Copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes

Article abstract of DOI:10.1021/ol403263c

A novel and highly practical reaction for the copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes is presented here. This methodology provides a general and straightforward way to synthesize a variety of useful CF₃-containing nitriles, which can be used for further preparation of pharmaceutically and agrochemically important compounds in synthetic organic chemistry.

Full text of DOI:10.1021/ol403263c

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Intermolecular Cyanotrifluoromethylation of
Alkenes
Yu-Tao He,† Lian-Hua Li,† Yan-Fang Yang,† Zhao-Zhao Zhou,† Hui-Liang Hua,† Xue-Yuan Liu,†
and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou, 730000,
P.R. China
S
* Supporting Information
ABSTRACT: A novel and highly practical reaction for the
copper-catalyzed intermolecular cyanotrifluoromethylation of
alkenes is presented here. This methodology provides a
general and straightforward way to synthesize a variety of
useful CF3-containing nitriles, which can be used for further
preparation of pharmaceutically and agrochemically important
compounds in synthetic organic chemistry.
Scheme 1. Previous and Present Works
rganic compounds bearing trifluoromethyl groups have
Oattracted ever-increasing interest of chemists due to
potential improvement in lipophilicity and bioactivity, and a
series of trifluoromethylated derivatives have been prepared as
pharmaceuticals, agrochemicals, and functional materials.1,2 As
a powerful synthetic tool in this area, transition-metal-mediated
or -catalyzed trifluoromethylation reactions have provided a
number of useful methods to construct a C−CF3 bond from
aryl,3 aryl halides,4 alkynes,5 and the corresponding boronic
acids.6 In recent years, the trifluoromethylation of alkenes,
especially unactivated alkenes, has become a research hotspot
and effective methods have been studied intensively.7 In 2011,
the Buchwald, Liu, and Wang groups reported the copper-
catalyzed electrophilic allylic trifluoromethylation of alkenes
(Scheme 1a).8 Furthermore, our group, as well as those of
Buchwald, Sodeoka, Liu, and Nevado, independently demon-
strated the trifluoromethylation of alkenes which involves a
pattern of intramolecular cyclization in the presence of a copper
catalyst (Scheme 1b).9 However, the work for the trifluor-
omethylation of alkenes based on the intermolecular
difunctionalization strategy is quite rare,10 and most of these
three-component reactions require photoredox catalyst
(Scheme 1c).11 Thus, the introduction of a CF3 group
synchronously with another important functional group into
alkenes is highly desirable.
synthetic chemistry. Due to our ongoing interest in the
synthesis of CF3-containing compounds, we envisioned that the
intermolecular difunctionalization of alkenes which involves the
C−CN and C−CF3 bond formations could be achieved
concurrently in one pot. Herein, we reported a new powerful
protocol for the cyanotrifluoromethylation of alkenes with the
use of a hypervalent iodine reagent and trimethylsilyl cyanide
(TMSCN) as the cyano source under copper catalysis (Scheme
1d). It should be indicated that, at the same time as we finished
In this context, we were interested in the use of a copper
catalyst for directed cyanotrifluoromethylation of alkenes.
Nitriles, holding the post of remarkably versatile building
blocks in numerous organic transformations such as carboxylic
acids, amines, amides, ketones, and aldehydes,12 are widely
known as an important class of organic compounds, which are
found in a number of pharmaceuticals, agricultural chemicals,
and optoelectronic materials.13 Since the unique role of the
cyano group, its introduction into organic molecules,
particularly by a catalytic protocol, is an important topic in
́
this work, Szabo and co-workers reported the cyanotrifluor-
omethylation of styrenes with an electron-deficient double
bond in the presence of CuCN.14 Nevertheless, the reaction
Received: November 13, 2013
Published: December 13, 2013
© 2013 American Chemical Society
270
dx.doi.org/10.1021/ol403263c | Org. Lett. 2014, 16, 270−273

