Decarboxylative allylation of trifluoroethyl sulfones and approach to difluoromethyl compounds

Article abstract of DOI:10.1021/ol302589w

Allyl carbonates undergo palladium-catalyzed decarboxylative allylation of trifluoroethyl phenyl sulfones. The success of the allylation, which is not efficient under typical strong base-mediated conditions, is the result of mild conditions thanks to a progressive delivery of ethoxide. Indeed, ethyl allyl carbonates act as a latent source of ethoxide for generation of the trifluoroethyl carbanion that reacts with the π-allylpalladium complex. The utility of the method is illustrated in a new approach to difluoromethyl compounds.

Full text of DOI:10.1021/ol302589w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Decarboxylative Allylation of
Trifluoroethyl Sulfones and Approach
to Difluoromethyl Compounds
Norio Shibata,*,† Kazunobu Fukushi,† Tatsuya Furukawa,† Satoru Suzuki,†
Etsuko Tokunaga,† and Dominique Cahard‡
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan, and UMR 6014 CNRS
ꢀ
COBRA, Universite et INSA de Rouen, 76821 Mont-Saint-Aignan, France
nozshiba@nitech.ac.jp
Received September 20, 2012
ABSTRACT
Allyl carbonates undergo palladium-catalyzed decarboxylative allylation of trifluoroethyl phenyl sulfones. The success of the allylation, which is
not efficient under typical strong base-mediated conditions, is the result of mild conditions thanks to a progressive delivery of ethoxide. Indeed,
ethyl allyl carbonates act as a latent source of ethoxide for generation of the trifluoroethyl carbanion that reacts with the π-allylpalladium complex.
The utility of the method is illustrated in a new approach to difluoromethyl compounds.
Within the ever-growing field of organofluorine chem-
istry, finding novel applications for simple and easily
available fluorinated building blocks is of prime interest
and highly challenging. In this context, new reactions that
allow the introduction of fluoroalkyl moieties into organic
molecules are eagerly sought after.1 Among the variety of
synthetically important fluoroalkyl groups, fluoromethyl
groups represented by CF3, CF2H, and CFH2 are the
smallest units that are known to play important roles in
a wide field of science, especially in medicinal chemistry.2
Therefore, development of efficient methods for the synthe-
sis of fluoromethylated compounds is in great demand.
Trifluoromethyl trimethylsilane, Me3SiÀCF3, called the
RuppertÀPrakash reagent, is one of the most successful
trifluoromethyl anion sources to obtain trifluoromethyl-
ated compounds.3 A difluoromethyl variant of this reagent,
Me3SiÀCF2H, has also been investigated.4 Unlike the huge
amount of information reported in the chemistry of fluoro-
methyl anions,Àthe potential of the trifluoroethyl carba-
nion CF3CH2 has been scarcely explored essentially
because of the feared defluorination reaction.5 Undeniably,
the alkylation of carbanions bearing a trifluoromethyl
(3) (a) Prakash, S. G. K.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b)
Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008, 19,
2633.
(4) (a) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13,
5342. (b) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(5) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41,
817.
(6) (a) Komatsu, Y.; Sakamoto, T.; Kitazume, T. J. Org. Chem. 1999,
64, 8369. (b) Sato, K.; Takiguchi, Y.; Yoshizawa, Y.; Iwase, K.; Shimizu,
Y.; Tarui, A.; Omoto, M.; Kumadaki, I.; Ando, A. Chem. Pharm. Bull.
2007, 55, 1593. (c) Yamauchi, Y.; Katagiri, T.; Uneyama, K. Org. Lett.
2002, 4, 173. (d) Fuchigami, T.; Nakagawa, Y. J. Org. Chem. 1987, 52,
5276. (e) Ishikawa, N.; Yokozawa, T. Bull. Chem. Soc. Jpn. 1983, 56,
724. (f) Yokozawa, T.; Nakai, T.; Ishikawa, M. Tetrahedron Lett. 1984,
25, 3987. (g) Yokozawa, T.; Nakai, T.; Ishikawa, M. Tetrahedron Lett.
1984, 25, 3991. (h) Qian, C.-P.; Nakai, T. Tetrahedron Lett. 1990, 31,
7043. (i) Fujita, M.; Hiyama, T. Bull. Chem. Soc. Jpn. 1987, 60, 4377. (j)
Grellepois, F.; Kikelj, V.; Coia, N.; Portella, C. Eur. J. Org. Chem. 2012,
509.
