Copper-and iron-catalyzed decarboxylative tri-and difluoromethylation of α,β-unsaturated carboxylic acids with CF3SO2Na and (CF2HSO2)2Zn via a radical process

Article abstract of DOI:10.1021/ol3034059

A copper-catalyzed decarboxylative trifluoromethylation of various α,β-unsaturated carboxylic acids by using a stable and inexpensive solid, sodium trifluoromethanesulfinate (CF₃SO₂Na, Langlois reagent), was developed. In addition, an iron-catalyzed difluoromethylation of aryl-substituted acrylic acids by using zinc difluoromethanesulfinate (DFMS, (CF₂HSO₂)₂Zn, Baran reagent) via a similar radical process was also achieved.

Full text of DOI:10.1021/ol3034059

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper- and Iron-Catalyzed
Decarboxylative Tri- and
Difluoromethylation of r,β-Unsaturated
Carboxylic Acids with CF3SO2Na and
(CF2HSO2)2Zn via a Radical Process
Zejiang Li, Zili Cui, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou Gansu 730000, P. R. China
liuzhq@lzu.edu.cn
Received December 13, 2012
ABSTRACT
A copper-catalyzed decarboxylative trifluoromethylation of various r,β-unsaturated carboxylic acids by using a stable and inexpensive solid,
sodium trifluoromethanesulfinate (CF3SO2Na, Langlois reagent), was developed. In addition, an iron-catalyzed difluoromethylation of aryl-
substituted acrylic acids by using zinc difluoromethanesulfinate (DFMS, (CF2HSO2)2Zn, Baran reagent) via a similar radical process was also
achieved.
The introduction of fluorinated moieties into organic
molecules such as pharmaceuticals and agrochemicals can
often change their chemical and biological properties.1
Hence, the fluorination and trifluoromethylation reactions
have drawn much attention recently.2 In the past several
years, strategies for trifluoromethylations of arenes have
been well established.3 However, only a few approaches to
the synthesis of CvinylÀCF3 bonds have been developed by
Buchwald,4 Hu,5 Liu,6 and Shen7 et al. (Scheme 1). It is
seen from Scheme 1 that most of these systems suffer from
using expensive and relatively unstable trifluoromethylat-
ing reagents. Herein, we wish to report a copper-catalyzed
decarboxylic trifluoromethylation of R,β-unsaturated car-
boxylic acid by using a stable and inexpensive solid,
sodium trifluoromethanesulfinate (CF3SO2Na, Langlois
reagent). In addition, an iron-catalyzed difluoromethyla-
tion of R,β-unsaturated carboxylic acid by using zinc
difluoromethanesulfinate (DFMS, (CF2HSO2)2Zn, Baran
reagent) via a similar radical process is also achieved.
(3) For selected reviews, see: (a) Tomashenko, O. A.; Grushin, V. V.
Chem. Rev. 2011, 111, 4475. (b) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470. (c) Besset, T.; Schneider, C.; Cahard, D. Angew.
Chem., Int. Ed. 2012, 51, 5048. (d) Studer, A. Angew. Chem., Int. Ed.
2012, 51, 8950. For selected recent examples, see: (a) Cho, E. J.; Senecal,
T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science
2010, 328, 1679. (b) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 3648. (c) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.
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Xiao, J.-C. Angew. Chem., Int. Ed. 2011, 50, 1896. (e) Parsons, A. T.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120. (f) Xu, J.; Fu, Y.;
Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Liu, L. J. Am.
Chem. Soc. 2011, 133, 15300. (g) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.;
Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410. (h)
Kawai, H.; Furukawa, T.; Nomura, Y.; Tokunaga, E.; Shibata, N. Org.
Lett. 2011, 13, 3596. (i) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012,
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Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012,
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2012, 51, 540.
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r
10.1021/ol3034059
XXXX American Chemical Society

