Phase transfer catalyzed alkylation of phenylacetonitrile and its derivatives with dimeric quaternary ammonium compounds

One of the most significant application areas of green chemistry is phase-transfer catalysis. Monomeric quaternary ammonium salts, such as tetrabutylammonium bromide, are frequently employed as phase-transfer catalysts in organic synthesis reactions involving Phase Transfer Catalysis. In recent years, it has been noted that dimeric quaternary ammonium compounds exhibit superior surface-active properties compared to their monomeric analogues. Therefore, it is reasonable to assume that dimeric quaternary ammonium compounds may offer improved performance in phase-transfer catalyzed organic syntheses relative to monomeric counterparts. Verapamil, which is used in the treatment of cardiac arrhythmia and hypertension; Sibutramine, an anti-obesity and antidepressant drug; and Anastrozole, an effective medication for the treatment of advanced postmenopausal breast cancers, all involve the phase-transfer catalyzed alkylation of phenylacetonitriles as a key intermediate step in their synthesis. In this study, the phase-transfer catalyzed alkylation of phenylacetonitrile and its derivatives was investigated using dimeric quaternary ammonium salts (gemini surfactants) as catalysts. For this purpose, quaternary ammonium-type gemini surfactants with varying spacer chain lengths (n = 2, 6, 10) and hydrophobic alkyl chain lengths (R = 10, 12, 16) were first synthesized. Subsequently, the synthesized gemini surfactants were employed as phase-transfer catalysts in the alkylation of phenylacetonitrile and its derivatives, namely 3,4-dimethoxyphenylacetonitrile and 4-(trifluoromethyl)phenylacetonitrile. The yields obtained using the gemini surfactants were compared with those achieved using the classical phase-transfer catalyst tetrabutylammonium bromide (TBAB). In the presence of gemini surfactants, phase-transfer catalyzed C-alkylation of phenylacetonitrile and its derivatives with primary alkyl halides resulted in highly complex product mixtures, yielding inefficient outcomes. However, when 1,5-dibromopentane was used as the alkyl halide, the formation of a six-membered ring was observed, prompting the study to evolve towards cycloalkylation. Cycloalkylation reactions of phenylacetonitrile, 3,4-dimethoxyphenylacetonitrile, and 4-(trifluoromethyl)phenylacetonitrile in the presence of gemini surfactants provided yields comparable to those obtained with TBAB, with some gemini surfactants exhibiting even superior performance. The structures of the synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, and mass spectrometry. These results demonstrate that gemini surfactants can be employed as phase-transfer catalysts in the cycloalkylation of phenylacetonitrile and its derivatives, representing a promising alternative to conventional quaternary ammonium salts for such transformations.