4
Tetrahedron
80 °C and solvent from toluene to CPME (cyclopentylmethyl
In conclusion, the monomethylation of amines with
ether) improved the yield up to 98%.
paraformaldehyde in proportions close to the stoichiometry in the
presence of CaH2 as source of hydrogen and palladium on carbon
as catalyst has been studied. Selectivity in monomethylated
products from 46 to 100% has been observed on different amines
(anilines, benzylamines, alkylamines and amino acids) over 15
examples. With an increase of the quantity of paraformaldehyde
and calcium hydride, dimethylated amines were also synthesized
in good isolated yields.
In most cases, when the amines were isolated as chlorohydrate
salts, poor yields were observed. However, the corresponding
oxalic acid salts were isolated in good to excellent yields (56-
98%, Scheme 3). The crude reaction mixture was diluted in
diethyl ether and filtered through a pad of celite. To this solution
an ethanolic solution of oxalic acid was added, allowing the
precipitation of the corresponding N,N-dimethylammonium
oxalate salts. For example, N,N-dimethylanilinium oxalate 1c
was isolated in high yields (>98%) both from the reaction of
aniline 1a and N-methylaniline 1b. Anilines were converted to
the corresponding N,N-dimethylammonium salts 16c, 4c, 8c, 17c
and 18c in good to excellent yields (from 66% to 92%).
Although, quick look at the results may not show strong
electronic effects, it seems that anilines bearing electrondonating
group lead to higher yields than the ones bearing
electronwidrawing group (for example 4c, 92% versus 18c,
85%). In contrast, steric hindrance may play a bigger effect; the
anilines bearing ortho substituents lead to ammonium salts in
moderate yields (16c in 66% and 17c in 72%).
Acknowledgments
C.G. held a doctoral fellowship from La Région Rhône-Alpes
financed to the amount of 32 116 euros. The authors are grateful
for the access to the MS analysis at the Centre Commun de
Spectroscopie de Masse and NMR facilities at the Université
Lyon 1. E. M. deeply acknowledges the Institut de Chimie de
Lyon (ICL) for financial support for scientific instrument.
References and notes
The same reaction conditions can be applied to the primary
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Scheme 3. Dimethylation of amines
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Quality of palladium on carbon differs often from suppliers
and batches creating reproducibility issues and use of a higher
loading of catalyst than necessary (>5 mol%). Hence, we
investigated the in situ generation of palladium (0) on charcoal
from Pd(OAc)2 and charcoal inspired by the work of Felpin and
Fouquet.32 We carried out the reaction of aniline with
paraformaldehyde under the optimized conditions of
monomethylation using Pd(OAc)2 (2 mol%) and the quantity of
calcium hydride was raised to 120 mol% in order to have enough
reductant for the in situ reduction of Pd(OAc)2 (Scheme 4). The
conversion and selectivity for N-methylaniline were lower than
with commercially available Pd/C. A conversion of aniline 1a of
58% was observed and a selectivity for the N-methylaniline 1b of
81% versus 92% conversion and 90% selectivity with
commercial Pd/C.
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Scheme 4. Methylation of amine with Pd(0) generated in situ