Metal-free catalyst for the chemoselective methylation of amines using carbon dioxide as a carbon source

Article abstract of DOI:10.1002/anie.201407689

N-methylation of amines is an important step in the synthesis of many pharmaceuticals and has been widely applied in the preparation of other key intermediates and chemicals. Therefore, the development of efficient methylation methods has attracted considerable attention. In this respect, carbon dioxide is an attractive C₁ building block because it is an abundant, renewable, and nontoxic carbon source. Consequently, we developed a highly chemoselective, metal-free catalytic system that operates under ambient conditions for the N-methylation of amines. The methylation of amines with CO₂ as C₁ source and Ph₂SiH₂ as reducing agent was achieved with an N-heterocyclic carbene (NHC) as the catalyst. The catalyst is tolerant toward a variety of functional groups (including esters and ethers, nitro, nitrile, and carbonyl groups, and unsaturated C-C bonds); the reaction uses commercially available reagents and can be performed on a gram scale.

Full text of DOI:10.1002/anie.201407689

Angewandte
Chemie
DOI: 10.1002/anie.201407689
Methylation
Hot Paper
Metal-Free Catalyst for the Chemoselective Methylation of Amines
Using Carbon Dioxide as a Carbon Source**
Shoubhik Das, Felix D. Bobbink, Gabor Laurenczy, and Paul J. Dyson*
Abstract: N-methylation of amines is an important step in the
synthesis of many pharmaceuticals and has been widely
applied in the preparation of other key intermediates and
chemicals. Therefore, the development of efficient methylation
methods has attracted considerable attention. In this respect,
carbon dioxide is an attractive C1 building block because it is
an abundant, renewable, and nontoxic carbon source. Con-
sequently, we developed a highly chemoselective, metal-free
catalytic system that operates under ambient conditions for the
N-methylation of amines.
catalyst for the synthesis of N-methylated compounds from
amines, nitriles, and nitro compounds, also employing CO2
and H2 to generate the methyl group.[10]
Harsh reaction conditions and poor functional-group
tolerance led to the application of other reducing agents,
such as hydrosilanes,[11] which, when applied with homoge-
neous ruthenium- and zinc-based catalysts, afforded N-
methylated compounds under comparatively mild reaction
conditions.[12,13] Nevertheless, the development of new effi-
cient and chemoselective catalysts for this type of reaction
(employing CO2 as a C1 source) remains important.
C
arbon dioxide is an abundant, safe, and renewable carbon
source and therefore an attractive C1 building block for the
formation of organic molecules.[1–5] Indeed, much progress has
been made in the catalytic activation of CO2 by reactive
substrates, such as epoxides, alcohols, amines, and alkynes, to
À
À
form new C O and C C bonds and, in some cases, industrial
processes have been developed.[6] In contrast, the formation
À
of C N bonds using CO2 as a C1 source to afford N-
methylated compounds remains challenging, although several
promising systems have been reported (Scheme 1). Nonethe-
less, the development of highly active catalysts for this
transformation could have a significant impact on future
chemical resources, with the sustainable replacement of toxic
organic reagents in a number of chemical processes.
N-methylated compounds are important intermediates in
the chemical industry,[7] the functionality being found in
medicines, agrochemicals, dyes, and perfumes. Currently,
formaldehyde is used in industrial N-methylations, whereas
methyl iodide and dimethylsulphates are usually employed in
methods on a small scale.[8] As CO2 is cheap, abundant and,
nontoxic, it represents an ideal alternative to these environ-
mentally hazardous and toxic reagents.
In seminal papers, Beller et al. and Leitner et al. described
ruthenium-based catalysts that mediated the N-methylation
of amines using CO2 and H2 as sources for the methyl group.[9]
Subsequently, Shi et al. reported a new heterogeneous
Scheme 1. Methods of N-methylation using CO2 as a C1 source.
a) Currently known routes. b) New route using commercially available
reagents, enabling gram-scale reactions, and characterized by unprece-
dented functional-group tolerance.
We decided to evaluate suitable organocatalysts for this
type of transformation,[14] in part because of their low cost and
low toxicity. Notably, N-heterocyclic carbenes (NHCs) have
attracted much interest,[15] as they can behave as nucleophiles
and may activate CO2 to form imidazolium carboxylates.[16]
The propensity of NHCs to form carboxylates could be
exploited to give metal-free catalysts for the transformation
of CO2.
In the course of identifying and optimizing key reaction
parameters for the reaction of N-methylaniline (1a) with
Ph2SiH2 as a model system, several NHCs were investigated
as potential catalysts (Table 1). In the presence of 5 mol% of
NHC B and 3 equiv of diphenylsilane, the corresponding N,N-
[*] Dr. S. Das, F. D. Bobbink, Prof. Dr. G. Laurenczy,
Prof. Dr. P. J. Dyson
Institut des sciences et ingꢀnierie chimiques
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
CH-1015 Lausanne (Switzerland)
E-mail: paul.dyson@epfl.ch
[**] We thank the Swiss Competence Centre in Energy and Mobility
(CCEM) HyTech project and the CTI Swiss Competence Center of
Energy Research (SCCER) on Heat and Electricity Storage for
financial support. We are grateful to Joachim Weber for assistance
with synthesis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407689.
