Alkene trifluoromethylation coupled with C-C bond formation: Construction of trifluoromethylated carbocycles and heterocycles

Article abstract of DOI:10.1002/anie.201210250

The combo pack: Copper-catalyzed trifluoromethylation of alkenes bearing an allylic proton combined with C-C bond formation affords the title compounds in good to high yields (see scheme). The reactions are faster than allylic trifluoromethylation, especially in 1,4-dioxane. A unique 1,6- oxytrifluoromethylation occurred instead of an anticipated seven-membered ring forming carbotrifluoromethylation reaction.

Full text of DOI:10.1002/anie.201210250

Angewandte
Chemie
DOI: 10.1002/anie.201210250
Trifluoromethylation
À
Alkene Trifluoromethylation Coupled with C C Bond Formation:
Construction of Trifluoromethylated Carbocycles and Heterocycles**
Hiromichi Egami, Ryo Shimizu, Shintaro Kawamura, and Mikiko Sodeoka*
The trifluoromethyl group is of great interest in pharmaceut-
ical chemistry, agrochemistry, and materials science because
of its unique properties,[1] and great efforts have been made to
develop reactions for its introduction into organic mole-
cules.[2] Indeed, many methods for formation of not only Csp2
À
CF3, but also Csp3 CF3 bonds have been developed.[3,4]
À
À
Nevertheless, new synthetic methods to form C CF3 bonds,
especially Csp3 CF3 bonds, in a wider range of molecular
À
contexts are still needed.
Regarding trifluoromethylation of the C C bond,[5]
=
a notable development has been the deprotonative trifluoro-
methylation of simple alkenes, a method reported in 2011
(Scheme 1a).[5a–c] In contrast, we recently reported[6] the
trifluoromethylation of allylsilanes using the CuI/Togniꢀs
reagent (1)[7] system. Based on the resulting mechanistic
insight, oxytrifluoromethylation of styrene derivatives was
achieved under mild reaction conditions and direct synthesis
of b-trifluoromethylstyrene derivatives from styrenes was
demonstrated.[8] Szabꢁ and co-workers also independently
studied the oxytrifluoromethylation of multiple bonds with
the CuI/1 system,[9a] and Zhu and Buchwald developed an
intramolecular reaction of simple alkenes[9b] in the wake of
their deprotonative trifluoromethylation.[5a]
Scheme 1. a) Reported electrophilic trifluoromethylation.[5,6]
b) Trifluoromethylation coupled with construction of carbocycles and
heterocycles.
Following from our previous studies, we investigated
=
difunctionalization-type trifluoromethylation of the C C
tetrahydroquinoline, are also found in many bioactive com-
pounds, and their trifluoromethylated derivatives may exhibit
altered potency. It is well known that treatment of an alkene
bearing allylic protons under trifluoromethylation conditions
provides the deprotonative trifluoromethylation product
(Scheme 1a).[5,6] Difunctionalization-type trifluoromethyla-
tion of unactivated alkenes, especially those having allylic
protons, is still challenging (Scheme 1b). Based on our
previous mechanistic insights,[6,8] we considered that the
acceleration of the reaction by orbital interactions between
the alkene and aryl group would favor the desired trifluor-
bond,[10] thus focusing on the use of carbon nucleophiles. In
2012, Liu and co-workers reported the palladium/ytterbium-
catalyzed oxidative aryl trifluoromethylation of activated
alkenes using a combination of TMSCF3/CsF/PhI(OAc)2.[11]
Although Liuꢀs method provided structures bearing a trifluor-
omethyl group, only oxindole synthesis from a,b-unsaturated
amide derivatives was demonstrated. Other types of carbo-
cycles and heterocycles, such as indane, tetralin, indoline, and
[*] Dr. H. Egami, R. Shimizu, S. Kawamura, Prof. Dr. M. Sodeoka
Synthetic Organic Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
E-mail: sodeoka@riken.jp
À
omethylation reaction coupled with intramolecular C C
bond formation. Herein we report the copper-catalyzed
=
carbotrifluoromethylation of simple C C bonds, using the
Dr. H. Egami, S. Kawamura, Prof. Dr. M. Sodeoka
Sodeoka Live Cell Chemistry Project, ERATO
Japan Science and Technology Agency
CuI/1 system, as well as a unique 1,6-oxytrifluoromethylation
reaction.
