c a c i d (68) 69 u p o n a c e t y l a t i o n ( 5 7 ) .

by

T h u s , u p o n treat

m e n t w i t h a l k a l i a n d a c i d i f i c a t i o n of t h e p h e n y l a n a l o g u e of p o u n d gave

and

T h e structures w e r e c o n f i r m e d 66,

the

was obtained. T h i s c o m

A c e t y l a t i o n of

66

afforded

a

m o n o - O - a c e t y l d e r i v a t i v e w h o s e N M R s p e c t r u m s h o w e d o n l y one i m i n o


192

ASCORBIC

ACID

p r o t o n i n s t e a d of t w o i n its p r e c u r s o r . T h e s t r u c t u r e has b e e n c o n f i r m e d b y d e t a i l e d mass spectroscopy, a n d

1 3

C N M R and

1 5

N N M R spectroscopy.

T h e s t r u c t u r e w a s q u e s t i o n e d w h e n e l e c t r o n i m p a c t mass

spectroscopy

d e t e c t e d a m o l e c u l a r i o n p e a k t w o mass u n i t s h i g h e r t h a n

expected.

C a r e f u l experiments at l o w t e m p e r a t u r e r e v e a l e d t h a t t h e m o l e c u l a r i o n


d i s p r o p o r t i o n a t e s w h e n h e a t e d , g i v i n g a n i o n of 65

M i x e d b i s h y d r a z o n e s (25,26,61)

(58,59).

of t y p e 42 w e r e s i m i l a r l y t r a n s

f o r m e d i n t o 67 u p o n t r e a t m e n t w i t h c u p r i c c h l o r i d e ( 3 0 ) .

The

bis(o-

c h l o r o p h e n y l ) a n a l o g u e of 41 gave the c o r r e s p o n d i n g o - c h l o r o d e r i v a t i v e of 66 w i t h o u t loss of c h l o r i n e atoms (40), ous studies i n the c a r b o h y d r a t e series. h y d r a z o n e ) (41)

as w a s a n t i c i p a t e d f r o m p r e v i B r o m i n a t i o n of the b i s ( p h e n y l -

afforded the p - b r o m o p h e n y l a n a l o g u e (66)

T o synthesize the t r i a z o l e (71),

a n o t h e r a p p r o a c h (63)

w h e r e d e h y d r a t i o n of the m i x e d h y d r a z o n e o x i m e (70) a n h y d r i d e afforded the t r i a z o l e Reduction of Bishydrazones. bis(phenylhydrazone)

(41)

(61)

(62). was used, w i t h acetic

(71). C a t a l y t i c h y d r o g e n a t i o n (64)

gave the d i a m i n o d e r i v a t i v e (73).

of the De

r i v a t i v e s of the latter w e r e p r e p a r e d b y r e a c t i n g it w i t h different a l d e h y d e s to g i v e i m i d a z o l i n e d e r i v a t i v e s (74) l i t h i u m a l u m i n u m h y d r i d e afforded as 75

(65).

R e d u c t i o n of 41 w i t h

a product tentatively formulated

(53).



8.

E L ASHRY

193


75 Reaction

of DHA with Amino

Acids

A m i n o acids are q u i c k l y deaminated b y L-ascorbic a c i d , l e a d i n g to b r o w n i n g reactions (66).

I n t h e presence of o x y g e n , i r o n , a n d a s c o r b i c

a c i d o r D H A , t h e a m i n o acids gave a m m o n i a , c a r b o n d i o x i d e , a n d a n aldehyde

w i t h one c a r b o n less t h a n t h e o r i g i n a l a c i d

(67,68). T h e

a l d e h y d e s are i s o l a t e d as d i m e d o n e d e r i v a t i v e s a n d a r e u s e f u l f o r i d e n t i fication

of t h e a m i n o acids. I n t h e presence of c o p p e r a n d U V l i g h t , t h e

d e a m i n a t i o n is i n c r e a s e d . T h e r e d c o l o r (69-73) f o r m e d u p o n r e a c t i o n of D H A w i t h a m i n o acids w a s u s e d f o r t h e i r d e t e c t i o n .

R e c e n t studies

(74-78) of t h e r e a c t i o n of D H A w i t h a m i n o acids l e d t o t h e i s o l a t i o n of a p r o d u c t t h a t changes r e a d i l y t o a n o v e l , stable, free r a d i c a l species


194

ASCORBIC

identified

as t r i ( 2 - d e o x y - 2 - L - a s c o r b y l ) a m i n e

(76).

