Selective Monomethylation of Amines with Methanol as the C1 Source

Article abstract of DOI:10.1002/anie.201801524

The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.

Full text of DOI:10.1002/anie.201801524

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Accepted Article
Title: Selective Monomethylation of Amines Using Methanol as the C1
Source
Authors: Geunho Choi and Soon Hyeok Hong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801524
Angew. Chem. 10.1002/ange.201801524
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10.1002/anie.201801524
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COMMUNICATION
Selective Monomethylation of Amines Using Methanol as the C1
Source
Geunho Choi and Soon Hyeok Hong*
Dedicated to Professor Young Keun Chung on the occasion of his honorable retirement
Abstract: The N-monomethyl functionality is a common motif in a
variety of synthetic and natural compounds. However, facile access
to such compounds remains a fundamental challenge in organic
synthesis owing to selectivity issues caused by overmethylation. To
address this issue, the selective, catalytic monomethylation of various
structurally and functionally diverse amines including typically
problematic aliphatic primary amines was developed using methanol
as the methylating agent, which is a sustainable chemical feedstock.
Kinetic control of the aliphatic amine monomethylation was achieved
using a readily available ruthenium catalyst under an adequate
temperature and hydrogen pressure. Various substrates including
bio-related molecules and pharmaceuticals were selectively
monomethylated, demonstrating the general utility of the developed
method.
suffer from a narrow scope of aliphatic amines and low selectivity
to N-monomethylamine.
N-methylation is one of the most fundamental C–N bond forming
reactions in organic chemistry. The N-methyl group is commonly
found in natural products and bioactive molecules[1] and plays an
important role in various biological processes where some
congeners show enhanced activity compared to that of non-
methylated precursors.[2] Although N-monomethylation of amines
seems to be relatively easily accomplished using a methylating
reagent such as a methyl halide via an SN2 mechanism,
overmethylation presents a serious issue due to the increased
nucleophilicity of the amine following monomethylation as well as
the smallest size of the methyl group among the alkyl groups.[3]
Therefore, to prevent the overmethylation, conventional
syntheses of N-monomethylamines from primary amines require
protection and deprotection steps that reduce the atom-efficiency
of the overall process.[4]
Scheme 1. Synthetic strategies for N-monomethylation of primary amines
Methanol can serve as a sustainable and atom-economical
C1 source for the methylation of amines as it only produces water
as a byproduct when a borrowing hydrogen methodology is
applied.[10] However, because of the higher enthalpy of the
dehydrogenation of methanol (ΔHo = +92.4 kJ mol-1 in gas phase)
as compared with other alcohols such as ethanol (ΔHo = +68.6 kJ
mol-1 in gas phase), the use of methanol has been relatively
limited as compared with that of other higher alcohols.[11] In
addition, due to the significantly decreased steric effects,
selective monomethylation is more difficult to achieve with
methanol.[7a] Although the monoalkylation of aliphatic amines via
dehydrogenative C–N coupling reactions has been well
established with various alcohols,[12] N-methylation using
methanol has only been developed for the dimethylation of
The selectivity problem has been addressed in literature to
some extent, yet most accounts have focused on the N-
monomethylation of less nucleophilic aromatic amines.[5] Limited
methods have been reported for aliphatic amines (Scheme 1a).
For example, the Dalcanale group used a host-guest approach
and MeI to achieve selective N-monomethylation of aliphatic
amines.[6] N-monomethylation using other electrophiles, such as
MeOTf, dimethyl phosphite, or dimethyl carbonate, have also
been explored.[7] However, the aforementioned approaches could
be viewed as non-environmentally benign or inefficient with
regards to atom-economy. Recently, more atom-economical
[8]
approaches that feature CO2 and paraformaldehyde[9] as the
aliphatic amines[10, 13] or the monomethylation or dimethylation of
methylating reagents were also reported, but these methods
13c, 14]
aromatic amines[10,
(Scheme 1b). Overall, the selective
monomethylation of aliphatic amines using methanol has not
been well presented. The first methylation using methanol was
developed by the Grigg’s group in 1981, yet a narrow substrate
scope was reported.[15] Since then, to the best of our knowledge,
only two examples of the monomethylation of amino alcohols
using methanol were reported, albeit with poor selectivity and
under harsh supercritical conditions (300 °C and a pressure
greater than 8 MPa).[16] Herein, we describe the development of
[*]
G. Choi, Prof. Dr. S. H. Hong
Department of Chemistry, College of Natural Science, Seoul
National University, 1 Gwanak-ro, Seoul 08826 (South Korea)
E-mail: soonhong@snu.ac.kr
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201801524
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a selective N-monomethylation method using methanol as the C1
source with a commercially available Ru catalyst, which could be
applied to structurally and functionally diverse aliphatic and
aromatic amines, including biologically relevant substrates
(Scheme 1c).
yield of 1b (82%, entry 7). Decreasing the catalyst loading by half
resulted in a decreased conversion (34%, entry 8).
Table 1. Optimization of N-monomethylation[a]
In the previous reports, formamide was synthesized using
amine and methanol as the C1 source via the dehydrogenation of
the hemiaminal intermediate.[17] We hypothesized that the
pathway for the monomethylamine could be controlled through
the dehydration of the hemiaminal intermediate under reducing
conditions. Hydrogen gas was chosen as the reducing agent
because H2 could retard the dehydrogenation of hemiaminal A,
and could facilitate the hydrogenation of imine B, which would
form via dehydration of hemiaminal A (Scheme 2). It was
envisioned that further methylation of the secondary amine could
be kinetically controlled by suitable catalytic conditions, as the
formation of the charged iminium intermediate D could have a
higher activation barrier than that of the neutral imine B.
Entry
1[b]
2
Time[h]
6
T [°C]
150
150
150
130
120
110
120
120
Conv.[%]
95
1b [%]
61
1c [%]
1d [%]
5
-
29
7
6
65
57
3
12
>99
>99
51
33
55
32
-
12
9
4
12
55
5
12
41
1
6
12
18
13
-
-
7
24
93
82
5
-
6
8[c]
24
34
30
-
[a] Reaction condition: 1a (1 mmol), methanol (1.5 mL), 1 (2 mol%), and H2
(4.0 MPa) in a closed vessel; yields were determined by 1H NMR using p-
xylene as an internal standard. [b] H2 2.0 MPa. [c] Catalyst 1 (1 mol%)
With the optimal conditions in hand (entry 7, Table 1), the
scope of the N-monomethylation reaction was investigated
(Scheme 3 and Scheme S2). For aliphatic amines, the resulting
reaction mixture was directly subjected to a Boc protection
protocol for facile isolation of the products (Scheme 3).
Benzylamine gave 77% of the N-monomethylated amine (1bb).
Benzylamine derivatives in the 2, 3, and 4-position with methyl
substituents afforded the corresponding secondary amines in
excellent yields (2bb–4bb). Benzylamines with both electron
donating and deficient groups resulted in the corresponding
products (5bb–7bb) in good yields. Other aliphatic amines (8a–
12a), including cyclic (10bb) and acetal-containing (11bb)
substrates provided moderate to good yields of the desired
products. To our delight, amines with pyridine and thiophene
heterocycles were also tolerated to afford the monomethyl amines
in excellent yields (13bb and 14bb). Methylation of 1-
adamantylamine (15bb), which is bulky α-tertiary amine, took
place with good selectivity upon addition of 3 equiv of water.[18] It
is also worth mentioning that no epimerization occurred at the
stereogenic center of the amine (α-position; 16bb). Interestingly,
secondary amines were smoothly converted into tertiary amines
(17b and 18b). Aromatic amines exhibited little reactivity under
the optimal catalytic conditions,[19] such that a primary aliphatic
amine could also be selectively methylated in an excellent yield
even in the presence of a secondary aromatic amine (20bb).
Further investigations revealed that aromatic amines could also
be selectively methylated, with no formamide product, under the
modified reaction conditions without H2 in excellent yields (19b
and Table S2). Various aromatic amines were smoothly
methylated (22b–28b) including amines with heterocycles (26b
and 27b) and bulky naphthylamine (28b) without H2. Substrates
with reducible functional groups such as olefin, alkyne, nitrile, and
ester were not tolerant under the reaction conditions. To our
Scheme 2. Proposed reaction pathway
Initial attempts using benzylamine (1a) and methanol in the
presence of Ru-MACHO-BH (1, Scheme 3) did not yield any of
the methylated product. Instead, N,N-benzylmethylformamide
(1d) and N-benzylformamide (1e) resulting from the formylation of
the amine were obtained (Scheme S1). Consistent with our
previous assumption, in the presence of H2, the formamide
formation reactions were dramatically suppressed and
monomethylated N-methyl benzylamine (1b) was produced in
61% yield (entry 1, Table S1). Inspired by this result, various
transition metal complexes, which are known to mediate
hydrogen transfer reactions, were screened, and 1 was identified
as the most efficient catalyst with the highest yield of 1b. No
products were detected in the absence of the catalyst (entry 9,
Table S1).
Further optimization studies were performed using complex 1
(Table 1). Increasing the hydrogen pressure (from 2.0 to 4.0 MPa)
improved the selectivity (entries 1–2, Table 1). Although
prolonged reaction times (from 6 to 12 h) led to the complete
conversion of the amine, the selectivity of the monomethylated
product 1b (33%) decreased significantly, with dimethylated
product 1c (55%) being the major product (entry 3). The reaction
temperature critically affected both conversion and selectivity
(entries 3–6). Reducing the temperature to 120 °C and extending
the reaction time to 24 h afforded both the best selectivity and
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surprise, when aliphatic primary and secondary amines were
present in the same molecule, the primary amine underwent
selective methylation to secondary amines (21bb) with only a
trace amount (<2%) of the undesired methylated product (21c’,
Scheme S2). To the best of our knowledge, this is the first
example among N-methylation protocols that highlighted the
reactivity difference between aliphatic primary and secondary
amines. Overall, the protocols could be applicable to both
aliphatic and aromatic amines with an appropriate level of chemo-
selectivity with respect to N-methylation.
