Copper-catalyzed C(sp3)-C(sp3) bond formation using a hypervalent iodine reagent: An efficient allylic trifluoromethylation

Article abstract of DOI:10.1021/ja207775a

An efficient copper-catalyzed allylic trifluoromethylation reaction has been developed. This reaction provides a general and straightforward way to synthesize allylic trifluoromethylated compounds under mild conditions.

Full text of DOI:10.1021/ja207775a

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Copper-Catalyzed C(sp3)ÀC(sp3) Bond Formation Using a Hypervalent
Iodine Reagent: An Efficient Allylic Trifluoromethylation
Xi Wang, Yuxuan Ye, Songnan Zhang, Jiajie Feng, Yan Xu, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
S Supporting Information
b
Table 1. Evaluation of Different CF3 Sourcesa
ABSTRACT: An efficient copper-catalyzed allylic trifluo-
romethylation reaction has been developed. This reaction
provides a general and straightforward way to synthesize allylic
trifluoromethylated compounds under mild conditions.
olecules bearing trifluoromethyl groups have been widely
applied in the fields of functional materials, agrochemicals,
M
and pharmaceuticals.1,2 The unique properties of trifluoromethy-
lated compounds include high electronegativity, hydrophobicity,
metabolic stability, and bioavailability, which account for the sig-
nificance of developing new methods for the introduction of
trifluoromethyl groups into organic molecules.3 Trifluoromethy-
lation of aryl, vinyl, and allyl halides4 and the corresponding boron
reagents5 employing catalytic or stoichiometric amounts of copper
species has provided a number of useful methods to access these
trifluoromethyl-containing compounds. In particular, general
trifluoromethylation methodology for aryl chlorides has been
developed by Buchwald and co-workers.6 Moreover, recent work
on direct replacement of aryl7 and alkynyl8 CÀH bonds with
CÀCF3 bonds has attracted great attention. The remarkable
developments in this area have demonstrated the possibility of
streamlining the synthetic route for functionalized aromatics
while avoiding the use of halides.
a Reaction conditions: 1a (0.5 mmol), MeOH (1 mL). b Isolated yields.
c Other CF3-containing byproducts were detected (e5%). For details,
see the Supporting Information.
On the other hand, palladium-catalyzed direct functionaliza-
tion of allylic CÀH bonds leading to CÀO, CÀN, or CÀC bond
formation is a valuable complement to the well-known TrostÀ
Tsuji reaction.9 More recently, cheaper catalysts such as copper10,11
or iron12 complexes have also been employed to accomplish the
direct allylic CÀH transformation. Herein we report a copper-
catalyzed allylic trifluoromethylation reaction using a hyperva-
lent iodine reagent. This methodology represents a rare example
of highly efficient direct trifluoromethylation of terminal olefins.13
At the outset of this investigation, we screened the combina-
tions of transition-metal catalysts, oxidants, and trifluoromethyl
sources that were essential for allylic trifluoromethylation (Table 1).
After some initial experiments, we concluded that CuCl is a
suitable catalyst in this transformation. However, no product was
observed when we employed TMSCF3 2a (RuppertÀPrakash
reagent)14 as the trifluoromethyl source in the presence of CsF
and PhI(OAc)2 with CuCl as the catalyst (entry 1). Other oxidants
such as tert-BuOOH could not achieve this transformation (entry 2).
Subsequently, we focused our attention on electrophilic trifluo-
romethylation reagents. Trifluoromethylation with 2b (Umemoto
reagent)15 failed (entry 3). To our surprise, the hypervalent
iodine(III) reagent 2c (Togni reagent),16,17 which is easily accessible
from commercially available 2-iodobenzoic acid, provided the
desired product in 89% isolated yield (entry 4). Only a trace
amount of product was obtained when we used another Togni
reagent, 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (2d),
as CF3 source (entry 5). For comparison, other transition-metal
complexes were also studied under identical reaction conditions.
The reaction of 1a with 2c in the presence of FeCl2 or Fe(OAc)2
as the catalyst formed the product in only a barely detectable
amount (∼5%). Other transition-metal catalysts, such as Pd-
(OAc)2, CoCl2, Co(OAc)2, and Mn(OAc)2, showed no catalytic
reactivity.
Upon optimization of the reaction conditions, we proceeded
to test a series of olefins to explore the generality of this method
(Table 2). The reaction of simple alkenes proceeded efficiently
(entries 1 and 2). Notably, the aliphatic aldehyde group, which is
Received: August 17, 2011
Published: September 21, 2011
r
2011 American Chemical Society
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Table 2. Allylic Trifluoromethylation with Hypervalent Iodine(III) Reagent 2ca
a The reaction was conducted on a 0.5 mmol scale in 1 mL of MeOH, except for entry 3, where 1 mL of DMF was used. The ratio of 1 to 2c ranged from
1:1.6 to 2:1. For details, see the Supporting Information. b Isolated yields. c The branched product was detected as a minor product (in entry 10, linear:
