Novel Rearrangement of 5-Arylazo-2-thiohydantoin

Novel Rearrangement of 5-Arylazo-2-thiohydantoin Derivatives with Alkali and Aromatic Amines A. F. A. Shalaby, H. A. Daboun, and M. A. Abdel Aziz Chemistry Department, Faculty of Science, Cairo University Giza, Egypt Z. Naturforsch. 38 b, 937-941 (1978); received March 16, 1978 2-Thiohydantoin Derivatives, Alkali Amines, Aromatic Amines 5-Arylazo-2-thiohydantoin derivatives (2a,c) were cleaved and rearranged by aqueous sodium hydroxide to give the corresponding l-aryl-Zl 2 -l,2,4-trazole-5-imino-3-carboxylic acids (3a-c). 3 a was decarboxylated to 1-phenyl-Zl2-1,2,4-triazoline-5-imine (o). Hydrolysis of 5-arylazo-l-phenyl-2-thiohydantoins (6a-c) behaved in different manner affording l-aryl-4-phenyl-zl 2 -l,2,4-triazoline-5-thione-3-carboxylic acids (7a-c). Fusing (2a-c) with aromatic amines at high temperature gave the corresponding anilides (8a-h). Treatment of 5-arylidene-2-thiohydantoin derivatives (9a-c) with hydrazine hydrate gave colourless products of thioureido cinnamic acid hydrazide derivatives (lOa-c), while refluxing ö-arylidene-2-methylmercaptohydantoin ( l l a - d ) with hydrazine hydrate and/or benzophenone hydrazone gave the corresponding glycocyamidine derivatives ( 1 2 a - g ) . It was reported that in an alkaline solution 5substituted-2-thiohydantoins (1) ionise as weak acids to give the corresponding anions [ l , 2] and they are also hydrolysed slowly with ring fission to give the thioureido acids [3]. This last reaction was

R

"^c—c=o I I HN^ ^NH

Ar-NH-N=C

C=0

I

HN

OH"

NH

V

2a: Ar = C6H5 2b: A r = O-CH3 • C 6 H 4 2c: Ar = P-CH3 • C6H4

Ar-N

N

I

HN=C

Y

II

C-COOH H

3a: Ar = C6H5 3 b : A r = O-CH3• C 6 H 4 3c: Ar=p-CH3 C6H4

Also 3 a was obtained b y heating 5-phenylazo-2methylmercaptohydantoin (4) [5] with aqueous sodium hydroxide.

C

sII 1

Ph-NH-N=C-

studied spectrophotometrically and in alkaline solution the spectra changed from those characterised of 2-thiohydantoins to those characteristic of the thioureido acids. When the solutions were made strongly acid, these changes were reversed [4]. Although the reaction of alkali with 5-substituted-2-thiohydantoins yielding substituded thioureido acids has been studied, no attention has been paid to the hydrolysis of the corresponding 5-hydrazo-2-thiohydantoin derivatives in which the electron withdrawing group i.e. the arylazo group attached to carbon-5. Treatment of 5-arylazo-2-thiohydantoins ( 2 a - c ) with aqueous sodium hydroxide affected heteroring opening followed b y recyclisation via loss of hydrogen sulphide with the formation of l-aryl-Zl 2 l,2,4-triazole-5-imino-3-carboxylic acids (3a-c).

Requests for reprints should be sent to Prof. Dr. A. F. A. Shalaby, Chemistry Department, Faculty of Science, Cairo University, Giza, Cairo, Egypt.

-C = 0

H-N

N

C I

SCH,

The acids 3 a - c gave the correct analytical data and gave effervescence with sodium bicarbonate solution. 3 a was decarboxylated to l-phenyl-zl 2 l,2,4-triazoline-5-imine (5) [6] b y heating it under reduced pressure in an oil bath at 140-150 °C. The product was further characterised b y the formation of its picrate and b y comparison with a sample previously prepared from N-phenylguandinine nitrate and formic acid [6]. Ph-N

N

I

II

HN=C.

