A general catalytic methylation of amines using carbon dioxide

Article abstract of DOI:10.1002/anie.201301349

Putting CO₂ to work: Carbon dioxide is shown to be a general and selective methylating reagent for secondary and primary, aromatic and aliphatic amines under reductive conditions. A variety of tertiary amines are obtained from CO₂ and commercially available silanes in high yields with good tolerance to nitrile, olefin, ether, ester, and hydroxy groups. Copyright

Full text of DOI:10.1002/anie.201301349

Angewandte
Chemie
DOI: 10.1002/anie.201301349
Homogeneous Catalysis
A General Catalytic Methylation of Amines Using Carbon Dioxide**
Yuehui Li, Xianjie Fang, Kathrin Junge, and Matthias Beller*
Dedicated to Bayer on the occasion of its 150th anniversary
Carbon dioxide is the most abundant carbon source respon-
sible for the generation of all organic compounds in nature. Its
use as an inexpensive and nontoxic C1 feedstock is of
increasing interest for the production of value-added chem-
Herein, we describe for the first time a single Ru complex
that is able to convert carbon dioxide and amines into various
kinds of N-methylated products. Our initial design was
motivated by previous reports on the dehydration of primary
amides using silanes and the hydrosilylation of carboxylic acid
[
1]
icals. Owing to its high stability, well designed activation of
[
24–30]
CO and a thermodynamic driving force are required for
derivatives by us and other groups.
Hence, we started to
2
efficient transformations. In this respect, in recent years
important developments in the conversion of carbon dioxide
into formates, methanol (methoxides), and methane have
investigate the reaction of carbon dioxide and N-methylani-
line (1a) in the presence of silanes as a model system
(Table 1). To identify active catalysts around 15 different
metal precursors including Ru, Rh, Cu and Fe complexes and
12 phosphine and nitrogen ligands were tested using phenyl
silane as reductant (Figure S1 and Table S2).
[
2–5]
been reported.
For example, under hydrosilylation con-
ditions CO is reduced to silyl formates in the presence of
2
catalytic amounts of organic bases, Ru complexes, or Cu
[
6–9]
complexes;
its reduction to silyl methoxides can be
As shown in Table 1, commercially available [RuCl2-
[
10]
catalyzed by N-heterocyclic carbenes; and, when catalyzed
by Zr /B(C F ) , frustrated Lewis pairs/B(C F ) , or Ir-pincer
complexes, it can even be reduced to methane.
(dmso) ] (dmso = dimethylsulfoxide) proved to be the best
4
IV
catalyst precursor, giving dimethylaniline in 70% yield
(Table 1, entry 3); no reaction occurred without the catalyst.
6
5
3
6
5
3
[
11–13]
Notably,
using hydrogen, the reduction of CO2 to formic acid
derivatives can be catalyzed by Rh, Ir, Ru, and Fe com-
To our delight, using nBuPAd (4 mol%; Ad = adamantyl)
2
improved the yields up to 92% (Table 1, entry 5; see also the
[14–18]
[31]
plexes.
achieved using Ru -pincer complexes and multi-catalyst
More recently, its reduction to methanol has been
Supporting Information, Figure S1). Using other types of
II
metal complexes, hydrosilanes, or solvents led to much lower
reactivity (2–63% yield; Table 1, entries 6–9). However,
when using highly polar acetonitrile as the solvent, the best
[
19]
cascade catalysis.
Though there exists numerous reactions between amines
[
32]
and CO , to the best of our knowledge there is only one
reactivity was obtained (98% yield; Table 1, entry 10).
2
example known that describes the synthetically interesting
Methylation reactions of nitrogen compounds are of
major importance in biology, for example, in epigenetics,
embryonic development, and some cancer growth. Therefore,
the methylation of different types of amines was studied in
methylation of amines by CO . More specifically, Vaska and
2
co-workers reported the formation of methylamine as a minor
[
20]
product using Ru or Os complexes. However, it was later
suspected that an alkyl group exchange was (partially)
[
21]
responsible for the methylamine product. Hence, it remains
that no general catalytic methylation reactions using carbon
dioxide is known to date. Instead, activated methyl com-
pounds, such as methyl iodide, dimethyl sulfate, MeOTf,
diazomethane, and reductive amination systems (HCHO/
Table 1: Ruthenium-catalyzed methylation of 1a with carbon dioxide and
phenylsilane.
