快捷合成2,5取代的四氮唑

A new alkylation reaction of monosubstituted tetrazoles via the diazotization of aliphatic amines is reported. This method enables preferential formation of 2,5-disubstituted tetrazoles. A one-pot 1,3-dipolar cycloaddition/diazotization sequence starting from widely available nitriles is also described. Azide residues are quenched in the second step with the nitrite reagent, thus limiting the intrinsic risk associated with trimethylsilyl azide. The reaction conditions were compatible with several functional groups, including thiocyanates, which afford preferentially disubstituted 2-alkyl-5-(substituted-thio)tetrazoles.

General Procedure A for the Alkylation of 5-Monosub-stituted Tetrazoles.

In a round-bottom flask with a magnetic stirring bar was suspended 5-monosubstituted tetrazole (0.500 mmol, 1.00 equiv) in EtOAc (4 mL). The resulting suspension was stirred at room temperature. 1,3-(2,2-Dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) was added, followed by the amine (1.25 mmol, 2.50 equiv). The flask was placed in an oil bath, and the mixture was heated at 80 °C for 16 h. The solvent was removed under reduced pressure, and the crude mixture was purified by flash chromatography.

General Procedure B for One-Pot Cycloaddition−Diazotization Reaction.

In a round-bottom flask with a magnetic stirring bar, nitrile (0.500 mmol, 1.00 equiv) was diluted in toluene (1.5 mL). The resulting mixture was stirred at room temperature. Dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv) was added, followed by azidotrimethylsilane (0.099 mL, 0.750 mmol, 1.50 equiv). The flask was placed in an oil bath, and the mixture was heated at 110 °C for 4 h (procedure B1) or 16 h (procedure B2). The mixture was cooled to room temperature, and toluene (2.5 mL) was added, followed by 1,3-(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) and the amine (1.25 mmol, 2.50 equiv). The flask was placed in an oil bath, and the mixture was heated at 110 °C for 16 h. The mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the crude mixture was purified by flash chromatography.

https://doi.org/10.1021/acs.joc.1c01585

标签： Tetrazole