Efficient Cobalt-Catalyzed Methylation of Amines Using Methanol

Article abstract of DOI:10.1002/adsc.201701044

The methylation of amines using methanol is a promising route to synthesize N-methylamines, and the development of cheap and efficient catalytic system for this reaction is of great significance. Herein, we reported a cobalt (Co)-based catalytic system, which was in situ formed from commercially available Co precursor and a tetradentate phosphine ligand P(CH₂CH₂PPh₂)₃ combined with K₃PO₄. This catalystic system was very effective for the selective production of dimethylated products from aliphatic amines and monomethylated ones from aromatic amines. The reaction mechanism was further investigated by control and isotope labelling experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.201701044

Title: Efficient Cobalt-Catalyzed Methylation of Amines Using Methanol
Authors: Zhenghui Liu, Zhen-Zhen Yang, Xiaoxiao Yu, Hongye Zhang,
Bo Yu, Yanfei Zhao, and Zhimin Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701044
Link to VoR: http://dx.doi.org/10.1002/adsc.201701044

10.1002/adsc.201701044
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Efficient Cobalt-Catalyzed Methylation of Amines Using
Methanol
Zhenghui Liu,†a, b Zhenzhen Yang,†a Xiaoxiao Yu,a, b Hongye Zhang,a Bo Yu, a Yanfei
Zhaoa and Zhimin Liu*a, b
a
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Colloid, Interface and Thermodynamics, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China. E-mail: liuzm@iccas.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China.
b
†
These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
using reducing agents such as silanes or boranes
has been presented for the production of N-
methylamines under milder conditions, however,
availability and energy requirements for the
reducing reagents, as well as the E factor caused
by the by-products still remain an issue.[9-10]
Although the use of H2 can overcome these
limitations, precious metal catalysts and high
pressure are still required.[1, 5]
N-methylation of amines using methanol is a
promising green and sustainable method for
synthesis of N-methylamines with H2O as the
only byproduct. The main challenge lies in the
requirement of higher activation energy for
methanol dehydrogenation (ΔH = +84 kJ mol-1)
compared with other higher alcohols (e.g. ΔH
(EtOH) = +68 kJ mol-1).[11] Apparently, the
energy barrier to the activation of smaller
alcohols appeared to be too uphill.[12] Up to now,
methylation of amines with methanol has been
achieved over expensive and rare second/third-
Abstract. The methylation of amines using methanol is a
promising route to synthesize N-methylamines, and the
development of cheap and efficient catalytic system for this
reaction is of great significance. Herein, we reported a
cobalt (Co)-based catalytic system, which in situ formed
from commercially available Co precursor and
a
tetradentate phosphine ligand P(CH2CH2PPh2)3 combined
with K3PO4. This catalystic system was very effective for
the selective production of dimethylated products from
aliphatic amines and monomethylated ones from aromatic
amines. The reaction mechanism was further investigated
by control and isotope labelling experiments.
Keywords: Amines; C-N bond formation; Cobalt;
homogeneous catalysis; Alkylation
Development of novel methods for amine
synthesis is of paramount importance in organic
chemistry.[1] N-methylamines are key structure
motifs in various biologically active natural
compounds and hence are an integral part of
tremendous pharmaceutical and agrochemical
products (for example, Lexapro, Venlafaxine,
Pheniramine and Piriton).[2] General methods to
introduce methyl group often involve the use of
hazardous methylating agents, such as methyl
iodide, dimethyl sulfate or diazomethane,
accompanied with the drawbacks of low product
selectivity, toxic byproduct generation, expensive
and tedious downstream processing.[3] In
addition, industrial production of methyl amines
still depends on the reductive amination using
row
transition-metal
catalysts
such
as
homogeneous Ru[13-15] and Ir[16-17] complex, and
heterogeneous Lewis acid catalysts under harsh
reaction
conditions
(>240
oC).[18]
The
replacement of the scarce and expensive noble
metals by cheaper, more abundant and less toxic
first-row transition metals, such as iron or cobalt,
is of significance from the view point of the
sustainable development. Although N-alkylation
of amines or C-alkylation of ketones with higher
alcohols has been realized taking Fe,[19] Co,[20-26]
Mg[12] and Mn[27] complexes in the presence of
base, ligands or other additives, methanol was
scarcely utilized in these catalytic systems.
