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Reactions of Amino Acids on 2-Methylmercaptohydantoin Derivatives. Synthesis of Imidazoimidazoline and Imidazoquinazoline Derivatives

H. A. Daboun*, A. M. Abd-Elfattah, M. M. Hussein, and A. F. A. Shalaby C h e m i s t r y D e p a r t m e n t , F a c u l t y o f S c i e n c e , C a i r o U n i v e r s i t y , G i z a , E g y p t

Z . N a t u r f o r s c h . 8 6 b , 3 6 6 - 3 6 9 ( 1 9 8 1 ) ; r e c e i v e d O c t o b e r 2 9 , 1 9 8 0

A m i n o A c i d s , 2 - M e t h y l m e r c a p t o h y d a n t o i n s , I m i d a z o i m i d a z o l i n e s , I m i d a z o q u i n a z o l i n e s

T r e a t m e n t o f 5 - a r y l i d e n e - 2 - m e t h y l m e r c a p t o h y d a n t o i n s (la-d) a n d 5 - a r y l a z o - 2 - m e t h y l -m e r c a p t o h y d a n t o i n s ( 3 a , b ) w i t h g l y c i n e i n a c e t i c a c i d g a v e 5 - a r y l i d e n e - N 2 - c a r b o x y -m e t h y l g l y c o c y a m i d i n e s (2a-d) a n d 5 - a r y l a z o - N 2 - c a r b o x y m e t h y l g l y c o c y a m i d i n e s (4a, b) r e s p e c t i v e l y . 2 a , b , d w e r e c y c l i s e d w i t h a c e t i c a n h y d r i d e t o g i v e i m i d a z o i m i d a z o l i n e d e r i v a t i v e s ( 5 a - e ) . 2 - M e t h y l m e r c a p t o - 3 - p h e n y l h y d a n t o i n ( 7 ) r e a c t e d w i t h a n t h r a n i l i c a c i d t o g i v e 9 w h i c h p r e v i o u s l y p r e p a r e d b y t h e a c t i o n o f a n i l i n e o n e t h y l 2 - m e t h y l t h i o - 4 - o x o -3 , 4 - d i h y d r o - 3 - q u i n a z o l i n y l a c e t a t e ( 8 ) . A r y l i d e n e s l a - c , l O a - c a n d a r y l a z o d e r i v a t i v e s 3 a, b r e a c t e d w i t h a n t h r a n i l i c a c i d t o g i v e i m i d a z o q u i n a z o l i n e d e r i v a t i v e s lla-f a n d 1 2 a , b , r e s p e c t i v e l y .

Johnson et al. [1] reported that 5-benzal-2-alkyl-mercaptohydantoin reacted with methylamine to give 5-benzal-N2-methylglycocymidine. In our pre-vious publication [2], aromatic amines were found to react with 5-arylidene- and/or 5-arylazo-2-methyl-mercaptohydantoin derivatives to give the cor-responding N2-arylglycocyamidines without affect-ing the hetero ring opening.

Investigating the action of glycine on 5-arylidene-2-methylmercaptohydantoins (la-d) [3], the hetero ring proved to be stable and condensation occurred with the formation of 5-arylidene-N2-carboxy-methylglycocyamidines (2a-d).

Ar-CH=C-I

,N NH,

SCHj

1

H Ar-CH=C C=0

HN NH

H N-CHjCOOH

l a : A r = C 6 H 5 ; l b : A r = j D - C H 3 O C 6 H 4 ; l c : A r = o - C l - C 6 H 4 ; I d : A r = _ p - C 1 C 6 H 4 .

2 2 a : A r = C 6 H 5 ;

2 b : A r = p - C H 3 0 - C 6 H 4 ;

2 c : A r = o - C l - C 6 H 4 ;

2 d : A r - ^ - C l - C 6 H 4 .

Similarly, 5-arylazo-2-methylmercaptohydantoins (3 a, b) [4] gave 5-arylazo-N2-carboxymethylglyco-cyamidines (4 a, b).

Ar-N=N-CH C = 0 I I

HN .N

Y SCH,

Ar-N=N-CH—C = 0 I I

HN NH C

3 a : A r = C 6 H 5 ;

3 b : A r = j 9 - C H 3 - C 6 H 4 .

