April 20, 1957
BROMINATION OF ~ , ~ - N A P H T H O S U L T A M S
methanol and concentrated on a steam-bath under an air jet in an unsuccessful attempt to induce crystallization. Chromatographic separation of a sample of the oily residue on alumina permitted the isolation of 1.02 g. of crystalline material (m.p. 158-160’). Recrystallization from benzene and ethanol afforded a solid of m.p. 160-1G1.5°. The yield, extrapolated from a plot of the weight of the eluted material versus fraction number, was 90% of the theoretical amount, while the material balance for the chromatograph was 91.57’0. Anal. Calcd. for CaoHzoO: C, 90.88; H, 5.09. Found: C,91.21, 90.82; H, 5.28,4.78. The infrared spectrum of this substance, determined in Nujol mull, has bands assignable to para-substitution
[CONTRIBUTIONFROM
THE
1945
(848 cm.-l), a mono-substituted benzene ring (698 cm.-l) and a conjugated five-membered cyclic ketone (1717 cm.-l). I t is noteworthy that only one major peak was detected in a plot of the weight of the eluted material versus fraction number. Similarly the infrared spectrum of a sample of the oil which was subsequently chromatographed indicated the presence of only the conjugated carbonyl group (1726 cm.+, CS2).
Acknowledgment.-The authors are indebted to the Office of Ordnance Research, U. S . ilrmy (Contract No. DA-l1-022-ORD-874), for partial support of this investigation. URBASA, ILLINOIS
DEPARTMENT O F CHEMISTRY, FACULTY O F SCIENCE, CAIRO UNIVERSITY]
The Chemistry of Sultams. 11. Chloromethylation and Bromination of Substituted 1,8-Naphthosultam. Reaction of 1,8-Naphthosultam with Organic Halides BY AHMEDMUSTAFA AND MOHAMED IBRAHIM ALI RECEIVED OCTOBER 8. 1956 N-Arylsulfonyl derivatives of 1,8-naphthosultam (IIIa,b) undergo chloromethylation to yield the corresponding 4-chloromethyl derivatives (IVa,b), together with V in the case of IIIa. IVa is readily reduced to 4-methyl-N-phenylsulfonyl-l,8naphthosultam, and both IVa,b condense with fi-cresol and with 2,4-dimethylphenol to give the products VIIa-d (Table I), respectively. Whereas the bromination of N-methyl-1,8-naphthosultam leads to the formation of the monobromo derivative IXb and to the dibromo derivative (Xb), lT-acetyl-1,8-naphthosultamleads mainly to the formation of the monobromo derivative IXc. Similarly, the bromination of the N-aroyl- and N-arylsulfonyl derivatives yields monobromo derivatives, presumably the 4-bromo compounds. The 2,4-dibromo derivatives (Xc,d) now have been prepared by acetylation and by benzoylation of 2,4-dibromo-l,8-naphthosultam. A number of new N-substituted 1,8-naphthosultams (XIa-h, XIIa-f) (Tables I1 and 111)have been synthesized for pharmacological testing. Water-soluble salts of 1,8-naphthosultam with piperidine, benzylamine and cyclohexylamine now have been prepared.
(a) Chloromethy1ation.-Recently, it has been shown2 that 1,s-naphthosultone (I) condenses with paraformaldehyde and hydrogen chloride in the presence of anhydrous zinc chloride to form 4chloromethyl-1-naphthol-8-sulfonic acid sultone (11) (cf. A). 02s-0
tional crystallization of the crude reaction product failed to reveal the presence of any other isomer. I t seemed probable, by analogy with the behavior 02S-XSO2Ar I /
02s-0 I11
I
02S-NS02Ar I /
IV
I1
We now have investigated the behavior of the N-arylsulfonyl derivatives of 1,8-naphthosultam, the nitrogen analog of I, toward chloromethylating agent^.^ Thus, when an acetic acid solution of N-phenylsulfonyl-l,8-naphthosultam (IIIa) is treated with paraformaldehyde, hydrogen chloride and zinc chloride under the same experimental conditions for the chloromethylation of I, 4chloromethyl- N-phenylsulfonyl- 1,&naphthosultam (IVa), is obtained together with a high melting substance which analyzes correctly for a compound like V. Similarly, 4-chloromethyl-N-($-tolylsulfonyl)-l,8-naphthosultam(IVb) is obtained from N-(p-tolylsulfonyl) -1,S-naphthosultam (IIIb). Although substitution may occur in more than one way, only one product was isolated. Frac(1) Part I, A. Mustafa and M. I . Ali, THISJOURNAL, 11, 4593 (1955). (2) G.Schetty. Helo. Chim. A d a , 33, 24 (1949). (3) Cf. A. Mustafa, Chem. Reos., 54, 195 (1954). (4) R . Adams, “Organic Reactions,” Vol. I, John Wiley and Sons, Inc.. N e w York, N. Y.,1942, p. 85.
a, Ar = CsHs; b, Ar = CoHaCHs-p
of I and with a-naphthyl ether^,^.^ that the chloromethyl group in IV occupied the 4-position of the nucleus in preference to the %position.’ IVa,b are valuable intermediates for the production of 4-substituted derivatives of 1,&naphthosultam. Thus, when IVa is treated with zinc dust and acetic acid, it is reduced readily to 4-methyl-Nphenylsulfonyl-1,8-naphthosultam(VI). Condensation of IVa and IVb with $-cresol and with 2,4dimethylphenol leads to the formation of VIIa-d, respectively. (5) There have been several reports of the reactions of 1.8-naphthosoltam and its N-substituted derivatives, which show similarity to a naphthol and a-naphthyl ethers, e.g., the behavior of 1,s-naphthosultam toward chlorine (T.Zincke and G.Schiirmann, Ann., 413, 718 (1916)), in condensation with isatin. isatin chloride and isatinanilide (P. Friedlander and L. Sander, Ber., 17, 637 (1924), W. Kanig and E. Wagner, ibid., 61, 1056 (1924)),and in coupling with diazotized solutions (W. Konig and J , Keil, i b i d . , 65, 2149 (1922), W. Konig and K . Kohler, ibid., 56, 2139 (1922)).