Recently, Betller et al. reported a lutidine-based
Mn PNP-pincer complex for the selective N-
methylation of aromatic amines with methanol in
the presence of KOBu-t.[28]
toxic
formaldehyde
(Eschweiler-Clarke
methylation).[4] Hence, development of efficient
methylation protocols utilizing safer methylating
agents and cheaper catalytic systems is of
paramount importance and highly desirable.
Recently, reductive methylation of amine with
CO2,[5-6] dimethyl carbonate,[7] or formic acid[8]
1
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10.1002/adsc.201701044
Advanced Synthesis & Catalysis
Table 1. Cobalt-catalyzed N-methylation of morpholine
(1a) with MeOH.a)
Herein, we presented
a
cobalt-based
catalytic system, which was generated in situ
from a commercially available Co precursor and
a tetradentate phosphine ligand P(CH2CH2PPh2)3
(PP3) combined with K3PO4, for the methylation
of amines to the corresponding methyl-
substituted products, using methanol as the
methylating reagents and reducing agent. This
catalytic system was very effective for the
selective production of dimethylated products
from aliphatic amines and of monomethylated
ones from aromatic amines. The reaction
mechanism was further investigated by control
and isotope labelling experiments.
Ent [Co]
ry
Base
ligan
d
1a
2a
Con Yiel
v./
d/%b
b)
)
%
<1
95
3
1
-
-
-
<1
91
1
<1
7
2
3
Co(ClO4)2·6H2O
-
K3PO4
K3PO4
K3PO4
-
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
PP3
PP3
-
PP3
PP3
PP3
PP3
PP3
PP3
4
5
6
Co(ClO4)2·6H2O
Co(ClO4)2·6H2O
Co(acac)2
<1
8
>99 >99
>99 94
>99 94
93
93
84
Initially, the methylation reaction of morpholine
(1a) with methanol was selected to screen the
reaction conditions. As shown in Table 1, almost no
N-methylmorpholine (2a) was formed when blank
experiment was performed in the absence of any
7
8
9
10
11
12
13
Co(BF4)2·6H2O
CoCl2·6H2O
Co(NO3)2·6H2O
Co(OAc)2·4H2O
Co(acac)2
Co(acac)2
Co(acac)2
89
85
77
Na3PO4 PP3
K2CO3 PP3
KOBu- PP3
o
catalyst and ligand at 140 C within 24 h (<1%)
>99 83
91
(Table 1, entry 1). However, in the presence of cobalt
precursor (Co(ClO4)2·6H2O) in combination with the
ligand (PP3) and base (K3PO4), 91% yield of 2a was
obtained (Table 1, entry 2), indicating the high
efficiency of this cobalt-based catalytic system.
Besides the product 2a, trace amount of 2,6-
dimethylmorpholine was also detected as a by-
product. Subsequently, the influences of the metal
centers, ligands as well as the bases on the reaction
were investigated. It was indicated that the yields of
2a were sharply decreased to <1%~7% in the absence
of PP3 or K3PO4 (entries 2 vs. 3~5), suggesting that
besides the cobalt catalyst the ligand (PP3) and the
base (K3PO4) were indispensible for getting high 2a
yields. The catalytic activities of other cobalt
precursors including Co(acac)2, Co(BF4)2·6H2O,
CoCl2·6H2O, Co(NO3)2·6H2O and Co(OAc)2·4H2O,
were also tested in the presence of PP3 and K3PO4,
and the 2a yields of 85%~>99% were achieved
(entries 6-10). Especially, Co(acac)2 affored a 2a
yield of >99% without any byproduct (entry 6).
Hence Co(acac)2 was selected for further
investigation.