† Nagoya Institute of Technology.
‡
ꢀ
Universite et INSA de Rouen.
(1) (a) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed.
2012, 51, 5048. (b) Ni, C.; Hu, J. Synlett 2011, 770. (c) Shibata, N.;
Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, No.65. (d) Hu,
J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (e) Ma, J.-A.;
Cahard, D. J. Fluorine Chem. 2007, 128, 975. (f) Shibata, N.; Ishimaru,
T.; Nakamura, S.; Toru, T. J. Fluorine Chem. 2007, 128, 469.
€
(2) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
Purser, S.; Moore, P. R.; Swallowb, S.; Gouverneur, V. Chem. Soc. Rev.
ꢀ
ꢀ
2008, 37, 320. (c) Begue, J. P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley-VCH: Weinheim, Germany,
2008. (d) O'Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
r
10.1021/ol302589w
XXXX American Chemical Society

group is one of the most difficult tasks in carbanion chem-
istry. Although some reactions of such carbanions have been
reported,6 practical alkylation of trifluoroethyl carbanions
and their synthetic application remain important synthetic
challenges. Since our research group has recently focused on
the synthetic utility of monofluoromethylated phenylsulfone
derivatives such as FBSM7,8 and FBDT,9 we next became
interested in 2,2,2-trifluoroethyl phenylsulfones, CF3CH-
RSO2Ph 1,10À12as precursors of trifluoroethyl carbanions
CF3CRHÀ. In addition to the utility of the phenylsulfonyl
group in synthetic organic chemistry, the trifluoroethyl
phenylsulfonyl moiety itself is of great importance as a key
component in biologically active compounds, for example,
stromelysin-1, a potent inhibitor of MMP-3.13
sulfone derivatives 3 that feature a tertiary or a quaternary
trifluoromethylated carbon center. The products obtained
are of great interest not only as components of biologically
active compounds but also as precursors of difluoromethy-
lated compounds after three successive reductive treatments
(Scheme 1).
Scheme 1. Strategies for Allylation of Trifluoroethyl Sulfones 1
An early study by Uneyama and Momota in 1989 revealed
that alkylation of the phenylsulfonyl 2,2,2-trifluoroethyl
carbanion is problematic.12 After careful investigation, 3
equiv of LDA and tetraethylammonium chloride in THF-
HMPA plus 10 equiv of methyl iodide provided the methy-
lation product in 80% yield. However, allyl iodide gave the
allylated 2,2,2-trifluoroethyl phenylsulfone in only 12%
yield and other alkylating agents (ethyl iodide, benzyl
bromide) failed to react. In 2011, we reported a new
approach toward R-carbonyl CF3-bearing quaternary cen-
ters based on a palladium-catalyzed intramolecular decar-
boxylative allylation.14 We surmised that failures en-
countered in allylation of the trifluoroethyl carbanion in
the studies by Uneyama would be solved under the neutral
reaction conditions of an intermolecular palladium-
catalyzed decarboxylative allylation. The generated trifluoro-
ethyl carbanions CF3CRHÀ should be dually stabilized
by the electron-withdrawing phenylsulfonyl group and the
cationic allyl palladium ligand.15,16 Herein, we report effi-
cient conditions for allylation of 2,2,2-trifluoroethyl phenyl-
sulfones 1 through a palladium-catalyzed decarboxyl-
ative allylation with allyl carbonates 2 to provide allylated
Our investigations started with the reaction conditions
for the decarboxylative allylation of R-trifluoromethyl
β-keto esters:14 2.5 mol % tris(dibenzylideneacetone) di-
palladium [Pd2(dba)3] and 1,2-bis(diphenylphosphino) ethane
(dppe) in THF. Under these conditions in the presence of
ethyl allyl carbonate 2a, the allylation of phenyl trifluoroethyl
phenylsulfone 1a takes place within 1 h at 40 °C to provide
the desired allylated phenyl trifluoroethyl phenylsulfone 3a in
92% yield (Table 1, entry 1). Further optimization of the
reaction conditions using a variety of palladium(II) sources,
ligands including mono- and bidentate phosphines, solvents,
and various ligand-to-palladium ratios did not improve the
yields (see Table S1 in the Supporting Information).
