Cinnoline chemistry. XII. The synthesis of 6‐fluoro‐4‐methylcinnoline and other cinnolines as potential antitumor agents

Abstract

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...

Synthesis of hydroxylated tryptanthrins as possible metabolites and characterization

“…Electrospray ionization (ESI) mass spectrometry (MS) experiments were performed on an LCQ advantage-trap mass spectrometer (Thermo Finnigan, San Jose, CA, USA). The prerequisite isatoic anhydrides (3) were prepared as previously reported in the literature by either oxidation of isatin with CrO 3 [25] or reaction of suitably substituted anthranilic acid with triphosgene [26]. 4-Methoxyisatin (4b) and 6-methoxyisatin (4d) were prepared by Friedel-Crafts acylation of 2-(hydroxyimino)-N-(3-methoxyphenyl)acetamide [27].…”

Design, synthesis and biological activity evaluation of regioisomeric spiro-(indoline-isoxazolidines) in the inhibition of TNF-α-induced ICAM-1 expression on human endothelial cells

“…mp 160 C). 16 Preparation of 5-fluouroisatin (3a). Obtained as a golden yellow solid in 72% yield, mp 223-225 C (lit.…”

“…mp 225 C). 16 Preparation of ethyl(5-fluoro-2-oxo-1,2-dihydro-3(H)-indol-3ylidene)-acetate (5a)/ethyl(2-oxo-1,2-dihydro-3(H)-indol-3-ylidene)-acetate (5b). A mixture of compound 3a/3b (0.05 mol) and ethoxycarbonylmethylene-triphenyl-phosphorane (0.05 mol) was dissolved in glacial acetic acid (60 mL) and heated for 4 h at 80 C. 18 Acetic acid was removed under vacuum and the residue was washed onto a filter funnel with a small quantity of methanol.…”

“…We first started with the synthesis of 4-fluoroisonitrosoacetanilide (2), which was prepared in 90% yield by refluxing equimolar amounts of 4-fluoroaniline (1), chloral hydrate and hydroxylamine hydrochloride in water along with few drops of concentrated hydrochloric acid for 2 h; compound 2 was then cyclized by dissolving it in concentrated H 2 SO 4 and heating the reaction mixture for 12 h at 80 C to get 5-fluoroindoline-2,3-dione (3a) in 72% yield (Scheme 1). 16 Compounds 5a and 5b were synthesized in 72% and 69% yields, respectively, by the condensation of the commercially available ethoxycarbonylmethylenetriphenylphosphorane (4) with 5-fluoroindoline-2,3-dione (3a) and the commercially available indoline-2,3-dione (3b), respectively, in glacial acetic acid at 80 C (Scheme 2). 17,18 Two series of spiro-(indoline-isoxazolidines), viz.…”

A green synthesis of isatoic anhydrides from isatins with urea–hydrogen peroxide complex and ultrasound

“…HPLC-MS analyses were performed on an Agilent 1100 apparatus. A Luna C18 [29], 250-252°C [36], 240°C (dec) [37]; 2b: 265-268°C [29], 270°C (dec) [38]; 2c: 278-281°C [39], 265-268°C [40]; 2d: 270-275°C [29], 270-275°C [40]; 2e: 233°C (dec) [41], 245°C (dec) [42]; 2f: 224-232°C [29], 244-245°C [43].…”