[
a]
[
22]
reductant), are often used for this purpose. However, the
toxicity of most of these reagents and/or the limited substrate
scope attract organic chemists to extend this research area. In
this regard, it is interesting to note that the use of dimethyl
carbonate or methanol as eco-friendly alternatives has been
[b]
Entry
[M]
Ligand
Silane
Yield [%]
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Fe(OAc)2
[RuCl (dmso) ]
[RuCl (dmso) ]
[RuCl (dmso) ]
[Ru(acac)3]
[{RuCl (C H )} ]
[RuCl (dmso) ]
2 4
–
–
–
PPh3
nBuPAd2
nBuPAd2
nBuPAd2
nBuPAd2
nBuPAd2
nBuPAd2
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
–
–
70
53
92
2
23
63
21
98
2
4
[
23]
more recently reported as well.
2
4
2
4
2
6
6
2
[
c]
[*] Dr. Y. Li, X. Fang, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V.
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
[RuCl (dmso) ]
[RuCl (dmso) ]
2
4
(EtO) MeSiH
2
[
d]
10
PhSiH3
2
4
[
a] Reaction conditions, unless otherwise noted: 1.0 mmol 1a, catalyst
Homepage: http://www.catalysis.de
(
(
2 mol%), ligand (4 mol%), silane (4 equiv), toluene (10 mL), CO2
[**] We thank the financial support from the state of Mecklenburg-
30 bar), 1008C, 16 h. [b] Determined by GC using n-hexadecane as an
Vorpommern and the BMBF.
internal standard. [c] Silane (2 equiv) was used. [d] MeCN as solvent.
Ac=acetyl, acac=acetylacetonate, Ad=adamantyl, Tf=trifluorome-
thanesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301349.
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[
a]
Table 2: A general catalytic methylation of amines from CO2.
[
b]
[b]
Entry
1
1
2
Yield [%]
86
Entry
12
1
2
Yield [%]
81
[
c]
c]
2
3
81
75
13
14
85
82
[
[
[
c]
c]
[c]
4
5
97
76
15
16
Bn NH
Bn NMe
98
99
2
2
[c]
nHex NH
nHex NMe
2
2
[
[
[
c]
c]
c]
[c]
6
7
8
73
71
61
17
18
19
94
75
72
[
c]
9
1
72
70
20
84
83
[
c]
0
21
1
1
82
22
63
[
[
a] Reaction conditions: substrate (0.5 mmol), silane (4 equiv to amine moiety), toluene (2–10 mL), 10–36 h. [b] Yield of isolated product.
c] Determined by GC using n-hexadecane as an internal standard. Bn=benzyl.
more detail (Table 2). When aromatic secondary amines were
used as substrates, the desired products were obtained in 71–
olefins, and esters was obtained, which is not achievable with
other known reductions for carbon dioxide.
9
6
7% yield (Table 2, entries 1–7). A slight drop in reactivity to
1% yield is seen for the methylation of the heterocyclic 2-N-
Next, we were interested in the reactions of more
challenging primary amines. Gratifyingly, these compounds
also proved to be good substrates with somewhat longer
reaction times. Even sterically hindered 2,6-di-isopropyl
aniline was fully converted after 24 h and the dimethylated
product was obtained in 84% yield (Table 2, entry 20).
Moreover, reactions of diamine substrates gave the corre-
sponding di- and trimethylated diamines in good to excellent
yields. Although more than three kinds of byproducts were
found in both cases, 83% and 63% yields of the desired
products were obtained, respectively, after increasing the
methylaminopyridine (Table 2, entry 8). In general, dialkyl-
amines showed higher reactivity than aniline derivatives
(
Table 2, entry 16 vs. entry 6).
For most of the cases, full and clean conversion was
observed, with yields of 70–99% in 10 h (Table 2, entries 9–
7). From a biochemical point of view, it is interesting to note
1
that the methylation process also proceeds well with amino
acid esters, thus demonstrating the potential chemoselectivity
of this method. Indeed, under our reducing conditions good
tolerance to other types of reducible groups such as nitriles,
2
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reaction time to 36 h (formamide byproducts were obtained
in up to 10% yield; Table 2, entries 21–22).
urea 8 is formed first, followed by reduction to 9. Finally, slow
ring opening forms the monomethylated intermediate, which
immediately undergoes further methylation to yield the
dimethylated product 10. To further support this assumption,
we performed the reduction of 8 independently with phenyl-
silane (2 equiv). Indeed, using [RuCl (dmso) ] (5 mol%) at
After the successful methylation of the different types of
amines, we were interested in exploring the selective meth-
ylation of amino alcohols, a structural motif that occurs widely
in natural amines and manmade bioactive compounds. As an
example, ephedrine (3) was used as a substrate and provided
the desired N-methylephedrine (4) in 73% yield with
a chemoselectivity of > 7:1 [Eq. (1)], although full conversion
2
4
1108C in toluene gave 9 and 10 in 71% and 28% yield,
respectively, in the presence of CO (30 bar). As shown in
2
Equation (4), other ureas such as N,N’-diphenyl-N,N’-dime-
thylurea (11) can also be quantitatively reduced to give
[31]
dimethylaniline (2a) and N-methylaniline (1a).
was not obtained, owing to the production of trace amounts of
N-formylephedrine. Thus, the selective methylation of amino
alcohols without protection/deprotection steps is indeed
possible with this method.