To achieve carbotrifluoromethylation of a simple alkene
bearing allylic protons, it is important to prevent competitive
deprotonative trifluoromethylation of the alkene.[5,6] Com-
pound 2a was used as a test substrate for the screening of
reaction conditions (Table 1). Use of [(MeCN)4Cu]PF6 in
CH2Cl2 at room temperature selectively afforded the depro-
tonative trifluoromethylation product 4a in low yield
(entry 1). The carbotrifluoromethylation product 3a was
obtained in 18% yield in 1,2-dichloroethane (DCE) at
808C, but 4a was again the major product (entry 2). Surpris-
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
R. Shimizu, Prof. Dr. M. Sodeoka
Graduate School of Science and Engineering
Saitama University
255 Shimo-okubo, Sakura-ku, Saitama 338-8570 (Japan)
[**] This work was supported in part by a Grant-in-aid for Young
Scientists (B) from the MEXT (No. 23750116) and by Project
Funding for Basic Science from RIKEN.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210250.
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Table 1: Screening of reaction conditions.[a]
Table 2: Trifluoromethylation of simple alkenes coupled with construc-
tion of carbocycles.[a]
Entry
Cat.
Solvent
Yield [%][b]
4a
3a
1[c]
2
3
4
5
6
7
8
9
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
CuI
CuI
CuI
CuI
CuI
CuI
CH2Cl2
DCE
DCE
CHCl3
EtOH
DMF
1,4-dioxane
1,4-dioxane[f]
1,4-dioxane
1,4-dioxane
2
18
58
57
26
50
64[e]
78[e]
59
0
19
43
12
22
4
22
trace
trace
10
CuOAc
Cu(OAc)2
10
0
[a] The reactions were carried out with copper salt (10 mol%) and
1 (1.2 equiv) at 808C on a 0.2 mmol scale, unless otherwise mentioned.
[b] Determined by 19F NMR analysis of the reaction mixture using
trifluorotoluene as an internal standard. [c] Run at 238C. [d] Not
detected. [e] Yield of isolated product. [f] Degassed solvent was used.
DMF=N,N-dimethylformamide.
ingly, CuI provided 3a in 58% yield, together with 4a in 12%
yield (entry 3). It was found that the solvent affected the
product selectivity (entries 3–7). The reaction of 2a in 1,4-
dioxane afforded the desired product 3a with high selectivity
(entry 7). Dissolved oxygen in the solvent interfered with the
desired reaction and 1 was partly decomposed when solvent,
which was not degassed, was used. A higher yield was
observed in degassed solvent (entry 8). Copper(II) species did
not work for this reaction. For example, no reaction was
observed with Cu(OAc)2 (entry 10).
[a] The reactions were carried out with CuI (10 mol%) and 1 (1.2 equiv)
in degassed 1,4-dioxane at 808C, unless otherwise mentioned. [b] Yield
determined by 1H NMR analysis of a mixture with 2b. [c] Run in CH2Cl2.
[d] Run at 408C. [e] Run in DCE. [f] Yield of diastereomeric mixture.
difficulty to provide the carbocyclic product 3k having
a quaternary carbon center, bearing a trifluoroethyl group,
in 98% yield. To our delight, 2l and 2m bearing no
quaternary carbon atom selectively afforded the desired
corresponding carbocyclic products 3l and 3m in 76% and
61% yields, respectively. The reaction of the biaryl compound
2n bearing methylene protons positioned between a phenyl
group and a vinyl group also proceeded without difficulty. The
corresponding carbocycle 3n was obtained in 95% yield and
no deprotonative trifluoromethylation product was observed.
Reaction of the substrate having an oxygen substituent, 2o,
also proceeded smoothly at 408C in CH2Cl2 to give 3o in good
yield (diastereomeric mixture, d.r. = 1:0.8).
This reaction system was successfully applied to N-
protected allylaniline and homoallylaniline derivatives, thus
affording trifluoromethylated heterocycles (Table 3). The
reaction of N-Boc-allylaniline 5a gave 6a in 85% yield.
This reaction could be also applied to TBS-protected allylani-
line, that is, 5b afforded the corresponding heterocyclic
product 6b in good yield. Substituents on the phenyl ring had
a negligible impact on these reactions, and high yields of the
corresponding indoline derivatives 6c–e were obtained.[13]
Six-membered-ring formation was faster than that of five-
membered-ring formation, as in the case of carbocycles, and
6 f was produced in 93% yield within 1 hour.
