.
Angewandte
Communications
DOI: 10.1002/anie.201405779
Heterocycles
À
Catalytic Methylation of C H Bonds Using CO2 and H2**
Yuehui Li, Tao Yan, Kathrin Junge, and Matthias Beller*
À
Abstract: Formation of C C bonds from CO2 is a much
sought after reaction in organic synthesis. To date, other than
À
C H carboxylations using stoichiometric amounts of metals,
À
base, or organometallic reagents, little is known about C C
bond formation. In fact, to the best of our knowledge no
À
catalytic methylation of C H bonds using CO2 and H2 has
been reported. Described herein is the combination of CO2 and
H2 for efficient methylation of carbon nucleophiles such as
indoles, pyrroles, and electron-rich arenes. Comparison experi-
ments which employ paraformaldehyde show similar reactivity
for the CO2/H2 system.
À
Scheme 1. a) Known C H carboxylation from CO2. b) This work on
À
C H methylation from CO2 and H2.
C
O2 is the most abundant carbon source on earth and
provides the basis for all organic matter. With the increased
availability of renewable energy for the future it also might
become a more important feedstock for the chemical industry.
Hence, new valorizations of CO2 are of general interest for
chemistry and are highly desired for the production of bulk
and fine chemicals.[1,2] Clearly, today most of the catalytic
À
(weakly) activated C H bonds with CO2 lead to carboxylic
acid derivatives. In contrast to these reactions, our concept
involves reactions of CO2 with C H bonds under reductive
conditions (hydrogen). To the best of our knowledge such
reactions have not been described yet and are complementary
to known reactions in which the corresponding methylated
products are generated.
For our initial investigations, the carboxylation of indole
(1a) under reduction conditions (reductive methylation) was
À
À
À
reactions using CO2 in industry involve C N or C O bond
formation to give urea, carbonates, etc. Regarding C C bond-
À
forming reactions, the functionalization of alkenes, alkynes,
allenes, organohalides, organometallic reagents, or carbon
nucleophiles to generate carboxylic acids (and their deriva-
tives) is important in basic science.[3] In this respect, the
groups of Nolan, Hou, and Zhang recently reported
M(NHC)-catalyzed carboxylations (M = Au or Cu, NHC =
N-heterocyclic carbene) of (hetero)arenes or terminal
alkynes.[4] Despite these interesting developments, use of
benign CO2 still constitutes a major challenge because of the
thermodynamic stability of the parent molecule.[5] So far,
chosen as a benchmark system because of the importance of
C(sp ) H bond methylation for the synthesis of bioactive
2
À
compounds.[8] As an example, nosiheptide (multhiomycin),
a protein medicine, contains the 3-methyl indole moiety.[9]
Notably, current methods for the introduction of a methyl
group to indoles generally proceeds through several steps, for
example, formylation/reduction with formyl chloride or use of
toxic methylation reagents (e.g., methyl iodide and dimethyl
sulfate).[10]
À
a major drawback of most of the known C C bond-forming
reactions using CO2 is the requirement of stoichiometric
amounts of expensive (organo)metallic reagents or bases to
activate the respective carbon nucleophiles. Therefore, the
Based on previous literature on catalytic reduction of CO2
and carboxylic acid derivatives,[11,18] ruthenium triphos based
catalysts were screened. During this work (see Schemes S1
and S2 in the Supporting Information), indoline and 2-methyl
indoline (2a) were obtained as major products, and no 3-
methyl indole was observed. This outcome is in agreement
with a recent report by Klankermayer, Leitner, and co-
workers, who describe the formation of 2a.[12] However, we
observed the formation of the bis(indole) 4a in up to 10%
yield under specific reaction conditions.[13] It seems probable
that the carbon atom of -CH2- in 4a should come from CO2. In
general, 4a is produced by nucleophilic addition of indole to
formaldehyde.[14] This result implies that CO2 and hydrogen
can be used as a formaldehyde surrogate, further indicating
the possibility of utilizing CO2, by way of formaldehyde, for
the methylation of C H bonds.
Along with this discovery, we studied the methylation of
2-methyl indole (1b) to suppress unwanted side-reactions
(Table 1; see Table S1 in the Supporting Information).[14]
Indeed, the desired methylated product 3b was obtained as
À
discovery of new transformations of C H bonds using CO2
and cheap reductants, such as H2, is highly desired.[6]
Herein we disclose the first direct catalytic methylations
of (hetero)arenes using CO2 and hydrogen. Based on our
recent efforts on N-methylation of amines using CO2, we
À
became interested in exploring related C C bond forma-
tions.[7] As shown in Scheme 1 known functionalizations of
[*] Dr. Y. Li, T. Yan, 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
[15,16]
À
[**] This work was supported by the state of Mecklenburg-Vorpommern
and the BMBF.
Supporting information for this article is available on the WWW
10476
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 10476 –10480