Metal-free aryltrifluoromethylation of activated alkenes

Article abstract of DOI:10.1002/anie.201307377

Metal-free: The first metal-free aryltrifluoromethylation of activated alkenes has been developed. With this method, trifluoromethylated isoquinolinediones, spirobicycles, oxindoles, and α-aryl-β- trifluoromethylamides were obtained with high control of the regioselectivity. Copyright

Full text of DOI:10.1002/anie.201307377

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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
under http://dx.doi.org/10.1002/anie.201307377.
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Scheme 3. Formation of other trifluoromethylated products. [a] For
reaction conditions, see Scheme 2.
5a–d were isolated in good yields. The double bond was
also amenable to structural variations, so that 5e and 5 f could
be also efficiently obtained. Trisubstituted alkenes were also
tested (R4 = Me), and the cyclized aryltrifluoromethylation
product 5g was isolated as a 2:1 mixture of diastereoisomers.
The presence of an aromatic substituent on the nitrogen atom
of 4g was compatible with the reaction conditions. In contrast,
reactions of N-tosylated substrates did not afford the
expected oxindoles, but different trifluoromethylated com-
pounds. Upon reduction of the amount of 1 to 1.5 equivalents
and the addition of NaHCO3 (1 equiv), we were able to
observe the clean formation of a-aryl-b-trifluoromethyl
amides 6.[11b] These compounds result from a remarkable
series of transformations, including alkene trifluoromethyla-
tion, which is followed by a formal intramolecular 1,4-aryl
Scheme 2. Scope of the metal-free aryltrifluoromethylation reaction.
Reaction conditions: CH3CN (0.5m), 808C, 12 h. Yields of isolated
products after purification by column chromatography on silica gel are
given. [a] Major diastereoisomer shown. [b] Reaction in the absence of
base, with nBu4NI (50 mol%).
diastereoisomers in a ratio of approx-
imately 2.3:1 in 68% yield in the
presence of nBu4NI (50 mol%;
Scheme 3). The structure of the
major isomer was confirmed by
X-ray diffraction analysis.[13] A sim-
ilar outcome was obtained when the
N-benzyl-substituted substrate 3m
was employed; a phenyl substituent
at the olefin was also well tolerated,
as 3n was obtained in 60% yield as
a single isomer. Interestingly, 2,4,6-
trimethoxy-substituted 2o delivered
trifluoromethylated spirobicycle 3o
as the sole reaction product in 62%
yield.[16,17]
This metal-free aryltrifluorome-
thylation of alkenes was extended to
the synthesis of oxindoles[5,6] by
employing a,b-unsaturated amides
4.[18] Different substitution patterns
on the aromatic ring and various alkyl
or aryl groups on the nitrogen atom
(R1 and R2 of compound 4;
Scheme 4) were well-tolerated, and
Scheme 4. Synthesis of trifluoromethylated oxindoles and a-aryl-b-trifluoromethylamides. Yields of
isolated products after purification by column chromatography on silica gel are given. Products
5a–g were obtained under conditions A: 1 (2 equiv), CH3CN (0.5m), 808C, 12 h. Products 6h–p
were obtained under conditions B: 1 (1.5 equiv), NaHCO3 (1 equiv), CH3CN (0.5m), 808C, 12 h.
the trifluoromethylated oxindoles Bn=benzyl, Phth=phthaloyl.
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migration, desulfonylation, and H atom abstraction. First, we
studied variations in the substitution pattern of the aryl group
that is directly bonded to the nitrogen atom of the tosyl
amides (R1; Scheme 4). Thus, ortho-substituted arenes were
converted into products 6h–j in moderate to good yields (52–
68%). The introduction of electron-deficient groups such as
CF3 (6k) did not seem to interfere with the reaction. The
substitution pattern on the aromatic ring of the sulfonamide
group (R2; Scheme 4) was also explored. Substrates with
para-tert-butyl or para-methoxy sulfonamide substituents
were efficiently transformed into the corresponding b-tri-
fluoromethylamides 6l and 6m, respectively. The reaction is
completely regioselective, as the 1,4-migration of the aryl
group takes place exclusively through the carbon atom that
was bonded to the SO2 group in the starting material. Thus,
substrates bearing indane, 1,4-dioxolane, or biphenyl sulfonyl
moieties (4n–p) were transformed into amides 6n–p in good
yields. Control experiments for the identification of the
intermediates involved in these transformations were also
designed.[12] The 1H NMR spectra recorded for the crude
mixtures at the end of the reaction indicated the presence of
CF3I and the tetrabutylammonium salt of 2-iodobenzoic acid
(7).[19] In a sealed NMR tube, a 1:1 mixture of 1 and nBu4NI in
CD3CN was heated to 808C for 16 h. 1H and 19F NMR
spectroscopy confirmed the sole presence of salt 7 and CF3I
(Figure 1a). A solution of 2a was then added, and the mixture
was heated to 808C for another 12 h. The starting material
was recovered intact, which demonstrates that in situ-gener-
ated CF3I is not a productive trifluoromethylating agent in
these transformations. In contrast, when the mixture of 1 and
nBu4NI was heated to 808C for two hours, we could observe
the disappearance of 1 and the formation of a new inter-
mediate, along with formation of the salt 7 in a ratio of
approximately 2:1 (Figure 1b). When a solution of 2a was
added to this mixture, full conversion into 3a was observed.
We assume that reagent 1 reacts with IÀ to form an iodonium
complex I, which is in line with the species detected by
HRMS-ESI. The spectroscopic characterization of I showed
13
À
a quartet (J = 3.0 Hz) for the C signal of the C H atom in
the a position of the iodine atom that is due to through-space
interactions with the CF3 group, thus supporting a 10-I-3
structure[20] for this reaction intermediate.[8a,12] The reactions
of 2a and 4l in the presence of di-tert-butylated hydroxyto-
luene
(BHT)
or
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) led to the desired products in yields almost
comparable to those obtained under the standard conditions.
When these reactions were followed by 19F NMR spectros-
copy, the corresponding TEMPO–CF3 adducts could not be
detected, which points towards a non-radical mechanism for
these transformations; this finding is in contrast to the radical
trifluoromethylation of isonitriles that was recently reported
by Studer and co-workers, and which proceeded under similar
conditions.[21] A mechanistic proposal that is compatible with
these experimental observations is summarized in Scheme 5.
In the first step of the reaction, tetrabutylammonium iodide
seems to activate the Togni reagent, thus generating the
highly reactive iodine(III) intermediate I. This highly electro-
philic species then reacts with the activated double bond to
Figure 1. Characterization of the active species.
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Keywords: alkenes · arenes · iodine ·
.
Togni reagent · trifluoromethylation
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À
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Received: August 21, 2013
Revised: September 12, 2013
Published online: October 31, 2013
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