N-CHjCOOH

4 a : A r = C 6 H 5 ;

4 b : A r = ^ - C H 3 C 6 H 4 .

The products 2a-d and 4 a, b are soluble in aqueous sodium hydroxide and sodium carbonate solutions. The IR spectrum of 2 a shows absorption bands characteristic for carboxylic group.

Cyclisation of the products 2 a, b, d was affected by refluxing with acetic anhydride to give 3-aryl-idene-2,3,5,6-tetrahydro-l H-imidazo[l,2-a]imid-azole-2,5-dione (5a-c).

Ar-CH=C 0 = 0 I I

o»c c I II CH2—N

Ar-CH = C C = 0 I w

N CH,

I H-N

5 a : A r = C 6 H 5 ;

5 b : A r = j 9 - C H 3 O C 6 H 4 ;

5 c : A r = i ) - C l - C 6 H 4 .

The products 5 a-c are insoluble in sodium carbonate solution. Also, the absence of absorption characteristic for carboxylic group in IR spectrum of compound 5 a is taken as an evidence of cyclic structure proposed for these compound. Although two isomeric structures are possible for the cyclisa-tion products (c/. structures 5 and 6), the structure 5 was considered most likely based on analogy to the well established behaviour of 5-arylidene-2-carbo-ethoxymethylmercaptohydantoins on cyclisation under similar conditions [5].

It was reported that anthranilic acid condensed with 3-aryl-2-thiohydantoins at position 4 and 5 to give 2-thiono-3-aryl-4,5-(4'-hydroxy)-2',3'-quino-linoimidazolidine [6, 7]. We found that 2-methyl-mercapto-3-phenylhydantoin (7) (prepared from 3-phenyl-2-thiohydantoin [8] (as in Lempert and Breuer methylation [9]) reacted with anthranilic

acid to give l-phenyl-imidazo[2,l-b]quinazoline-2,5(lH,3H)-dione (9) in quantitative yield which proved to be identical with that previously prepared from ethyl 2-methylthio-4-oxo-3,4-cühydro-3-quin-azolinylacetate (8) with aniline and aniline hydro-chloride [10].

CH,—C=0 I N.

R w N " P h *

T SCH,

7 (^HJC00C

2HS

a .

COOH

CHJ—C«0 I I N N-Ph

• o=c c

To condense the aromatic aldehydes Trials were done with methylene group in 9. By fusing anthra-nilic acid with 5-arylidene-2-methyl-mercapto-hydantoins (la-c) and/or 5-arylidene-3-phenyl-2-methylmercaptohydantoins [11] 10 a-c at 150 °C the products l l a - f were formed, which were also obtained by boiling the reactants in glacial acetic acid.

Ar-CH=C- -C»0

10

1 0 a : A r = C 6 H 5 ; 1 1 a : A r = C 6 H 5 ; R = H ; 1 0 b : A r = j o - C H 3 0 • C 6 H 4 ; 1 1 b : A r = j o - C H 3 0 • C 6 H 4 ; 1 0 c : A r = o - C l C 6 H 4 . R = H ;

1 1 c : A r = o - C l C 6 H 4 ; R H •

l i d : A r = R = C 6 H 5 ; l i e : A r = j D - C H 3 O C 6 H 4 ;

R - C ß H ö ; 1 1 f : A r = o - C l • C e H 4 ;

R = C ß H ö .

The infrared spectrum of 1 1 d was characterised by the presence of the absorption bands at 1710 cm - 1

and 1742 cm-1 due to the presence of the two carbonyl groups, whereas the absence of the -NH absorption band in the compound l i d was in favour of the cyclic structure proposed for the products l l a - f .

On the other hand, the coloured arylazo deriva-tives 3 a, b when treated with anthranilic acid in presence of acetic acid afforded the products 12 a, b.

Ar-N=N-CH C = 0 I I

0=C C

1 2 a : A r = C 6 H 5 ;

1 2 b : A r = p - C H 3 C 6 H 4 .

Experimental All melting points are uncorrected. IR spectra

were recorded on a Pye Unicam SP-1000 spectro-photometer. Analytical data were performed in the analytical data.

