Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

Abstract

Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized.

Oxidative Cyclization of 4-(2-Aminophenyl)-4-oxo-2-phenylbutanenitriles into 2-(3-Oxoindolin-2-ylidene)acetonitriles

“…This procedure is a modified one-pot version of the method reported in the literature. 15 4-(2-Aminophenyl)-2-phenyl-4-oxobutyronitrile 18 ( 6aa ) (250 mg, 1.00 mmol), DMSO (0.8 mL), and KOH (224 mg) were mixed in a 25 mL round-bottom flask and stirred at room temperature for 30–40 min. Then, acetic acid (8.5 mL) and hydrazine hydrate (98%, 4 mL) were added and the reaction mixture was heated under reflux for 4 h. After this period, the solution was allowed to cool down and then poured down into 100 mL of crushed ice.…”

“…Additional purification can be achieved by recrystallization from EtOH of i -PrOH. The title compound was obtained as a white solid, mp 306.5–308.9 °C ( i -PrOH), lit 15 mp 308–310 °C, R f 0.34 (acetone). Yield 148 mg (0.57 mmol, 57%).…”

“…1 H NMR spectra was identical to that reported in the literature. 15 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.00 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.65–7.56 (m, 4H), 7.55–7.48 (m, 1H), 7.43 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.23 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H), 5.72 (s, 2H); 13 C{ 1 H} NMR (101 MHz, DMSO- d 6 ) δ 155.6, 142.7, 141.8, 134.3, 131.9, 129.6 (2C), 129.4 (2C), 128.5, 127.7, 120.8, 120.5, 119.5, 111.7, 103.8; FTIR (film, NaCl, cm –1 ): 3483, 3277, 3118, 1624, 1540, 1459, 1441, 1383, 1356, 1230, 1244, 1160, 1145; HRMS (ESI TOF) m / z : (M + H) + calc’d for C 16 H 13 N 4 261.1135; found 261.1131 (1.4 ppm).…”

“… 2 − 7 2-Alkylideneindolin-3-one derivatives bearing a single indoline moiety or two remotely positioned indoline subunits are found in nature and are endowed with important biological activities as well. 8 − 15 2-Alkylideneindolin-3-ones bearing a conjugated nitrile function (i.e., 2-(3-oxoindolin-2-ylidene)acetonitriles 1 ) were used as advanced precursors in the synthesis of pyridazino[4,3- b ]indoles 2 , which possess strong inhibitory activity against Mycobacterium tuberculosis ( Scheme 1 ). 16 Recently, we have communicated on the unexpected formation of 2-alkylideneindolin-3-ones taking place upon treatment of ortho -nitrochalcones with potassium cyanide and acetic acid in methanol.…”

The Reaction of 6-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one with Benzene-1,2-diamine: Synthesis and Chemistry of N-(2-Aminophenyl)-2-hydroxy-5-methylbenzimidoyl Cyanide

“…Recently, we expanded this family of dithiazolylidenes to analogues of electron-rich pyridols, 16 and, in 2018, Thiéry et al reported the reaction of Appel salt 1 with indolin-2ones. 31 The absence of additional chemistry of dithiazolylidene 8 is surprising. Compound 8 has a deep-purple color, owing partly to its ortho-quinone methide structure, and to a strong contribution of a charge-separated resonance form.…”