With this data in hand, we propose the following two
reaction pathways for direct methylation with carbon dioxide
(as shown in Scheme 1): 1) Formation of formamide occurs
With respect to the mechanism, CO may be first reduced
through direct reduction of CO to generate A, followed by
2
2
to formamide, which is then reduced to the methylamine
product in a route similar to known reductive amination
deoxygenative reduction to produce the corresponding meth-
ylamine product. 2) Dehydration of ammonium carbamate
[
31]
methods using HCHO. However, under dehydrating con-
ditions, ureas should be formed as the major products from
[
33]
CO2 and amines.
To understand the sequential trans-
formation in more detail, control experiments were carried
out by using specific 1,2-diamines as starting material to
[33]
capture key intermediates.
After testing different 1,2-
diaminobenzenes and 1,2-ethylendiamines, we were able to
isolate some interesting intermediates, such as the corre-
sponding methylene diamines from the reduction of ureas.
Under the standard conditions using N,N’-dimethyl-1,2-phe-
nylenediamine (5) as substrate, the dimethylated compound
Scheme 1. Proposed pathways for the methylation of amines with
carbon dioxide.
2
w was obtained as the main product, accompanied by the
under hydrosilylative conditions to generate urea B, followed
methylene diamine (6) in 21% yield [Eq. (2)]. Interestingly,
by reduction to the desired product and one molecule of
starting material in the presence of a proton.
[
35]
In conclusion, we have demonstrated for the first time that
the general methylation of organic substrates using silanes
and CO as a simple carbon source is possible. Applying
2
a readily available ruthenium complex and a commercially
available ligand, various kinds of aromatic and aliphatic,
secondary and primary amines were successfully transformed
into the desired tertiary amines and diamines with good to
excellent yields. Notably, various functional groups are
tolerated under these conditions, which is not known for
other methods of carbon dioxide reduction. Furthermore, the
selective reduction of ureas is possible under similar reaction
conditions. An important goal for the future is the develop-
when changing the solvent from toluene to acetonitrile, the
chemoselectivity is inverted to give 6 as the major product,
which should be formed through deoxygenative reduction of
the corresponding urea. Otherwise, strong base and higher
temperature are required for the synthesis of this product
from 5 or reaction intermediates and byproducts. Under
catalytic conditions, the more bulky aromatic diamine 7 gave
three major products: 13% of N,N’-diphenylethyleneurea (8),
[
34]
ment of similar reactions using more benign H as the
2
[
36]
reductant.
7
6% of 1,3-diphenylimidazolidine (9), and 10% of the
dimethylated product 10 [Eq. (3)]. In this reaction sequence
Experimental Section
General procedure for the methylation reaction in a parallel pressure
reactor: RuCl (dmso) (4.9 mg, 10 mmol) and nBuPAd2 (7.2 mg,
2
4
20 mmol) were added to an autoclave containing a stirring bar.
Under Ar flow, dry toluene (1.5 mL), PhSiH (250 mL, 2.0 mmol), and
3
amine substrate (0.5 mmol) were added. After pressurizing with CO2
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Angewandte
Communications
to 30 bar, the mixture was stirred at 1008C for a certain time period.
The yield can be determined by GC using n-hexadecane as an internal
standard. To isolate the products, the reaction mixture was cooled to
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2
II
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Received: February 15, 2013
Published online: && &&, &&&&
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Keywords: carbon dioxide · methylation · reduction ·
.
ruthenium · silanes
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Angewandte
Chemie
Communications
Homogeneous Catalysis
Y. Li, X. Fang, K. Junge,
M. Beller*
&&&& — &&&&
Putting CO to work: Carbon dioxide is
tertiary amines are obtained from CO2
2
A General Catalytic Methylation of
Amines Using Carbon Dioxide
shown to be a general and selective
methylating reagent for secondary and
primary, aromatic and aliphatic amines
under reductive conditions. A variety of
and commercially available silanes in
high yields with good tolerance to nitrile,
olefin, ether, ester, and hydroxy groups.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!