Organic Letters
Letter
requires stoichiometric amounts of CuCN and has a low
substrate scope.
Table 2. Copper-Catalyzed Cyanotrifluoromethylation of
Various Alkenes
a
At the outset of our studies, we chose styrene 1a as the
model substrate to optimize the reaction conditions (Table 1).
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
solvent
DMF
t (h)
yield (%)
1
CuCl (10)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
34
35
38
30
28
36
61
25
20
23
79
69
82
83
NR
2
CuI (10)
DMF
3
CuCN (10)
DMF
4
CuF2 (10)
DMF
5
Cu(OAc)2 (10)
Cu(MeCN)4PF6 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (20)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
−
DMF
6
DMF
7
DMF
8
CH3CN
DCM
9
10
11
12
13
14
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
c
15
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), TMSCN (0.3
mmol), copper catalyst, solvent (2.0 mL), 60 °C, under argon.
Isolated yield. Without Cu(OTf)2.
b
c
Initially, the reaction was carried out with TMSCN (1.5 equiv)
and Togni’s reagent 215 (1.2 equiv) in the presence of 10 mol
% CuCl in DMF at 60 °C for 1.0 h. Gratifyingly, the desired
cyanotrifluoromethylation product 4,4,4-trifluoro-2-phenylbuta-
nenitrile (3a) was isolated in 34% yield (Table 1, entry 1).
Inspired by this result, different copper complexes, such as CuI,
CuCN, CuF2, Cu(OAc)2, Cu(MeCN)4PF6, and Cu(OTf)2,
were applied into the reaction separately (Table 1, entries 2−
7). It showed that Cu(OTf)2 performed well and increased the
yield to 61% (Table 1, entry 7). Meanwhile, screening of
solvents revealed that DMSO was the best for the reaction
(Table 1, entries 8−11). The loading of the catalyst and the
reaction time were evaluated as well, and we obtained the best
result as an 83% yield under the optimized conditions by using
5 mol % Cu(OTf)2, TMSCN (1.5 equiv) and Togni’s reagent 2
(1.2 equiv) in DMSO at 60 °C for 0.5 h (Table 1, entry 14).16
The controlled experiments indicated the copper reagent was
essential in catalyzing the reaction (Table 1, entry 15).
With the optimized conditions in hand (Table 1, entry 14),
we next investigated the scope of alkenes in the cyanotri-
fluoromethylation process. As shown in Table 2, in most cases,
alkenes 1a−1z proceeded smoothly to transform into the
cyanotrifluoromethylation products 3a−3z in moderate to
good yields, and the substrates bearing electron-donating
groups gave higher yields than those containing electron-
withdrawing groups on the aromatic rings. The halogen
substituents, including fluoro, chloro, and bromo, were found
to be tolerated under the optimized reaction conditions.
Naphthalenes bearing vinyl groups at positions 1 and 2 afforded
the desired products in 65% (3o) and 74% (3p) yield,
respectively. No reaction occurred in the case of α-
methylstyrene 1q, which is likely due to the difficulty in
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), TMSCN (0.3
mmol), Cu(OTf)2 (0.01 mmol), DMSO (2.0 mL), 60 °C, 0.5 h, under
b
argon, isolated yield. Structure of the major diastereomer is shown.
c
The ratio of diastereomers was determined by crude 19F NMR.
forming the iodo(III) cyclopropane B due to the effect of steric
hindrance. However, 1,2-disubstituted alkenes were found to
undergo the desired transformation and gave a mixture of
diastereoisomers 3r (dr = 3:1) and 3s (dr = 10:1).
Encouraged by these promising results, we next applied the
cyanotrifluoromethylation process to examine some linear
olefins. The reactions of simple alkenes proceed smoothly,
which gave the corresponding products in excellent yields (3v
and 3w). The NMR-based structure was further confirmed by
X-ray crystallography of 3x, which was obtained when 1x was
used as the substrate. Terminal olefins bearing a benzoate
group was also well tolerated in this reaction, with the desired
product being obtained in 86% yield (3z). The scope of alkenes
demonstrated the wide compatibility of this new methodology
in organic synthesis.
As alluded to earlier, the produced cyanotrifluoromethylation
products are versatile synthetic intermediates, and they could
be used to generate CF3-containing products resulting from
reaction of the cyano group. For instance, the CN group in the
product 3a was readily reduced to the CF3-containing amine 5a
in the presence of BH3·SMe2 as a reductant, while the
271
dx.doi.org/10.1021/ol403263c | Org. Lett. 2014, 16, 270−273