N

CH

Hydrolysis of 5-arylazo-l-phenyl-2-thiohydantoins ( 6 a - c ) occurred in different manner. The

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A. F. A. Shalaby et al. • Novel Rearrangement of 5-Arylazo-2-thiohydantoin Derivatives

938

in alkyline medium and the corresponding 1-phenyl hetero-ring fission occurred with the formation of 1 - aryl - 4 - phenyl-A 2 -1,2,4 - triazoline - 5 - thione - 3 - car- 5 - benzy Imercapto -1 H -1,2,4 - triazole - 3 - car b o x y ani lide was separated, which on refluxing with hydroboxylic acids ( 7 a - c ) . In this reaction the presence chloric acid solution till the odour of the benzylof substituent at N - l favoured the rearrangement thiol could not be detected, l-phenyl-zl 2 -l,2,4-triawhich took place with the elimination of a molecule zoline-5-one-3-carboxyanilide was separated which of ammonia faster than hydrogen sulphide as shown was proved b y an authentic sample [8]. in the previous case. When the yellow 5-arylidene-2-thiohydantoin Ar-N N -C = 0 Ar-NH-N=Cderivatives ( 9 a - c ) were treated with hydrazine OH" I II I I hydrate in absolute ethyl alcohol at room tempera^C C-COOH Ph-N NH S x c / N ture, colourless products of thioureido cinnamic I Ph acid hydrazide derivatives ( l O a - c ) were obtained. 7a: Ar = C 6 H 5 6a: Ar = C6H5 W h e n ( l O a - c ) was heated with glacial acetic acid, 7b: Ar = 0-CH3 • C6H4 cyclization occurred with the formation of the 6 b : A r = O-CH3 • C 6 H 4 7 c : Ar = p - C H 3 C 6 H 4 6C: Ar = P-CH3 • C6H4 parent substances. The obtained products 7 a - c gave the correct CONH-NH 2 Ar-CH=C-C = 0 Ar-CH = Canalytical data. They are colourless and show NH2 NH2^ I acidic property. HN N-H HN NH2 In a previous publication [7] aromatic amines were found to react with 5-arylazo-2-methylmercaptohydantoin derivatives to give the corresponding glycocyamidines without affecting the heteroring opening. N o w b y fusing 2 a - c with aromatic amines i.e. aniline, o-toluidine and p-toluidine in an oil bath at 140-150 °C afforded the corresponding 1-aryl-Zl 2 -l,2,4-triazoline-5-thione-3-carboxyanilide (8a-h). While fusion of 6 a - c , having a phenyl substituent at N - l , with the previous aromatic amines under the same experimental conditions afforded the starting materials unchanged. This proved that the phenyl group connected to the nitrogen at position-1 stabilized the hetero-ring of 2-thiohydantoin. 2a-c

RNH2

MO-ISO'C^

Ar-N S=C

N

V

Y

9 a : Ar = C 6 H 5 9 b : Ar = p-CH 3 0-C 6 H 4 9 d : Ar = o-Cl • C 6 H 4

When 5-arylidene-2-methylmercapto hydantoin derivatives ( l l a - d ) was refluxed with hydrazine hydrate and/or benzophenone hydrazone in boiling acetic acid till the odour of methanethiol could not be detected, the corresponding glycocyamidine derivatives ( 1 2 a - g ) were obtained.

C-CONHR C=0

I

8e:

Ar = R = C6H5 Ar = C6H5; R = P-CH3 • C6H4 A r = O-CH3 •C 6 H 4 ; R = C 6 H 5 Ar = R = 0-CH3 • C 6 H 4 A r = o-CH3 •C 6 H 4 ; R = p - C H 3 • C 6 H

Sh:

Ar = R = P-CH3 • C6H4

8d:

10a: Ar = C 6 H 5 10 b: Ar = P-CH3O • C 6 H 4 10c: Ar = o-Cl • C 6 H 4

Previously we studied the reactivity of the thione group present in 5-arylidene-2-thiohydantoin aiming to transfer it into the corresponding glycocyamidine derivatives. This transformation was achieved b y heating 5-benzylidene-2-methylmercaptohydantoin with aniline [7].

Ar-CH=C8a: 8b: 8c:

11

S

8 f : Ar = p-CH.3 • C 6 H 4 ; R = C 6 H 5 8 g : Ar = p-CH3 • C 6 H 4 ; R = 0-CH3

I

HN

NH 2 -NH 2

XT I

SCH,

4

• C6H4

lla:Ar = l i b : Ar = 11c: Ar = l i d : Ar =

C 6 H5 o-Cl • C6H4 m-N0 2 • C6H4 p-CH 3 0 C 6 H 4

The structure of these products (8a-h) was inferred from the analytical data and the formation of the appropriate acid; when 8 a was hydrolysed with 7 0 % alcoholic potassium hydroxide afforded 1 - phenyl -A2-1,2,4- triazoline - 5 - thione - 3 - carboxylic acid [8]. Also 8 a was alkylated with benzyl chloride


