Iron‐Catalyzed Selective N‐Methylation and N‐Formylation of Amines with CO₂

Abstract

We herein describe an efficient iron‐catalyzed selective N‐methylation and N‐formylation of amines with CO2 and silane using mono‐phosphine as ligand. With commercially available [CpFe(CO)2]2 as catalyst, Fe‐catalyzed methylation of amines was achieved with triphenylphosphine as a ligand. Using tributylphosphine as a ligand, Fe‐catalyzed formylation of amines was realized at a lower temperature. The method was successfully applied in the late‐stage methylation and formylation of drug molecules containing amine moiety.magnified image

Mesoionic N-heterocyclic olefin catalysed reductive functionalization of CO2 for consecutive N-methylation of amines

“…10,11 Thus, use of CO 2 as a methylating reagent under a reductive atmosphere is an attractive alternate to produce N-methyl amines through direct functionalization of amines. In the last decade, several metal catalysts [12][13][14][15][16][17][18][19][20][21] and a few metal-free catalysts [22][23][24][25] were reported for this catalytic transformation in presence of hydrosilanes as a reducing agent and all of these studies were carried out at an elevated temperature. However, these methods have very limited potential towards consecutive N-methylation involving primary amines.…”

Recent Trends in Upgrading of CO2 as a C1 Reactant in N‐ and C‐Methylation Reactions

“…It is important to note that the most abundant metal in the earth and inexpensive Fe complexes could also serve as an efficient catalyst. The research group of Xia demonstrated homogeneous [CpFe(CO) 2 ] 2 catalyst in combination with triphenylphosphine or tributylphosphine as ligands for N ‐methylation and N ‐formylation of amines in the presence of CO 2 and PhSiH 3 [26] . The reaction conditions were optimized using N ‐ethylaniline as a model substrate (Table 4).…”

“…It is also noteworthy that the authors further extended the scope of the method to the late‐stage N ‐methylation of biologically active pharmaceuticals (atomoxetine, sertraline, cinacalcet, and paroxetine) and obtained the respective N ‐methylated products in moderate to good yields (30‐78%) (Scheme 7). [26] …”

Dirhodium-Catalyzed Chemo- and Site-Selective C–H Amidation of N,N-Dialkylanilines

“…The present method is assumed to be potentially useful for the application to late-stage functionalization of bioactive molecules containing aromatic N-methyl group. 18…”

“…It is worthy to note that benzylic methyl C(sp 3 )-H bonds of toluene were totally inactive for amidation, even when toluene was used as a solvent (entry 15). Use of bases such as Li2CO3, Na2CO3, Cs2CO3, or Rb2CO3 did not improve the yield of the amidation reaction (entry 15 vs [16][17][18][19][20]. Finally, the yield of amidation was improved by use of 10 equivalents of the substrate to afford the desired 2aa in 79% yield (entry 21).…”