N-Alkylation of functionalized amines with alcohols using a copper–gold mixed photocatalytic system

Abstract

Direct functionalization of amino groups in complex organic molecules is one of the most important key technologies in modern organic synthesis, especially in the synthesis of bio-active chemicals and pharmaceuticals. Whereas numerous chemical reactions of amines have been developed to date, a selective, practical method for functionalizing complex amines is still highly demanded. Here we report the first late-stage N-alkylation of pharmaceutically relevant amines with alcohols at ambient temperature. This reaction was achieved by devising a mixed heterogeneous photocatalyst in situ prepared from Cu/TiO2 and Au/TiO2. The mixed photocatalytic system enabled the rapid N-alkylation of pharmaceutically relevant molecules, the selective mono- and di-alkylation of primary amines, and the non-symmetrical dialkylation of primary amines to hetero-substituted tertiary amines.

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

“…The Pd/TiO 2 photocatalyst was recyclable at least 4 times (entries 4−7). Other photocatalysts, such as Ag (4 wt %)/TiO 2 , 20 Cu (5 wt %)/TiO 2 , 21 and the Cu−Au mixed photocatalytic system 21 promoted reaction of 1a less efficiently than Pd/TiO 2 (entries 8−10 vs entry 1). Only marginal or trace amounts of desired product were formed by employing Au (5 wt %)/TiO 2 , 27 Pt (5 wt %)/TiO 2 , 22 or pristine TiO 2 (entries 11−13).…”

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 ) .…”

TiO2‐Based Photocatalysis at the Interface with Biology and Biomedicine

“…However, there are already several examples that demonstrate the viability of using SC photocatalysts to induce organic transformations . Some specific reactions promoted by TiO 2 are the oxidation of aliphatic and aromatic systems, or alcohols; the conversion of lactic acid into acetaldehyde; the synthesis of α‐chloro aryl ketones from aryldiazonium salts and terminal alkynes; Ullmann reactions; the conversion of amines to imines; the N‐alkylation of amines with alcohols; the addition of amines to deficient alkenes; heterocyclic functionalizations; the Huisgen [3+2] cycloaddition of azides and alkynes; or the addition of thiols to alkenes …”