Ar-CH=C I

C=0

HN

N-H

I

x

11c /

N-NR-

12a: Ar = C 6 H 5 ; R 2 = H 2 12b: Ar = o-Cl • CgH^; R2 = H2 12c: Ar = m-N0 2 • C 6 H 4 ; R2 = H2 12 d: Ar = p-CH 3 0-C 6 H 4 ; R 2 = Ho 12e: Ar = C 6 H 5 ; R = C(C 6 H 5 ) 2 12f: At = o-Cl • C 6 H 4 ; R 2 = C(C 6 H 5 ) 2 12g: Ar = to-N02 • C 6 H 4 ; R 2 = C(C6H5)2

939 A. F. A. Shalaby et al. • Novel Rearrangement of 5-Arylazo-2-thiohydantoin Derivatives Experimental Action of aqueous sodium hydroxide on 5-arylazo2-thiohydantoins (2a-c) 1 g of each of 2 a - c was added to 25 ml of sodium hydroxide (2%) and the reaction mixture was refluxed for 1 h. It was cooled and acidified with cold sulphuric acid till complete precipitation. The products were collected and crystallised from ethyl alcohol as colourless substances (3a-c). The acids (3a-c) are soluble in aqueous sodium hydroxide and gave effervescence with sodium bicarbonate solution. 3 a : m.p. 204 °C; yield 85%. Analysis: CgHs02N4 Calcd C 52.95 H 3.92 Found C 53.0 H 3.9

N 27.45, N 27.5.

3 b : m.p. 199 °C; yield 78%. Analysis: C10H10O2N4 Calcd C 55.04 H 4.58 H 4.6 Found C 55.1

N 25.68, N 25.7.

3 c : m.p. 216 °C; yield 80%. Analysis: C10H10O2N4 Calcd C 55.04 H 4.58 H 4.5 Found C 55.1

N 25.68, N 25.7.

Action of aqueous sodium hydroxide on 5-phenylazo-2-methylmercaptohydantoin (4) A mixture of 1 g of 4 and 25 ml of sodium hydroxide (2%) was refluxed for 1 h. The reaction mixture was completed as above and the solid so obtained was crystallised from ethyl alcohol as colourless crystals, m.p. 204 °C. It was proved to be 3 a by melting point and mixed melting point determinations. Decarboxylation of l-phenyl-A2-l,2,4-triazoline5-imino-3-carboxylic acid (3 a) The acid 3 a (1.0 g) was heated at 140-150 °C in an oil bath under reduced pressure (water pump) till the evolution of gas stopped. It was cooled and the residual solid was extracted with benzene and left to evaporate slowly at room temperature. The obtained solid was crystallised from ethanol as colourless crystals, m.p. 157 °C. It was proved to be l-phenyl-Zl 2 -l,2,4-triazoline-5-imino (5) [6] b y melting point and mixed melting point determinations. Picrate of l-phenyl-5-imino-A2-l,2,4-triazoline (5) T o a mixture of 0.2 g of 5 in 10 ml of acetone, a concentrated solution of picric acid was added drop wisely. The reaction mixture was left at room temperature till complete precipitation. The separated yellow crystals were collected by filtration and crystallised from ethyl alcohol (m.p. 175 °C) and it was identical with an authentic sample [6] b y melting point and mixed melting point determinations.

Action of aqueous sodium hydroxide on 5-arylazo-l-phenyl-2-thiohydantoin (6 a - c ) 1 g of each of 6 a - c was refluxed in 25 ml of sodium hydroxide ( 2 % ) for 1 h, the reaction mixture was cooled and worked up as above. The products were crystallised from ethyl alcohol as colourless crystals of 7 a - c . The acids 7 a - c are soluble in aqueous sodium hydroxide and gave effervescence with sodium bicarbonate solution. 7 a : m . p . 132 °C; yield 8 2 % . Analysis: C1sHu.O2.NzS Calcd C 60.60 H 3.70 Found C 60.5 H 3.7

N 14.14 N 14.2

S 10.77, S 10.8.

7 b : m.p. 117 °C; yield 7 9 % . Analysis: CizHwOzNzS Calcd C 61.73 H 4 . 1 8 Found C 61.8 H 4.2

N 13.50 N 13.6

S 10.28, S 10.3.

7 c : m.p. 155 °C; yield 7 7 % . Analysis: C16H13O2N3S Calcd C 61.73 H 4.18 Found C 61.7 H 4.2

N 13.50 N 13.5

S 10.28, S 10.2.

Action of aromatic amines on 5-arylazo-2-thiohydantoin (2 a - c ) A mixture of each of 2 a - c (1.0 g) and the appropriate amine (2 ml) was heated at 140-150 °C in an oil bath for 4 h. It was cooled and triturated with dilute ethanol. The obtained solid was crystallised from hot ethanol as colourless crystals of the corresponding anilides (8a-h) (cf. Table I). The products are insoluble in dilute sodium hydroxide solution and gave reddish brown colour when treated with concentrated sulphuric acid. Alkaline hydrolysis of 5-thione-3-carboxyanilide

l-phenyl-A2-l,2,4-triazoline(8 a)

A mixture of 8 a (1.0 g) in 30 ml of ethanolic potassium hydroxide (70%), was refluxed for 1 h on a water bath. It was cooled, diluted with water, acidified with cold hydrochloric acid, and extracted with chloroform. The extract layer was dried over anhydrous sodium sulphate, filtered and evaporated. The residual solid was crystallised from ethyl alcohol as colourless crystals m.p. 181 °C, it was proved to be 1 -phenyl-zl 2 -1,2,4-triazoline-5-thione3-carboxylic acid (8) by melting point and mixed melting point determinations. Benzylation of 3-carboxyanilide

l-phenyl-A2-l,2,4-triazoline-5-thione(8 a)

T o a solution of 0.5 g of 8 a dissolved in a mixture of 15 ml aqueous sodium hydroxide (2%) and 15 ml of ethyl alcohol, was added 2 ml of benzyl chloride drop wisely. The reaction mixture was shaken for 1 h and was left aside overnight at room tem-


A. F. A. Shalaby et al. • Novel Rearrangement of 5-Arylazo-2-thiohydantoin Derivatives

940

Table I. l-Aryl-Zl2-l,2,4-triazoline-5-thione-3-carboxyanilide (8a-h). Com- m.p. pound [°C]

Yield

Formula

Carbon Calcd Found

Analysis [ % ] Hydrogen Nitrogen Calcd Found Calcd Found

8a 8b 8c 8d 8e 8f 8g 8h

75 73 70 70 69 68 68 65

C15H12ON4S

60.81 61.93 61.93 62.96 62.96 61.93 62.96 62.96

4.05 4.51 4.51 4.93 4.93 4.51 4.93 4.93

246 240 222 238 260 233 225 275

[%]

C16H14ON4S Ci6H14ON4S C 17 HI 6 ON 4 S Ci7HI6ON4S Ci6H14ON4S C17H16ON4S Ci7HI6ON4S

60.9 62.0 61.9 63.0 62.9 61.9 63.0 62.9

perature. The obtained solid was collected by filtration and recrystallised from ethyl alcohol as colourless crystals m.p. 145 °C (yield 88%). Analysis: C22H18ON4S Calcd C 68.39 Found C 68.4

H 4.66 H 4.7

N 14.50 N 14.5

Acid hydrolysis of 1-phenyl-5-benzylmer 1,2,4-triazole-3-carboxyanilide

S 8.29, S 8.3.

capto-1H-

The obtained benzyl derivative (0.5 g) was refluxed in a mixture of ethyl alcohol (20 ml) and concentrated hydrochloric acid (5 ml) on a water bath. The reaction mixture was heated for 4 h till the odour of the evolved thiol could not be detected. It was cooled and the precipitated product was filtered off and recrystallised from ethyl alcohol as colourless substance of l-phenyl-Zl 2 -l,2,4-triazoline5-one-3-carboxyanilide, m.p. 231 °C. It was identical with an authentic sample by melting point and mixed melting point determinations [8]. Formation of a-thioureido cinnamic acid hydrazide derivatives (10 a) To a suspension of each of the yellow substances 9 a - c (35 ml mole) in 50 ml of ethyl alcohol was added 8 ml of hydrazine hydrate. The reaction mixture was stirred at room temperature for five hours. During the reaction the yellow substances disappeared gradually and colourless product began to deposit. After complete precipitation the products were collected by filtration. The products were dissolved in ether, filtered and left to evaporate slowly at room temperature precipitating the colourless thioureido hydrazide (lOa-c). 10a: m.p. 145 °C; yield 9 0 % . Analysis: C10H12ON4S Calcd C 50.84 H 5.08 Found C 50.9 H 5.1

N 23.72 N 23.7

S 13.55, S 13.6.

10b: m.p. 192 °C; yield 8 9 % . Analysis: CuIInON Calcd C 52.80 H 5.60 Found C 52.8 H 5.6

N 22.40 N 22.4

S 12.80. S 12.7.

