Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds

Abstract

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4'-pyrano[2,3-c]pyrazol], spiro[indoline-3,5'-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3'-indoline] and spiro[benzo[g]chromene-4,3'-indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.

Scheme 1. Synthesis of spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one derivatives catalyzed by indium trichloride.

Scheme 2. The one-pot, multi-component synthesis of bis-spirooxindoles in PEG-400/K₂CO₃ at room temperature.

Scheme 3. Synthetic approaches for the formation of spiro[indoline-3,4′-pyrano[2,3-c]pyrazol], spiro[indoline-3,5′-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3′-indoline] and spiro[benzo[g]chromene-4,3′-indoline] (5a–q).

Scheme 4. A plausible mechanism for the formation of 5 in catalyst-free conditions.