ChemInform Abstract: First Example of a New Multicomponent Reaction of a Tetrahydropyridine Ring Expansion.

Abstract

In a continuation of work on the synthesis of eightand nine-membered nitrogen-containing heterocycles [1-3] and on the use of the Ugi reaction in the synthesis of benzodiazepine derivatives [4], we decided to develop a new isocyanide multicomponent reaction (MCR) using the reaction which we have discovered for the tandem expansion of heteroannelated tetrahydropyridines and azepines under the influence of activated alkynes. The experimental data we obtained earlier allowed us to suggest with certainty that propiolic acid, in contrast to its esters did not give products of the ring expansion with heteroannelated tetrahydropyridines. We have proposed that if propiolic acid was used as the carboxylic component in the Passerini reaction [5] then the oxoethylpropiolate A formed in situ, being an activated alkyne, might react with heteroannelated tetrahydropyridines introduced in this reaction as a fourth component. As a model experiment, we studied a MCR with tetrahydrothienopyridine 1 [6], butyraldehyde (2), propiolic acid (3), and isonitrile 4. The reaction was carried out at a temperature of -5 to 0°C in an atmosphere of argon. As a result the required thienoazocine 5 was isolated from the reaction mixture in a yield of 32%. Thus, we have found the first example of a multicomponent reaction for the expansion of a tetrahydropyridine ring. Despite the small yield of the required azocine, this reaction may serve as an effective method for the synthesis of difficult to obtain derivatives of medium nitrogen heterocycles. H and C NMR spectra were recorded with a Bruker WP-400 spectrometer (400 and 100 MHz respectively) in CDCl3 solution with TMS as internal standard. The assignment of the signals in the H NMR spectra was based on the data from the H-H COSY experiment. IR spectra of nujol mulls were recorded on an Infralum FT-801 Fourier spectrometer. The LC/MS spectra were obtained with a system which included an Agilent 1100 series liquid chromatograph and an Agilent Technologies LC/MSD VL mass spectrometer (electrospray injection, APCI), ELSD Sedex 75 detector. Butyraldehyde (2), propiolic acid (3), and the isonitrile 4 were commercial products. The aldehyde 2 was distilled at normal pressure under argon before use in the reaction, the other reagents were used without additional purification.