Selective Monomethylation of Amines with Methanol as the C₁ Source

Abstract

The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…By using the novel Ru catalyst 370 (Scheme ), they achieved monomethylation of amines by using methanol as the C 1 source and hydrogen gas as the reducing agent. A possible mechanism is shown in Scheme …”

“…As discussed in Section 3.2, mono N‐methylation of aliphatic primary amines by using DMC, MeB(OH) 2 , MeI, MeOH, dimethyl phosphite and trimethyl phosphate, peroxides, and HCHO as the methyl source is very challenging. Two significant breakthroughs in this respect are exemplified in Table and Figure . Indeed, the demand for a simple, convenient, straightforward, and highly selective mono N‐methylation of aliphatic primary amines is still much desired.…”

“…Ap ossible mechanism is shown in Scheme 34. [230] The hemiaminal 371 is formedf rom ap rimary amine and the aldehyde, which is formed from methanol by ah ydrogenborrowing approach. Hydrogen gas (H 2 )i su sed to retard the dehydrogenation of 371,t hus the formation of 374 is not favored.…”

“…Twos ignificant breakthroughs in this respecta re exemplified in Ta ble 37 [229] andF igure 12. [230] Indeed, the demand for a simple, convenient,s traightforward, and highly selectivem ono N-methylationo fa liphatic primary amines is still much desired.…”

Selective N‐Monomethylation of Anilines with Methanol Catalyzed by Commercial Pd/C as an Efficient and Reusable Catalyst

“…realized the first homogenously Rh, Ir phosphine complexes‐catalyzed N ‐methylation of amines by methanol in 1981 . Since then, a few homogeneous Ru, Ir, Fe, Mn, and Co complexes have been further developed for the N ‐methylation of amines by methanol. However, these homogeneous catalytic systems cannot be reused, which seriously limited large‐scale industrial applications.…”