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Table 1: Optimization of the reaction conditions for N-methylaniline
(1a) as a model substrate.[a]
Entry
Catalyst
Silane
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
–
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
PhSiH3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
19
25
91
79
78
84
33
48
32
87
0
A
B
C
D
B
B
B
B
B
B
B
B
Me(OEt)2SiH
PMHS
9
TMDSO
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
DMF
10
11
12
13
acetonitrile
toluene
1,4-dioxane
THF
0
7
[a] Reaction conditions: N-methylaniline (0.5 mmol), catalyst (5 mol%),
silane (1.5 mmol), solvent (4 mL), CO2 (1 atm), 508C, 24 h. [b] Yield
determined by GC using decane as an internal standard. PMHS=po-
lymethylhydrosiloxane and TMDSO=tetramethyldisiloxane.
Scheme 2. Catalytic N-methylation of amines 1a–14a using CO2 and
Ph2SiH2 as the source of the methyl group. Reaction conditions:
substrate (0.5 mmol), catalyst B (5 mol%), Ph2SiH2 (3 equiv), DMF
(4 mL), CO2 (1 atm), 508C, 24–48 h. Please note: shown structures are
those of substrates 1a–14a, the yields are those of the corresponding
N-methylated products. [b] Yields determined by GC using decane as
an internal standard. [c] 4 equiv of silane were used.
symmetric and nonsymmetric amines were also subjected to
the optimized reaction conditions, and the reaction worked
well with these substrates (substrates 4a–6a). Moreover,
a para-bromo-substituted amine (substrate 2a) gave the
corresponding product in 78% yield. It is noteworthy that
reductive dehalogenation was not observed. The catalyst is
also tolerant toward heteroaromatic amines such as picoline,
indoline, and 1,2,3,4-tetrahydroquinoline (substrates 7a–9a).
Additionally, primary amines react in a similar fashion to
secondary amines, forming dimethylated products (substrates
10a–14a). Notably, the reaction may also be performed on
a multigram scale without any special precautions.
As N-methylation has been shown to significantly
increase the cytotoxicity of drug molecules, we next evaluated
the use of NHC B in the N-methylation of complicated
molecules (Figure 1).[18–20] For this purpose, nortryptyline,
cinacalcet, duloxetine, and sertraline were selected, as they
have different complex structures that include aromatic,
aliphatic, heterocyclic, and alicyclic groups. It was possible to
N-methylate these substrates and obtain pure products in
good yields without special precautions regarding degrada-
tion.
dimethylaniline (1b) was obtained in 91% yield (Table 1,
entry 3). Other NHCs also showed activity, but gave the
product in lower yields.
We also investigated the influence of different silanes
(Table 1, entries 6–9) and solvents (entries 10–13) on the
reaction. Other silanes, such as TMDSO, PMHS, and MeSi-
(OEt)2H, were less effective reducing agents under the
optimized reaction conditions, although PhSiH3 showed
good activity in the formation of 1b. Catalysis was suppressed
in other solvents, such as toluene, THF, and 1,4-dioxane,
whereas the use of acetonitrile led to only a slightly decreased
yield compared to that observed in DMF. DMF is known to
activate CO2, which could be the case in this reaction.[17]
Based on the optimized reaction conditions, the scope of
the NHC-catalyzed methylation reaction was explored using
catalyst B (Scheme 2). Aromatic, heteroaromatic, and ali-
phatic amines reacted smoothly and the corresponding
products were obtained with yields of up to 84%. Aromatic
amines with both electron-donating and electron-withdraw-
ing substituents at the para position reacted well, whereas
amines with electron-withdrawing groups were sluggish.
Steric hindrance on both sides of the amine (substrates 10a
and 11a) has a minimal effect on the product yield. Different
The functional-group tolerance of the catalyst was
studied using some particularly challenging substrates with
different functional groups attached to different parts of the
substrate. By positioning these functionalities either at the
2
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Figure 1. Pharmaceuticals 15a–18a, which were subjected to the
catalytic N-methylation using CO2 and Ph2SiH2 as the source for the
methyl group. Please note: shown structures are those of substrates
15a–18a, the yields are those of the corresponding N-methylated
products, obtained using the optimized reaction conditions (Table 1,
entry 3).
Scheme 4. Demonstration of chemoselectivity in an N-methylation
reaction.