75
t
14
15
16
17
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
KOAc
KOH
KBr
PP3
PP3
PP3
tripho
s
91
61
12
7
80
48
7
K3PO4
3
18
19
20
Co(acac)2
Co(acac)2
Co(acac)2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
dppe
PPh3
biPy
PP3
PP3
PP3
PP3
PP3
9
7
3
71
93
57
99
77
2
3
<1
64
91
56
94
71
21c) Co(acac)2
22d) Co(acac)2
23e) Co(acac)2
24f) Co(acac)2
25g) Co(acac)2
a)
Reaction conditions: 1a 1 mmol, Co species 5 mol%,
The bases also had significant influence on the
reaction (Table 1, entries 6, 11-16). The yield of 2a
was decreased from >99% to 77% when Na3PO4 was
used in stead of K3PO4, probably owing to the
decreased basicity (entry 6 vs. 11). Other basic
potassium salts such as K2CO3, KOBu-t and KOAc
displayed moderate catalytic efficiency, offering
75%~83% yields of 2a (entries 12-14). However,
inferior catalytic efficiency was observed in the case
of KOH (2a yield: 48%, entry 15), while KBr only
gave a 2a yield as low as 7% (Entry 16). The ligands
also played an important role in the reaction. Other
commercially available tri-, bi- as well as
monodentate phosphine ligands, for example, triphos,
dppe and PPh3 afforded very low yields of 2a (entries
17-19). In addition, no catalytic efficiency was
observed when nitrogen-containing ligand BiPy was
utilized (Entry 20). The effects of the other reaction
parameters including temperature, catalyst loading,
ligand 5 mol%, base 1 mmol, MeOH 3 mL, oil bath 140
b)
oC, 24 h.
Determined by GC using dodecane as an
internal standard. c) 120 oC. d) Co(acac)2 2.5 mol%, PP3 2.5
e)
f)
g)
mol%.
K3PO4 0.5 mmol.
Reaction time 12 h.
Reaction time 6 h.
K3PO4 amount and reaction time on the reaction were
also investigated. It was indicated that the reaction
temperature was crucial to achieve high catalytic
efficiency, with the 2a yield decreasing to 64% as the
o
temperature decreased to 120 C (Entry 21). When
the catalyst loading of Co(acac)2/PP3 was decreased
to 2.5 mol%, 91% yield of 2a could still be obtained,
while decrease of the K3PO4 amount to 0.5 equiv. led
to only 56% yield of 2a (entry 23). The reaction was
almost completed within 12 h, with a 2a yield of 94%
obtained (entry 24), and a 2a yield of 71% was
detected within only 6 h (entry 25). Based on the
2
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10.1002/adsc.201701044
Advanced Synthesis & Catalysis
above experiments, the optimized reaction conditions
were obtained as listed in Scheme 1.
methanol for both primary/secondary aliphatic
amines and primary aromatic amines.
Subsequently, methylation of a broad range of
amines including aliphatic secondary and primary
amines and anilines was investigated under the
optimized reaction conditions (Scheme 1). Besides
morpholine (1a), other aliphatic secondary amines
could be well methylated using methanol in the
presence of Co(acac)2/PP3/K3PO4, giving the
corresponding products in good to excellent yields
(85% - >99% for 2a-2d). N- methylbenzylamines
with both electro-donating and electro- withdrawing
groups all exhibited excellent reactivity under our
reaction conditions, giving 85%-93% yields for 2e-2g.
For all the aliphatic primary amines investigated,
dimethylated products were obtained. Benzylamine
(1h) and those functionalized with electro-donating
group (1i and 1j) were all dimethylated, with
excellent product yields for 2h-2j (91%-95%), while
those substituted with electron-withdrawing groups
displayed slightly inferior reactivities, with 81% yield
of 2k and 78% yield of 2l. For n-butylamine (1m),
N,N-dimethylbutylamine (2m) was obtained in a
yield of 80%.
Significantly different results were obtained for
the methylation of aromatic amines. For the
methylation of aniline (1n), only monomethylated
product N-methylaniline (2n) was obtained in a yield
of 95% without dimethylated product under the
optimized conditions. Even 2 equiv. of K3PO4 was
used, 2n was still the main product in a yield of 95%.
