Reports: B1
43948-B1 Stereospecific Intramolecular Carbenoid Insertions on Furanose Platforms as a Route to Branched-Chain Sugars, C-Glycosides and Fused Heterocycles
We have continued to investigate the application of carbenoid insertion chemistry for the formation of carbon-carbon bonds on conformationally restricted furanose platforms. The method holds great promise for the stereospecific formation of chiral heterocycles, including those related to C-glycosides, and the frameworks of several classes on natural products. During this work we have observed several unexpected side-reactions that have been studied further with carbohydrate substrates and, more recently, with non-sugar precursors. The overall project has resulted in the successful insertion of rhodium-stabilized carbenoids into various furanose-derived platforms, with the formation of enantiometrically pure bis-furan products, and the unexpected side-reactions have lead to optically pure carbohydrate-derived ethers through insertion into H2O, as well as the more recent development of easily handled aryl sulfonyl azides as useful and safe azidation reagents.
Our preliminary work on sugar-derived diazoesters led to the discovery of a new one-pot synthesis of glycosyl azides from the corresponding lactol precursors and we have continued to expand the scope of this reaction to non-carbohydrate alcohols and subsequently to sequential one-pot processes such as 1,2,3-triazole synthesis. Deprotonation of the alcohol with NaH, followed by displacement of azide from a suitable arylsulfonyl azide by the alkoxide, gives an intermediate sulfonate ester; subsequent displacement on an alkyl or acyl halide with azide anion affords the alkyl or acyl azide. Reaction progress is monitored conveniently using IR spectroscopy since each of the azide species involved (sulfonyl, ionic, alkyl, or acyl) has a distinct absorbance frequency. We have studied the use of different bases and found that NaH affords optimal yields (80-95%) but also gives products of oxidation (to the ketone) and SNAr processes on more hindered secondary alcohol substrates. A variety of typical amines that were studied are ineffective in this chemistry except for DBU, which promotes alcohol to azide formation in good yields but which also reacts with the arylsulfonyl azide to generate an ionic organic azide salt. This accounts for incomplete alcohol to azide conversion, however this side-reaction also leads to a very useful non-metallic source of ionic azide that we have developed further.
DBU displaces the azide group from p-acetamidobenzenesulfonyl azide in acetonitrile at room temperature to generate anionic azide. Various different solvents have been investigated in this reaction with ethanol being found to be convenient both from the perspective of reasonable reaction time, but also from a sustainability view. Treatment of p-ABSA with DBU in ethanol at 70 oC in a synthesis microwave results in complete conversion to ionic azide in 15 minutes as judged by IR analysis of the reaction solution. Subsequent addition of alkyl or acyl halide then results in the clean formation (IR analysis) of either the highly useful alkyl or acyl azide. Isolation of each potentially dangerous azide product is unnecessary and subsequent reaction, for example with terminal alkynes in the presence of a Cu(I) catalyst, is proving to be a promising route to 1,2,3-triazoles in one flask from the precursor alkyl or acyl halide. We have now shown that it is possible to generate a variety of 1,2,3-triazoles quickly and in high yield using this method, which constitutes a “green” one-pot approach to these useful materials: azide anion generation, alkyl or acyl azide formation, followed by Cu(I)-catalyzed heterocycle synthesis all in one flask without the need to isolate any of the potentially dangerous intermediate species.