Preparation of 5-arylidene-N2-carboxymethylglyco-cyamidine derivatives (2a-d)

A mixture of 0.0041 mole of each of 5-arylidene-2-methylmercaptohydantoin (la-d) [3] and 0.0042 mole of glycine was heated in 20 ml glacial acetic acid. During the reaction the odour of methane thiol could easily be detected, and after about 1/2 h, white precipitate was separated. When the reaction was completed, it was left to cool at room temperature. The product was filtered, washed with water and crystallised from diluted dimethyl formamide as 2a-d.

2a-d are all colourless. They gave no colour with concentrated sulphuric acid. They were soluble in sodium hydroxide and sodium carbonate solutions.

2a: m.p. 260 °C; yield 70%. Analysis: Ci2Hn03N3

Calcd C 58.78 H 4.49 N 17.14, Found C 58.8 H 4.5 N 17.1.

2b: m.p. 263 °C; yield 65%. Analysis: C I 3 H I 3 0 4 N 3

Calcd C 56.73 H 4.73 N 15.27, Found C 56.8 H 4.7 N 15.3.

2c: m.p. 250 °C; yield 75%. Analysis: CI 2 HI 0 O 3 N 3 C1

Calcd C 51.61 H 3.58 N 15.05 Found C 51.6 H 3.6 N 15.1

2d: m.p. 269 °C; yield 70%. Analysis: CI2HIO03N3C1

Calcd C 51.61 H 3.58 N 15.05 Found C 51.5 H 3.6 N 15.1

Cl 12.72, Cl 12.7.

Cl 12.72, Cl 12.7.

Preparation of 5-p-tolylazo-2-methylmercapto-hydantoin (3 b)

To 5-p-tolylazo-2-thiohydantoin [4] (0.06 mole) dissolved in a mixture of aqueous sodium hydroxide (8%, 33 ml) and ethyl alcohol (33 ml), was added the methyl iodide (0.066 mole). The deep red colour of the reaction mixture gradually changed to orange, followed by precipitation of the product. The reac-tion mixture was left overnight at room tempera-ture. The solid, obtained, was collected by filtration and recrystallised from dilute ethyl alcohol as 3b, m.p. 169 °C; yield 75%. Analysis: C11H12ON4S

Calcd C 53.23 H 4.84 N 22.58 S 12.90, Found C 53.3 H 4.9 N 22.4 S 13.0.

Preparation of 5-arylazo-N2-carboxymethylglyco-cyamidine derivatives (4 a, b)

A mixture of 0.004 mole of each of 5-arylazo-2-methylmercaptohydantoin (3a, b) [4] and 0.0041 mole of glycine was heated in 20 ml glacial acetic acid. During the reaction the odour of methane thiol could easily be detected. When the reaction was completed, it was left to cool at room temperature, and the separated substance was filtered, washed with water and crystallised from the proper solvents as yellow crystals of 4 a, b. They are soluble in sodium hydroxide and sodium carbonate solutions. They gave orange colour with concentrated sulphuric acid.

4 a was crystallised from dilute dimethyl formamide, m.p. 277 °C; yield 80%. Analysis: C11H11O3N5

Calcd C 50.57 H 4.21 N 26.82, Found C 50.6 H 4.2 N 26.9.

4b was crystallised from acetic acid, m.p. 268 °C; yield 75%. Analysis: C12H13O3N5

Calcd C 52.36 H 4.73 N 25.45, Found C 52.4 H 4.8 N 25.4.

Cyclisation of the products 2 a, b, d A suspension of each of 2 a, b, d (1 g) in acetic

anhydride (10 ml) was heated till all the solid substance dissolved. The reaction mixture was refluxed for 4 h. It was cooled, poured into ice cold water and the separated product was collected by filtration and recrystallised from acetic acid, as colourless crystals of 5a-c.

The solid product was insoluble in sodium hydroxide and sodium carbonate solutions and gave no colour with concentrated sulphuric acid.

5a: m.p. 247 °C; yield 70%. Analysis: C12H9O2N3

Calcd C 63.44 H 3.96 N 18.5, Found C 63.5 H 4.0 N 18.5.

