R'cx'"Me. Preparation of an aromatic hydroxylamine and some cyclic hydroxamic acids, and their reaction with hydrochloric acid

Transcription

1 Preparation of an aromatic hydroxylamine and some cyclic hydroxamic acids, and their reaction with hydrochloric acid R. T. COUTTS AND N. J. POUND Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta Received November 18, 1969 The reduction of 2,3-dimethyl-4-(o-nitrophenylthio)-l-pheny-3-pyrazoin-5-one by sodium borohydride and palladium-charcoal gave the corresponding hydroxylamine. The action of hydrochloric acid on this hydroxylamine gave the p-chloroamine. In a similar manner, treatment of some 2H-1,4-benzothiazine and -benzoxazine hydroxamic acids with hydrochloric acid resulted in the formation of 7-chloro-2H-l,4-benzothiazine and -benzoxazine lactams. Canadian Journal of Chemistry, 48,1859 (1970) Reduction of aromatic nitro-compounds by sodium borohydride catalyzed by palladiumcharcoal gives the corresponding amines rapidly, and in good yields (1). No intermediate compounds are isolated (1) although evidence is available that the reduction proceeds via the hydroxylamine; reduction of various (o-nitropheny1thio)acetates and related compounds by means of sodium borohydride and palladiumcharcoal gives derivatives of the N-hydroxy compound, 3,4-dihydro-4-hydroxy-2H-1,4-ben- zothiazine (2-4). R'cx'"Me NHR 0 yn\me Ph 2 R R' a H H b Ac H c H C1 d Ac C1 e OH H In the present study an aromatic nitrocompound, with a bulky substituent in the orthoposition, was reduced with catalyzed sodium borohydride and an aromatic hydroxylamine has been isolated. Reduction of 2,3-dimethyl-4- (0-nitrophenylthio) - I -phenyl-3-pyrazolin-5-one (1) gave two products of which the amine (2a) was the minor one. In contrast, the same amine was the only product obtained when 1 was re- duced using iron and ferrous ammonium sulfate. The major product of the catalyzed sodium borohydride reduction of 1 was a chlorine-contain- ing compound, C,,H,,ClN,OS. The introduction of the chlorine atom occurred during the work-up procedure in which hydrochloric acid was added to decompose the unreacted sodium borohydride. A structure (2c) has been assigned to this product. Its formation suggested that the reduction of 1 had proceeded only as far as the hydroxylamine, 2e, which was subsequently attacked by the chloride ion to yield 2c as illustrated in Scheme 1. The location of the chlorine atom in 2c was inferred (a) from the ample literature evidence that when hydrochloric acid and other nucleophilic reagents react with aromatic hydroxylamines, p-substituted amines are the major products (5-7); (b) from the nuclear magnetic resonance (n.m.r.) spectrum of the aromatic protons in the chlorinated ring (Fig. l), (c) from the observation that only p-substitution was observed in related reactions described below; and (d) from the report (8) that 6-chloro-lhydroxy-4-quinolones are formed when o-nitrobenzaldehyde reacts with ethyl acetoacetate and

2 CANADIAN JOURNAL OF CHEMISTRY. VOL. 48, 1970 FIG. 1. The n.m.r. spectrum (aromatic ring protons) of 4-(2-amino-5-chlorophenylthio)-2,3-dimethyl-l-phenyl-3- pyrazolin-5-one (2c). related compounds in the presence of hydro- pound (3) was the product of the oxidation of the chloric acid. hydroxylamine (2e) by hydrogen peroxide. It was apparent that if hydrochloric acid was excluded from the reaction, reduction of 1 should yield 2e. Reduction of 1, therefore, was repeated except that acetic acid was used in the work-up &x=n-$j procedure, and 4-(0-hydroxylaminopheny1thio)- 3 2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (2e) was obtained. This structure was assigned for the following reasons. The compound analyzed