Chemical

ACID

studies

u s i n g acetone d e r i v a t i v e s a n d analogous c o m p o u n d s ( 7 9 ) c o n f i r m e d t h e s t r u c t u r e of 76; t h e s t r u c t u r e of t h e free r a d i c a l , o b t a i n e d u p o n its o x i d a t i o n , r e t a i n e d t h e s y m m e t r i c a l s t r u c t u r e . E l e c t r o c h e m i c a l studies

(80)

s h o w t h a t 76 is o x i d i z e d i n a q u e o u s s o l u t i o n i n t w o r e v e r s i b l e , one-elec t r o n transfer steps o n m e r c u r y or p l a t i n u m electrodes.

T h e first step

occurs t h r o u g h t h e d i a n i o n a n d its p r o d u c t is a n u n u s u a l l y stable b l u e a n i o n r a d i c a l , w h i c h gives a c h a r a c t e r i s t i c e l e c t r o n s p i n resonance s i g n a l .


T h e p r o d u c t of t h e s e c o n d step of o x i d a t i o n is l a b i l e a n d is s l o w l y c o n v e r t e d i n t o a r e d p i g m e n t , w h o s e s t r u c t u r e is f o r m u l a t e d as t h e o x i d i z e d f o r m of bis ( 2 - d e o x y - 2 - L - a s c o r b y l ) a m i n e ( 8 1 ) , p r e s u m a b l y b y h y d r o l y s i s w i t h s p l i t t i n g of L - a s c o r b i c a c i d . D H A reacted w i t h p-aminobenzoic chloric acid affording

a c i d i n t h e presence

of h y d r o

6-carboxy-2-hydroxy-4-hydroxymethylquinoline

(77) ( 8 2 ) .

Bound Form of L-Ascorbic

Acid

A f t e r t h e c h a r a c t e r i z a t i o n of v i t a m i n C as a s c o r b i c a c i d , i t w a s o b s e r v e d t h a t t h e content of a s c o r b i c

a c i d i n some vegetables

(83,84)

increases w h e n b o i l e d or c o o k e d . T h e increase is b e l i e v e d t o b e c a u s e d b y l i b e r a t i o n of b o u n d a s c o r b i c a c i d (85,86,87). (87)

T h e name

ascorbigen

w a s g i v e n to t h a t substance t h a t w a s later s e p a r a t e d

(88) a n d

synthesized

(89,90,91).

Ascorbigen

was synthesized

either f r o m

3-

hydroxy indole a n d ascorbic a c i d or f r o m indole, formaldehyde, a n d ascorbic acid.


8.

Nitrogen Derivatives of L-Ascorbic

E L ASHRY

Acid

195

Acknowledgments I a m indebted to C . Schuerch a n d H . E l K h a d e m for their encourage ment. Y.

I express m y sincere

E l Kilany,

N . Rashed,

t h a n k s t o a l l p a r t i c i p a n t s i n this A . Amer, A . Moussad,

study:

M . Shoukry, a n d

F . Singab.


