Preparation and Reactions of 4-Arylazo-3-Methyl-2-Isoxazolin-5-Thiones

Arylazoisoxazolinthiones: Preparation and Reactions of 4-Arylazo-3-methyl-2-isoxazolin-5-thiones

NAZMI A. KASSAB*, SANAA. 0. ABD ALLAH, and SAID A. ELB AH A TI

Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt

(Z. Naturforsch. 33 b, 75-79 [1978]; received August 24, 1977)

Alkylation, Grignard's Reaction, Arylazoisoxazolinimines, Arylazoisoxazolinhydrazones, Ring Cleavage

The arylazo derivatives (2) of 3-methyl-2-isoxazolin-5-thione were prepared. Alkylation of 2 with alkyl halides results in the formation of the S-alkyl derivatives (5). The S-acetate esters undergo thermal isomerisation to the corresponding 1,2,3-triazole derivatives (6). The thiones 2 condense with hydrazines and primary amines to afford the corresponding 5-hydrazones and 5-imines (8) and (10), respectively. Treatment of 2 with hydrazine hydrate and Phenylhydrazine in boiling alcohol effects ring cleavage with the formation of 9.

Four potentially tautomeric structures (1-4) for azo7 and thiocarbonyl groups. This assignment (X = 0) are possible for 4-arylazo-3-methyl-2- is in contrast with the favoured hydrazo structure4 isoxazolin-5-ones, which have been extensively for the original oxygen analogue (1) (X = 0). The studied owing to their biological evaluation1-3. UV spectra of compounds 2 (X = S) show a notice- Recently4, the arylhydrazono structure (1) was able red shift compared with the spectra of the favoured on the basis of spectral data. But, little arylhydrazonoisoxazolones (1). attention has been paid for the arylazoisoxazolin- Subjecting the 4-arylazo-3-methyl-2-isoxazolin- thione analogues. 5-thiones (2 a-c) to the action of different alkylating The present investigation deals with the synthesis agents such as, chloroacetamide, phenacyl bromide and chemical behaviour of 4-arylazo-3-methyl- and ethyl bromoacetate afforded the corresponding 2-isoxazolin-5-thiones (1-4, X = S) towards a coloured S-alkylated arylazo derivatives (5a-i). variety of nucleophilic and alkylating reagents to The IR spectra of the S-alkylated derivatives gain an insight into the structure of azo compounds. exhibit an absorption around 1600 cm-1 characteristic for azo group. Subjecting compound 5 a to mild H -N-C—C-X Ar-N-N-C—C= Ar—N=N—C—C=X Ar—N=N—C=C—SX treatment with ethanolic hydrochloric acid effected I I II I I I 3 C"V H3C"CV> alkylmercaptan elimination to afford the original H 4 - phenylhydrazono - 3 - methyl - 2 - isoxazolin - 5 - one (la). a: Ar = C6H5, b: Ar = C6H4CH3-2>, Refluxing the deeply coloured 4-arylazoisoxazole- c: Ar = C6H4Cl-p. 5-thioacetate esters (5g-i) in benzene yielded the The 4-arylazo-3-methyl-2-isoxazolin-5-thiones products 6a-c. The 1,2,3-triazole structure assigned were prepared by refluxing 4-arylhydrazono-3- for compound 6 is inferred from the fact that they methyl-5-isoxazolinone (la-c)5-3 and phosphorus are colourless and their IR spectra exhibit two pentasulphide in toluene. The infrared spectra of carbonyl absorption bands at vc=o 1725 (-COOEt) the thione derivatives reveal the absence of characteristic N-H or S-H absorption, thus excluding Ar-fjl—y N^p-C0-S-CH2C00Et structures 1, 3 and 4 and favouring the azo structure (2) (X = S) by exhibiting absorption characteristic CH3 6 a-c

