Photocatalytic N-Methylation of Amines over Pd/TiO₂ for the Functionalization of Heterocycles and Pharmaceutical Intermediates

Abstract

Amines in heteroaromatic systems and pharmaceutical intermediates were functionalized through N-methylation with methanol using a palladium-loaded titanium dioxide (Pd/TiO2) photocatalyst. This method provides access to a series of tertiary N-methylamines bearing NO O-, and/or S-containing heteroaromatic functionalities from primary/secondary amines and methanol under mild reaction conditions. Facile syntheses of several pharmaceuticals containing N-methyl or ethyl groups, as well as related deuterated drugs, was achieved through the late-stage functionalization of amines.

Ag(I)/TiO2-Photocatalyzed N-Methylation of Amino Acids with Methanol

“…Unfortunately, irradiation of polar amino acids such as lysine, serine, threonine, arginine, tyrosine, asparagine, glutamine, aspartic acid, and glutamic acid (without protection of the corresponding side chains) under the standard conditions resulted in the formation of complex mixtures. As in the case of our previous work, the N-methylation of L-proline (16) proceeded smoothly to give 17 in 81% yield (S/R ratio >98:2, Scheme 2).…”

Ag(I)/TiO2-Photocatalyzed N-Methylation of Amino Acids with Methanol

“…Unfortunately, irradiation of polar amino acids such as lysine, serine, threonine, arginine, tyrosine, asparagine, glutamine, aspartic acid, and glutamic acid (without protection of the corresponding side chains) under the standard conditions resulted in the formation of complex mixtures. As in the case of our previous work, the N-methylation of L-proline (16) proceeded smoothly to give 17 in 81% yield (S/R ratio >98:2, Scheme 2). A trial on the dimethylation of L-cysteine (18) furnished mono-methylated N,S-acetal 19 in 68% yield (Scheme 3).…”

Simple RuCl3‐catalyzed N‐Methylation of Amines and Transfer Hydrogenation of Nitroarenes using Methanol

“…Later, Watanabe and co‐workers [23] used RuCl 3 .nH 2 O/P(OBu) 3 catalytic system for N ‐methylation of amines with methanol at 180 °C, but the substrate scope is very narrow. After their seminal work, many groups have extended the state of selective N ‐methylation of amines or nitroarenes with methanol in presence of noble‐ [3a–e,h,l‐q,s,u‐z,aa, ac‐ae,24] and non‐noble metals ‐ [3f,g,i–k,r,t, ab, af‐ag] . Regarding ruthenium catalysis, to date only five homogeneous catalytic systems are reported ( Figure 1 ) .…”