The Langlois reagent was first developed in the 1980s,
for use as an electrophilic trifluoromethyl radical in the
addition of electron-rich double bonds and arenes.8 In
2011, Baran et al. reported a very efficient trifluoromethy-
lation of heterocycles by using the inexpensive and bench-
top stable solid CF3SO2Na.9 They also developed a direct
radical difluoromethylation of heteroarenes by using DFMS.10
Very recently, Sanford reported a copper-mediated trifluoro-
methylation of aryl boronic acids by using the Langlois
reagent.11 However, to the best of our knowledge, no
examples of metal-catalyzed direct formation of CvinylÀCF3
bonds by using Langlois’ reagent as well as CvinylÀCF2H
bond formation using DFMS have been reported.
tri- and difluoromethyl-substituted (E)-alkenes has been
developed.
Scheme 1. Formation of CvinylÀCF3/CvinylÀCF2H Bonds
On the other hand, a series of decarboxylative CÀC bond
formation reactions have been developed by Myers,12
Goossen,13 and Liu14 et al.15 over the past several years.
Very recently, we reported the first example of decarbox-
ylative olefination of various sp3 CÀH bonds via radical
additionÀelimination reactions of vinylic carboxylic
acids with alcohols, ethers, and hydrocarbons.16 Of par-
ticular interest in the radical processes, we began to
wonder whether CvinylÀCF3/CvinylÀCF2H bonds could
be constructed by a similar radical additionÀelimination
reaction of R,β-unsaturated carboxylic acids with a tri-
and difluoromethyl radical. Fortunately, an econom-
ical, convenient, and selective access to a variety of
(4) (a) Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552. (b)
Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed.
2012, 51, 2947.
(5) He, Z.; Luo, T.; Hu, M.; Cao, Y.; Hu, J. Angew. Chem., Int. Ed.
2012, 51, 3944.
(6) Xu, J.; Luo, D. F.; Xiao, B.; Liu, Z. J.; Gong, T. J.; Fu, Y.; Liu, L.
Chem. Commun. 2011, 4300.
(7) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342.
Initially, we chose 2,5-dimethoxycinnamic acid as the model
substrate to optimize suitable conditions for this reaction
(Table 1; see also the Supporting Information (SI)). It was
found that the catalyst and radical initiator greatly effect
(8) (a) Tordeux, M.; Langlois, B. R.; Wakselman, C. J. Org. Chem.
1989, 54, 2452. (b) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron
Lett. 1991, 32, 7525. (c) Billard, T.; Langlois, B. R. Tetrahedron 1999, 55,
8065. (d) Tommasino, J. B.; Brondex, A.; Medebielle, M.; Thomalla, M.;
Langlois, B. R.; Billard, T. Synlett 2002, 1697.
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Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411.
(10) 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.
reaction efficiency. The CuSO4 5H2O was more efficient
than copper(II) salts such as Cu(OTf)2, Cu(OAc)2, Cu-
(acac)2, CuO, CuCl2, CuF2, CuBr2, Cu(OAc)2 H2O, etc.
3
ꢀ
3
(entries 1À5). Other copper(I) salts such as CuCl, CuBr,
CuI, Cu2O, and (PPh3)2CuNO3 and other metal salts such
as Fe(OAc)2, Mn(OAc)2 4H2O, Co(OAc)2 4H2O, etc.
3
3
are less effective than CuSO4 5H2O (see the SI). The
3
desired product was isolated in 66% yield by using 10 mol %
CuSO4 5H2O. However, addition of 5 mol % and 15 mol %
€
(11) Ye, Y.; Kunzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979.
3
(12) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem.
Soc. 2002, 124, 11250. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6,
433.
catalysts led to generation of the product in 54% and 47%
yields, respectively (entries 6 and 7). A mixed solvent of
CH2Cl2/H2O was proven to be more efficient than others
such as CH3CN/H2O, tBuOH/H2O, acetone/H2O, AcOH/
H2O, etc. (entries 8 and 9). The yield decreased to 32%
when 3 equiv of TBHP as the radical initiator were used
(entry 10). Other radical initiators such as di-tert-butyl
peroxide (DTBP), dicumyl peroxide (DCP), H2O2, K2S2O8,
and benzoyl peroxide (BPO) were found to be less effi-
cient than TBHP (see the SI). The desired product was
obtained in 45% and 40% yields at 25 and 80 °C,
respectively (entries 11 and 12). It is worth noting that
(E)-1,4-dimethoxy-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene
was obtained as the major product and the ratio of E/Z was
up to 98/2.
(13) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rodrı
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (c) Goossen, L. J.;
Goossen, K.; Rodrıguez, N.; Blanchot, M.; Linder, C.; Zimmermann, B.
Pure Appl. Chem. 2008, 80, 1725. (d) Rodrıguez, N.; Goossen, L. J.
´
guez, N.; Melzer, B.; Linder, C.; Deng, G.;
´
´
Chem. Soc. Rev. 2011, 40, 5030. (e) Dzik, W. I.; Lange, P. P.; Goossen,
L. J. Chem. Sci. 2012, 3, 2671.
(14) (a) Zhang, S.-L.; Fu, Y.; Shang, R.; Guo, Q.-X.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 638. (b) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu,
L. Angew. Chem., Int. Ed. 2011, 50, 4470. (c) Shang, R.; Liu, L. Sci. China
Chem. 2011, 54, 1670.
(15) For selected examples, see: (a) Cornella, J.; Lu, P.; Larrosa, I.
Org. Lett. 2009, 11, 5506. (b) Jana, R.; Trivedi, R.; Tunge, J. A. Org.
Lett. 2009, 11, 3434. (c) Torregrosa, R. R. P.; Ariyarathna, Y.;
Chattopadhyay, K.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 9280.
(d) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
592. (e) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49,
2768. (f) Hu, P.; Shang, Y.; Su, W. Angew. Chem., Int. Ed. 2012, 51, 5945.
(g) Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898.
(16) Cui, Z.; Shang, X.; Shao, X. F.; Liu, Z. Q. Chem. Sci. 2012, 3,
2853.
To examine the scope of this system, the decarboxylative
coupling reactions of various cinnamic acids with sodium
B
Org. Lett., Vol. XX, No. XX, XXXX

