Regioselective intramolecular dipolar cycloaddition of azides and unsymmetrical alkynes

Abstract

Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.

Figure 1

Representative examples of biologically active molecules containing 1,2,3-triazoles.

Scheme 1

Two step triazole formation ^a Isolated yields after purification over silica gel. ^b Diastereomeric ratios determined by ¹H NMR analysis on crude material.

Scheme 2

One-pot propargylation/cycloaddition ^a Isolated yields after purification over silica gel. ^b Diastereomeric ratios determined by ¹H NMR analysis on crude material. ^c Reaction run using achiral allenylsilane 4b.

Scheme 3

Silyl ether synthesis

Scheme 4

Propargylations and dipolar cycloadditions with substituted silyl ethers ^a All yields refer to isolated products after purification over silica gel. ^b All diastereomeric ratios were determined by ¹H NMR analysis on crude material. ^c The (S_a) enantiomer of the allenylsilane 1 was used for the propargylation reaction. ^dCycloaddition reaction run in chlorobenzene at 150 ºC.