Having established optimized reaction conditions, we next
examined the scope of this reaction (Table 2). Other five-
membered-ring products (3b–d) were obtained in good
yields. The reaction of 2b bearing a methoxy group at the
m-position proceeded smoothly to give the cyclized product
in 91% yield. Cyclization proceeded predominantly at the
position ortho to the methoxy group (regioisomers 3b = 63%;
3b’ = 28%). The substrate bearing a naphthyl group, 2d,
which could potentially provide both five- and six-membered-
ring products, gave only the five-membered-ring product 3d
in 77% yield. In contrast to this, it was found that formation of
six-membered rings (3e–j) was much faster than that of five-
membered rings, and no deprotonative trifluoromethylation
product was observed, even in chlorinated solvents. The
substrate 2e afforded the corresponding product 3e in 89%
yield even at 408C in CH2Cl2. Although electronic effects at
the phenyl ring affected the reaction rate, good to high yields
of the carbotrifluoromethylation products were obtained. The
TBS group remained intact under the reaction conditions
used, and the nonprotected phenol derivative was successfully
converted into the corresponding product 3h in 66% yield.[12]
Bromine and chlorine on the phenyl ring were tolerant of the
reaction conditions (3i, 3j). A methyl group on the terminal
olefin (R3 = Me) did not affect the desired reaction, and the
reaction of compound 2k proceeded at 408C without
In anticipation of seven-membered ring forming carbotri-
fluoromethylation of alkenes, the substrate 7a was exposed to
the described reaction conditions. To our surprise, the 1,6-
oxytrifluoromethylation product 8a was obtained in 77%
2
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Table 3: Carbotrifluoromethylation of N-protected allylanilines and
reaction of copper iodide with 1. The alkene moiety is first
activated by an electrophilic active species, then electron
homoallylaniline.[a]
=
À
transfer from the aryl ring through the C C bond and C C
bond formation would occur. Based on the fact that the
reaction of the six-membered ring was faster than that of the
five-membered ring, we believe that acceleration by orbital
interaction of aryl ring and alkene is crucial for this carbotri-
fluoromethylation.
In summary, we have achieved copper-catalyzed trifluor-
omethylation of simple alkenes bearing allylic protons,
À
coupled with Csp3 CAr bond formation. These reactions
provide trifluoromethylated carbocycles and heterocycles in
good to high yields. We propose that orbital interactions
between the alkene and aryl ring promotes the desired
reaction. In addition, our finding of 1,6-oxytrifluoromethyla-
tion through a 1,5-hydride shift raises the interesting possi-
bility of trifluoromethylation-initiated remote functionaliza-
tion. Further investigations of this reaction system and
mechanistic studies are under way in our laboratory.
[a] The reactions were carried out with CuI (10 mol%) and 1 (2 equiv) in
degassed 1,4-dioxane at 808C, unless otherwise mentioned. [b] Run for
1 h.
yield, and no carbocyclic product was observed (Scheme 2).
Similar results were obtained in the reactions of 7b and 7c. In
these reactions, deprotonative trifluoromethylation products
were isolated in 7%, 8%, and 25% yield from 7a, 7b, and 7c, Experimental Section
General procedure for trifluoromethylation of simple alkenes cou-
respectively. We suppose that this reaction proceeds by a 1,5-
hydride shift and trapping of an intermediate by 2-iodoben-
zoate generated from 1.
pled with construction of carbocycles: CuI (3.8 mg, 10 mol%) and
Togniꢀs reagent (1; 76 mg, 1.2 equiv) were weighed and added to
a Schlenk flask, which was flame-dried under vacuum. The flask was
evacuated and back filled with nitrogen. Degassed 1,4-dioxane
(1 mL) and 2a (55.3 mg, 0.2 mmol) were then added. The reaction
mixture was stirred for 12 h at 808C and diluted with ethyl acetate
(5 mL). The solution was washed with aqueous NaHCO3 and brine.
The organic layer was dried over MgSO4. After filtration, the organic
solvent was evaporated and the residue was subjected to column
chromatography on silica gel (n-hexane/ethyl acetate 20:1) to give the
trifluoromethylated product 3a (53.9 mg, 78%) as a colorless oil.
Received: December 23, 2012
Published online: && &&, &&&&
Keywords: alkene · copper · fluorine · heterocycles ·
.
homogeneous catalysis
Scheme 2. 1,6-Oxytrifluoromethylation of alkenes.
The proposed mechanism is illustrated in Scheme 3.
Although the true active species is not clear, we speculate
that an electrophilic active species would be generated by the
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À
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4
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Trifluoromethylation
H. Egami, R. Shimizu, S. Kawamura,
M. Sodeoka*
&&&& — &&&&
Alkene Trifluoromethylation Coupled with
À
C C Bond Formation: Construction of
Trifluoromethylated Carbocycles and
Heterocycles
The combo pack: Copper-catalyzed tri-
fluoromethylation of alkenes bearing an
methylation, especially in 1,4-dioxane. A
unique 1,6-oxytrifluoromethylation oc-
curred instead of an anticipated seven-
membered ring forming carbotrifluoro-
methylation reaction.
À
allylic proton combined with C C bond
formation affords the titled compounds
in good to high yields (see scheme). The
reactions are faster than allylic trifluoro-
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5
These are not the final page numbers!