ACS Catalysis
Letter
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6
the transition metal catalyst activates methanol in situ by
dehydrogenation, forming formaldehyde, which condenses with
the amine to give another transient imine intermediate that
upon catalytic (transfer) hydrogenation forms the N-methy-
lated amine. Water is the only byproduct in this reaction and,
hence, could be considered as a promising green and
sustainable alternative N-methylation protocol, if methanol is
moderate yields (30−76%) with limited substrate scope.
A
cyclopentadienyl Ru−PPh complex was reported by Zotto et
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37
al. for the N,N-dimethylation of aliphatic amines at 100 °C;
however, the catalyst was shown to be inactive for the
methylation of anilines. Recently, Li and co-workers have
reported the first Ir-catalyzed methylation of aryl sulfonamides
providing N-monomethylated products in 71−97% isolated
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available through sustainable technologies.
N-Methyl amines are present in many important drug
yields; however, the reaction requires higher temperatures of
150 °C and stoichiometric amounts of a strong base. Crabtree
and co-workers reported selective N-monomethylation of
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5
39
molecules and bioactive natural products (Figure 1). In many
various anilines under microwave irradiation conditions at 120
°C using an iridium carbene complex catalyst in the presence of
1−5 equiv of KOH to achieve up to 95% yield. In general, these
reported catalyst systems require either harsh reaction
conditions or more than stoichiometric amounts of base to
achieve high yields when methanol is used as the methylating
agent following hydrogen borrowing strategy. Moreover, a
catalyst that works for both aromatic and aliphatic amines is
rare.
In our continued efforts to develope efficient methods for N-
40
alkylation using alcohols, we became interested in developing
efficient and selective N-methylation protocols for both
aromatic and aliphatic amines that work under relatively mild
operating conditions, preferably using readily available catalysts.
Herein, we report a highly efficient homogeneous ruthenium
catalyst for the selective N-monomethylation of aryl amines as
well as N,N-dimethylation of aliphatic amines using methanol
under mild operating conditions in the presence of 5 mol % of
LiOtBu.
Figure 1. Representative examples from pharmaceuticals containing
N-methylamines.
cases, the synthesis of selective N-monomethylated arylamine
intermediates is either challenging or requires many synthetic
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manipulations. A direct and selective N-monomethylation
using methanol could offer an alternative and attractive pathway
to access these intermediates in an efficient way.
RESULTS AND DISCUSSION
■
Initial optimization studies using methanol for the N-
methylation of aniline showed that homogeneous ruthenium
catalysts obtained in situ from [RuCl (p-cymene)] and a
Selective double N-methylation of aliphatic amines using
methanol could also be promising toward the synthesis of
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2
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important drugs such as Lexapro, Venlafaxine, Phenir-
bidentate phosphine ligand such as dpePhos could catalyze the
formation of N-methylaniline in 52% yield in the presence of
0.5 equiv of KOtBu as a base at 120 °C for 18 h (Table 1, entry
1). The yield was improved to 72% when [RuCp*Cl ] (Ru-2)
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amine, Piritone, etc. However, a major problem with
activation by dehydrogenation of methanol is that it requires
higher activation energy compared with other higher alcohols
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−1
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(
e.g. ethanol (ΔH = +84 vs +68 kJ mol )), thus posing
was used as the catalyst precursor (entry 2). Other common
challenges for its activation under relatively mild conditions.
In the past, N-methylation of amines with methanol was
mainly carried out using Lewis acid catalysts under harsh
ruthenium catalyst precursors (Ru-3−Ru-6 and RuCl ·xH O;
3
2
entries 3−7) gave inferior results compared with that of
[RuCp*Cl ] (Ru-2); hence, Ru-2 was selected as the catalyst
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reaction conditions. Supercritical methanol was also used in
the presence of solid acid−base bifunctional catalysts that give a
mixture of mono- and dimethylated amine products at 300 °C
precursor for further investigations.
A quick screening of different bases (entries 8−10) revealed
LiOH to be a better choice compared with KOtBu, resulting in
up to 89% yield. Several bidentate phosphine ligands
(XantPhos, NiXantPhos, dppf, dppe, BINAP) were examined
in the presence of 0.5 equiv of LiOH because the base at 120
°C gave inferior results (entries 11−18) compared with
dpePhos. Interestingly, quantitative yield was achieved when
0.5 equiv of LiOtBu (entry 19) was used as a base instead of
LiOH, even at a lower temperature of 100 °C after 24 h (entry
20). Interestingly, the amount of base could be further reduced
to 0.05 equiv without a significant decrease in the product yield
(entry 21). Reducing the temperature under this condition
decreased the yield to 82%; however, the yield was improved to
96% upon increasing the reaction time to 36 h (entry 22). The
amount of methanol can be reduced to 0.5 mL without
significant change in the product yield. Control experiments in
the presence of either 0.5 equiv of LiOtBu with no Ru catalyst
(entry 23) or the Ru catalyst in the absence of LiOtBu (entry
24) gave no product, indicating the requirement of both the Ru
catalyst and a suitable base for this N-methylation reaction. Any
31d,e
and 80 atm pressure in a continuous flow reactor.
In
contrast, room temperature N-methylation was reported to be
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possible using photocatalysts based on Pd/TiO
or Ag/
2
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3
TiO2 that selectively give the dimethylated product from the
respective primary amine under suitable UV irradiation.
Palladium on carbon (Pd/C or Pd(OH) /C) in the presence
2
of molecular hydrogen was reported to give the corresponding
tertiary methyl amine from primary or secondary amino acids at
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room temperature.
So far, only a few studies on transition metal-catalyzed N-
methylation of amines using methanol following hydrogen
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borrowing strategy have been reported.
Watanabe et al.
reported the first Ru-catalyzed N-methylation of various
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anilines at 180 °C. A high catalyst loading (20 mol % of
Ru) was employed to afford moderate yield (30−80%) of the
N-methylated amine products. Naskar and Bhattacharjee
described a cationic Ru−PPh complex for N-methylation of
3
aminoarenes to give the corresponding N-methyl arylamines in
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083
ACS Catal. 2015, 5, 4082−4088