A Solvent-Free and Formalin-Free Eschweiler-Clarke Methylation for Amines

Abstract

Primary and secondary amines are N-methylated by a mixture of paraformaldehyde and oxalic acid dihydrate in good to excellent yields. The reaction proceeds without involvement of organic solvents and toxic formalin. Reaction temperatures of 100 C are required for the decomposition of oxalic acid into the intermediate formic acid which acts as the actual reductant. The reaction conditions have been optimized, and the mechanism has been elucidated by means of deuteration experiments.

Synthesis of the perdeuterated cellulose solvents N‐methylmorpholine N‐oxide (NMMO‐d11) and N,N‐dimethylacetamide (DMAc‐d9)

“…to 1) of sulfuric acid. Larger amounts favored the formation of the bislactone [1,4]dioxane-2,5-dione. Dimethyl diglycolate (2) underwent H/D-exchange (499%) in CD 3 OD/CH 3 ONa.…”

“…Following the latter approach, acetic acid-d 4 (10) was converted into its isopropyl ester (11) 4 , and Zn/DCl, was even inferior. In the overall sequence, the yield of N,N-dimethylacetamide-d 9 (14) referred to acetic acid-d 4 (10) was 24% (Scheme 2, i: iPropOH, H 1 (cat.…”

“…Dimethyl diglycolate (2) underwent H/D-exchange (499%) in CD 3 OD/CH 3 ONa. The obtained tetradeutero-diglycolic acid dimethylester (3) was used without further purification in the subsequent reduction (LiAlD 4 in THF), 1 providing diethylene glycol-d 8 (4). During addition of the reducing reagent, the reaction temperature must not exceed À101C, whereas subsequent heating of the mixture is crucial to ensure a complete reaction at 'both sides' of the diglycolate.…”

“…7,8,9 Applied in a molar ratio of 1:2, ammonium carbonate and methanol-d 4 Intermediate (17) was further reacted in an autoclave at 2501C with acetic acid-d 4 (10) in the presence of the same acidic aluminum oxide catalyst (Brockmann grade I) used in the previous step. 10 Quantitative conversion was achieved in a neat gas phase/solid phase reaction within 1 h, and the alumina was easy to separate by simple filtration.…”

“…3 Upon hydrogenation, the solvent system releases hydrochloric acid which concomitantly converts the released amine into its hydrochloride. Hydrochloride 7 was directly converted into Nmethylmorpholine-d 11 (8) according to an Eschweiler-Clarke protocol 4 and oxidized without further purification with 2 equivalents of 30% H 2 O 2 4 added slowly at 01C. The target compound NMMO-d 11 (9) was purified by Kugelrohr sublimation in high vacuum.…”