To demonstrate this chemoselective potential, catalyst B
was used to prepare naftifine (Scheme 4), an antifungal drug
for the topical treatment of fungal infections.[21] Most of the
previous routes to this drug include the use of stoichiometric
reagents, although catalytic routes have been reported.[22,23]
We prepared naftifine in two catalytic steps with an overall
yield of 58%. First, (E)-N-(naphthalen-1-ylmethyl)-3-phenyl-
prop-2-en-1-amine was obtained in 70% yield from naphtha-
len-1-ylmethanamine and cinnamyl alcohol using 1 mol%
[Pt(cod)Cl2].[23] Second, the application of our N-methylation
protocol gave the product in 83% yield.
Isotopically labelled bioactive compounds are widely used
to study interactions with lipid membranes, proteins, nucleic
acids, etc.[24] Thus, catalyst B was used to prepare 13C-labelled
naftifine in 78% yield (Scheme 5) using 13CO2. The catalyst
showed excellent selectivity as the double bond was not
reduced. Indeed, this methodology is attractive compared to
alternative routes, which require expensive labelled alkylat-
ing reagents, for example, 13CH3I.[25]
Scheme 3. Functional-group tolerance of the N-methylation of amines
19a–26a using CO2 and Ph2SiH2 as the source of the methyl group.
Reaction conditions: substrate (0.5 mmol), catalyst B (5 mol%),
Ph2SiH2 (3 equiv), DMF (4 mL), CO2 (1 atm), 508C, 24–48 h. Please
note: shown structures are those of substrates 19a–26a, the yields are
those of the corresponding N-methylated products.
aryl or at the amine moieties, steric influences were mini-
mized (Scheme 3). Remarkably, without further optimization,
nitrile and nitro groups, double and triple bonds, and ether-
and ester-substituted amines were well tolerated, providing
the corresponding N-methylated amines in good to excellent
yields. Moreover, the methylation was chemoselective, even
in the presence of a ketone group, which is known to be much
more reactive toward reduction.[21] The reduction of other
functional groups was not observed in any of these reactions,
thus demonstrating the excellent chemoselectivity of the
catalyst. To the best of our knowledge, this chemoselectivity is
unparalleled, that is, it cannot be achieved by other catalysts/
routes, and was further verified by exploring reactions of 1:1
mixtures of acetophenone, benzonitrile, methyl benzoate, and
nitrobenzene with N-methylaniline under the optimized
conditions. Again, while the amines were N-methylated, the
other substrates were not reduced.
Scheme 5. Chemoselective synthesis of [N-13CH3]-naftifine using 13CO2.
In summary, we have employed a metal-free catalyst for
the efficient methylation of various amines using CO2 as a C1
source combined with hydrosilane as the reducing agent. The
catalyst tolerates a broad range of substrates/functional
groups. In addition, selective N-methylation of several drug
molecules and the synthesis of naftifine was also achieved. As
demonstrated in the chemoselective synthesis of naftifine, this
catalyst could find uses in the sustainable synthesis of highly
functionalized molecules including natural products and in
the selective labelling of molecules with 13CH3 groups.
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Experimental Section
General procedure for the methylation reaction: Imidazolium salt
(0.10 mmol) and sodium hydride (0.10 mmol) were dissolved in 2 mL
of solvent in a 10 mL Schlenk flask and stirred for 30 min to generate
the carbene (0.05 mmolmLÀ1 solution). The solution was then kept
under nitrogen atmosphere without stirring until the inorganic salts
settled at the bottom of the Schlenk flask. 1 mL of this carbene
solution was transferred into a dry three-neck flask (after three
vacuum and CO2-purge cycles), already charged with the starting
materials and connected to the CO2 balloon. Next, 3 mL of solvent
and 3 equiv of diphenylsilane were introduced. The reaction was
monitored by TLC and GC-MS. Upon completion, 3 mL of a satu-
rated aqueous solution of NH4F were added and the reaction mixture
stirred at room temperature overnight. Excess ethyl acetate was
added to afford a clear solution and aqueous work-up was performed.
The combined organic layers were dried with anhydrous sodium
sulfate, and the product was purified by column chromatography
using ethyl acetate/pentane and 1 vol% of triethylamine. Note: the
silanol by-product (Ph2SiHOH) was removed during the chromato-
graphic step and, as the amount of silane reagent increased, the rate of
the reaction increased.
Received: July 28, 2014
Published online: && &&, &&&&
Keywords: carbon dioxide · methylation ·
.
N-heterocyclic carbenes · organocatalysis ·
sustainable chemistry
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Communications
Methylation
The methylation of amines with CO2 as C1
source and Ph2SiH2 as reducing agent
was achieved with an N-heterocyclic
carbene (NHC) as the catalyst. The
catalyst is tolerant toward a variety of
functional groups (including esters and
ethers, nitro, nitrile, and carbonyl groups,
S. Das, F. D. Bobbink, G. Laurenczy,
P. J. Dyson*
&&&& — &&&&
Metal-Free Catalyst for the
Chemoselective Methylation of Amines
Using Carbon Dioxide as a Carbon Source
À
and unsaturated C C bonds), uses com-
mercially available reagents, and can be
performed on a gram scale.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!