41% and 42% yield, respectively. No products were
obtained by coupling (E)-3-(pyridine-3-yl)acrylic acid with
NaSO2CF3 under these conditions.
Table 1. Modification of the Typical Reaction Conditionsa
Table 2. Copper-Catalyzed Decarboxylative Trifluoromethyla-
tion of Cinnamic Acids with Sodium Trifluoromethanesulfinatea
radical
catalyst
(mol %)
initiator
(equiv)
solvent
(v/v, V)
entry
1
yield (%)b
_
_
TBHP (5) CH2Cl2/H2O
(2.5/1, 3.5 mL)
2
Cu(OTf)2 (10)
TBHP (5) CH2Cl2/H2O
(2.5/1, 3.5 mL)
56
66
54
52
54
47
60
59
32
45
40
3
CuSO4 5H2O (10) TBHP (5) CH2Cl2/H2O
3
(2.5/1, 3.5 mL)
4
Cu(acac)2 (10)
Cu(OAc)2 (10)
TBHP (5) CH2Cl2/H2O
(2.5/1, 3.5 mL)
5
TBHP (5) CH2Cl2/H2O
(2.5/1, 3.5 mL)
6
CuSO4 5H2O (5)
TBHP (5) CH2Cl2/H2O
(2.5/1, 3.5 mL)
3
7
CuSO4 5H2O (15) TBHP (5) CH2Cl2/H2O
3
(2.5/1, 3.5 mL)
8
CuSO4 5H2O (10) TBHP (5) CH3CN/H2O
3
(2.5/1, 3.5 mL)
9
CuSO4 5H2O (10) TBHP (5) Acetone/H2O
3
(2.5/1, 3.5 mL)
10
11c
CuSO4 5H2O (10) TBHP (3) CH2Cl2/H2O
3
(2.5/1, 3.5 mL)
CuSO4 5H2O (10) TBHP (5) CH2Cl2/H2O
3
(2.5/1, 3.5 mL)
12d CuSO4 5H2O (10) TBHP (5) CH2Cl2/H2O
3
(2.5/1, 3.5 mL)
a Reaction conditions: 2,5-dimethoxycinnamic acid (0.5 mmol),
NaSO2CF3 (1.5 mmol), TBHP (70% aqueous), 2.5 h. b Isolated yields.
c The reaction was conducted at 25 °C. d The reaction was conducted at
80 °C.
trifluoromethanesulfinate were studied (Table 2). The
coupling reaction of NaSO2CF3 with cinnamic acids bear-
ing electron-donating groups such as OMe, OH, NH2,
NMe2, and OEt afforded the corresponding products in
moderate to high yields (2aÀ2e). p-Methylcinnamic acid
gave 2f in 56% yield. In addition, meta-andortho-substituted
cinnamic acids also gave moderate yields of the prod-
ucts (2g, 2h, and 2i), which indicated that the steric effect
in the aromatic core is not pronounced. Moreover, the
desired products were isolated in good to high yields by
using highly substituted aryl acrylic acids (2jÀ2p). It is
noteworthy that (2E,4E)-5-phenylpenta-2,4-dienoic acid
could also generate the desired product 2q in 48% yield
under the reaction conditions. Interestingly, 4-chloro- and
4-nitrocinnamic acids gave 1-(4-chlorophenyl)-3,3,3-
trifluoropropan-1-one (2r) and 1-(4-nitrophenyl)-3,3,3-
trifluoropropan-1-one (2s), respectively. Surprisingly,
(E)-2-(2-carboxyvinyl)benzoic acid gave the desired pro-
duct 2t in 68% yield, and no ketones were observed. It is also
worth noting that heteroarene substituted acrylic acids
also gave the desired products (2u and 2v). A N-heteroarene
such as indole and N-methyl pyrrole substituted acrylic
acids gave bis-trifluoromethylated product 2w and 2x in
a Reaction conditions: cinnamic acid (0.5 mmol), NaSO2CF3 (1.5
mmol), CuSO4 5H2O (0.05 mmol), TBHP (2.5 mmol, 70% aqueous),
3
CH2Cl2/H2O (v/v = 2.5/1, 3.5 mL), 50 °C. b Reaction time, indicated by
TLC. c Isolated yields. d Ratio of E/Z was determined by 19F NMR of the
crude product mixture. e Ratio of (E,E)/(E,Z).
Inspired by Baran’s work,10 we began to wonder whether
other radicals such as a difluoromethyl radical could also
add to the R,β-unsaturated carboxylic acids followed by
elimination of CO2 to form a series of difluoromethyl-
substituted alkenes. Fotunately, iron-catalyzed decar-
boxylative difluoromethylation of electron-rich aryl-
substituted acrylic acids by using DFMS ((CF2HSO2)2Zn,
Baran reagent) via a similar radical process is also achieved,
(17) (a) Prakash, G. K. S.; Ganesh, S. K.; Jones, J. P.; Kulkarni, A.;
Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012,
51, 12090. (b) He, Z.; Hu, M.; Luo, T.; Li, L.; Hu, J. Angew. Chem., Int.
Ed. 2012, 51, 11545.
Org. Lett., Vol. XX, No. XX, XXXX
C