As the reaction time was prolonged to 72 h, a high 2n
yield of 95% together with trace amount of N,N-
dimethylaniline was detected. This indicates that 2n
could not be further methylated under the
experimental conditions, which was consistent with
the experimental results catalyzed by Ru complex
reported before.[13] Other aromatic amines all
produced monomethylated products in the optimized
catalytic system. For electro-withdrawing groups
substituted anilines, 95% yield of 2o was achieved,
and comparatively, a slightly lower yield of 2p (87%)
was obtained, probably owing to the higher steric
hindrance of trifluoromethyl group. For nitrile group
substituted aniline (1q), the nitrile group was well
reserved, with 95% yield of the corresponding
methylated product 2q achieved, which was apt to be
reduced under H2 atmosphere. For the anilines with
electron-donating groups, 95% and 88% yields of 2r
and 2s were obtained, respectively. To study the
effect of positions of the substituted groups in the
benzene ring, meta- and ortho- subtituted anilines
were also used to conduct the methylation reaction.
The 2t-2v yields of 82%-95% illustrated the excellent
catalytic efficiency of our catalytic system to various
substituted aromatic amines. 2-Aminonaphthalene
(1w) with bulkier aromatic group also exhibited high
reactivity, with a 84% yield of 2w achieved. Hence,
from the above results it can be deduced that the Co-
based catalytic system developed in this work was an
highly efficient one for the methylation reaction by
a
Scheme 1. Methylation of amine with MeOH. Reaction
conditions: amine 1 mmol, Co(acac)2 5 mol%, PP3 5 mol%,
K3PO4 1 mmol, MeOH 3 mL, 140 oC, 24 h, unless
b
c
otherwise stated. K3PO4 2 mmol. Reaction time 72 h.
Number in the bracket was yield of N,N-dimethylaniline.
Yields of 2a-2d, 2m were determined by GC using
dodecane as an internal standard. Yields of 2e-2l and 2n-
2w were isolated yields, and the corresponding yields
determined by NMR were shown in SI. For details of
yields determination, see SI.
To explore the possible reaction mechanism,
some control and deuterium-labeling experiments
were performed. In the methylation/formylation
reaction with methanol catalyzed by Ru or Ir
complexes, formaldehyde was detected as an
intermediate, which was formed through the
[13, 29]
dehydrogenation of methanol.
Notably, the
formation of formaldehyde was detected using
dimedone solution (for experimental details, see SI).
In addition, paraformaldehyde instead of methanol
was examined for the methylation of morpholine (1a)
in the presence of Co(acac)2/PP3 without K3PO4. As
shown in Scheme 2a, 72% yields of methylated
product 2a was obtained using formaldehyde in
methanol,
indicating formaldehyde
as
the
intermediate could participate in the methylation
3
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10.1002/adsc.201701044
Advanced Synthesis & Catalysis
reaction in our catalytic system. Comparatively, using
methanol as the reaction media without formaldehyde
and K3PO4, only 5% yield of 2a was achieved
(Scheme 2b), illustrating the important role of base in
the formation of formaldehyde from methanol.
Taking secondary amine as an example, firstly, a Co-
methoxy complex (II) is formed in the presence of
base after coordination of Co species with PP3 (I),
which then transforms into Co-hydride (III)
intermediate through β-hydride abstraction, releasing
formaldehyde. The reaction of formaldehyde with the
amine produces methanolamine, which further
coordinates with Co-hydride (III) and forms
intermediate IV. Hydrogen transfer within IV leads
to formation of the Co-methylamine complex (V),
which releases the methyl amine product through re-
coordination of Co complex with methoxide. This is a
classical borrowing hydrogen strategy,[13, 30] during
which only one hydrogen atom is abstracted. During
the reaction process, two hydrogen atoms of the
terminal methyl group definitely come from the
methyl group of methanol, while the third hydrogen
atom may be introduced from methyl or hydroxyl
group of methanol as well as the hydrogen of the
amine due to the hydrogen exchange of intermediate
III with active hydrogen in the reaction system.
Therefore, for secondary amine, only product with
one hydrogen different from that of the methyl group
in the solvent was observed in the deuterium-labeling
experiments (Scheme 2e and 2f), while for primary
amine, products with one or two hydrogen atoms
different from that of the methyl group in methanol
was observed (Scheme 2g), as two methyl group
formation processes were needed. The possible
mechanism for the first methylation step of primary
amines is shown in Scheme S1 (SI).
