Regioselective Titanium Tetrachloride Mediated Five Membered Hetero-Cyclisations

Abstract

Highly regioselective titanium IV mediated, Dieckmann type cyclisation in the synthesis of 5-membered nitrogen and sulfur heterocycles is described.

IICT Communication No. 3477

Notes

IICT Communication No. 3477

The sulfur based substrates were prepared by Michael addition of alkyl thioglycolate on alkyl acrylates. The nitrogen based substrates were prepared by Michael addition of alkylamines on alkyl acrylate followed by the treatment of the product with alkylbromoacetate.

All products gave satisfactory spectroscopic data.

General Procedure: To a solution of 1M TiCl₄ in CH₂Cl₂ (1 eq.) at −10°C was added the diester (1 g) in CH₂Cl₂ (20 ml) and stirred at the same temperature for 0.5 h. Et₃N (2.2 eq.) was added dropwise slowly and stirred for additional 2 h. The reaction mixture was poured into 10% aq. NaCl solution and the pH was made basic (≃ 8) with Et₃N. The precipitated salts were filtered and washed with CH₂Cl₂. The organic layer was dried (Na₂SO₄), concentrated and chromatographed (silica gel) to yield the pure cyclic β-keto esters in 40–60% yield.

The N-phenyl substituted diester failed to give the required product and resulted largely in the recovery of the starting material under the conditions described in ref 8. Modification of the reaction conditions for this and similar other N-aryl substrates is underway.

Attempts to synthesize oxygen heterocycles using this method were unsuccessful.