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Table 1: Ruthenium-catalyzed methylation of N-methyl aniline with CO2
Table 2: Ruthenium-catalyzed methylation of substituted aromatic
and molecular hydrogen.[a]
amines with CO2 and molecular hydrogen.[a]
Entry Aniline
1
Product
t [h] Yield [%][b]
Entry
Acid (mol%)
T [Co]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
–
140
140
140
140
120
100
150
10
22
22
22
22
22
10
2
2
3
2a 22
90
90
HNTf2 (0.5)
HNTf2 (2.5)
HNTf2 (5)
HNTf2 (5)
HNTf2 (5)
HNTf2 (5)
11
84
97
81
58
99
2
3
3a 10
4a 10
[a] Reaction conditions: N-methylaniline 1 (1.0 mmol), [Ru(triphos)-
(tmm)] (2.5 mol%), THF (2 mL), CO2/H2 (20/60 bar); [b] Yield deter-
mined by gas chromatography using n-dodecane as internal standard.
4
35
4[c]
5
6
5a 20
5a 20
73
70
conversion of 1 in 10 h affording 1a in 99% yield (Table 1,
entry 7). The conversion/time profile under these conditions
is shown in the Supporting Information. In subsequent
experiments, full conversion of the starting material was
also achieved when using different acids such as methanesul-
fonic acid (MSA) and p-toluenesulfonic acid (p-TsOH; see
the Supporting Information for details).
The methylation of various substituted secondary anilines
under the standard reaction conditions was investigated
(Table 2). When halogen-substituted anilines were used, the
desired products were obtained in high yields up to 90% for
3-fluoro-N,N-dimethylaniline (2a; Table 2, entry 1) and 4-
chloro-N,N-dimethylaniline (3a; Table 2, entry 2). The elec-
tron-donating methoxy group in the 4-position of the
aromatic ring of 4 significantly reduced the reactivity
(Table 2, entry 3). When indoline 5 was used, the correspond-
ing N-methylated product 5a was obtained in respectable
73% yield (Table 2, entry 4). Indole 6 gave the same product
5a in similar yield through concomitant hydrogenation of the
5[c]
6
7
7
8
7a 15
8a 48
64
27
[a] Reaction conditions: Substituted aromatic amine (1.0 mmol), [Ru-
(triphos)(tmm)] (2.5 mol%), HNTf2 (5 mol%), THF (2 mL), CO2/H2
(20/60 bar), 1508C; [b] Yield determined by GC using n-dodecane as
internal standard. [c] Yield determined by NMR spectroscopy.
tuted N,N-dimethylanilines (Table 3). The use of aniline (9)
itself afforded the corresponding dimethyl aniline 1a in 94%
yield (Table 3, entry 1). 4-Chloroaniline (10) gave 4-chloro-
N,N-dimethylaniline (3a) in 93% yield (Table 3, entry 2),
providing an interesting building block for further function-
alization at the chloro substituent. Fluorine-containing pri-
mary anilines, such as 2-fluoroaniline (11) and 3-trifluoro-
methyl-p-toluidine (12) also provided the dimethlyated
products in excellent yields (Table 3, entries 3 and 4), thereby
giving access to fluorine-substituted tracers for 19F-NMR-
based screening in metabolism studies.[16] Even highly sub-
stituted 2,4,6-trimethylaniline (13) afforded 13a with a yield
of 84% (Table 3, entry 5).
Finally, we investigated the possibility to use this new N-
methylation reaction in a sequential hydrogenation/methyl-
ation reaction to access unsymmetrical methyl/alkyl anilines
from the corresponding amides. As prototypical substrate,
acetanilide (14) was transformed successfully to N-ethyl-N-
methylaniline (14a) in 69% yield (Scheme 2). Since mono-
amidation is much more readily achieved than monoalkyla-
tion, this unprecedented sequence offers a synthetically
powerful method for the construction of unsymmetrical
dialkyl anilines using CO2 and H2.
=
C C double bond (Table 2, entry 5). A slightly lower yield of
64% was obtained for the direct methylation of N-cyclo-
hexylaniline (7; Table 2, entry 6). Diphenylamine (8) showed
very low reactivity (Table 2, entry 7), and secondary alkyl
amines were not methylated.
For the aryl,alkyl-amines 1–6 the results suggest a qual-
itative trend towards lower reactivity with increasing basicity
of the substrate. This was tentatively associated with a reduced
availability of protons inhibiting the formation of the active
[Ru(triphos)H]+ species. In agreement with this consider-
ation, higher loadings of the acid cocatalyst were found to
highly promote the reactivity of 4-methoxy-N-methylaniline
(4; for more details see the Supporting Information).
The dimethyl aniline moiety is widely found in many
bioactive compounds, pharmaceuticals, and materials such as
edrophonium-based compounds, which are used as cholines-
terase inhibitor,[13] mifepristone, which is a progestational
hormone antagonist,[14] and eserine, which is a binding agent
for molecularly imprinted polymers (MIPs) used in molecular
imprinting technology.[15] Thus we attempted to extend the
scope of the direct methylation reaction to primary substi-
tuted anilines leading directly to the corresponding substi-
Since amides are readily reduced under the established
catalytic conditions, a plausible reaction pathway for the
2
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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