Scheme 2. Control experiments and deuterium-labeling
experiments. Reaction conditions: amine
1
mmol,
Co(acac)2 5 mol%, PP3 5 mol%, K3PO4 1 mmol, solvent 3
o
mL, 140 C, 24 h, unless otherwise stated. For a~d, no
K3PO4 was added. For e~g, deuterium solvent was added.
For MS spectra of the product, see SI.
Deuterium-labeling experiments were also
carried out to further track the source of the methyl
group. As shown in Scheme 2c and 2d, the molar
ratio of 2a to the mono-deuterated 2a was both 10:1
for the methylation of 1a with formaldehyde in
CD3OD or CH3OD, indicating that the methyl group
mainly came from formaldehyde and the minor
mono-deuterated 2a may be obtained through
additional H/D exchange of the cobalt-hydride
intermediate (Scheme 3, III). Subsequently, the
methylation of 1a was further conducted in the
presence of Co(acac)2/PP3/K3PO4 using CD3OD or
CH3OD under the optimal reaction conditions. It can
be seen from the results (Scheme 2e and 2f) that the
three hydrogen atoms of methyl groups in 2a were
composed of two from the methyl group of methanol
CD3OD or CH3OD and one from hydroxyl group of
methanol or amine substrate 1a, implying the
involvement of dehydrogenation of methanol to form
formaldehyde and then hydrogen transfer from
cobalt-hydride intermediate (H/D exchange) to the
methyl amine product during the reaction process.
Based on the above results, a possible reaction
pathway was proposed as illustrated in Scheme 3.
Scheme 3. Proposed reaction mechanism for the
methylation of amines (secondary) with methanol
catalyzed by Co(acac)2/PP3/K3PO4.
In summary, a commercially available and
efficient cobalt-based catalytic system was developed
for the methylation of amines with methanol to the
corresponding
methyl-substituted
products,
generating dimethylated products for aliphatic amines
4
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10.1002/adsc.201701044
Advanced Synthesis & Catalysis
and monomethylated ones for aromatic amines with
high yields. Reaction mechanism investigation
showed a hydrogen-borrowing process.
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Experimental Section
General procedure for the N-methylation reaction
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To a stainless steel autoclave with a Teflon tube (25 mL
inner volume), Co(acac)2 (0.05 mmol), PP3 (0.05 mmol),
K3PO4 (1 mmol), amine (1 mmol) and MeOH (3 mL) was
added under N2 atmosphere successively. The autoclave
o
was sealed and stirred at 140 C for desired time. After
reaction, the autoclave was cooled down to room
temperature. Product yields of 2a-2d and 2m were
determined by GC using dodecane as an internal standard.
Products yields of 2e-2l and 2n-2w were firstly determined
by NMR using CH3NO2 as an internal standard and CDCl3
as solvent, and then isolated by column chromatography on
silica gel using petroleum ether/ethyl acetate/small amount
of triethylamine as eluent and identified by NMR and MS
spectra.
[22] S. P. Midya, A. Mondal, A. Begum, E. Balaraman,
Synthesis 2017, 49, 3957-3961.
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Org. Lett. 2017, 19, 1080-1083.
Acknowledgements
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The authors thank the National Natural Science Foundation of
China (Nos. 21673256, 21402208, 21403252).
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5
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10.1002/adsc.201701044
Advanced Synthesis & Catalysis
COMMUNICATION
Efficient Cobalt-Catalyzed Methylation of Amines
Using Methanol
Aromatic Aliphatic
or
Adv. Synth. Catal. Year, Volume, Page – Page
Co(acac)2/L/Base
or
MeOH
Zhenghui Liu,†a, b Zhenzhen Yang,†a Xiaoxiao
Yu,a, b Hongye Zhang,a Bo Yu, a Yanfei Zhaoa and
Zhimin Liu*a,b
L = P(CH2CH2PPh2)3
78%~99%, 23 examples
6
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