N-formylation and N-methylation of amines using metal-free N-heterocyclic carbene catalysts and CO2 as carbon source

PROTOCOL

N-formylation and N-methylation of amines using metal-free N-heterocyclic carbene catalysts and CO2

as carbon source

Felix D Bobbink, Shoubhik Das & Paul J Dyson

Institut des Sciences et Ingnierie Chimiques, cole Polytechnique Fdrale de Lausanne (EPFL), Lausanne, Switzerland. Correspondence should be addressed to P.J.D. ([email protected]).

Published online 26 January 2017; http://dx.doi.org/10.1038/nprot.2016.175

Web End =doi:10.1038/nprot.2016.175

N-formylation and N-methylation of amines are important reactions that are used to produce a wide range of key intermediates and compounds. This protocol describes the environmentally benign N-formylation and N-methylation of primary and secondary amines using carbon dioxide (CO2) as the carbon source, hydrosilanes as reductants and N-heterocyclic carbenes (NHCs) as catalysts. Using

CO2 as a reagent has the advantage of low cost and negligible toxicity. However, the catalyst is air-sensitive and must be generated fresh before use; consequently, the techniques used to prepare and manipulate the catalyst are described. The synthetic approach described in this protocol does not use any toxic reagents; using the appropriate catalyst, N-formylated or N-methylated products can be obtained with high selectivity. The overall time for catalyst preparation and for conducting several catalytic reactions in parallel is 1548 h, depending on the nature of the substrates.

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INTRODUCTION

CO2 has emerged, in recent years, as an environmentally benign reagent in the synthesis of fine chemicals. Given that this compound is an abundant greenhouse gas, its use as a synthetic substrate can also be viewed as complementing carbon capture and storage approaches. Of the various reactions reported1, the reductive functionalization of amines with CO2 has emerged as a highly viable approach. For example, Beller et al.2,3 and Leitner et al.4 have reported well-defined metal catalysts (i.e., catalysts comprising metal centers with well-defined ligands) that use hydrogen as the reducing agent to afford N-methylated products. Although these catalysts operate at low loadings, the requirement for high pressures of CO2 and hydrogen (2060 atm) makes the use of stainless steel autoclaves necessary. In 2012, Cantat et al.

described the highly selective N-formylation of amines, imines and other substrates using an NHC-type catalyst in the presence of CO2 (1 atm) and polymethylhydrosiloxane (PMHS), the latter being a nontoxic by-product of the silicone industry5.

Cantat extended this approach to N-methylation using...