AHMEDMUSTAFA AND MOHAMED IBRAHIM ALI
1946
Vol. 70
The behavior of VIIIb and VIIIc toward excess (b) Bromination.-Whereas the action of bromine on an acetic acid solution of 1,8-naphthosul- of bromine may simulate, in some respects, the betam (VIIIa) gives 2,4-dibromo-l,8-naphthosul- havior of N-alkylaniline and acetanilide toward the tam (Xa),6,7the action of the same reagent on a electrophilic attacking reagent, giving both ortho 02S-?iSO~CoI15 1
1
0~7--pS0~-4r
CH8 \'Ira, Ar = CS&; R = H b , A r = CeH5; R = CH3 c , Ar = C6HICH3-p; R = H d , A r = CeH4CH3-p;R = CHJ
02s-?--I:
02s-N-R
VI11 a,R=H b, R = CIIj C, R = COCE17 0LS-s -11
IS COCsHs e , R = S02CsH5 f , I< = s02C&cIIs-p tl,
R
c; R = COCHY d , R = COCSHL
chloroform solution of N-acetyl-l,8-naphthosulBr tam (VIIIc) leads to the formation of a monobromo derivative,s which is believed to be more likely N- and para substitution in the first case and almost exclusively para substitution in the case of acetanilacetyl-4-bromo-1,S-naphthosultam (IXc). We now have carried out the bromination of ide. This, perhaps, may be attributed to steric VIIIc after the procedure described by DannerthjB hindranceg; meanwhile other factors,'O e.g., the and obtained a product of a melting point ranging permanent inductive effect of substituentsll on the between 164-167'. When VIIIc is allowed to re- nitrogen atom are undoubtedly involved. conact with an excess of bromine (up to 2 moles) in (c) Reaction with Organic Halides.-In acetic acid a t room temperature, an 80% yield of a nection with a study of the pharmacological action product that melts a t 180°, presumably IXc, is ob- of sulfur-containing compounds against bilharziatained. Fractional crystallization of the crude sis,'* a number of K-substituted derivatives of product failed to reveal the presence of any other 1,S-naphthosultam now have been prepared. The isomer. It is not identical with N-acetyl-2,4- imino group in VIIIa has assumed an acid nature, dibromo-1,8-naphthosultam(Xc), obtained by the owing to the influence of the negative SOn group.3 action of acetic anhydride on Xa. &'hen IXc is Thus, when a suspension of the sodium salt of treated with hot aqueous sodium hydroxide, 4- VIIIa in ethyl alcohol is allowed to react with a-halo-esters (e.g., ethyl chloroformate, ethyl bromo-l&naphthosultam (IXa) is obtained. Similarly, the action of bromine on an acetic acid chloroacetate and ethyl bromomalonate) with 01or a chloroform solution of N-aroyl and N-arylsul- haloketones (e.g., chloroacetone, phenacyl bromide fonyl derivatives of 1,8-naphthosultam (VIIId-f) and p-bromophenacyl bromide), with alkyl halides leads to the formation of N-benzoyl-4-bromo- (e.g., allyl bromide) and with aralkyl halides (e.g., (IXd), 4-bromo-N-phenylsulfonyl- (IXe) and 4- p-nitrobenzyl chloride), the corresponding N-subbromo-N-p-tolylsulfonyl-l,8- naphthosultam (IXf), stituted, 1,s-naphthosultam derivatives (XIa-11) respectively. IXd and IXe also have been ob- are obtained, respectively. Similarly, the action tained when a pyridine solution of I X a is treated of methylene iodide and ethylene bromide yields with benzoyl chloride and with benzenesulfonyl X I I a and XIIb, re~pectively.'~ The reaction product with ethylene bromohydrin chloride, respectively. The dibromo derivative of VIIId now has been obtained by the action of and VIIIa was isolated as its benzoyl derivative X I (R = CH2CH20COC6H6). X I d forms an oxime benzoyl chloride on Xa. When an acetic acid solution of N-methyl-l,8- readily when treated with hydroxylamine hydronaphthosultam (VIIIb) is treated with bromine chloride in the presence of sodium acetate. Acid chlorides condense readily with 1,S-naph(one mole), a monobromo derivative presumably 4-bromo-N-methyl-1,s-naphthosultam (IXb), is ob- thosultam in presence of pyridine to give crystalline tained exclusively, whereas the treatment of compounds, believed to have a structure like, for (9) E. E. Royals, "Advanced Organic Chemistry," Prentice-Hall, VIIIb with an excess of bromine (two moles) leads Inc., New York. PIT.Y . , 1454, p 430. to the formation of 2,4-dibromo-N-methy1-1,8(lo) See R. J. W.Le F e m e , J . Chem. Sor., 977, 980 (1933); 1501 naphthosultam (Xb) in an almost quantitative (1934); S. N. Ganguly and I