Requests for reprints should be sent to Dr. N. A. a: Ar = C6H5, KASSAB, Department of Chemistry, Faculty of b: Ar = C6H4CH3 ?3, Science, King Abdul Aziz Univ., Jeddah, Saudi Arabia. c: Ar = CeELjCl-p. 76 N. A. Kassab et al. • Arylazoisoxazolinthiones and at vc=o 1690 (-CO-S-) and the UV spectrum The simplicity, good yield, and straight forward for 6 a exhibits absorption at Amax 280 nm. These products isolation of the investigated reactions findings are in accord with structure 6, which would provide a method for preparation of compounds be expected to arise by a transformation analogous 8-10. to the known thermal isomerisation of 4-phenylazo- 3-methyl-5-phenylisoxazole to 5-benzoyl-4-methyl- Ar-N=N-C=C-S-R Ar-N=N—C—CONHNHPh H3C-C Ö RX R1NHNH2 H3C-C( 2-phenyl-1,2,3-triazole SN0H N Et OH Reflux Treatment of the thiones 2 a-c with phenyl - 5 a-i 9 a-c magnesium bromide effected 1,2-addition on the EtOH/Reflux thiocarbonyl group followed by hydrogen sulphide Ar-N=N-C = C-Pi h Ar-N-N-C—C-N-NHPh elimination to yield the corresponding coloured H3C-C 0 H3C-C V./ 4-arylazo-3-methyl-5-phenylisoxazoles (7a-c). The PhMgBr PhNHNH2 structure of 7 was established by spectral and analytical data, basides 7 a is identical with an 9 authentic sample . Ar- N=N-C—C-NR Ar-N-N-C—C-N-NH? I I I I Z H3C-C 0 The behaviour of the isoxazolinone ring towards H3C-C 0 \i/ RNH2 NH2NH2 N' the action of hydrazines has been intensively 8 d-f investigated, to afford either cyclic or acyclic products depending on the nucleophile or on the Experimental temperature conditions. Thus, penylhydrazine reacts with 4-arylhydrazono-3-methyl-2-isoxazolin-5-ones Melting points are uncorrected. IR spectra were obtained as a KBr disc with a Pye-Unicam SP 1100 (1) at room temperature to yield the arylhydrazones spectrophotometer. Ultraviolet and visible measure- of acetoacetic arylhydrazides10. On the other hand, ments were made with a Pye-Unicam SP 8000 hydrazine hydrate or Phenylhydrazine reacts with 1 spectrophotometer. in boiling alcohol to give the 4-arylhydrazones of 3-methyl-2-pyrazolin-5-onesu. Now, treatment of 4-Arylazo-3-methyl-2-isoxazolin-5-thiones (2 a-c) the thiones 2 a-c with molar ratio of phenyl- 2 a-c were prepared by refluxing each of la-c (10 g) and phosphorus pentasulphide (11 g) in hydrazine or hydrazine hydrate at room tempera- 100 c. c. of toluene for 1 h. The mixture was filtered ture affords the deeply coloured 4-arylazo-3-methyl- and cooled to give 2 a-c, in a yield that varies 2-isoxazolin-5-hydrazones (8a-f) or its tautomer. (50-70%). 2a-c were all crystallized as deep red The structure assigned for 8 was established based crystals from ethanol (Table I). The IR spectrum on analytical and IR spectra revealing C=N and of 2 Bi clS cl typical example for 2 a-c show absorption at vc=n 1620 cm-1, vn=n 1590 cm-1 and vc=s N-H absorptions. Boiling 8 a-c in alcohol effected 1325 cm-1. UV absorption spectrum in dioxan ring cleavage yielding 9 a-c. exhibits absorption at A max 410 nm (e 11.471). Compounds 9 a-c are obtained directly from 2 a-c by the action of Phenylhydrazine in boiling ethanol. 4-Arylazo-5-alJcylthio-3-methylisoxazoles (5 a-i) The IR spectra of 9a-c show absorption at VN-H General procedure: Each of 2a-c (1.0 g) was 1 -1 3320 cm- , Vc=o 1660 cm (amide I) and VN=N dissolved in 20 ml of ethanolic potassium hydroxide (10%) and the solution was refluxed for 20 min, 1600 cm-1. Further evidence for 9 a-c is their then to the solution was added either chloroacet- cyclisation to the corresponding 4-arylazo-3-methyl- amide, phenacylbromide or ethyl bromoacetate in l-phenyl-2-pyrazolin-5-ones12 by the action of acetic molar quantities. The reaction mixture was refluxed acid. for 20 min and left to cool. The separated crystals were filtered off, washed with water several times Refluxing 2 a-c with alcoholic solution of aniline and crystallized from ethanol. 5 a-i are all yellow or benzylamine causes hydrogen sulphide evolution coloured and listed in Table I. and the formation of the 4-arylazo-3-methyl-2- IR spectrum of 5 a as an example of the S-acet- isoxazolin-5-imines (lOa-f). The structure of 10 amide derivatives 5 a-c show absorption at VNH, was assigned on the basis of spectral and analytical 3360 and 3190 cm-1, vc=o 1670 cm-1 (amide I stretching), VC=N 1620 cm-1 and at VN=N 1590 cm-1. date baside refluxing 10 a with ethanolic hydro- IR spectrum of 5 d as an example of the S-phenacyl chloric acid afforded the corresponding 4-phenyl- derivatives 5 d-f show absorption at rc=o 1725 cm-1, hydrazono-3-methyl-5-isoxazolone (1 a). VC=N 1620 cm-1, VN=N 1600 cm-1. N. A. Kassab et al. • Arylazoisoxazolinthiones 77

Table I. Analytical data for 2 a-c and 5a-i.

Calcd Compound m.p. Yield Formula Analysis Found [°C] [%] (mol. wt.) C H N S 2a 125 70 C10H9N3OS 54.79 4.14 19.17 14.60 (219.2) 54.48 4.00 18.81 14.22 2b 145 65 C11H11N3OS 56.65 4.75 18.02 13.72 (232.22) 56.34 4.28 17.92 13.51

2c 175 75 CIOH8C1N3OS - - 16.55 12.61 (253.7) - - 16.38 12.45 5a 127 60 C12H12N4O2 S 52.17 4.38 20.28 11.58 (276.2) 52.00 4.26 20.12 11.39 5b 172 80 C13H14N4O2 s 53.79 4.86 19.30 11.02 (290.25) 53.42 4.51 19.18 10.89 5c 158 75 CI2HuC1N402S - - 18.02 10.30 (310.7) - 17.68 10.18 5d 138 63 C18H15N3O2S 64.09 4.48 12.46 9.48 (337.3) 63.87 4.29 12.27 9.31 oe 122 58 CI9H17N302S 64.95 4.88 11.96 9.11 (351.3) 64.87 4.69 11.85 9.01 of 133 70 Ci8H14C1N302S — - 11.29 8.60 (371.8) - - 11.10 8.52 5g 110 75 CI4H15N303S 55.08 4.95 13.77 10.40 (305.3) 54.87 4.63 13.48 10.36

5h 88 50 Ci5H17N303S 56.42 5.37 13.16 10.02 (319.3) 56.33 5.26 12.87 9.91 oi 85 60 CI4H14C1N303S - - 12.36 9.41 (339.8) - - 12.16 9.20