Organic Letters
Letter
cyanotrifluoromethylation product 3a could also convert to the
CF3-containing carboxylic acid 5b in an excellent yield of 89%
easily (Scheme 2). Thus, the copper-catalyzed intermolecular
cyanotrifluoromethylation reaction proved to be synthetically
useful in organic chemistry.
Scheme 4. Proposed Mechanism
Scheme 2. Further Synthetic Transformation
To gain further understanding about the reaction mecha-
nism, inhibition experiments were conducted. When 1.2 equiv
of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added
into the reaction system, the desired transformation was found
to be completely inhibited and only a small amount of the
TEMPO−CF3 adduct was detected (Scheme 3a). Furthermore,
intermediate E can be further oxidized to the cationic
intermediate F, and then the cationic intermediate F is attacked
by TMSCN to deliver the final cyanotrifluoromethylation
product 3a.
In summary, we have developed a copper-catalyzed
intermolecular cyanotrifluoromethylation of alkenes based on
the difunctionalization strategy. This methodology allows a
broad substrate scope, including styrene derivatives and
aliphatic olefins with a catalytic amount of copper. The highly
practical reaction provides access to a variety of useful CF3-
containing nitriles, which can be used as remarkably versatile
building blocks in synthetic organic chemistry. Further
investigations of the mechanistic details and applications of
this reaction are currently underway in our laboratory.
Scheme 3. Trapping Experiments (Ts = 4-
Methylbenzenesulfonyl)
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, spectral data for all new
compounds, crystallographic data, and CIF information for 3x
are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
additional direct evidence for the radical mechanism was the
reaction of N,N-diallyl-4-methylbenzenesulfonamide 4 under
the standard reaction conditions, which gave a cyclization of
cyanotrifluoromethylation product 6 in 77% yield (dr = 2.8:1)
(Scheme 3b). However, when BHT (2,6-di-tert-butyl-4-methyl-
phenol) was added as a radical scavenger, to our surprise, the
desired product was obtained with a decreased yield (56%)
(Scheme 3c), which was different from the result of TEMPO.
We hypothesized that TEMPO on one hand was the effect of a
radical scavenger, and on the other hand it might destroy
Togni’s reagent or interact with Cu(II). According to the
experimental results and related published research studies in
this field, we proposed two probable mechanisms (Scheme
4).8,9c,10c,17 In path a, a copper catalyst activates Togni’s reagent
2, leading to the cationic active species A, which reacts with the
styrene 1a resulting in the iodo(III) cyclopropane B. Then the
iodo(III) cyclopropane B is trapped by TMSCN to generate
the intermediate C; after reductive elimination from C, the
cyanotrifluoromethylation product 3a is obtained. In path b,
Togni’s reagent 2 undergoes copper-assisted single-electron-
transfer (SET) oxidation to generate the CF3-containing radical
species D. The CF3 radical, which is released from
decomposition of the radical species D, reacts with the styrene
1a leading to the radical intermediate E. The radical
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liangym@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation
(NSF21072081) and the National Basic Research Program of
China (973 Program) 2010CB8-33203 for financial support.
We also acknowledge support from the “111” Project and
Program for Changjiang Scholars and innovative Research
Team in University (IRT1138).
REFERENCES
■
(1) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Kirsch, P. In
Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany,
2004. (c) Uneyama, K. In Organofluorine Chemistry; Blackwell: Oxford,
U.K., 2006. (d) Ojima, I. In Fluorine in Medicinal Chemistry and
272
dx.doi.org/10.1021/ol403263c | Org. Lett. 2014, 16, 270−273

