.
Angewandte
Communications
DOI: 10.1002/anie.201307377
Aryltrifluoromethylation
Metal-Free Aryltrifluoromethylation of Activated Alkenes**
Wangqing Kong, Maria Casimiro, Noelia Fuentes, Estꢀbaliz Merino, and Cristina Nevado*
The introduction of trifluoromethyl groups into organic
molecules has found widespread use in medicinal chemistry
because of the improved properties (including permeability
and metabolic stability) that fluorine-containing compounds
[1,2]
À
display compared to their C H counterparts.
Transition-
metal-catalyzed trifluoromethylation reactions have been
developed, as they feature mild reaction conditions and
high functional-group compatibility.[3] In this context, reac-
tions that involve the selective difunctionalization of alkenes
have received increasing attention, as they enable the
À
À
formation of C C/C–heteroatom and C CF3 bonds in
a single synthetic operation. Thus, efficient methods for
oxotrifluoromethylation[4] and aryltrifluoromethylation reac-
tions that are catalyzed by Pd[5] or Cu[6] complexes have been
devised. In contrast, metal-free processes have been much
less explored.[7] The Togni reagent (1) has become the most
popular stoichiometric source of the CF3 moiety in both
metal-catalyzed and metal-free alkene trifluoromethylation
reactions, owing to its stability, versatility, and commercial
accessibility. Activation of the hypervalent iodine–CF3
reagent 1 can occur by single electron transfer (SET) with
copper salts[3f,g] or sodium aminoalkoxide in stoichiometric
amounts[7] to generate a CF3 radical (CF3C), which can further
react with unactivated alkenes. On the other hand, activation
of 1 in the presence of copper or zinc complexes[8] can
Scheme 1. Metal-free aryltrifluoromethylation of alkenes.
monium iodide (30 mol%) and NaHCO3 (1 equiv), the
trifluoromethylated isoquinolinedione 3a could be obtained
in 85% yield. Other additives, such as trimethylsilyliodide
(TMSI) or KI, also delivered the desired product, albeit with
lower efficiency.[12] Substitution with a tert-butyl group at the
meta position of the amide led to product 3b in 78% yield. A
derivative of gallic acid produced the corresponding isoqui-
nolinedione 3c in 68% yield.
A substrate with a para-chlorobenzoate substituent on the
nitrogen atom was converted into 3d, the structure of which
was confirmed by X-Ray diffraction analysis.[13] When a tri-
substituted alkene (R5 = Me) was used, the cyclized aryltri-
fluoromethylation product 3e was obtained in 59% yield as
a 8:1 mixture of diastereoisomers, thus showing that good
levels of stereocontrol could be attained in these trans-
formations (Scheme 2).
We decided to further explore the regioselectivity of this
benzannulation.[14] Various substrates bearing nonsymmetric
arenes were synthesized. Interestingly, in the presence of
electron-withdrawing groups at the R1 position, the para
cyclization products 3 f–h were selectively obtained.[15] Fur-
thermore, para/meta was preferred to ortho/meta benzannu-
lation, as 3i was obtained as single product from the reaction
of 2i. Substrate 2j, in which the alkyl group on the nitrogen
atom has been replaced by a m-CF3-C6H4 group, offered four
different sites for cyclization (Scheme 2): positions a or b to
give the corresponding trifluoromethylated oxindoles, and
positions c or d to give regioisomeric isoquinolinediones. The
reaction proceeded with excellent site control, and the 6-
membered-ring product 3j was formed as a single regioiso-
mer. Interestingly, the more sterically demanding substrate
2k afforded the expected product 3k, together with com-
pound 3k’’ in a 5:1 ratio and 51% yield (Scheme 3). Product
3k’’ is formed by a formal 1,2-migration of the amide group,
trifluoromethylation, and cyclization. The 2,4-dimethoxyben-
zamide 2l delivered spirobicyclic compound 3l as a mixture of
+
generate an electrophilic source of CF3 (CF3 ) in situ, which
can further interact with both activated and unactivated
olefins. We envisioned that alternatively, the reactivity of
iodine(III) in 1 could be enhanced by the presence of a soft
nucleophile, in analogy to the well-established late-transition-
metal-free activation of ArI(X)(Y) species.[9] Because of our
ongoing interest in the development of methods for the
selective oxidative difunctionalization of alkenes,[10] particu-
larly those using iodonium species,[11] we decided to test this
hypothesis for the development of a metal-free aryltrifluoro-
methylation of alkenes. Herein, we present the realization of
this concept, which was achieved through the combination of
the Togni reagent (1) with substoichiometric amounts of
tetrabutylammonium iodide (Scheme 1).
Our study commenced with the reaction of methacryloyl
benzamide (2a) with 1.[12] In the presence of tetrabutylam-
[*] Dr. W. Kong, M. Casimiro, Dr. N. Fuentes, Dr. E. Merino,
Prof. Dr. C. Nevado
Organic Chemistry Institute, Universitꢀt Zꢁrich (Switzerland)
E-mail: nevado@oci.uzh.ch
[**] The European Research Council (for the ERC Starting Grant 307948)
and the Novartis Foundation are kindly acknowledged for financial
support. Prof. Anthony Linden is kindly acknowledged for deter-
mining the X-ray crystal structures of 3d and 3l.
Supporting information for this article is available on the WWW
13086
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 13086 –13090