R = satisfactorily for C17H17N,02S; its mass spec- o ~:"\.e trum showed weak M' and TM-21' ions and an P h [M- 161 ' ion of appreciable gbunhance, charac- In view of the findings just described, the teristic of an aromatic hydroxylamine (9); NH reduction of (0-nitropheny1thio)acetic acid (4) by and OH stretching bands were observed in the means of sodium borohydride and palladiuminfrared (i.r.) spectrum, and the product readily charcoal was reinvestigated. Previously (3) we had reduced Tollen's reagent. concluded that an unexpected product of this Another reduction of the pyrazolone (1) by reduction was the sulfone, 3,4-dihydro-3-0x0-2Hmeans of sodium borohydride and palladium- 1,4-benzothiazine-1, I-dioxide (5). Its melting charcoal was performed in which the filtrate from point, i.r. spectrum, and analytical data were all the reaction was not acidified. The major product isolated then was the azoxy compound,-namely uno2 2,2'-bis [4-(2,3-dimethyl-1-phenyl-3-pyrazolin-5- SCHzCOOH onyl)thio]azoxybenzene (3), the structure of which was confirmed by means of elemental H analysis and i.r. and mass spectra. The same corn

3 COUTTS AND POUND: AROMATIC HYDROXYLAMINE AND HYDROXAMIC ACIDS consistent with such a conclusion. However, the possibility of the product being a chloro-compound was not considered at that time. A mass spectrum of this product has now been recorded and this has revealed that the compound was not 5; it had a molecular formula C,H,ClNO,S. Its n.m.r. spectrum showed a complex signal for the aromatic protons, the pattern of which (Fig. 2) was consistent with a 1,2,4-trisubstituted benzene derivative. The product, therefore, was suspected to be 7-chloro-3,4-dihydro-3-oxo-2H- 1,4-benzothiazine (6). The possibility that the product was the isomer (7) was very unlikely but as the m.p. of the product isolated by us and that of 7 were identical, it was necessary to prepare a sample of 6-chloro-3,4-dihydro-3-oxo-2H-1,4- benzothiazine (7) for direct comparison with our product. Reduction of (4-chloro-2-nitrophenylthio)acetic acid with sodium hydrosulfite, using the reported (10) method, gave the required lactam (7) which was shown by a comparison of i.r. and n.m.r. spectra (Figs. 2 and 3) and a mixed melting point to differ from 6. The formation of 6 can be explained in a FIG. 3. The n.m.r. spectrum (aromatic ring protons) of 6-chloro-3,4dihydro-3-oxo-2H-1,4benzothiazine (7). manner similar to that described for 2c. It apparently involves the nucleophilic attack of a chloride ion on the protonated hydroxamic acid as illustrated in Scheme 2. The authenticity of this mechanism was substantiated when it was found that the lactam (6) was the product isolated in 81 % yield when 3,4-dihydro-4-hydroxy-3-0x0-2H-1,4-benzothiazine (8) was treated with hydrogen chloride. FIG. 2. The n.m.r. spectrum (aromatic ring protons) of 7chloro-3,4dihydro-3-oxo-2H-1,4-benzothiazine (6).

4 1862 CANADIAN JOURNAL OF CHEMISTRY. VOL. 48, 1970 This novel reaction offers a means of preparing 7-chlorobenzothiazines which are not readily available by conventional reductive methods of synthesis. Such methods would require (2-nitro- 5-ch1orophenylthio)acetic acid as a starting material for the preparation of 6, but this acid is not available by the action of thioglycolic acid on 2,4-dichloronitrobenzene, because of the reactivity of both chlorine atoms. In the same way, the action of hydrogen chloride on 6-chloro-3,4-dihydro-4-hydroxy-3-0x0-2H- l,4-benzothiazine (9) gave an excellent yield of 6,7-dichloro-3,4-dihydro-3-oxo-2H-1,4- benzothiazine (10). The structure of 10 was readily deduced from its n.m.r. spectrum which indicated the absence of ortho- and metacoupling in the aromatic signal (1-proton singlets at z 2.80 and 2.32) and which verified that the attack of the chloride ion was at the ring position para to the nitrogen function. This new synthetic method is not restricted to the preparation of benzothiazines. Related benzoxazines can also be obtained in the same way. Thus, reduction of methyl o-nitrophenoxyacetate gave the zinc complex of 3,4-dihydro-4-hydroxy- 3-0x0-2H-1,4-benzox~zine(11). Treatment of this complex with hydrochloric acid gave the expected hydroxamic acid (12) (Scheme 3) but, in addition, a neutral compound was isolated. Its mass and i.r. spectra and elemental analysis were consistent with this compound being 7-chloro-3,4- dihydro-3-oxo-2h-l,4-benzoxazine (13). The same product (13) is formed in 79 % yield by the action of hydrochloric acid on the hydroxamic acid (12). Similarly, a solution of 2-ethyl-3,4- dihydro-4-hydroxy-3-0x0-2h- 1,4- benzoxazine (14) in sodium carbonate solution, on acidifying with hydrochloric acid, gave a chloro-compound, presumably 7-chloro-2-ethyl-3,4-dihydro-3-oxo- 2H-1,4-benzoxazine (15). Experimental Melting points are uncorrected. The i.r. spectra were recorded as Nujol mulls. Mass spectra were measured with an A.E.I. MS-9 spectrometer, and n.m.r. spectra were recorded on a Varian A-60 spectrometer using DMSO-d6 as solvent. Chemical shifts are expressed in 7 units with TMS as standard. Reduction of 2,3-Dimethyl-4-(0-nitropheny1thio)-Iphenyl-3-pyrazolin-5-one (I) (i) A solution of sodium borohydride (1.02 g) in water (15 ml) was added in three equal portions at 5 min intervals to a suspension of the title compound (11) (2.01 g) and 10% palladium-on-charcoal (0.11 g) in dioxane (100 mi) through which nitrogen gas was bubbled. After 15 min, the suspension was filtered and the colorless filtrate was acidified with dilute hydrochloric acid, then reduced in volume to near dryness. Chloroform (50 ml) was added and the resulting pale brown solution was extracted repeatedly with dilute hydrochloric acid. The combined acid extract (250 ml) was made alkaline with 50% sodium hydroxide solution over ice then extracted with chloroform. Evaporation of the dried chloroform solution gave a pale brown solid (1.41 g) which, when crystallized from benzene then ethanol, gave 4-(2-amino-5-chlorophenylthio) -2,3-dimethyl-I-phenyl-3- p vrazolin-5-one (2c) as a colorless solid, m.p O. The i.r. spectrum: 3400, 3320 (NHZ); 1642 (-0); 812 (CH) cm-'. The n.m.r. spectrum: 7.58 and 6.80 (3-proton singlets) (CH3); 4.26 (2-proton broad singlet) (NH,); (8-proton aromatic signal) (Fig. 1). Mass spectrum: 345 (M+, 62 %) 347 (25 %). Anal. Calcd. for Cl,H16CIN30S: C, 59.04; H, 4.66; N, Found: C, 59.41; H, 5.12; N, Treatment of 2c (0.17 g) with acetic anhydride in the usual manner gave the acetate(2d) (0.14 g) which crystallized from benzene as a colorless solid, m.p '. The i.r. spectrum: 3320 (NH); 1700 and 1641 (C=O); 812 (CH) cm-'. Anal. Calcd. for Cl9HI8CIN3OZS: C, 58.83; H, 4.68; CI, 9.14; N, Found: C, 59.08; H, 5.09; Cl, 8.90; N, (ii) Reduction (i) was repeated on the title compound

5 COUTTS AND POUND: AROMATIC HYDR LOXYLAMINE AND HYDROXAMIC ACIDS 1863 (2.24 g) except that the filtrate was acidified with acetic acid. Evaporation of the acidified filtrate gave a brown oil which, when triturated with ethanol then washed with water, left a yellow solid (1.5 g). Crystallization from ethanol gave 4-(0-hydroxylaminophenylthio)-2,3-dimethyl- I-phenyl-3-pyrazolin-5-one (2e) as a bright yellow solid, m.p " (dec.) which reduced Tollen's reagent. The i.r. spectrum: 3245 (broad, NH and OH); 1619 (C=O) cm-'. Mass spectrum: 327 (M+, 1 %), 325 (573, 311 (25 %). Anal. Calcd. for C17H17N302S: C, 62.36; H, 5.23; N, Found: C, 62.28; H, 