Catalytic C-H α-trifluoromethylation of α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ol5004498

A copper(I)-catalyzed, regioselective C-H α-trifluoromethylation of α,β-unsaturated carbonyl compounds using Togni's reagent was developed. Diverse substrates, including enones as well as α,β- unsaturated esters, thioesters, and amides, stereospecifically afforded the corresponding (E)-α-trifluoromethylated products in moderate to high yields. Further, this method was applied to the C-H trifluoromethylation of drugs.

Full text of DOI:10.1021/ol5004498

Letter
pubs.acs.org/OrgLett
Catalytic C−H α‑Trifluoromethylation of α,β-Unsaturated Carbonyl
Compounds
Zhongxue Fang,† Yongquan Ning,† Pengbing Mi,† Peiqiu Liao,† and Xihe Bi*,†,‡
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A copper(I)-catalyzed, regioselective C−H α-trifluoro-
methylation of α,β-unsaturated carbonyl compounds using Togni’s
reagent was developed. Diverse substrates, including enones as well as
α,β-unsaturated esters, thioesters, and amides, stereospecifically afforded
the corresponding (E)-α-trifluoromethylated products in moderate to
high yields. Further, this method was applied to the C−H
trifluoromethylation of drugs.
he trifluoromethyl (CF3) group is an essential structural
Tmotif in diverse pharmaceuticals, agrochemicals, and
organic materials.1 Therefore, extensive efforts are directed
toward developing methods for introducing the CF3 group to
organic molecules.2 To date, methodologies based on func-
tional group transformations to trifluoromethyl have been a
major focus of study.3 C−H bond functionalization would be
the most efficient method for incorporating the CF3 group into
complex molecules. In this context, remarkable progress on the
direct C−H trifluoromethylation has been witnessed in the past
few years.4 Diverse C−H bonds, such as (hetero)aryl,5 alkenyl,6
alkynyl,7 allylic,8 activated alkyl,9 and azomethine,10 have been
trifluoromethylated. Despite the diversity, there are still many
disadvantages in most of these reactions, e.g., a low level of
regioselectivity, limitation to electron-rich π-systems, or
Figure 1. Direct trifluoromethylation of alkenyl C−H bonds of
dependence on an auxiliary directing group for regiocontrol.
electron-deficient olefins.
Therefore, the development of a general, regioselective C−H
trifluoromethylation, particularly related to the electron-
deficient π-systems, remains highly desirable.
catalyzed transformations of inert chemical bonds,16 we herein
α,β-Unsaturated carbonyls that contain an electron-deficient
carbon−carbon double bond are not only versatile synthetic
intermediates but also a structural motif in biologically active
molecules.11 Consequently, the regioselective trifluoromethyla-
tion of the alkenyl C−H bonds would be of great interest;
however, such reactions have been rarely reported.5b,12−14 Loh
and co-workers developed a stereoselective β-trifluoromethyla-
tion of acrylamides using Togni’s reagent (1),12 even though
both a tosyl-protected imide, as the directing group, and an
occupied α-position of acrylamides were essential for the
report a regioselective C−H α-trifluoromethylation of α,β-
unsaturated carbonyls using Togni’s reagent, affording (E)-
specific products (Figure 1d).
The reaction conditions were optimized by the reaction of
chalcone (2a) and Togni’s reagent (1) as the model reaction.