which has never been reported before.17 Under the typical
reaction conditions, various difluoromethyl-substituted
(E)-alkenes have been selectively isolated in relatively low
to moderate yields (Table 3, entries 1À5). Electron-deficient
aryl-substituted acrylic acids gave very low yields of the
desired products under these conditions.
then proceeds via an elimination of carbon dioxide and
Cu(I) to generate the product. Oxidation of Cu(I) by the
hydroxyl radical in the presence of cinnamic acid would
regenerate the cupric cinnamate. Another possible process
similar to the KharaschÀSosnovsky reaction19 involving a
Cu(III) intermediate cannot be ruled out at this time.
Table 3. Iron-Catalyzed Decarboxylative Difluoromethylation
of Cinnamic Acids with Zinc Difluoromethanesulfinatea
Scheme 2. Possible Mechanism
In conclusion, we report a convenient copper(II)-
catalyzed trifluoromethylation reaction of various acrylic
acids with a stablesolid, NaSO2CF3. Thismethodprovides
a useful and practical strategy for stereospecific synthesis
of CF3-substituted E-alkenes. Various arenes, including
indolesand divinyl carboxyl acids, are compatiblewiththis
decarboxylative CÀC bond formating reaction. Further-
more, an iron-catalyzed difluoromethylation of electron-
rich aryl-substituted acrylic acids is also developed by
using DFMS in a similar radical process, which can be
used to stereospecifically prepare HCF2-substituted
E-alkenes. This system provides a novel pathway for the
construction of CvinylÀCF3/CvinylÀCF2 bondsvia a radical
additionÀelimination process. This method is limited to
aryl-substituted acrylic acid substrates. Alkyl-substituted
acrylic acidsfailedtogivethedesiredproductswhich might
be due to the stability of the radical intermediate. Further
investigation of this procedure focusing on this disadvant-
age is underway in our laboratory.
a Reaction conditions: cinnamic acid (0.5 mmol), Zn(SO2CF2H)2
(1.5 mmol), FeSO4 7H2O (0.05 mmol), TBHP (2.5 mmol, 70% aqueous),
3
CH2Cl2/H2O (v/v = 2.5/1, 3.5 mL), 50 °C. b Isolated yields. c Ratio of
E/Z was determined by 19F NMR of the crude product mixture.
A plausible mechanism that is consistent with our pre-
vious work and the literature precedent16,18 is depicted in
Scheme 2. The trifluoromethyl radical will be generated by
the reaction of tert-butyl peroxide with NaSO2CF3 and
Cu(II).8 Reaction of the acrylic acid with Cu(I) reduced
from the former step would generate a salt of Cu(II)
carboxylate in the presence of TBHP. Addition of the
trifluoromethyl radical at the R-position of the double
bond in cupric cinnamate would give radical A, which
Acknowledgment. This project is supported by the Na-
tional Science Foundation of China (Nos. 21002045,
21272096) and the Fundamental Research Funds for the
Central Universities (lzujbky-2012-55).
Supporting Information Available. Full experimental
details and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Russell, G. A.; Ngoviwatchai, P. J. Org. Chem. 1989, 54,
1836. (b) Xiang, J.; Fuchs, P. L. J. Am. Soc. Chem. 1996, 118, 11986.
(19) Kharasch, M. S.; Sosnovsky, G. J. Am. Soc. Chem. 1958, 80, 756.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX