Carbonyl olefination of N-substituted tetrahydroquinoline-6-carbaldehydes

Tetrahydroquinolines are important structural fragments of many biologically active compounds exhibiting antifungal, antitumor, antiviral and neurotropic properties. This paper presents methods for the synthesis of N-substituted tetrahydroquinoline-6-carbaldehydes and a study of the possibility of their olefination using the Wittig and Horner – Wadsworth – Emmons methods. As a result of the interaction of N-alkyl- and N-acylhydroquinolines with the Vilsmeier – Haack complex, N-substituted tetrahydroquinoline-6-carbaldehydes have been obtained in yields of 77–85%. Olefination of the obtained carbaldehydes by the Wittig reaction using triphenylalkylphosphonium salts has made it possible to obtain a number of N-substituted derivatives, including: (E)-3-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)acrylonitriles, (E)-1-phenyl-3-(2,2,4- trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)prop-2-en-1-ones, ethyl (E)-3-(N-benzoyl-7-methoxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl) acrylate. It has been found that when this interaction is extended to N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde and N-benzyl-2,2,4-trimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde, difficult-to-separate mixtures are formed, which is explained by the presence of a methylene-active benzyl group in these compounds, which in the presence of sodium methylate can enter into condensation with the aldehyde fragment. The application of the Horner – Wadsworth – Emmons reaction for the olefination of N-methyl- and N-benzyl-1,2,3,4-tetrahydroquinoline-6-carbaldehydes using dimethyl (cyanomethyl) phosphonate has made it possible to synthesize (E)-3-(Nmethyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl) acrylonitrile, (E)-3-(N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl) acrylonitrile and (E)-3-(-N-benzyl-2,2,4-trimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl) acrylonitrile with yields of 83–89%. Analysis of the ¹H NMR spectra has showed that all the synthesized olefination products are in the form of E-isomers. The obtained results demonstrate the potential of using the developed methods for the synthesis of new tetrahydroquinoline derivatives.