5.34; N, (iii) Reduction (i) was repeated on the title compound (1.01 g). The filtrate was not acidified. It was evaporated to dryness and the resulting semi-solid extracted with hot ethanol (3 x 10 ml). On concentration of the ethanol solution, 2,2'-bis[4-(2,3-dimethyl-1-phenyl-3-pyrazolin-5- onyl) thio]azoxybenzene (3) (0.48 g) separated as an orange solid and had m.p " (dec.) when crystallized from dimethylsulfoxide-ethanol. The i.r. spectrum: 1668 (C=O) cm-l. Mass spectrum: 634 (M+, 0.3%), 618 (2 %). Anal. Calcd. for C34H30N603S2: C, 64.33; H, 4.76; N, Found: C, 63.63; H, 4.39; N, (iv) Powdered iron (2.07 g) and ferrous ammonium sulfate (0.57 g) were suspended in a solution of the title compound (1.01 g) in ethanol (80 ml) and the mixture was heated under reflux for 90 min. The hot solution was filtered with the aid of Celite. Evaporation of the colorless filtrate gave an off-white solid (0.82 g). Crystallization from ethanol gave 4-(0-aminopheny1thio)-2,3-dimethyl-1- phenyl-3-pyrazolin-5-one (24) as a colorless solid, m.p ", which on diazotization and coupling with rj-naphthol gave a red dye. The i.r. spectrum: 3400,3318 (NH,); 1642 (C=O) cm-'. Mass spectrum: 311 (M+, 63 %). Gal. Calcd. for C17H17N30S: C, 65.57; H, 5.50; N, Found: C, 65.55; H, 5.84; N, Treatment of 24 (1.05 g) with acetic anhydride in the usual way gave the acetate (2b) (0.89 g), m.p ' (from ethanol). The i.r. spectrum: 3250 (NH); 1700 and 1650 (C=O) cm-'. Anal. Calcd. for Cl9Hl9N3O2S: C, 64.52; H, 5.42; N, Found: C, 64.49; H, 5.81; N, Oxidation of Hydroxylamine (2e) 4-(0-Hydroxylaminophenylthio) -2,3 -dimethyl-1- phenyl-3-pyrazolin-5-one (0.48 g) was suspended in dioxane (30mI) and 30% hydrogen peroxide solution (5 ml) was added gradually with stirring. Reaction was continued for 18 h during which time the starting material dissolved and a yellow precipitate (0.17 g) formed. Recrystallization from DMSO-ethanol gave the azoxy compound (3), m.p " (dec.), the i.r. spectrum of which was superimposable on that of the product obtained in the reduction of 1 (method (iii)). 6,7-Dichloro-3,4-dihydro-3-oxo-2H-l,4-benz0thiazine (10) Hydrogen chloride was bubbled through a methanolic solution (10 ml) of 6-chloro-3,4-dihydro-4-hydroxy-3-0x0-2H-1,4-benzothiazine [prepared by the literature (3) method] (0.22 g) for 2 min at 5". The solution was set aside at room temperature for 3 h then evaporated to dryness. The resulting grey solid (0.23 g) was crystallized from ethanol to yield the title compound, m.p '. The i.r. spectrum: 3170 (NH), 1678 (C=O) cm-'. The n.m.r. spectrum: 6.47 (2-proton singlet) (CH,); 2.80 (1-proton singlet) (C5-H); 2.32 (I-proton singlet) (C8-H); (I-proton broad singlet) (NH). Anal. Calcd. for C8H5C12NOS: C, 41.04; H, 2.15; N, Found: C, 40.94; H, 2.42; N, Reduction of (0-Nitropheny1thio)acetic Acid (4) The title compound was reduced with sodium borohydride and palladium~harcoal in dioxane as described previously (3). The product, m.p " was 7-chloro- 3,4-dihydr0-3-0~0-2H-l,4-benzothiazine (7), lit. (12) m.p. 206". The i.r. spectrum: 3180 (NH), 1688 (C=O) cm-'. Mass spectrum: 199 (M+, loo%), 201 (35%). The n.m.r. spectrum : 6.50 (2-proton singlet) (CH,) ; (3-proton aromatic signal) (Fig. 2); (1-proton broad singlet) (NH). Anal. Calcd. for C8H6CINOS: C, 48.13; H, 3.03; N, 7.02; S, Found: C, 48.55; H, 3.03; N, 6.92; S, Chloro-3,4-dihydro-3-oxo-2H-I,4-benzothiazine (7) This compound was prepared by the reported method (10). The i.r. spectrum: 3185 (NH), 1670 (C=O) cm-'. The n.m.r. spectrum: 6.50 (2-proton singlet) (CH,); (3-proton aromatic signal) (Fig. 3); (I-proton broad singlet) (NH). Action of Hydrochloric Acid on the Zinc Complex of 3,4-Dihydro-4-hydroxy-3-0x0-2H-I,4-benzoxazine (11) The crude zinc complex was prepared from ethyl o-nitrophenoxyacetate by a previously reported method (14). The sample was purified by dissolving it in dimethylsulfoxide, filtering off the insoluble zinc, then reprecipitating the complex by pouring the filtrate into ethanol. Crystallization from ethanol gave a flocculent white precipitate, m.p. 1360'. The i.r. spectrum: 1631 cm-' (chelated -0). Anal. Calcd. for C16HlZN~06Zn: C, 48.82; H, 3.07; N, Found: C, 48.99; H, 2.81; N, A suspension of the zinc complex (0.15 g) in dilute hydrochloric acid (5 ml) was stirred for 2 h and the resulting light brown suspension was extracted with chloroform. Evaporation of the chloroform gave a brown solid (71 mg) which was redissolved in chloroform. This solution was extracted with 10% aqueous sodium carbonate, dried and evaporated to yield 7-chloro-3,4- dihydro-3-oxo-2h-1,4-benzoxazine (13) (40 mg), as a white solid, m.p " when crystallized from methanol. Infrared spectrum: 3175 (NH), 1684 (GO), 800 (CH) cm-'. Mass spectrum: 183 (M+, loo%), 185 (35%). The n.m.r. spectrum: 5.42 (2-proton singlet) (CH,); very broad signal centered at 4.25 (NH); (3-proton aromatic signal). Anal. Calcd. for C8H6ClNo2: C, 52.34; N, 3.29; N, Found: C, 52.67; H, 3.52; N, The aqueous sodium carbonate solution described above was acidified with glacial acetic acid and extracted with chloroform. Evaporation of the chloroform extract gave 3,4-dihydro-4-hydroxy-3-oxo-2H-1,4-benzoxazine (12) (15 mg) as a white solid, m.p ' [lit. (13)

6 ~ 1864 CANADIAN JOURNAL OF CHEMISTRY. VOL. 48, 1970 m.p "J. Its infrared spectrum was superimposable The authors acknowledge meaningful discussions with on that of an authentic sample. Dr. R. A. Abramovitch, and thank Mrs. S. Li, Mr. The benzoxazine (13, 0.61 g) was also obtained by E. Mah, and Mr. W. F. Dylke for technical assistance. heating under reflux a suspension of 3,4-dihydro-4- hydroxy-3-oxo-2h-l,4-benzoxazine (12) (0.7 g) in dilute 1. T. N ~ H. C. ~ S. wood, ~ and ~ A. G. ~ WYLIE. ~ hydrochloric acid (15 ml) for 2.5 h. The cooled mixture J. Chem. Soc. 371 (1962). was extracted with chloroform: the latter was washed 2. R. T. COUTTS. H. W. PEEL. and E. M. SMITH.. Can. with sodium carbonate solution, then water, and evap- J. Chem. 43, '3221 (1965). ' orated to give 13, m.p ". 3. R. T. COUTTS, D. L. BARTON, and E. M. SMITH. Can. J. Chem. 44, 1733 (1966). Action of Hydrochloric Acid on 2-Ethyl-3,4-dihydro-4-4. R. T. Couns and E. M. SMITH. Can. J. Chem. 45, I~droxy-3-oxo-2H-l,4-benzoxazine (14) 975 (1967). A solution of the title compound (10 mg) in aqueous 5. E. BAMBERGER. Ann. 424, 233 and 297 (1921). sodium carbonate (20 ml) was acidified with concentrated 6. E. BAMBERGER. Ann. 441, 297 (1925). 7. G. R. ROBERTSON and R. A. EVANS. J. Org. Chem. hydrochloric acid and allowed to stand for 15 h. The (1940) \--.-,- crystalline product (5 mg), m.p ", was 7-chloro- 8. J. D. LOUDON and I. WELLING~. J. Chem. Soc. 2-ethyl-3,4-dihydro-3-oxo-2H-I,4-benzoxazine (15). The 3470 (1960). i.r. spectrum: 3190 (NH), 1696 (C=O), 798 (CH) cm-l. 9. R. T. Couns and GITA MUKHERJEE. Org. - Mass Mass spectrum: 21 1 (M+, 67 %), 213 (20%). Spectrom. 3, 63 (1970). Anal. Calcd. for C,oHloCIN02: N, Found: 10. R. N. PRASAD and K. TIETJE. Can. J. Chem. 44. N, ~ ~, 11. R. T. Cou-rrs and S. J. STOREY. Can. J. Pharm. The award of a Medical Research Council of Canada Studentship (to N.J.P.) and other M.R.C. financial assistance (grant No. MA 2993) is greatly appreciated. lk. W. Hindmarsh carried out this reaction. Sci. 2, 22 (1967). 12. G. VASILIU, 0. MAIOR, and N. ARSENESCU. An. Univ. Bucuresti, Ser. Stiint. Nat. 12, 47 (1963); Chem. Abstr. 64, (1966). 13. E. HONKANEN and A. I. VIRTANEN. Acta Chem.