We next examined the substrate scope for the decarbox-
ylative allylation under the best reaction conditions. Tri-
fluoroethyl phenylsulfones 1bÀg having a variety of
aromatic groups at the reaction center were effectively
allylated to provide the desired products 3bÀg that feature
a quaternary trifluoromethylated carbon center in 91 to
99% yields (entries 2À7). Substitution of the benzene ring
as well as group position did not affect yield and reactivity.
Alkyl, allyl, cinnamyl, and chloro substituted substrates
1hÀl were alsoefficiently transformedintothe correspond-
ing allylated trifluoroethyl phenylsulfones 3hÀl in over
90% yields. The reaction of nonsubstituted trifluoroethyl
phenylsulfone 1m with allyl ethyl carbonate (2a) or cinna-
myl ethyl carbonate (2b) provided the desired allylation
products 1j, k having a tertiary stereocenter, although the
yields were low due to competitive bis-allylation (entries
13À14). Fortunately, changing the ligand from dppe to
1,1’-bis(diphenylphosphino)ferrocene (dppf) improved the
yields of monoallylation significantly (entries 15 and 16),
while bis-allylation was selectively observed in a high yield
of 97% when 2 equiv of allyl carbonate were used in the
presence of dppe (entry 17). Evaluation of ethyl methallyl
carbonate (2c) in this decarboxylative process required
adjustment of the reaction conditions: rac-BINAP was
used asa diphosphine ligand in toluene at 110 °C. With this
appropriate protocol, products 3mÀo were obtained in
(7) FBSM: fluorobis(phenylsulfonyl)methane. (a) Fukuzumi, T.;
Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem., Int. Ed. 2006, 45, 4973. (b) Furukawa, T.; Kawazoe, J.; Zhang,
W.; Nishimine, T.; Tokunaga, E.; Matsumoto, T.; Shiro, M.; Shibata,
N. Angew. Chem., Int. Ed. 2011, 50, 9684. (c) Ogasawara, M.; Murakami,
H.; Furukawa, T.; Takahashi, T.; Shibata, N. Chem. Commun. 2009,
7366.
(8) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829.
(9) FBDT: 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide. Furukawa,
T.; Goto, Y.; Kawazoe, J.; Tokunaga, E.; Nakamura, S.; Yang, Y.;
Du, H.; Kakehi, A.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2010,
49, 1642.
(10) A series of 2,2,2-trifluoroethyl phenylsulfones CF3CHRSO2Ph 1
are readily synthesized from CF3CHRSPh (ref 11) by oxidation or
another method (ref 12). See Supporting Information for details.
(11) (a) Nakai, T.; Tanaka, K.; Setoi, H.; Ishikawa, N. Bull. Chem.
Soc. Jpn. 1977, 50, 3069. (b) Uneyama, K.; Momota, M. Tetrahedron
Lett. 1989, 30, 2265.
(12) Uneyama, K.; Momota, M. Bull. Chem. Soc. Jpn. 1989, 62, 3378.
(13) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv.
Synth. Catal. 2012, 354, 1141.
(14) Shibata, N.; Suzuki, S.; Furukawa, T.; Kawai, H.; Tokunaga, E.;
Yuan, Z.; Cahard, D. Adv. Synth. Catal. 2011, 353, 2037.
(15) For an example of intramolecular decarboxylative allylation,
see: (a) Weaver, J. D.; Tunge, J. A. Org. Lett. 2008, 10, 4657. (b) Weaver,
J. D.; Ka, B. J.; Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem.
Soc. 2010, 132, 12179.
(16) (a) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem.
Rev. 2011, 111, 1846. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 395. (c) Trost, B. M.; Crawley, M. Chem. Rev. 2003, 103, 2921.
B
Org. Lett., Vol. XX, No. XX, XXXX

77 to 98% yields (entries 18À20). The reaction of 1k with
2bproceededin the presence ofdppf togivesymmetrical 3p
in 96% yield (entry 21).
Table 1. Substrate Scope
yielda
entry
1
R1
2
ligand
3
(%)
Figure 1. Putative mechanism of decarboxylative allylation.