IR spectrum of 5 g as an example of the S-acetate benzene in 100 ml dry ether), a suspension of each esters (5g-i) show absorption at rc=o 1715 cm-1, of 2 a-c (2.0 g) in dry ether (100 ml) was added. The VC=N 1625 cm-1. reaction mixture was refluxed for 2 h, left to cool then decomposed with saturated ammonium chlo- 4- Thioxycarbonyl-2-aryl-5-methyl- 1,2,3-triazoles ride solution. The ethereal layer was separated, (6 a-c) dried (Na2S04) and allowed to evaporate slowly. They were obtained as colourless crystals by The oily residue was triturated with cold acetic acid refluxing compounds 5g-i in benzene for 3 h, then and the resulting solid was crystallized from acetic evaporated to dryness, the solid obtained was acid. crystallized from petrolium ether. 6 a-c are listed The 4-arylazo-5-phenyl-3-methylisoxazoles (7 a-c) in Table II. (Table II) are yellow to orange in colour. 7 a is The IR spectrum of 6 a eis ci typical example for identical m.p. and mixed m.p. with an authentic 6 a-c shows absorption at vc=o 1735 cm-1 (ester sample9. C=0), VC=O 1680 cm-1 (thiocarbonyl) and VC=N 1630 cm-1. The UV spectrum shows absorption at 4-Arylazo-3-methyl-2-isoxazolin-5-hydrazones (8 a-f) Amax 305 nm {e 17,000). General procedure: To each of 2a-c (1.0 g), Phenylhydrazine (1.0ml) or hydrazine hydrate Action of ethanolic hydrochloric acid on 5 a (1.0 ml) was added, and the mixture was left at A suspension of 5 a (1.0 g) in a mixture of ethyl room temperature till the odour of hydrogen- alcohol (10 ml) and hydrochloric acid (10 ml) was sulphide was no more detected. The reaction refluxed for 2 h and allowed to cool, then diluted mixture was treated with acetone and the solid with water and the solid product was crystallized formed was filtered off and crystallized from ace- from ethanol, m.p. 190 °C (yield 60%), proved to tone. be identical (m.p. and mixed m.p.) with 4-phenyl- 4-Arylazo-3-methylisoxazolin-5-phenylhydrazones hydrazono-3-methyl-2-isoxazolin-5-one5. (8 a-c) listed in Table II are orange-red crystals. The IR spectrum of 8 SI B/S Si typical example of the Action of phenylmagnesium bromide on 4-arylazo- phenylhydrazones (8 a-c) show absorption at VN=H -1 -1 1 3-methyl-2-isoxazolin-5-thiones (2 a-c) 3390 cm , VC=N 1620 cm and Vn=N 1580 cm- . General procedure: To a Grignard solution (pre- The UV spectrum for 8 a show absorption at Amax pared from 1.0 g magnesium and 9.0 g bromo- 280 and 440 nm. 78 N. A. Kassab et al. • Arylazoisoxazolinthiones

Table II. Analytical data for 6 a-c, 7 a-c, and 8a-f.

Calcd Compound m.p. Yield Formula Analysis Found [°C] [%] (mol. wt.) C H N S

6a 52 40 C14H15N3O3S 55.08 4.95 13.77 10.40 (305.3) 54.98 4.82 13.59 10.31

6b 92 35 CI5H17N303S 56.42 5.37 13.16 10.02 (319.3) 56.39 5.31 12.88 9.79 6c 82 50 C14H14CIN3O3S - - 12.36 9.41

(339.8) - - 12.11 9.26

7a 99 55 CI6H13N30 72.98 4.98 15.96 - (263.3) 72.78 4.68 15.86 - 7b 102 62 C17H15N3O 73.63 5.45 15.15 - (277.3) 73.50 5.38 14.95 - 7c 128 60 C16H12CIN3O - - 14.01 -

(297.8) - - 13.89 - 8a 204 80 C16H15N5O 65.51 5.15 23.88 - (293.3) 65.36 5.05 23.76 8b 200 75 C17H17N5O 66.43 5.58 22.79 (307.3) 66.40 5.46 22.68

8c 132 80 C16HI4C1N50 - - 21.35 (327.8) - - 21.16 8d 126 72 CioHuNsO 55.29 5.10 32.24 (217.2) 55.17 4.95 32.18

