Angewandte
Chemie
DOI: 10.1002/anie.201309761
À
C H Arylation
À
Ascorbic Acid as an Initiator for the Direct C H Arylation of
(Hetero)arenes with Anilines Nitrosated In Situ**
Fernando Pinacho Crisꢀstomo, Tomꢁs Martꢂn,* and Romen Carrillo*
Abstract: Ascorbic acid (vitamin C) has been used as a radical
À
initiator in a metal-free direct C H arylation of (hetero)arenes.
Starting from an aniline, the corresponding arenediazonium
ion is generated in situ and immediately reduced by vitamin C
to an aryl radical that undergoes a homolytic aromatic
substitution with a (hetero)arene. Notably, neither heating
nor irradiation is required. This procedure is mild, operation-
ally simple, and constitutes a greener approach to arylation.
T
he synthesis of (hetero)biaryl compounds has become one
of the most important reaction types in organic synthesis
owing to the high incidence of the biaryl structural motif in
biologically active molecules, natural products, and materials
chemistry.[1] In this regard, the direct C H arylation of arenes
À
is particularly attractive, because it avoids the traditional
double preactivation of the coupling partners. As a conse-
quence, the number of steps is reduced, less or no manipu-
lation of sensitive and often toxic reagents is required, and
À
less waste is generated. Numerous examples of the direct C
H arylation of arenes by the use of transition metals have
been reported.[2] However, their cost effectiveness and the
presence of transition-metal impurities in the final product
affect the practical applicability of transition-metal-mediated
reactions. Such environmental and economic concerns have
motivated the development of plenty of transition-metal-free
synthetic methods.[3] Regarding intermolecular C H aryla-
À
tion reactions of (hetero)arenes, there are a few reported
metal-free variants,[4–6] but in most cases harsh conditions,
such as the use of strong bases and high temperatures, are
required (Scheme 1a). Recently, an elegant and mild
approach was suggested by Kçnig and co-workers: photo-
chemical reduction of arenediazonium ions by an organic
photocatalyst (Scheme 1a).[7] Indeed, arenediazonium ions
function as one-electron oxidizing agents, and therefore, in
reactions with suitable reducing agents, free radicals are
Scheme 1. a) Previous strategies for metal-free intermolecular direct
À
C H arylation of (hetero)arenes, and b) our method. Boc=tert-butoxy-
carbonyl, FG=functional group, TMS=trimethylsilyl, Tf=trifluoro-
methanesulfonyl.
generated,[8] which can undergo a homolytic aromatic sub-
stitution (Gomberg–Bachmann reaction).[9] In this regard,
there is solid evidence that l-threo-ascorbic acid (hereafter
referred to as ascorbic acid or vitamin C) is able to act as
a reductant towards arenediazonium ions to generate aryl
radicals in the absence of metals.[10] Surprisingly, the synthetic
applicability of ascorbic acid as a radical promoter has never
been evaluated, even though it is a perfect candidate for an
environmentally benign synthetic procedure. We herein
[*] Dr. F. P. Crisꢀstomo, Dr. T. Martꢁn, Dr. R. Carrillo
Instituto de Productos Naturales y Agrobiologꢁa, CSIC
Francisco Sꢂnchez, 3, 38206 La Laguna, Tenerife (Spain)
E-mail: tmartin@ipna.csic.es
Dr. T. Martꢁn, Dr. R. Carrillo
Instituto Universitario de Bio-Orgꢂnica “Antonio Gonzꢂlez”
CIBICAN, Universidad de La Laguna
À
describe an operationally simple metal-free direct C H
Francisco Sꢂnchez, 2, 38206 La Laguna, Tenerife (Spain)
arylation of (hetero)arenes with anilines that is promoted
by catalytic amounts of ascorbic acid, with no heating or
irradiation required (Scheme 1b).
[**] This research was supported by the Spanish MINECO, cofinanced
by the European Regional Development Fund (ERDF) (CTQ2011-
22653). F.P.C. thanks the CSIC for a JAE postdoctoral contract,
cofinanced by the FSE.
As a proof of concept, 4-chlorobenzenediazonium tetra-
fluoroborate in dimethyl sulfoxide (DMSO) was treated with
ascorbic acid (0.1 equiv)[11] in the presence of an excess
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 2181 –2185
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2181