Scheme 3. Monomethylation of amines using methanol as C1 Source. [a] Aliphatic amine conditions: amine (1 mmol), methanol (1.5 mL), 1 (2 mol%), and H2 (4
MPa) at 120 °C oil bath for 24 h in a closed vessel; Boc-protection was conducted after the reaction for facile isolation of the product; isolated yields after Boc
protection. [b] Aromatic amine conditions: amine (1 mmol), methanol (2 mL), and 1 (5 mol%) at 150 °C oil bath for 24 h in a closed vessel. [c] 2.0 MPa of H2. [d]
140 °C. [e] 110 °C. [f] 130 °C. [g] 3 eq. of H2O. [h] 12 h. [i] 160 °C. [j] 0.3 eq. of K2CO3
Next, the developed methodology was applied for the
monomethylation of bio-related compounds or pharmaceuticals.
For example, putrescine, a diamine that is involved in a biological
to the presence of an acidic phenol. The addition of 0.3 equiv of
K2CO3 provided the methylated product 30bb in a moderate yield
(34%). Memantine (31a) and mexiletine (32a), a commercially
pathway,[20] was monomethylated to give a moderate yield (29bb). available Alzheimer drug[22] and anesthetic reagent,[23]
Tyramine, a noradrenaline transporter,[21] exhibited poor reactivity
(10% yield of 30b) under the optimized conditions, most likely due
respectively, were successfully converted into methylated
products in good yields (64% and 71%, respectively). 1,3-
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Dimethylbutylamine (DMBA) (33a), which was reported as a
pressor substance,[24] also showed moderate reactivity (35%).
Oenethyl (34bb)[25] was synthesized from the precursor in a good
yield (76%) using the developed methodology. Finally, the
methylation protocol was applied for the last step in a multi-step
synthesis of atomoxetine (35bb), which is among the top 100
best-selling ADHD drugs,[26] resulting in a good yield (65%).
consumed (Figure 1). The results indicated that primary amines
were more reactive in the methylation when both primary and
secondary amines were present in the reaction mixture. A
moderately low temperature was preferred for selectivity, as the
initially formed monomethylated product could be further
methylated at a higher temperature of 150 °C (Figure S5) implying
that kinetic control is critical to the reaction.
To understand the unusual selectivity of primary amines over
secondary N-methyl amines, the reaction profile was investigated.
Complete conversion of primary amine 1a to N-methyl amine 1b
was observed under the developed conditions (Figure S1).
Dehydrogenation of methanol was suggested as the rate-limiting
step based on the primary KIE of methanol (kH/kD = 4.51) and the
zeroth order to the concentration of 1a (Figures S1 and S2). In the
absence of H2, formamide was formed as the major product
(Figure S3 and Scheme S1), which is consistent with the
literature.[27] When 1d was subjected to the developed reaction
conditions, the formation of 1b and 1c was observed, suggesting
that the amide reduction and amine formylation reactions were
reversible (Scheme S3). These results indicated that the addition
of H2 inhibited the dehydrogenation steps to generate e and d,
letting the dehydration pathways more productive (Scheme 2). As
no amide product was generated in the case of the aromatic
amine without H2 (19a), dehydrogenation of the hemiaminal
intermediates from aromatic amines may be less favored than
dehydration even in the absence of H2, which would lead to the
selective methylation.[28]
In conclusion, N-monomethylation of amines was achieved in
a highly selective manner using methanol as the C1 source.
Various amines including challenging aliphatic primary amines,
aromatic amines, and bio-related compounds were selectively
monomethylated in moderate to excellent yields with good
functional group tolerance. By adjusting the reaction conditions,
aliphatic amines were selectively methylated in the presence of
aromatic amines. In addition, primary amines were also
selectively monomethylated even in the presence of secondary
amine moieties. Control experiments indicated that the presence
of hydrogen was essential to control dehydration over
dehydrogenation of the hemiaminal intermediate. Reaction
temperature was found to be important for kinetically controlling
the selectivity between N-monomethylation and N,N-
dimethylation. The present study demonstrated that selectivity
control in N-methylation—a fundamentally challenging task in
traditional organic synthesis—can be achieved via transition
metal catalysis with high atom-economy using methanol as the
methylating reagent.
Acknowledgements
This work was supported by the National Research Foundation of
Korea
(NRF-2015M3D3A1A01065480,
NRF-
2014R1A2A1A11050028, and NRF-2014R1A5A1011165).
Keywords: N-monomethylation • primary amine • methanol •
dehydrogenation • ruthenium
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Entry for the Table of Contents
COMMUNICATION
Geunho Choi, Soon Hyeok Hong*
Page No. – Page No.
Selective monomethylation of amines
using methanol as the C1 source
Primary, be secondary, not tertiary! Selective N-monomethylation of primary
amines using methanol as the C1 source is developed using a commercially
available Ru catalyst. Kinetic control under proper temperature and hydrogen gas
enables the selective monomethylation of both aliphatic and aromatic amines,
which is challenging to control via traditional synthetic methods.
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