6-Fluoro-4-methylcinno1ine (IX) has been synthesized in eight steps from 4-flU01-0aniline. A s e r i e s of styryl and pyridylethenyl cinnolines have been prepared from 6fluoro-4-methylcinnoline (IX) , 4-methylcinnoline and 4-methylcinnoline-%oxide. Furtherm o r e , a series of 4-substituted benzylthiocinnolines have been prepared.The antitumor activity of 4-benzylthio-, 4-(2,4-dichlorobenzy1thio)-and 4,6-bis(2,4-dichlorobenzylthio)cinnoline (4) provided the stimulus for the synthesis of the substituted cinnolines reported in this paper.6 -Fluoro -4methylcinnoline w a s needed as an intermediate f o r these syntheses. To prepare it, 4-fluoroaniline (I) was allowed to r e a c t with chloral hydrate and hydroxylamine using the general procedure of Marvel and H i e r s (5) a s a model. The product, 4-fluoroisonitrosoacetanilide (11) was obtained in 92% yield. Compound I1 was converted into 5-fluoroisatin (111) in 72% yield when i t was heated with sulfuric acid. 5-Fluoroisatin (n1) was readily converted into the corresponding fluoroisatoic anhydride (IV) in 73% yield by allowing it to react with chromium trioxide in acetic acid-acetic anhydride solution. The fluoroisatoic anhydride (W) was hydrolyzed in hydrochloric acid solution into 2-amino-5-fluorobenzoic acid (V) in 81% yield. The acid (V) was readily esterified with methanol in the presence of d r y hydrogen chloride to give a 92% yield of methyl 2-amino-5-fluorobenzoate (VI) . The e s t e r (VI) was allowed to r e a c t with two moles of methyl magnesium iodide followed by hydrolysis and the expected 2 -(2 -amino-5-fluorophenyl) -2-propanol (VII) was obtained in 95% yield. Compound VII was dehydrated with phosphorus pentoxide in benzene solution to produce 2 -(2-amino -5 -fluoropheny1)propene (VIIn in about 50% yield. The substituted propene (VIII) was allowed to r e a c t with sodium nitrite in acid solution, whereupon the 6-fluoro-4methylcinnoline (ur) was obtained in 93% yield.The condensation of 6fluoro -4 -methyIcinnoIine (M) o r 4-methylcinnoline (6) with a series of aldehydes gave a s e r i e s of styryl-, pyridylethenyl-and furylethenylcinnolines (X-XXIV) ( Table I).4-Methylcinnoline -2 -oxide ( X X V ) (7a-b) gave 4-(4-dimethylaminostyryl)cinnoline-2-oxide (XXVI) and 4 -( 4 -nitrostyryl)c innoline-2 -oxide (XXVII) when allowed to r e a c t with 4 -dimethylaminobenzaldehyde and 4-nitrobenzaldehyde, respectively, in the p r esence of potassium ethoxide. However, when benzaldehyde was allowed to react with 4-methylcinnoline-2-oxide in the presence of potassium ethoxide and a n excess of benzaldehyde used as a solvent, the Noxide function was lost and 4-styrylcinnoline (XXVIII) was the product. This was established by a mixed melting point determination with a n authentic specimen (6). 4-Styrylcinnoline (XXVIII) was allowed to r e a c t with perphthalic acid and the product was assigned the structure 4styrylcinnoline -2oxide (XXM) on the basis of the similarity of the infrared spectra of XXM compared with those of XXVI and XXVII.In o r d e r to prepare ad...

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A series of 4‐mercaptocinnolines (4) monosubstituted with halogen in the benzenoid ring was obtained when the corresponding 4‐hydroxycinnolines were treated with phosphorus pentasulfide in either pyridine or toluene. On prolonged heating in either or the two solvents, the halogen atom in 6‐chloro‐ and 6‐bromo‐4‐hydroxycinnoline was simultaneously substituted with a mercapto group, thus yielding 4,6‐dimercaptocinnoline. Nucleophilic substitution of the halogen atom was also observed in the reaction of 6‐fluoro‐ and 7‐fluoro‐4‐hydroxycinnoline, while 8‐halo‐4‐hydroxycinnoline gave exclusively 8‐halo‐4‐mercapto‐cinnoline. From the reaction of 5‐halo‐4‐hydroxycinnoline the only identified products were 5‐halo‐4‐mercaptocinnolines. Previously unknown 4‐hydroxycinnolines were synthesized. 4‐Alkylmercaptocinnolines and 4,6‐dialkylmercaptocinnolines of pharmacological interest were prepared from the parent mercaptocinnoline or from the corresponding chlorocinnoline.

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