Selected results are shown in Table 1. Solvent has significant
influence on the reaction. For example, acetonitrile (CH3CN)
and toluene turned out to be ineffective (entries 1 and 2),
whereas the use of 1,4-dioxane afforded a trace amount of
desired product 3a (entry 3). The (E)-configuration of the
product was confirmed by the NOE experiments. Delightfully, a
good yield (78%) of 3a was obtained when dimethylformamide
(DMF) was used as the solvent (entry 4). In the control
experiment, the necessity of the copper catalyst was
demonstrated (entry 5). Other copper salts such as Cu2O
reaction (Figure 1a).13 The Wang and Szabo
́
groups reported
the C−H trifluoromethylation of quinones; however, other
types of electron-deficient double bonds could not be
functionalized (Figure 1b).14 Recently, the MacMillan group
reported the α-trifluoromethylation of methyluracil and flavone
by photoredox catalysis, one of the few examples known to date
for the C−H α-trifluoromethylation of α,β-unsaturated carbon-
yls (Figure 1c).5b,15 In continuation of our efforts on copper-
Received: February 11, 2014
Published: February 20, 2014
© 2014 American Chemical Society
1522
dx.doi.org/10.1021/ol5004498 | Org. Lett. 2014, 16, 1522−1525

Organic Letters
Letter
a
under the reaction conditions (3e, 3i, 3j, and 3n). The
stereoconfiguration of the α-trifluoromethylated enones was
established as E by the single-crystal diffraction (XRD) of
compound 3n. Interestingly, naphthalene-1,4-dione, previously
Table 1. Optimization of Reaction Conditions
́
used by Wang and Szabo under open-air conditions, was also a
suitable substrate under the current oxygen-free conditions,
affording the corresponding trifluoromethylated product (3l) in
70% yield. Furthermore, the quinolone derivative was subjected
to the C−H trifluoromethylation and afforded the correspond-
ing α-trifluoromethylated quinolone 3m in 50% yield, albeit
with a significant amount of substrate left.
Encouraged by the results obtained with the enones, we
employed this C−H α-trifluoromethylation protocol to other
α,β-unsaturated carbonyl systems, such as α,β-unsaturated
esters, thioesters, and amides. The results are shown in Scheme
2. All the reactions smoothly produced the corresponding α-
b
entry
[Cu]
CuI
solvent
yield (%)
1
2
3
4
5
6
7
CH3CN
toluene
1,4-dioxane
DMF
0
CuI
0
CuI
trace
78
0
CuI
−
DMF
Cu2O
Cu(OAc)2
CuI
DMF
48
30
DMF
c
8
DMF
15
a
b
Reactions were performed on 1.0 mmol scale, at 0.5 M. Yields refer
c
to isolated products. Under open-air conditions.
Scheme 2. C−H α-Trifluoromethylation of α,β-Unsaturated
Esters, Thioesters, and Amides
and Cu(OAc)2 with different valence states were screened in
DMF at 80 °C under a nitrogen atmosphere; poor to moderate
yields (30−48%) were obtained. A poor yield (15%) of 3b was
obtained under open-air conditions, proving the necessity for
oxygen-free conditions (entry 8). Consequently, the optimal
conditions listed in entry 4 were selected for further
investigations.
Diverse enones were investigated with the optimized catalyst
and reaction conditions (Scheme 1). In general, the enone
substrates bearing either electron-withdrawing or -donating
groups reacted smoothly with Togni’s reagent to afford the
corresponding trifluoromethylated products in moderate to
excellent yields. Remarkably, oxidation-sensitive groups, such as
phenolic hydroxyl and thienyl groups, were all well tolerated
Scheme 1. C−H α-Trifluoromethylation of Enones
trifluoromethylated products (5a−5k) in moderate to high
yields. The stereochemistry of products was also unambigu-
ously confirmed by the XRD of compound 5k. Notably, the
nitrogen-activated benzyl group (5j) and electron-rich arenes
(5a−5d, 5f, and 5i) that were reactive in electrophilic
trifluoromethylation reactions5,9 remained intact under our
trifluoromethylation conditions. In addition, the type of amides
did not affect the reaction outcome because the primary,
secondary, and tertiary amides were all compatible under the
reaction conditions (5g−5k). Taken together, the results listed
in Schemes 1 and 2 demonstrated the broad scope and
excellent regio- and stereoselectivity of this copper(I)-catalyzed
C−H α-trifluoromethylation of α,β-unsaturated carbonyl
1523
dx.doi.org/10.1021/ol5004498 | Org. Lett. 2014, 16, 1522−1525

Organic Letters
Letter
compounds. The presence of a trifluoromethyl moiety in the
product promises the subsequent conversion to more function-
alized trifluoromethylated compounds.11
The reactivities of different α,β-unsaturated carbonyls in the
copper(I)-catalyzed C−H α-trifluoromethylation were com-
pared by utilizing substrates 6a and 6b. We found that
cinnamamide had the highest reactivity because single α-
trifluoromethylation product 7a was obtained from substrate
6a. Enone and cinnamate showed similar reactivity, as
bistrifluoromethylated product 7b was obtained as the major
product from substrate 6b when using a reduced amount (1.0
equiv) of Togni’s reagent.