4.1 4.5 4.6 5.0 4.9 4.5 4.9 5.0

18.91 18.06 18.06 17.28 17.28 18.06 17.28 17.28

18.9 18.1 18.0 17.3 17.2 18.1 17.2 17.3

Sulphur Calcd Four 10.81 10.32 10.32 9.87 9.87 10.32 9.87 9.87

10.8 10.3 10.4 9.9 9.8 10.3 9.9 9.8

10c: m.p. 185 °C; yield 85%. Analysis: CwHuON ±SCl Calcd C44.36 H4.06N20.70 S 11.82 Cl 13.12. Found C44.4 H4.1 N20.7 S11.9 C113.2. Cyclisation of a-thioureido cinnamic acid hydrazide derivatives (lOa-c) a) In acid medium: A mixture of 1 g of each of 10 a - c and 30 ml of acetic acid was refluxed for 10 min. During the heating, the reaction mixture was changed into yellow colour. It was cooled and the obtained solid was collected by filtration. The products were crystallised from glacial acetic acid and identified as 5-arylidene-2-thiohydantoins (9 a - c ) by melting point and mixed melting point determinations. b) In alkaline medium: A mixture of 1 g of each of lOa-c and 20 ml (10%) aqueous sodium hydroxide was refluxed for 10 min. During the heating, the reaction mixture was changed into yellow colour, followed by precipitation of the product. It was cooled. The products were crystallized from glacial acetic acid and identified as 5-arylidene-2-thiohydantoin (9 a-c) by melting point and mixed melting point determinations. Action of hydrazine hydrate on lla-d A mixture of each of l l a - d (0.1 mole) and slight excess (0.11 mole) of hydrazine hydrate in 20 ml glacial acetic acid was refluxed for 4 h till the odour of methane thiol could not be detected. It was left to cool, and the separated product was washed with ethyl alcohol and crystallised from the proper solvent as coloured compounds of 5-arylidene-2-hydrazohydantoin derivatives (12a-d) (c/. Table II). Action of benzophenonehydrazone on 11 a-c A mixture of each of 11 a - c (0.1 mole) and (0.11 mole) of benzophenonehydrazone was dissolved in 25 ml glacial acetic acid. The reaction mixture was refluxed for 4 h till the odour of methane thiol could not be detected. It was left to cool. The obtained products were washed with ethyl alcohol, and crystallised from ethyl alcohol as coloured crystals of the crossed azine 12e-g (c/. Table II).


941 A. F. A. Shalaby et al. • Novel Rearrangement of 5-Arylazo-2-thiohydantoin Derivatives Table II. 5-Arylidene-2-hydrazohydantoin derivatives (12a-g). Com- m.p. pound [°C]

Yield

[%]

Solvent of crystn.

Formula

Carbon Calcd Found

12a 12 b 12c 12d 12e 12! 12g

70 70 65 68 80 75 78

Ethanol aq. DMF ( 7 0 % ) Ethanol Acetic acid Ethanol Ethanol Ethanol

Ci 0 H 1 0 ON 4 Ci 0 H 9 ON 4 Cl a

59.40 50.73 48.58 56.89 75.40 68.91 67.15

246 300 180 290 170 215 255

a Cl: Calcd. 15.01; Found 1 5 . 1 % ;

b

C10H9O3N5

CuH1202N4 C 2 3 HI 8 ON 4 C 23 Hi 7 ON 4 C1* C23H17O3N5

59.4 50.7 48.6 56.9 75.4 68.9 67.2

Analysis [ % ] Hydrogen Calcd Found

Nitrogen Calcd Found

4.95 3.80 3.64 5.17 4.91 4.24 4.13

27.72 23.67 28.34 24.13 15.30 13.98 17.03

5.0 3.8 3.7 5.2 5.0 4.3 4.2

27.8 23.7 28.4 24.2 15.3 14.0 17.0

Cl: Calcd. 8.86; Found 8.9°//o-

[1] V. du Vignead and D. B. Melville, The Chemistry of Penicillin, p. 269 Princeton Univ. Press, New Y o r k 1949. [2] J. T. Edward and S. Nielsen, J. Chem. Soc. 1957, 5080. [3] E. Ware, Chem. R e v . 46, 403 (1950). [4] G. W . Kenner, H. G. Khorona, and R . J. Stedman, J. Chem. Soc. 1953, 673.

[5] A . F. A . Shalaby, H . A. Daboun, and M. A . Abdel Aziz, Indian J. Chem. (6) 12, 577 (1974). [6] G. Pellizzari and C. Roncagliolo, Gazz. Chim. Ital (I) 31, 524. [7] A . F. A . Shalaby, H . A. Daboun, S. S. Boghdadi, and M. A . Abdel Aziz, Z. Naturforsch. 30b, 124 (1975). [8] A . Mustafa, A . H . Harshash, M. H . El-Nagdi, and F . Abdel All, Ann. Chem. 748, 79 (1971).