5b: m.p. 229 °C; yield 65%. Analysis: C13H11O3N3

Calcd C 60.70 H 4.28 Found C 60.8 H 4.3

N 16.34, N 16.4.

5c: m.p. 240 °C; yield 68%. Analysis: Ci2H802N3Cl

Calcd C 55.07 H 3.06 N 16.06 Cl 13.58, Found C 55.1 H 3.1 N 16.0 Cl 13.6.

Preparation of the bicyclic 1-phenylimidazo-[2,l-b]-quinazoline-2,5(lH,3H) dione (9)

l-Phenyl-imidazo[2,l-b]quinazoline-2,5 (1 H,3H) dione (9) was prepared from 5.8 g of 3-phenyl-2-thiohydantoin [8] dissolved in sodium hydroxide solution (16 ml, 12%) followed by the addition of 3.5 ml of methyl iodide in methanol (90 ml). The reaction mixture was stirred for one hour and left aside at room temperature overnight. The solution (contain compound 7) was evaporated to half its volume, diluted with 20 ml ethyl alcohol and 3.7 g of anthranilic acid was added to the dark purple solution. The reaction was refluxed for 1.5 h on water bath, till the complete precipitation of the colourless product. It was collected by filtration and recrystallised from dimethyl formamide as 9 m.p. 298 °C. It is proved to be identical with an authentic sample [10].

Action of anthranilic acid on 5-arylidene-2-methyl-mercaptohydantoin derivatives ( la-c)

Method A: A mixture of 0.004 mole of each of 1 a-c and 0.0041 mole of anthranilic acid was heated in an bath at 150-160 °C. During the reaction the odour of methane thiol could easily be detected and heating was continued for approximately 2 h. When the reaction was completed, it was left to cool at room temperature. It was washed with alcohol and the residual solid obtained, was crystallised from acetic acid as yellow crystals of 1 1 a-c (cf. Table I).

The solid product was insoluble in sodium hydroxide and sodium carbonate solutions and gave yellow colour when treated with concentrated sulphuric acid.

Method B: A suspension of 0.004 mole of each of 5-arylidene-2-methylmercapto hydantoin (la-c) and 0.0041 mole of anthranilic acid was heated in 20 ml glacial acetic acid. During the reaction the odour of methane thiol could easily be detected and the solution became dark brown. When the reaction was completed, it was left to cool at room tem-perature. The yellow crystalline substance was separated. The products were recrystallised from acetic acid and proved to be 1 1 a-c and identical with those obtained from Method (A) by melting point and mixed melting point determinations.

T a b l e I . 3 - A r y l i d e n e i m i d a z o [ 2 , l - b ] q u i n a z o l i n e - 2 , 5 ( l H , 3 H ) d i o n e ( l l a - f ) .

ANALYSIS [%] COMPOUND M.P. YIELD FORMULA CARBON HYDROGEN NITROGEN

[°C] [%] CALCD FOUND CALCD FOUND CALCD FOUND

11a 2 6 3 8 0 C17H11O2N3 7 0 . 5 9 7 0 . 6 3 . 8 1 3 . 8 1 4 . 5 3 1 4 . 6

lib 2 9 5 8 2 C18H13O3N3 6 7 . 7 1 6 7 . 7 4 . 1 4 . 2 1 3 . 1 7 1 3 . 2

11c 2 7 7 7 9 CI7H10O2N3C1* 6 3 . 0 6 6 3 . 1 3 . 0 9 3 . 1 1 2 . 9 8 1 3 . 0 lid 2 7 3 8 5 C23HI502N3 7 5 . 6 2 7 5 . 7 4 . 1 1 4 . 1 1 1 . 5 1 1 1 . 5

lie 2 4 5 8 6 C24H17O3N3 7 2 . 9 1 7 2 . 9 4 . 3 0 4 . 3 1 0 . 6 3 1 0 . 7

1 1 ! 2 1 9 9 0 C23H1402N3C1** 6 9 . 0 9 6 9 . 1 3 . 5 0 3 . 5 1 0 . 5 1 1 0 . 5

* C l : C a l c d 1 0 . 9 7 ; F o u n d 1 1 . 0 ; * * C l : C a l c d 8 . 8 9 ; F o u n d 8 . 8 9 % .