Organic Letters
Letter
Chemical Biology; Wiley-Blackwell: Chichester, U.K., 2009. (e) Muller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (f) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
(11) (a) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (b) Yasu, Y.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (c) Yasu,
Y.; Koike, T.; Akita, M. Org. Lett. 2013, 15, 2136. (d) Mizuta, S.;
Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill, M.;
(2) (a) Smart, B. E. Chem. Rev. 1996, 96, 1555. (b) Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. (c) Hird, M. Chem.
Soc. Rev. 2007, 36, 2070. (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12,
305. (e) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475. (f) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470.
(3) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
12644. (b) Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.;
Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947. (c) Wiehn, M. S.;
Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951.
(d) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
3648. (e) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 2878. (f) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S. J.
Am. Chem. Soc. 2011, 133, 7577. (g) Ye, Y.; Lee, S. H.; Sanford, M. S.
Org. Lett. 2011, 13, 5464. (h) Tomashenko, O. A.; Escudero-Adan, E.
C.; Belmonte, M. M.; Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50,
Wheelhouse, K.; Rassias, G.; Med
Chem. Soc. 2013, 135, 2505.
́
ebielle, M.; Gouverneur, V. J. Am.
(12) (a) Larock, R. C. In Comprehensive Organic Transformations;
Wiley-VCH: New York, 1989; p 819. (b) Fleming, F. F.; Zhang, Z.
Tetrahedron 2005, 61, 747.
(13) (a) Murdoch, D.; Keam, S. J. Drugs 2005, 65, 2379. (b) Ozoe,
Y.; Ishikawa, S.; Tomiyama, S.; Ozoe, F.; Kozaki, T.; Scott, J. G. ACS
Symp. Ser. 2007, 948, 39.
(14) Ilchenko, N. O.; Janson, P. G.; Szabo,
78, 11087.
́
K. J. J. Org. Chem. 2013,
(15) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem.Eur. J. 2006,
12, 2579. (b) Niedermann, K.; Fruh, N.; Vinogradova, E.; Wiehn, M.
S.; Moreno, A.; Togni, A. Angew. Chem., Int. Ed. 2011, 50, 1059.
(16) See the Supporting Information for detailed data.
(17) (a) Kamigata, N.; Fukushima, T.; Yoshida, M. Chem. Lett. 1990,
649. (b) Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W.
A., III; Groves, J. T. Science 2012, 337, 1322. (c) Yasu, Y.; Koike, T.;
Akita, M. Chem. Commun. 2013, 49, 2037. (d) Pair, E.; Monteiro, N.;
Bouyssi, D.; Baudoin, O. Angew. Chem., Int. Ed. 2013, 52, 5346.
(e) Liu, X.; Xiong, F.; Huang, X.; Xu, L.; Li, P.; Wu, X. Angew. Chem.,
Int. Ed. 2013, 52, 6962. (f) Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.;
Wang, M.; Liu, Q. Chem.Eur. J. 2013, 19, 9104.
7655. (i) Danoun, G.; Bayarmagnai, B.; Grunberg, M. F.; Goossen, L.
J. Angew. Chem., Int. Ed. 2013, 52, 7972.
̈
(4) (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 45,
1909. (b) Cho, E. J.; Senecal, T. D.; Zhang, T. Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (c) Mu, X.; Chen, S.; Zhen,
X.; Liu, G. Chem.Eur. J. 2011, 17, 6039. (d) Morimoto, H.;
Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793.
(5) (a) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(b) Luo, D.-F.; Xu, J.; Fu, Y.; Guo, Q.-X. Tetrahedron Lett. 2012, 53,
2769. (c) Weng, Z.; Li, H.; He, W.; Yao, L.-F.; Tan, J.; Chen, J.; Yuan,
Y.; Huang, K.-W. Tetrahedron 2012, 68, 2527. (d) Jiang, X.; Chu, L.;
Qing, F.-L. J. Org. Chem. 2012, 77, 1251.
(6) (a) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (b) Senecal, T.
D.; Parson, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174.
(c) Liu, T.-F.; Shen, Q.-L. Org. Lett. 2011, 13, 2342. (d) Xu, J.; Luo, D.
F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun.
2011, 47, 4300. (e) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134,
9034. (f) Novak, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int.
Ed. 2012, 51, 7767.
(7) (a) Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106. (b) Shimizu,
R.; Egami, H.; Hamashima, Y.; Sodeoka, M. Angew. Chem., Int. Ed.
2012, 51, 4577. (c) Gao, P.; Yan, X.-B.; Tao, T.; Yang, F.; He, T.;
Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. Chem.Eur. J. 2013, 19, 14420.
(8) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem. 2011, 123,
9286; Angew. Chem., Int. Ed. 2011, 50, 9120. (b) 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. (c) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410.
(9) (a) Mu, X.; Wu, T.; Wang, H.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2012, 134, 878. (b) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012,
134, 12462. (c) Egami, H.; Shimizu, R.; Kawamura, S.; Sodeoka, M.
Angew. Chem., Int. Ed. 2013, 52, 4000. (d) Kong, W.; Casimiro, M.;
Merino, E.; Nevado, C. J. Am .Chem. Soc. 2013, 135, 14480. (e) He, Y.-
T.; Li, L.-H.; Yang, Y.-F.; Wang, Y.-Q.; Luo, J.-Y.; Liu, X.-Y.; Liang, Y.-
M. Chem. Commun. 2013, 49, 5687. (f) Kim, E.; Choi, S.; Kim, H.;
Cho, E. J. Chem.Eur. J. 2013, 19, 6209.
(10) (a) Ignatowska, J.; Dmowski, W. J. Fluorine Chem. 2007, 128,
997. (b) Yajima, T.; Nagano, H.; Saito, C. Tetrahedron Lett. 2003, 44,
7027. (c) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu,
Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47, 6632. (d) Feng, C.; Loh,
T.-P. Chem. Sci. 2012, 3, 3458. (e) Janson, P. G.; Ghoneim, I.;
́
Ilchenko, N. O.; Szabo, K. J. Org. Lett. 2012, 14, 2882. (f) Li, Y.;
Studer, A. Angew. Chem. 2012, 124, 8345; Angew. Chem., Int. Ed. 2012,
51, 8221. (g) Egami, H.; Shimizu, R.; Sodeoka, M. Tetrahedron Lett.
2012, 53, 5503. (h) Lu, D.-F.; Zhu, C.-L.; Xu, H. Chem. Sci. 2013, 4,
2478. (i) Wu, X.; Chu, L.; Qing, F.-L. Angew. Chem., Int. Ed. 2013, 52,
2198. (j) Egami, H.; Kawamura, S.; Miyazaki, A.; Sodeoka, M. Angew.
Chem., Int. Ed. 2013, 52, 7841.
273
dx.doi.org/10.1021/ol403263c | Org. Lett. 2014, 16, 270−273