Based on the mechanistic studies and literature prece-
dents,6,10,14 a plausible reaction mechanism was proposed (with
2f as the example). As shown in Scheme 3, electrophilic Togni’s
Scheme 3. A Plausible Reaction Mechanism
In order to explore the synthetic potential of our method in
thelate-stage synthetic modifications, biologically active mole-
cules were subjected to the copper(I)-catalyzed trifluoro-
methylation protocol to prepare their CF3 analogs (Table 2).
Table 2. Direct C−H Trifluoromethylation of Drugs to Their
Analogs
reagent is first reduced by CuI to afford a CF3 radical by a
single-electron-transfer (SET) process, with the release of Cu2+
species. The CF3 radical then regioselectively attacks the α-
position of 2f that has a slightly higher electron density, thus
generating radical intermediate A. Following another SET
process, carbocation intermediate B is produced, with
regeneration of the active Cu(I) catalyst. Finally, product 3f
with the stable (E)-configuration is obtained after the
deprotonation.
In conclusion, we developed the first general, regioselective
C−H α-trifluoromethylation of α,β-unsaturated carbonyl
compounds using Togni’s reagent. This reaction allows diverse
substrates to afford the corresponding (E)-specific α-trifluoro-
methylated products in moderate to high yields. The value of
this transformation has been highlighted by the trifluoro-
methylation of biologically active molecules. The findings
described herein represent a significant advance in C−H
trifluoromethylation and also would inspire further research on
new radical α-C−H functionalization reactions of α,β-
unsaturated carbonyl compounds.18
a
Isolated yields.
For instance, a DNA deoxynucleotide (2′-deoxyuridine), an
antispasmodic drug (Hymecromone), a vitamin (flavone), and
an antiallergic drug (Tranilast) were each selectively trifluor-
omethylated at a single position in good yields (65−83%). The
structure of product TF-Tranilast was also confirmed by XRD.
TF-Tranilast and TF-Hymecromone were for the first time
prepared. In all these cases, highly regioselective reactions were
observed, presumably corresponding to the positions being
relevant to metabolic susceptibility. The simultaneous identi-
fication and capping of such positions with a CF3 group may be
useful in medicinal research.
Control experiments were carried out to offer insights into
the reaction mechanism. The deuterium labeling studies
showed no primary kinetic isotope effect (KIE) (KH/KD ≈ 1)
in an intermolecular competition experiment using deuterated
substrate 2k-d.17 In addition, a radical scavenger such as
TEMPO or oxygen significantly prohibited the reaction,
because only a trace amount of product 3a could be detected
by TLC in the reaction of 2a with Togni’s reagent. These
results clearly indicated that the reaction proceeded via a radical
trifluoromethylation process.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectra copies. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bixh507@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NSFC (21172029, 21202016,
21372038), NCET-13-0714, and PEYSJP (20140519008JH).
■
REFERENCES
■
(1) (a) Pursor, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320−330. (b) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881−1886.
̈
1524
dx.doi.org/10.1021/ol5004498 | Org. Lett. 2014, 16, 1522−1525

Organic Letters
Letter
(2) For recent reviews, see: (a) Besset, T.; Schneider, C.; Cahard, D.
Angew. Chem., Int. Ed. 2012, 51, 5048−5050. (b) Furuya, T.; Kamlet,
A. S.; Ritter, T. Nature 2011, 473, 470−477. (c) Tomashenko, O. A.;
Grushin, V. V. Chem. Rev. 2011, 111, 4475−4521.
(17) Gom
4963.
́
ez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857−
(18) For example of direct α-C−H arylation of enaminones, see: Ge,
H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130, 3708−
3709.
(3) For examples, see: (a) Chen, M.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2013, 52, 11628−11631. (b) Morimoto, H.; Tsubogo, T.;
Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793−
3798. (c) Xu, J.; Xiao, B.; Xie, C.-Q.; Luo, D.-F.; Liu, L.; Fu, Y. Angew.
Chem., Int. Ed. 2012, 51, 12551−12554. (d) Ye, Y.; Sanford, M. S. J.
Am. Chem. Soc. 2012, 134, 9034−9037. (e) Wang, X.; Xu, Y.; Mo, F.;
Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang, J. J. Am.
