Synthesis of indolines and indoles via intramolecular [4 + 2] cycloaddition of ynamides and conjugated enynes ; Synthesis of nitrogen heterocycles in supercritical carbon dioxide

Abstract

A general amination strategy for the N-alkynylation of carbamates, sulfonamides, and chiral oxazolidinones and imidazolidinones is described. A variety of substituted ynamides are available by deprotonation of amide derivatives with KHMDS followed by reaction with CuI and an alkynyl halide. Ynamides react with conjugated enynes in intramolecular [4 + 2] cycloaddition to afford substituted indolines that undergo oxidation with o-chloranil to furnish the corresponding indoles. The cycloaddition substrates are easily assembled from derivatives of 3-butynylamine by Sonogashira coupling with alkenyl halides followed by copper-catalyzed N-alkynylation with acetylenic bromides. Diynamides participate as particularly reactive 2[pi] components in the cycloaddition, providing access to indolines with carbon substituents at the C-7 position. Enynamides serve as 4[pi] components in a complementary version of the cycloaddition strategy which provides access to indoles and indolines substituted with substituents at C-4. These enyne cycloadditions take place upon heating the substrates at 110-210⁰C in toluene or 2,2,2- trifluoroethanol and in some cases can be achieved at 0⁰C to room temperature in the presence of Lewis acids such as Me₂A1C1.

(cont.) We have developed a "green" strategy to effect acyl-Pictet-Spengler reactions in multiphasic scCO₂/CO₂-expanded liquid media. These cyclizations of iminium ions provide tetrahydroisoquinolines and tetrahydro-[beta]-carbolines that have valuable medicinal properties. Critical to the success of these reactions is the in situ conversion of [beta]-arylethylamine reactants to c;arbamate derivatives by reaction with carbon dioxide and dialkyl carbonates. The application of this general strategy for utilizing amines in other carbon-nitrogen bond-forming reactions in environmentally-friendly media is under investigation.