Ruthenium‐Catalyzed Methylation of Amines with Paraformaldehyde in Water under Mild Conditions

Abstract

Methylated amines are highly important for a variety of pharmaceutical and agrochemical applications. Existing routes for their formation result in the production of large amounts of waste or require high reaction temperatures, both of which impact the ecological and economical footprint of the methodologies. Herein, we report the ruthenium-catalyzed reductive methylation of a range of aliphatic amines, using paraformaldehyde as both substrate and hydrogen source, in combination with water. This reaction proceeds under mild aqueous reaction conditions. Additionally the use of a secondary phase for catalyst retention and recycling has been investigated with promising results.

Ruthenium‐Catalyzed E‐Selective Partial Hydrogenation of Alkynes under Transfer‐Hydrogenation Conditions using Paraformaldehyde as Hydrogen Source

“…Recently, the number of reports on the use of C1 molecules such as formic acid, [21][22]24,26,28,30,[37][38][54][55][56][57] formaldehyde, [58][59][60][61] and methanol [62] as hydrogen sources in transfer-hydrogenation reactions are increasing. Although it has been considered frequently as an inexpensive and safer substitute for pressurized hydrogen gas [58,63] in transfer hydrogenations and reductions, formic acid suffers from some drawbacks.…”

“…To overcome the problem of acidity of formic acid in such reactions, application of methanediol produced from formaldehyde in aqueous solutions could be suitable since it is less acidic and therefore, applicable for acid sensitive substrates and reactions under base-free conditions. [58][59][60][62][63][64] In continuation of our work to generate dihydrogen from aqueous formaldehyde, [65][66] or in situ generated aqueous formaldehyde from methanol [62] and paraformaldehyde (pFA) [66] for hydrogenations or as energy carrier, we have also used these hydrogen sources in combination with [Ru(p-cymene)Cl 2 ] as pre-catalyst for transfer hydrogenation of alkenes (with methanol), [62] for formaldehyde dismutation (with pFA in water), [67] for reductive methylation (with pFA in water) [61] and most recently for reductive deamination of nitriles to alcohols (with pFA in water). [58] In terms of practical aspects, it turned out that the easy-to-handle non-volatile paraformaldehyde (oligomeric solid powder) is very convenient in comparison to the volatile C1-molecule competitors, methanol, aqueous formaldehyde and formic acid, while the hydrogen content of pFA is equal to formaldehyde referring to the monomer.…”

Convenient iron-catalyzed reductive aminations without hydrogen for selective synthesis of N-methylamines

“…Thus, the use of convenient reagents for selective methylation of life science molecules continues to be an important goal. In this regard, paraformaldehyde 40 – 42 , which is stable and easy to handle, can be a suitable methylation reagent.…”

Copper‐Catalyzed Formylation of Amines by using Methanol as the C1 Source

“…Following our research on the activation of C1 molecules for energy conversion processes [49,50] and synthetic applications, [51] we report herein av ery mild method for the formylationo f amines with methanolo rp araformaldehyde at low temperature with ac opper/TEMPO system as ar obust, selective, and cheap catalyst. For convenience and practicality,w eaimed to develop am ethodb ased on TEMPO, since it is much cheaper than ABNO and other nitroxyl radicals.…”