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 CO2emissions,numerous efforts have been devoted to development of synthetic protocols using CO2as 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 CO2and 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 K3PO4as an efficient catalyst. Preparations of a wide-scope drug-like amines with carbon-isotope label were also successfully achieved, enabling direct use of CO2in studies of drug absorption, distribution, metabolism and excretion.