Chem. Soc. 2013, 135, 10330−10333. (f) He, Z.; Luo, T.; Hu, M.; Cao,
Y.; Hu, J. Angew. Chem., Int. Ed. 2012, 51, 3944−3947. (g) Shimizu, R.;
Egami, H.; Hamashima, Y.; Sodeoka, M. Angew. Chem., Int. Ed. 2012,
51, 4577−4580.
(4) Liu, H.; Gu, Z.; Jiang, X. Adv. Synth. Catal. 2013, 355, 617−626.
(5) For recent examples, see: (a) Fujiwara, Y.; Dixon, J. A.; O’Hara,
F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle,
́
B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492,
95−99. (b) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480,
224−228. (c) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298−
1304. (e) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed.
2012, 51, 5048−5050. (f) Hafner, A.; Brase, S. Angew. Chem., Int. Ed.
2012, 51, 3713−3715. (g) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-
Q. J. Am. Chem. Soc. 2012, 134, 11948−11951. (h) Ball, N. D.; Kampf,
J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878−2879.
(6) For examples, see: (a) Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.;
Wang, M.; Liu, Q. Chem.Eur. J. 2013, 19, 9104−9109. (b) Egami,
H.; Shimizu, R.; Sodeoka, M. Tetrahedron Lett. 2012, 53, 5503−5506.
(c) Iqbal, N.; Choi, S.; Kim, E.; Cho, E. J. J. Org. Chem. 2012, 77,
11383−11387. (d) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458−
3462.
(7) (a) Aiguabella, N.; del Pozo, C.; Verdaguer, X.; Fustero, S.; Riera,
A. Angew. Chem., Int. Ed. 2013, 52, 5355−5359. (b) Chu, L.; Qing, F.-
L. J. Am. Chem. Soc. 2010, 132, 7262−7263. (c) Jover, J.; Maseras, F.
Chem. Commun. 2013, 49, 10486−10488.
(8) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 9120−9123. (b) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410−16413.
(c) 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, 15300−15303. (d) Chu, L.;
Qing, F.-L. Org. Lett. 2012, 14, 2106−2109.
(9) (a) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc.
2012, 134, 10769−10772. (b) Herrmann, A. T.; Smith, L. L.; Zakarian,
A. J. Am. Chem. Soc. 2012, 134, 6976−6979. (c) Allen, A. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986−4987.
(d) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
̌
2009, 131, 10875−10877. (e) Matousek, V.; Togni, A.; Bizet, V.;
Cahard, D. Org. Lett. 2011, 13, 5762−5765. (f) Mitsudera, H.; Li, C.-J.
Tetrahedron Lett. 2011, 52, 1898−1900. (g) Chu, L.; Qing, F.-L. Chem.
Commun. 2010, 46, 6285−6287. (h) Kieltsch, I.; Eisenberger, P.;
Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754−757.
(10) Pair, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O. Angew. Chem.,
Int. Ed. 2013, 52, 5346−5349.
(11) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829−2844.
(12) For the first report of Togni’s reagent, see: Eisenberger, P.;
Gischig, S.; Togni, A. Chem.Eur. J. 2006, 12, 2579−2586.
(13) Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52, 12414−
12417.
(14) (a) Wang, X.; Ye, Y.; Ji, G.; Xu, Y.; Zhang, S.; Feng, J.; Zhang,
Y.; Wang, J. Org. Lett. 2013, 15, 3730−3733. (b) Ilchenko, N. O.;
́
Janson, P. G.; Szabo, K. J. Chem. Commun. 2013, 49, 6614−6616.
(15) Uraguchi, D.; Yamamoto, K.; Ohtsuka, Y.; Tokuhisa, K.;
Yamakawa, T. Appl. Catal., A 2008, 342, 137−143.
(16) (a) Zhang, L.; Bi, X.; Guan, X.; Li, X.; Liu, Q.; Barry, B.-D.; Liao,
P. Angew. Chem., Int. Ed. 2013, 52, 11303−11307. (b) Xiong, T.; Li, Y.;
Bi, X.; Lv, Y.; Zhang, Q. Angew. Chem., Int. Ed. 2011, 50, 7140−7143.
(c) Zhang, L.; Liu, Z.; Li, H.; Fang, G.; Barry, B.-D.; Belay, T. A.; Bi,
X.; Liu, Q. Org. Lett. 2011, 13, 6536−6539.
1525
dx.doi.org/10.1021/ol5004498 | Org. Lett. 2014, 16, 1522−1525