8e 122 60 CUHI3N50 57.13 5.67 30.29 (231.2) 57.03 5.57 30.12 81 269 55 C10H10CIN5O - - 27.81 (251.7) - 27.68

4- Arylazo-3-methylisoxazolin-5-hydrazones (8 d-f) Cyclisation of 9 a to 4-phenylazo-l-phenyl-3-methyl- listed in Table II are yellow-orange crystals. The 5-pyrazolone IR spectrum of 8d as a typical example of 8 d-f A suspension of 9 a (1.0 g) in 20 ml acetic acid was shows absorption at *>NH2 3430 cm-1 and 3300 cm-1, refluxed for 3 h, left to cool, the solid crystals were VC=N 1625 cm-1 and at VN=N 1585 cm-1. The UV filtered off and then recrystallized from acetic acid, spectrum of 8d exhibits absorption at A max 420 nm. m.p. 156 °C (yield 45%), proved to be identical (m.p. and mixed m.p.) with an authentic sample12. Action of Phenylhydrazine on 2 a-c in boiling ethanol to afford 9 a-c 4-Arylazo-3-methyl-2-isoxazolin-5-imines (lOa-f) To a solution of 2 a-c (1.0 g) in ethanol (100 ml) Each of 2 a-c (1.0 g), aniline (1.0ml) or benzyl- was added 1.0 ml Phenylhydrazine, the solution was amine (1.0 ml) and ethyl alcohol (20 ml) were refluxed for 2 h or till the odour of hydrogen sul- refluxed on a water bath for 2 h or till the odour of phide ceased. The reaction mixture was left to cool hydrogen suphide ceased. The reaction mixture was and the solid crystals so obtained were filtered off cooled, the separated crystals were filtered off and and crystallized from ethanol. crystallized from ethyl alcohol. The oximes of a-arylhydrazono-acetoacetic The 4-arylazo-3-methyl-2-isoxazolin-5-phenyl- phenylhydrazide (9 a-c) listed in Table III are all iminies (10 a-c) listed in Table III are yellow yellow coloured crystals. The IR spectrum of 9 a coloured crystals. show absorption at VN-H 3320 cm-1, vc=o 1660 cm-1, The 4-arylazo-3-methyl-2-isoxazolin-5-benzyl- imines (10 d-f) listed in Table III are pale yellow VC=N 1630 cm-1, and at Vn=N 1590 cm"1. The UV spectrum show absorption at A max 430 nm. coloured crystals. The IR spectra of the imines lOa-f exhibit strong absorption around 1640 cm-1 and 1590 cm-1 for C=N and N=N absorptions. Conversion of 8 a-c to 9 a-c Their UV absorption spectra revealed absorption A solution of each of 8 a-c (1.0 g) in 20 ml ethanol around A max 420 nm. was refluxed for 2 h, the reaction mixture was left to cool, whereby yellow crystals were separated Action of ethanolic hydrochloric acid on 10 a filtered off and crystallised from ethanol. The A suspension of 10 a (1.0 g) in a mixture of ethyl- product so obtained proved to be identical with alcohol (10 ml) and hydrochloric acid (10 ml) was 9a-c by m.p. and mixed m.p. refluxed for 2 h and allowed to cool, then diluted N. A. Kassab et cd. • Arylazoisoxazolinthiones 79 with water and the solid was filtered off and crystal- 55%), proved to be identical with an authentic lized from ethanol to give la, m.p. 190 °C (yield sample5.

Table III. Analytical data for 9 a-c and lOa-f.

Calcd Compound m.p. Yield Formula Analysis Found [%] [°C] (mol. wt.) C H N

9a 213 50 CI6H17N502 61.72 5.50 22.50 (311.3) 61.46 5.38 22.21 9b 208 55 C17H19N5O2 62.75 5.89 21.53 (325.4) 62.58 5.75 21.36

9c 150 52 CI6HI6C1N502 - - 20.24 (345.8) - - 20.20

10 a 181 70 Ci6H14N40 69.05 5.07 20.13 (278.3) 68.78 4.91 20.00

10 b 137 72 Ci7HI6N40 69.84 5.52 19.17 (292.3) 69.68 5.35 19.02

10c 132 75 Ci6HI3C1N40 - - 17.90

(312.8) - - 17.68 lOd 90 78 Ci7HI6N40 69.84 5.52 19.17 (292.3) 69.71 5.38 19.00 lOe 127 65 Ci8H18N40 70.56 5.92 18.29 (306.3) 70.42 5.77 18.11

10 f 112 75 CI7HI5C1N40 - - 17.13

(326.8) - - 16.92

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