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37. El Khadem, H.; El Ashry, E. S. H. Carbohydr. Res. 1968, 7, 501. 38. El Khadem, H.; El Ashry, E. S. H. J. Chem. Soc. 1968, 2248. 39. El Khadem, H.; Meshreki, M. H.; El Ashry, E . S. H.; El Sekeili, M. Carbohydr. Res. 1972, 21, 430. 40. El Ashry, E. S. H.; Labib, G. H.; El Kilany, Y. Carbohydr. Res. 1976, 52, 200. 41. Fischer, R. Pharm. Ztg. 1934, 79, 1207. 42. El Ashry, E. S. H.; Nassr, M.; Singab, F. Carbohydr. Res. 1977, 56, 200. 43. Provost, C.; Fleury, M. Compt. Rend. 1964, 258, 587. 44. Fleury, M. Bull. Soc. Chim. Fr. 1966, 522. 45. Soliman, R.; El Ashry, E. S. H.; El Kholy, I. E.; El Kilany, Y. Carbohydr. Res. 1978, 67, 179. 46. El Khadem, H.; El Sahfei, Z. M.; El Ashry, E . S. H.; El Sadek, M. Carbohydr. Res. 1976, 49, 185. 47. Rao, J. M.; Nair, P. M. Tetrahedron 1970, 26, 3833. 48. Roberts, G. A. F. J. Chem. Soc. 1979, 603. 49. Poller, P.; Gelin, S. Tetrahedron 1980, 36, 2955. 50. Ohle, H. Ber. Dtsch. Chem. Ges. 1934, 67, 1750. 51. El Khadem, H.; El Ashry, E. S. H. J. Chem. Soc. 1968, 2248. 52. El Ashry, E. S. H.; Abdel Rahman, M. M.; Hazah, A.; Singab, F. Sci. Pharm. 1980, 48, 13. 53. El Khadem, H.; El Shafei, Z. M.; El Sekeili, M. J. Org. Chem. 1972, 22, 3523. 54. El Ashry, E. S. H.; El Kilany, Y. Carbohydr. Res. 1980, 80, C8. 55. El Khadem, H.; El Ashry, E. S. H. Carbohydr. Res. 1968, 7, 507. 56. El Khadem, H.; El Ashry, E. S. H. J. Chem. Soc. 1968, 2251. 57. El Khadem, H.; El Ashry, E. S. H. J. Heterocycl. Chem. 1973, 10, 1051. 58. El Khadem, H.; El Ashry, E . S. H.; Kreishman, G. P., presented at the 2nd Chem. Congr. North Am. Continent, San Francisco, 1980, Carb-11. 59. El Khadem, H.; El Ashry, E. S. H.; Jaeger, D. L.; Kreishman, G. P.; Foltz, R. L. J. Heterocycl. Chem. 1980, 17, 1181. 60. El Khadem, H.; Coxon, B. Carbohydr. Res., in press. 61. El Ashry, E. S. H.; Abdel Rahman, M. M. A.; Mancy, S.; El Shafei, Z. M. Acta Chim. Acad. Sci. Hung. 1977, 95, 409. 62. El Ashry, E. S. H.; El Kilany, Y.; Singab, F. Carbohydr. Res. 1980, 82, 25. 63. El Sekeili, M.; Mancy, S.; El Kholy, I. E.; El Ashry, E. S. H.; El Khadem, H. S.; Swartz, D. L. Carbohydr. Res. 1977, 59, 141. 64. Micheel, F.; Bode, G.; Siebert, R. Ber. Dtsch. Chem. Ges. 1937, 70, 1862. 65. Gross, B.; El Sekeili, M. A.; Mancy, S.; El Khadem, H. Carbohydr. Res. 1974, 37, 384. 66. Abderhalden, E. Wien. Klin. Wochenschr. 1937, 50, 815. 67. Abderhalden, E. Fermentforschung 1937, 15, 285. 68. Ibid., 1938, 15, 522. 69. Wurtz, B.; North, J. C. Compt. Rend. 1963, 256, 1388. 70. Mori, Y.; Kumano, S.; Nango, I.; Kano, M.; Eiyo To Shokuryo, 1967, 20, 211. 71. Ibid., 216. 72. Shamanna, R.; Lakshiminarayana, S. J. Agric. Food Chem. 1968, 16, 528. 73. Pohloudek-Fabini, R.; Fuerting, W. J. Chromatogr. 1964, 13, 139. 74. Namiki, M.; Yano, M.; Hayashi, T. Chem. Lett. 1974, 125. 75. Yano, M.; Hayashi, T.; Namiki, M. Chem. Lett. 1974, 1973. 76. Yano, M.; Hayashi, T.; Namiki, M. J. Agric. Food Chem. 1976, 24, 815. 77. Yano, M.; Hayashi, T.; Namiki, M. Agric. Biol. Chem. 1978, 42, 2239. 78. Hayashi, T.; Namiki, M. Tetrahedron Lett. 1979, 4476. 79. Hayashi, T.; Manou, F.; Namiki, M.; Tsuji, K., unpublished data. 80. Tsuji, T.; Hayashi, T.; Namiki, M. Electrochim. Acta 1980, 25, 605.


8. EL ASHRY Nitrogen Derivatives of L-Ascorbic Acid

Kurata, T.; Fujimaki, M.; Sakurai, Y. J. Agric. Food Chem. 1973, 21, 676. Hasselquist, H. Ark. Kemi 1964, 7, 121. Ahmad, B. Biochem. J. 1935, 275. McHenry, E. W.; Graham, M. L. Nature 1935, 135, 871. Guha, B. C.; Pal, J. C. Nature 1936, 137, 946. Ibid., 1937, 139, 844. Sen-Gupta, P. N.; Guha, B.C. Nature 1938, 141, 974. Prochazka, Z.; Sanda, V.; Sorm, F. Collect. Czech. Chem. Commun. 1957, 22, 333, 654. 89. Gimelin, R.; Virtanen, A. I. Ann. Acad. Sci. Fenn., Ser. A2 1961, 107. 90. Piironen, E.; Virtanen, A. I. Acta Chem. Scand. 1962, 16, 1286. 91. Virtanen, A. I.; Piironen, E. Suom. Kemistil. 1962, 35, 104.


81. 82. 83. 84. 85. 86. 87. 88.

197

RECEIVED for review January 22, 1981. ACCEPTED June 2, 1981.


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