branched = 11:1; in entry 11, linear:branched = 7:1). d E:Z = 10:1, as determined by 1H NMR analysis of the crude product. e Based on 19F NMR analysis
with C6H5CF3 as an internal standard.
usually fragile under oxidative conditions, remained intact in this
transformation. In this case, N,N-dimethylformamide (DMF)
should be used as the solvent instead of MeOH to avoid acetal
formation (entry 3). The tert-butyldimethylsilyl (TBDMS) ether
protecting group was also tolerated in the reaction, with the
desired product being obtained in excellent yield (entry 4). Other
linear allylic trifluoromethylated compounds were obtained in pre-
paratively useful yields (66À93%) when terminal olefins featur-
ing ester, amide, benzoate, benzenesulfonate, and phthalimide
functional groups were employed as substrates (entries 5À9).
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Scheme 1. Capture of CF3 Radical by TEMPO
standard reaction conditions (Scheme 1), and the TEMPO-
trapped complex 4 was detected by GCÀMS. The yield of 4 was
estimated as 44% on the basis of 19F NMR spectroscopic analysis.
Moreover, when TEMPO was added in the standard reaction
(Table 1, entry 1), the trifluoromethylation was totally shut down
and TEMPOÀCF3 adduct 4 was formed in 79% yield as estimated
by 19F NMR analysis. However, the allylÀTEMPO adduct was
not detected in our system.10b
These experimental results provided supportive evidence that
CF3 radical is likely involved as a reactive species in the reaction
mechanism. A mechanistic rationale involving several possible
pathways is outlined in Scheme 2. Initially, CuCl catalytically
activates 2c, leading to CF3-containing radical intermediate A.
Decomposition of radical intermediate A produces (2-iodoben-
zoyloxy)copper(II) chloride (B)10b with simultaneous release of
a CF3 radical. It is assumed that olefin substrate 1 undergoes
copper-assisted single-electron-transfer (SET) oxidation18 with
the hypervalent iodine(III) reagent to generate the correspond-
ing allyl radical 1A, which can be further oxidized to allyl cation
1B (path a). Subsequently, 1B is attacked by nucleophilic Cu-
(I)CF3 species, affording the final product. However, the radical
pathway involving the coupling of allyl radical and CF3 radical
(path b) cannot be ruled out. It is also possible that Cu(I)Cl is
directly oxidized by hypervalent iodine(III) reagent 2c to form
Cu(III) species C,19 which is highly electrophilic and has strong
oxidizing properties. Subsequently, allyl cation 1B would formed
from alkene substrate 1 by oxidation with Cu(III) species C
(path c). However, we could not trap the allyl radical using
TEMPO, and we have no evidence of the involvement of either
allylmetal species or trifluoromethylmetal species in the mecha-
nism. Therefore, the details of the CÀC bond-forming step are
not clear at the present stage.
Scheme 2. Mechanistic Rationale
In summary, an efficient copper-catalyzed allylic trifluoro-
methylation reaction has been developed. In this transformation,
formation of a C(sp3)ÀC(sp3) bond is achieved. This reaction
provides a general and straightforward way to construct allylic
trifluoromethylated compounds under mild conditions. The
reaction employs cheap copper chloride as the catalyst and a
hypervalent iodine(III) reagent as both the oxidant and the CF3
source. More importantly, simple alkenes can be used as substrates,
and the reaction tolerates a wide range of functional groups. Further
investigations to expand the scope of both the substrate and the
hypervalent iodine(III) reagent as well as to clarify the reaction
mechanism are currently underway in our laboratory.
Allyl substrates bearing an aromatic moiety yielded a mixture of
linear and branched isomers and also showed relatively low
efficiency (entries 10 and 11). Terminal olefins bearing an ester
group at the allylic position exhibited moderate reactivity in this
transformation because the reaction produced α,β-unsaturated
ester isomers of the substrate with a shift of the double bond
(entry 12). To our delight, cyclohexene and cycloheptene could
also react with 2c, affording the corresponding trifluoromethy-
lated cycloalkenes, albeit in moderate yields (entry 13). Finally, it
is noteworthy that a substrate featuring an exocyclic double bond
at the cyclohexyl ring could also be trifluoromethylated at slightly
elevated temperature, giving the corresponding CF3-containing
cyclohexane derivative 3o in acceptable yield (entry 15).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, and copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
wangjb@pku.edu.cn
For the reaction mechanism of this trifluoromethylation, it is
reasonable to conceive a pathway involving radical species according
to previous reports.10À12 To gain insight into the reaction me-
chanism, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a well-
known radical scavenger, was reacted with hypervalent iodine-
(III) reagent 2c in the presence of stoichiometric CuCl under the
’ ACKNOWLEDGMENT
This project was supported by the 973 Program (2009CB825300)
and the NSFC (Grants 20902005, 20832002, 21072009, and
20821062). The authors thank Mr. Di Qiu for helpful discussions.
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