Action of anthranilic acid on 5-arylidene-3-phenyl-2-methylmercaptohydantoin (10 a-c)

A suspension of each of 10 a-c (0.004 mole) and anthranilic acid (0.0041 mole) was heated in 20 ml glacial acetic acid. The reaction mixture was worked up as above. The products were filtered, recrystal-lised from acetic acid as yellow crystals of l ld- f (c/. Table I).

l ld- f are insoluble in sodium hydroxide and sodium carbonate solutions. They give yellow colour when treated with concentrated sulphuric acid.

Action of anthranilic acid on 5-arylazo-2-methyl-mercaptohydantoin derivatives (3 a, b)

A suspension of 0.004 mole of each of 3 a, b and 0.0041 mole of anthranilic acid was heated in 20 ml glacial acetic acid. When the reaction was completed and no odour of methane thiol could be detected, it

was left to cool at room temperature. The separated crystalline substance was filtered. The product was crystallised from the proper solvent as yellow crystals of 12 a, b. They are insoluble in sodium hydroxide and sodium carbonate solutions. They gave orange colour when treated with concentrated sulphuric acid.

12 a was crystallised from dilute dimethyl form-amide, m.p. 289 °C; yield 75%. Analysis: C16H11O2N5

Calcd C 62.95 H 3.61 N 22.95, Found C 63.0 H 3.6 N 22.9.

12b was crystallised from acetic acid, m.p. 242 °C; yield 70%. Analysis: C17H13O2N5

Calcd C 63.85 H 4.08 N 21.94, Found C 63.9 H4. 1 N21 .9.

[ 1 ] T . B . J o h n s o n a n d B . H . N i c o l e t , J . A m . C h e m . S o c . 3 7 , 2 4 1 6 ( 1 9 1 5 ) .

[ 2 ] A . F . A . S h a l a b y , H . A . D a b o u n , S . S . M . B o g h -d a d i , a n d M . A . A b d e l A z i z , Z . N a t u r f o r s c h . 3 0 b , 1 2 4 ( 1 9 7 5 ) .

[ 3 ] T . B . J o h n s o n a n d B . H . N i c o l e t , J . A m . C h e m . S o c . 3 4 , 1 0 4 8 ( 1 9 1 2 ) .

[ 4 ] A . F . A . S h a l a b y , H . A . D a b o u n , a n d M . A . A b d e l A z i z , I n d i a n J . C h e m . 1 2 , 5 7 7 ( 1 9 7 4 ) .

[ 5 ] A . F . A . S h a l a b y , H . A . D a b o u n , a n d M . A . A b d e l A z i z , Z . N a t u r f o r s c h . 3 1 b , 1 1 1 ( 1 9 7 6 ) .

[ 6 ] B . S a h o o , P . B . T r i p a t h y , a n d M . K . R o u t , J . I n d i a n C h e m . S o c . 3 6 , 4 2 1 ( 1 9 5 9 ) .

[ 7 ] B . K . S a b a t a , P . B . T r i p a t h y , a n d M . K . R o u t , J . P r o c . I n s t . C h e m i s t s ( I n d i a ) 3 2 , 1 4 7 ( 1 9 6 0 ) ; C . A . 5 5 , 4 5 0 7 f ( 1 9 6 1 ) .

[ 8 ] H . S h i r a i a n d T . Y a s h i r o , N a g o y a C h i r i t s u D a i -g a k u Y a k u g a k u b u K i y o 1 0 , 5 7 ( 1 9 6 2 ) ; C . A . 5 9 ,

1 1 4 7 2 b ( 1 9 6 3 ) . [ 9 ] K . L e m p e r t a n d J . B r e u e r , M a g y . K e m . F o l y o i r a t

6 9 , 3 2 3 ( 1 9 6 3 ) ; C . A . 5 9 , 1 3 9 6 7 b ( 1 9 6 3 ) .

[ 1 0 ] G . D o l e s c h a l l a n d K . L e m p e r t , B e r . 9 9 ( 5 ) , 1 5 3 2 ( 1 9 6 6 ) .

[ 1 1 ] H . L . W h e e l e r a n d C . A . B r a u t l e c h t , A m . C h e m . J . 4 5 , 4 4 6 ( 1 9 1 1 ) .