Commercial Pd/C-Catalyzed N-Methylation of Nitroarenes and Amines Using Methanol as Both C1 and H₂ Source

Abstract

Herein, we report commercially available carbon-supported-palladium (Pd/C)-catalyzed N-methylation of nitroarenes and amines using MeOH as both a C1 and a H2 source. This transformation proceeds with high atom-economy and in an environmentally friendly way via borrowing hydrogen mechanism. A total of >30 structurally diverse N-methylamines, including bioactive compounds, were selectively synthesized with isolated yields of up to 95%. Furthermore, selective N-methylation and deuteration of nimesulide, a nonsteroidal anti-inflammatory drug, were realized through the late-stage functionalization.

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

“…Remarkably, 1‐naphthylmethylamine was also converted to the corresponding N ‐methyl‐1‐naphthylmethylamine in 38 % yield (entry 23), which is an important precursor for the synthesis of terbinafine [33] and naftifine [3e] . Similarly, N ‐methylcyclohexylamine (entry 24), a key precursor for the synthesis of bromhexine, [3b] was also afforded in 75 % yield. Other secondary amines were also examined under standard conditions.…”

“…Interestingly, RuCl 3 .xH 2 O is used as a catalyst for various organic transformations [29] including reductive N ‐alkylation of nitroarenes using glycerol as hydrogen source [30] . Inspiring from these aforementioned reports and our interest in N ‐methylation [3b] and hydrogenation reactions, [31] we demonstrate the use of RuCl 3 .xH 2 O as a ligand‐free catalyst for selective N ‐methylation of amines using methanol and without external added hydrogen. This simple catalyst tolerates various amines bearing electron‐deficient and electron‐donating groups and allows them to transform into their corresponding N ‐methylated products in moderate to excellent yields.…”

“…Also, N ‐methylated amines play significant roles as building blocks in the synthesis of industrial chemicals, pharmaceuticals, agrochemicals, and life science materials [5] . Regarding their synthesis, a hydrogen‐borrowing approach represents a waste‐free process to generate diverse N ‐methylated molecules [1f,3a–r] . In addition, reductive amination of amines using CO 2 also constitutes a green methodology to produce N ‐methyl amines [6] .…”

“…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 ) .…”

Photocatalyzed Chemo‐Selective Alkylation of Quinones and Phenothiazinones with Alkyl Amides: Photophysical and Cytotoxic Activity Studies

“…One of the most significant challenges in synthetic chemistry is chemoselective functionalisation of molecules possessing multiple functional groups [9e–g] . Appealingly, the popular polar solvents N,N ‐dimethylacetamide (DMA, 2 b ) N, N ‐dimethylformamide (DMF, 2 d ) and other alkyl amides consists of several functional groups such as 2 amides (−NH), amidoalkyl (−NH(C=O)CH 3 ), dialkylamine (N(Me) 2 ), amido carbonyl (−NH(C=O)CH 3 ) and can be used as versatile synthon in organic transformations – [10a–] .…”