Scalable direct N-methylation of drug-like amines using 12CO2/13CO2 by simple inorganic base catalysis

With the growing urgency of potential catastrophic climate changes due to anthropogenic CO2 emissions, numerous efforts have been devoted to development of synthetic protocols using CO2 as a building block in organic reactions, but the general applicability to complex drug-like substrates remains a challenge. We develop a general protocol for scalable direct N-methylation of a wide-scope drug-like amines using CO2 and polymethylhydrosiloxane—a nontoxic, aerobically-stable hydrosilane considered as an industrial waste—via simple inorganic base catalysis. A rare application of the Sabatier principle in organic chemistry led to the discovery of cheap, nontoxic K3PO4 as an efficient catalyst. Preparations of a wide-scope drug-like amines with carbon-isotope label were also successfully achieved, enabling direct use of CO2 in studies of drug absorption, distribution, metabolism and excretion.