Green chem.: Sustainable organophosphorus catalyzed Staudinger reduction

Organic azides are important intermediates in the synthesis of nitrogen-containing compounds They are often used in click reaction, aza Wittig reaction, Staudinger reduction and other reactions Azide can be converted to amines by catalytic hydrogenation or LiAlH 4 reduction, but the tolerance of functional groups of these methods is very limited Therefore, Staudinger reduction has become a common method for the preparation of amines from azides The classical Staudinger reaction requires the use of stoichiometric triphenylphosphine and the production of triphenylphosphine by-product, so its atomic economy and purification effect are not ideal (scheme 1a) In 2012, van kalkeren et al Further developed the phosphorus catalyzed Staudinger reaction (scheme 1b, adv synth Catalyst., 2012, 354, 1417) by replacing triphenylphosphine with dibenzophosphorocene As the reduction of triphenylphosphine to triphenylphosphine requires more stringent reaction conditions, researchers have developed some pre catalysts to replace triphenylphosphine, which can be reduced in situ (scheme 1D) in aza Wittig or Mitsunobu reactions However, the reported organophosphorus catalytic reactions often require the use of environmentally harmful solvents and reducers, so they lack sufficient green chemical properties (source: Green chem.) recently, Professor Jasmin mecinovi ć of the University of radbold, the Netherlands, developed a green and sustainable Staudinger reaction The reaction takes polymethylhydrosiloxane (PMHS) as the green reducing agent, recyclable cyclopentyl methyl ether (cpme) as the solvent, only 3mol% The triphenylphosphine can catalyze the efficient conversion of organic azide substrate to amines The reaction has a wide range of functional group tolerance, and does not need to be purified by column chromatography, and can achieve gram scale preparation Relevant research results were published in green chem (DOI: 10.1039/c8gc02136h) Firstly, the reaction conditions were screened with 4-nitrophenylethyl azide as the substrate (Table 1) The conversion of 4-nitrophenylethylazide to 4-nitrophenylethylamine was successfully catalyzed by 3 mol% phosphorus catalyst 1-4 and triphenylphosphorus with PMHS as reducing agent and toluene as solvent It was found that the target product (entry 10) could be obtained in 97% yield by using cpme as solvent and 3 mol% triphenylphosphorus as catalyst under the condition of heating reflux When triphenylphosphine was used as catalyst or PMHS was removed, the reaction could not take place (source: Green chem.) then, the author studied the substrate applicability of the reaction (scheme 2) The results showed that the reaction had excellent functional group tolerance, and nitro, alkenyl, cyano, ester, amide, ketone, benzyl, heterocycle and other functional groups could be tolerated in the reaction In addition, the reaction conditions are also suitable for aliphatic azides, and the steric hindrance has a certain effect on the reaction Increasing the amount of triphenylphosphine can transform the secondary azide into the corresponding target product in good yield The third-order azides can not react (source: Green chem.) in order to further verify the practical application value of the reaction, the author investigated the reaction at gram scale 4.8 g of 4-nitrophenyl azide (25 mmol) and 3.7 g of phenylethyl azide (25 mmol) can be converted into corresponding amine hydrochloride in 97% and 88% yields respectively, and the purity can reach more than 98% without column chromatography purification Finally, the possible reaction mechanism is proposed: firstly, triphenylphosphine reacts with azide to form an intermediate of azolide and release a molecule of N2 Azolide is further reduced by PMHS to form a silicon amine species and triphenylphosphine Finally, the silicon amine is hydrolyzed to obtain an amine (source: Green chem.) conclusion: a triphenylphosphine catalyzed Staudinger has been developed by Professor Jasmin mecinovi ć of radbold University in the Netherlands The reaction uses polymethylhydrosiloxane as the green reducing agent and cyclopentyl methyl ether as the green solvent It has a wide range of functional group tolerance, and can be carried out in gram scale without post-treatment and purification process.