Communication
Abstract: A general catalytic protocol for the methylation
of amines has been developed applying, for the first time,
formic acid as the C1 building block and silanes as reduc-
ing agents. A broad range of aromatic and aliphatic, both
primary and secondary, amines has been converted to the
corresponding tertiary amines including [N-13C]-labelled
drugs in good to excellent yields under mild conditions.
Table 1. Methylation of N-methylaniline (1a): Testing different metal pre-
cursors.[a]
Entry
Catalyst
Conversion [%][b]
Yield [%][b]
2a 3a
1
2
3[c]
4[c]
5
6
7
8[d]
9
Fe(CF3SO3)2
Me2SAuCl
Pd(acac)2
Ru(acac)3
(NH4)2IrCl6
MeReO3
In(CF3SO3)3
[Pt] Karstedt’s catalyst
Pt(PPh3)4
Na2PtCl4
[Pt] Karstedt’s catalyst
–
91
87
99
98
99
85
90
>99
>99
>99
99
81
64
35
88
88
78
85
–
–
6
5
76
4
14
54
5
6
3
Methyl-substituted amines are valuable organic compounds in
both the bulk and fine chemical industries because of their use
in the manufacture of pharmaceuticals, agrochemicals, dyes,
etc.[1] Although the classic Eschweiler–Clarke methodology
using toxic formaldehyde as the C1 source prevails in indus-
try,[2] the most common methodology for methylations of
amines on the laboratory scale still makes use of activated
methyl compounds, such us methyl iodide, dimethyl sulfate,
MeOTf (OTf=trifluoromethanesulfonate) or diazomethane.[3]
Besides toxicity, the main drawback of these conventional
methylating reagents is the generation of stoichiometric
amounts of wasteful (in)organic salts. Thus, the development
of more environmentally acceptable processes that make use
of eco-friendly reagents is highly desired. In this regard, during
the last decade, dimethyl carbonate and methanol have been
presented as interesting green alternatives.[4] In addition, very
recently interesting N-methylations using CO2 have been re-
ported by Cantat et al., Klankermayer and Leitner et al., as well
as our group.[5–7] Unfortunately, so far the use of these attrac-
tive green alternatives requires high-temperature and/or pres-
sure operations, which make the laboratory-scale synthesis dif-
ficult.
1
>99
94
86
92
2
10
11[e]
12[f]
83
[a] Reaction conditions: 1a (0.5 mmol), HCO2H (2 equiv), PhSiH3 (3 equiv),
catalyst (1 mol%), nBu2O (1 mL). [b] Determined by GC using n-hexade-
cane as an internal standard. [c] acac=acetylacetonate. [d] HCO2H
(1.5 equiv), PhSiH3 (2.5 equiv), catalyst (0.5 mol%). [e] Catalyst (0.1 mol%).
[f] Without catalyst.
formic acid and silanes for the construction of the methyl
group under mild reaction conditions. At the start of our work,
the reaction of N-methylaniline (1a) with formic acid in the
presence of silanes at room temperature was investigated as
a benchmark system.[11] To identify active catalysts, we tested
different metal precursors by using phenylsilane as reductant.
As shown in Table 1, Pt metal precursors were the most active
catalysts (Table 1, entries 8–10) and to our delight, full conver-
sion with 99% yield of N,N-dimethylaniline (3a) was achieved
in the presence of 0.5 mol% of the commercially available so-
called Karstedt’s catalyst ([Pt(CH2=CHSiMe2)2O]) in the absence
of any additional ligand (Table 1, entry 8). Interestingly, even at
0.1 mol% catalyst loading, 3a was afforded in 92% yield
(Table 1, entry 11; see also Supporting Information, Table SI3).[12]
Without catalyst, N-methylformanilide (2a) was formed in 76%
yield and only traces of the dimethylated product 3a (2%)
were detected (Table 1, entry 12). Next, the methylation of 1a
was studied in the presence of different arylsilanes, polyme-
thylhydrosiloxane (PMHS) and alkoxysilanes (Table SI1 in the
Supporting Information). Among the various silanes tested, the
initially used phenylsilane remained as the best reagent, which
led to quantitative yield. Reaction in the absence of phenylsi-
lane gave no conversion towards the dimethylated product
3a. Notably, use of non-protic solvents, such as nBu2O, Et2O,
THF, toluene, or 1,4-dioxane have no noticeable influence on
the conversion and only slightly lower yields were obtained for
the last two solvents (Table SI2 in the Supporting Information).
Finally, optimal quantities of phenylsilane and formic acid were
found to be 2.5 and 1.5 equivalents, respectively (Table 1,
entry 8; see also Supporting Information, Table SI4).
Formic acid (FA) is one of the major products formed in bio-
mass processing and also easily accessible by hydrolysis of
methyl formate or by CO2 hydrogenation. Notably, it is a non-
toxic liquid, which is used for food preservation. In organic
synthesis, FA is well established in transfer hydrogenation reac-
tions,[8] and more recently formic acid has been intensely inves-
tigated as a suitable liquid for hydrogen production and as
a potential hydrogen storage material.[9] The reaction of
amines with formic acid to form the corresponding forma-
mides is well known.[10] Owing to its non-toxicity, biodegrada-
bility, and good reactivity with amines, FA offers great poten-
tial as a benign C1 feedstock for the synthesis of N-methyla-
mines after catalytic deoxygenation. However, to the best of
our knowledge, methylation reactions using formic acid as
a building block remain elusive under both heterogeneous
and homogeneous catalysis.
Herein, we describe for the first time a general and selective
Pt-catalyzed methylation of a range of amines employing
[a] Dr. I. Sorribes, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock
Albert Einstein Str. 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
After investigating the benchmark system, we were interest-
ed in the reaction of more challenging primary amines. By
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402124.
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Chem. Eur. J. 2014, 20, 1 – 7
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!