Scheme 2. Examples of Utility of 3j, 3k, and 3p
1
1a
1b
1c
1d
1e
1f
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2b
2a
2c
2c
2c
2b
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppf
3a
3b
3c
3d
3e
3f
92
91
98
97
93
91
99
91
93
90
97
95
20
29
58
52
97
95
77
98
96
2
4-MeC6H4
4-MeOC6H4
3,4-Me2C6H3
3,4-MeO2C6H3
4-iPrC6H4
4-tBuC6H4
Me
3
4
5b
6
7
1g
1h
1i
3g
3h
3i
8
9
CH2CH2CH2Ph
CH2CH=CH2
CH2CH=CHPh
Cl
10
11
12
13
14
15c
16d
17e
18f
19f
20f
21c,d,g
1j
3j
1k
1l
3k
3l
1m
1m
1m
1m
1m
1b
1j
H
1j
H
1k
1j
H
H
dppf
1k
3j
H
dppe
BINAP
BINAP
BINAP
dppf
Me
3m
3n
3o
3p
CH2CH=CH2
CH2CH=CHPh
CH2CH=CHPh
1k
1k
to afford compounds 6a,b that possess a difluoromethyl
group at a nonactivated position; such compounds are
otherwise difficult to obtain by other methods.17
a Isolated yield. b Reaction time was 2 h. c Reaction time was 8 h.
d Reaction was carried out at 60 °C. e 2 equiv of 2a were used. f Reaction
conditions: 1 (0.1 mmol), [Pd2(dba)3] (2.5 mol %), rac-BINAP (6 mol %),
toluene, reflux, 8 h. g 2 equiv of 2b were used.
In summary, we have developed a practical intermole-
cular decarboxylative allylation of trifluoroethyl phenyl-
sulfones 1 that provide medicinally attractive building
blocks 3.18 The decarboxylative allylation is remarkable
for its high yields and provides compounds that are not
accessible under conventional base-mediated allylations.
The products can be converted to difluoromethyl com-
pounds after removal of the traceless phenyl sulfonyl group.
This methodology introduces a novel approach to difluor-
omethyl compounds.17 Further utility of trifluoroethyl
phenylsulfones CF3CHRSO2Ph 1 as precursors of the tri-
fluoroethyl carbanions CF3CRHÀ are under investigation.
The reaction proceeds via an oxidative addition of the
allyl carbonate to the Pd(0)Àphosphine complex to form a
cationic π-allyl Pd complex with an ethoxide counteranion
and concomitant elimination of CO2. Substrate 1 is depro-
tonated by the ethoxide anion and reacts with the π-allyl
Pd complex leading to the product 3 and regeneration of
the Pd(0) catalyst in a reductiveelimination step(Figure 1).
To further demonstrate the utility of the products, two
examples of functional group transformation were per-
formed. The symmetric bis-allyl compound 3j was con-
verted to a synthetically attractive cyclopentene derivative
4 under Grubbs’ olefin metathesis conditions6j in 95%
yield (Scheme 2). The unsymmetric bis-allyl compound 3k
and symmetrical 3p were submitted to three successive
reductions, which include a reductive desulfonylation step
Acknowledgment. The authors thank the JSPS in Japan
and CNRS in France for financial support of this work
through a Joint Research Project. This study was financially
(18) We noticed that Mathew, Hu and co-workers reported similar
results at the international conference. See 20th International Sympo-
sium on Fluorine Chemistry 2012, Program & Abstracts, page 195
(Poster-5). It appeared after submission of this manuscript. Zhang,
W.; Zhao, Y.; Ni, C.; Mathew, T.; Hu, J. Tetrahedron Lett. 2012, 53,
in press, DOI: http://dx.doi.org/10.1016/j.tetlet.2012.09.094.
(17) (a) Prakask, S. G. K.; Hu, J. Acc. Chem. Res. 2007, 40, 921. (b)
Huang, W.; Ni, C.; Zhao, Y.; Zhang, W.; Dilman, A. D.; Hu, J.
Tetrahedron 2012, 68, 5137. (c) Fujiwara, Y.; Dixon, J. A.; Rodriguez,
R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.;
Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494.
Org. Lett., Vol. XX, No. XX, XXXX
C

supported in part by Grants-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science
and Technology (Project name: Advanced Molecular
Transformation by Organocatalysts) (Project name: Plat-
form for Drug Discovery, Informatics and Structural Life
Science). We also thank the Asahi Glass Foundation.
Supporting Information Available. Experimental de-
tails and copies of 1H, 13C, and 19F spectra are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX