NHC-Catalyzed Radical Trifluoromethylation Enabled by Togni Reagent

Article abstract of DOI:10.1021/acs.orglett.9b04203

An unprecedented carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent was developed, thus providing the β-trifluoromethyl-α-substituted ketones with a broad scope and moderate to high chemical yields. Notably, this process includes a single-electron-transfer process and utilizes the persistent N-heterocyclic-carbene-bound radical as a key intermediate to trigger the cascade radical cross-coupling.

Full text of DOI:10.1021/acs.orglett.9b04203

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
NHC-Catalyzed Radical Trifluoromethylation Enabled by Togni
Reagent
Bei Zhang, Qiupeng Peng, Donghui Guo, and Jian Wang*
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of
Education), Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: An unprecedented carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of
Togni reagent was developed, thus providing the β-trifluoromethyl-α-substituted ketones with a broad scope and moderate to
high chemical yields. Notably, this process includes a single-electron-transfer process and utilizes the persistent N-heterocyclic-
carbene-bound radical as a key intermediate to trigger the cascade radical cross-coupling.
ver the past few decades, fluorine (F) has received much
this case. Very recently, the Ohmiya group reported two elegant
Oattention owing to it is unique physiochemical and examples of NHC-catalyzed decarboxylative coupling of
aldehydes.13 In these reactions,14 the deprotonated Breslow
intermediate can serve as a single electron reductant to reduce
the redox-active esters, and the resulting alkyl radical could react
with the NHC-bound radical to deliver the cross-coupling
products. In fact, Fukuzumi and coworkers already disclosed the
single-electron-transfer (SET) process between the Breslow
intermediate and its persistent radical in 1997 (Scheme 1B).15 In
a continuation of our efforts in NHC organocatalysis16 and
inspiration from the previously mentioned literature, we report
herein a novel NHC-catalyzed radical trifluoromethylation
process enabled by Togni reagents (Scheme 1B). We envisioned
that the rapid generated CF3 radical via a SET process could
promote the cascade radical conjugate addition to alkenes,
followed by radical−radical cross-coupling to furnish β-
trifluoromethyl-α-substituted ketones.
We commenced our studies by investigating the reaction of 4-
Cl-benzaldehyde 1a, olefin 2a, and Togni reagent 3a as the
model substrates, Cs2CO3 as the base, and dichloromethane
(DCM) as the solvent, and the results are briefly summarized in
Table 1. When the triazolium precatalysts A−C were exploited,
the expected adduct was obtained in low yield (entries 1−3).
However, replacing catalysts A−C with the cycloheptane-fused
thiazolium precatalyst D gave the desired product 3a in 64%
yield (entry 4). Furthermore, when the cycloheptane-fused
biological properties.1 In particular, the trifluoromethyl (CF3)
group has been recognized as an important structural motif that
can enhance the metabolic stability, binding selectivity, and
lipophilicity of pharmaceuticals.2 Consequently, the develop-
ment of efficient methods for the installation of the “CF3” group
into target molecules has become a hot research field.3 In this
context, the direct cross-coupling reaction is one of the most
efficient methods to construct CF3−aryl molecules via a
C(sp2)−CF3 bond formation.4 These protocols can avoid the
use of expensive fluorinated building blocks but partially tolerate
the scope generality. In some molecules, the CF3 substitution is
anchored on the skeleton of drug candidates (Scheme 1C).5 In
these cases, the trifluoromethylation of alkenes has proven to be
a robust strategy via the direct C(sp2)−CF3 bond formation.
Despite these achievements in advancement, the development
of new and amenable protocols for the rapid and diverse
assembly of CF3-containing structures is still in a high demand.
On the contrary, N-heterocyclic carbenes (NHCs) as versatile
organocatalysts6 have enabled a variety of carbonyl molecules to
be transformed into significant intermediates, such as NHC-
bound acyl anion equivalents,7 acyl azoliums,8 enolates,9
homoenolates,10 and vinylogous enolates,11 which then react
with another counterpart, thus leading to a diverse set of
important structures. In 2018, Lin and Sun reported a nonradical
catalytic trifluoromethylation to achieve the C(sp3)−CF3 bond
via the NHC-bound homoenolate intermediates.12 It is worth
mentioning that the Togni reagent is used as an electrophile in
Received: November 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Catalytic Strategies for C(sp3)−CF3 Bond
Formation and Representative CF3-Containing Structures
Table 1. Optimization of the Reaction Conditions
b
entry cat.
CF3
base
solvent
yield (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
E
E
E
E
E
E
E
E
E
E
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3a
3a
3a
3a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TEA
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
toluene
MeCN
DCM + H2O (10 uL)
DCM + H2O (20 uL)
DCM + H2O (100 uL)
32
21
24
67
71
<5
<5
trace
trace
trace
trace
41
69
84
58
9
DBU
10
11
12
13
14
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), 3a−c (0.15
mmol), NHC cat. (20 mol %), Cs2CO3 (40 mol %), solvent (1.0 mL),
Ar, room temperature, 4 h. Isolated yield after column purification.
b
thiazolium derivative precatalyst E was tested, the reaction yield
of 3a was slightly increased to 71% (entry 5). After evaluating
bases and solvents, we found that a combination of Cs2CO3 as
the base and DCM/H2O as the solvent system was the best
choice (entries 8−15). An improvement in yield was found
when a suitable amount of water was used as the additive, but the
reason is unclear so far (entry 14). In addition, Togni I reagent
3b and Umemoto reagent 3c were also examined. However,
frustrated conversions were observed (entries 6 and 7).
With the optimal catalytic system in hand, we moved our
attention to explore the generality of this three-component
trifluoromethylation reaction. As illustrated in Scheme 2, by
reacting with 4-Cl-benzaldehyde 1a in the presence of Togni
reagent 3a, an array of aryl olefins were first examined. In the
reactions to generate the trifluoromethylated product 4, yields
were found to be less affected by the electronic properties of the
substituents on the aryl group in substrate 2 (4b−k). When the
heteroaryl olefins were reacted with aldehyde 1a under optimal
conditions, their corresponding adducts (4l−o) were obtained
as well. Reactions of functionalized olefins with aldehyde 1a also
gave the desired adducts in good yield (4p−s). In addition,
benzyl or alkyl olefin can participate in this reaction but is
tolerated in a low yield (4t and 4u). Notably, the pharmaceutical
derivative proved to be compatible with this system as well as
other substrates (4v).
Next, we turned our attention to investigate the scope of
aldehydes 1 (Scheme 3). Different substituents and substitution
patterns on the benzene skeleton were comprehensively
examined. Electron-withdrawing substituents such as CF3, F,
NO2, and CN (5b, 5c, 5f, 5g, and 5h) units on the phenyl ring of
the aldehyde substrates were well tolerated. Electron-releasing
groups such as methyl (5b and 5e) and alkyloxyl unit (5i) could
also be installed on the benzene scaffold of the aldehyde
substrates. It is worth noting that this protocol could be
extended to a variety of heteroaryl aldehydes, affording their
corresponding CF3-containing adducts (5k−v) in acceptable
yield under the current standard conditions. However, non-
aromatic aldehydes showed disappointing results. (See the
Supporting Information.)
Postulated mechanisms are illustrated in Scheme 4. In the
presence of a base, the NHC precatalyst was deprotonated to a
free carbene catalyst, which then combined with an aryl
aldehyde to generate the Breslow intermediate I. Meanwhile,
the single-electron reduction of the Togni reagent via the
electron-rich Breslow intermediate I occurred and resulted in a
CF3 radical and NHC-bound persistent radical II. The addition
of the CF3 radical to the olefin generated a CF3-containing alkyl
radical. Subsequently, a radical−radical cross-coupling between
the CF3-containing alkyl radical and the NHC-bound persistent
radical II forms the NHC-bound intermediate III (pathway A),
B
DOI: 10.1021/acs.orglett.9b04203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Olefins
Scheme 3. Scope of Aldehydes
a
Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), 3a (0.4 mmol),
cat. E (20 mol %), Cs2CO3 (40 mol %), DCM (2.0 mL), H2O (40
uL), Ar, room temperature, 4−12 h.
a
Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), 3a (0.4 mmol),
cat. E (20 mol %), Cs2CO3 (40 mol %), DCM (2.0 mL), H2O (40
uL), Ar, room temperature, 4−12 h.
on new NHC-bounded radicals and their applications in
asymmetric synthesis are currently ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
which undergoes acylation to release a free carbene catalyst for
the next catalytic cycle. In addition, the generated CF3-
containing alkyl radical also can react with the electron-rich
Breslow intermediate I to furnish another plausible NHC-bound
radical intermediate II′. Then, the NHC-bound radical
intermediate II′ turns to intermediate III via a SET process
(pathway B).
In conclusion, an NHC-catalyzed radical trifluoromethylation
enabled by a three-component reaction of aldehydes, olefins,
and Togni reagents has been developed. This process includes a
single-electron-transfer process and utilizes the persistent NHC-
bound radical as a key intermediate to trigger the cascade radical
cross-coupling. This new protocol allows the rapid assembly of
β-trifluoromethyl-α-substituted ketones from readily available
starting materials under mild conditions. Further investigations
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04203.
Experimental procedures, product characterization, and
copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangjian2012@tsinghua.edu.cn.
ORCID
Jian Wang: 0000-0002-3298-6367
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b04203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
L.; Mu, X.; Liu, W.; Wang, Y.; Mi, Z.; Li, C.-J. J. Am. Chem. Soc. 2016,
138, 5809−5812. (i) Corsico, S.; Fagnoni, M.; Ravelli, D. Photochem.
Photobiol. Sci. 2017, 16, 1375−1380. (j) Bacauanu, V.; Cardinal, S.;
Scheme 4. Postulated Mechanism
́
Yamauchi, M.; Kondo, M.; Fernandez, D. F.; Remy, R.; MacMillan, D.
W. Angew. Chem., Int. Ed. 2018, 57, 12543−12548. (k) Li, X. T.; Gu, Q.
S.; Dong, X. Y.; Meng, X.; Liu, X. Y. Angew. Chem., Int. Ed. 2018, 57,
7668−7672.
(5) Rice, K. D.; Kim, M. H.; Bussenius, J.; Anand, N. K.; Blazey, C. M.;
Bowles, O. J.; Canne-Bannen, L.; Chan, D. S.-M.; Chen, B.; Co, E. W.;
et al. Bioorg. Med. Chem. Lett. 2012, 22, 2693−2697.
(6) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
́
5606−5655. (b) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988−3000. (c) Cohen, D. T.; Scheidt, K. A.
Chem. Sci. 2012, 3, 53−57. (d) Grossmann, A.; Enders, D. Angew.
Chem., Int. Ed. 2012, 51, 314−325. (e) Izquierdo, J.; Hutson, G. E.;
Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686−
11698. (f) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F.
Nature 2014, 510, 485−496. (g) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−
9387. (h) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55,
14912−14922.
(7) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719−3726.
(b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639−647. (c) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182−1195.
(d) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42,
4906−4917.
(8) (a) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett.
2007, 9, 371−374. (b) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS
Catal. 2017, 7, 2583−2596.
(9) (a) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406−
16407. (b) Douglas, J.; Churchill, G.; Smith, A. D. Synthesis 2012, 44,
2295−2309.
(10) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205−6208. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370−14371. (c) Nair, V.; Vellalath, S.; Babu, B. P. Chem.
Soc. Rev. 2008, 37, 2691−2698. (d) Menon, R. S.; Biju, A. T.; Nair, V.
Chem. Soc. Rev. 2015, 44, 5040−5052.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(nos. 21871160 and 21672121), the “Thousand Plan” Youth
Program of China, and the Bayer Investigator Fellowship for
their generous financial support.
(11) (a) Shen, L. T.; Shao, P. L.; Ye, S. Adv. Synth. Catal. 2011, 353,
1943−1948. (b) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012,
134, 8810−8813. (c) Chen, X. Y.; Liu, Q.; Chauhan, P.; Enders, D.
Angew. Chem., Int. Ed. 2018, 57, 3862−3873.
REFERENCES
(1) (a) Jeschke, P. ChemBioChem 2004, 5, 570−589. (b) Mu
■
̈
ller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886. (c) Ametamey,
S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501−1516.
(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (e) O’Hagan,
D. Chem. Soc. Rev. 2008, 37, 308−319. (f) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330.
(g) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529−2591.
(12) (a) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew. Chem.,
Int. Ed. 2008, 47, 8727−8730. (b) Du, Y.; Wang, Y.; Li, X.; Shao, Y.; Li,
G.; Webster, R. D.; Chi, Y. R. Org. Lett. 2014, 16, 5678−5681.
(c) White, N. A.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 14674−14677.
(d) Rehbein, J.; Ruser, S.-M.; Phan, J. Chem. Sci. 2015, 6, 6013−6018.
(e) White, N. A.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 10112−10115.
(f) Zhang, Y.; Du, Y.; Huang, Z.; Xu, J.; Wu, X.; Wang, Y.; Wang, M.;
Yang, S.; Webster, R. D.; Chi, Y. R. J. Am. Chem. Soc. 2015, 137, 2416−
2419. (g) Li, B.-S.; Wang, Y.; Proctor, R. S.; Zhang, Y.; Webster, R. D.;
Yang, S.; Song, B.; Chi, Y. R. Nat. Commun. 2016, 7, 12933. (h) Yang,
W.; Hu, W.; Dong, X.; Li, X.; Sun, J. Angew. Chem., Int. Ed. 2016, 55,
15783−15786. (i) Chen, X.-Y.; Chen, K.-Q.; Sun, D.-Q.; Ye, S. Chem.
Sci. 2017, 8, 1936−1941. (j) Wang, Y.; Du, Y.; Huang, X.; Wu, X.;
Zhang, Y.; Yang, S.; Chi, Y. R. Org. Lett. 2017, 19, 632−635. (k) Wu, X.;
Zhang, Y.; Wang, Y.; Ke, J.; Jeret, M.; Reddi, R. N.; Yang, S.; Song, B. A.;
Chi, Y. R. Angew. Chem., Int. Ed. 2017, 56, 2942−2946. (l) Zhao, K.;
Enders, D. Angew. Chem., Int. Ed. 2017, 56, 3754−3756. (m) Regnier,
V.; Romero, E. A.; Molton, F.; Jazzar, R.; Bertrand, G.; Martin, D. J. Am.
Chem. Soc. 2019, 141, 1109−1117. (n) Song, Z.-Y.; Chen, K.-Q.; Chen,
X.-Y.; Ye, S. J. Org. Chem. 2018, 83, 2966−2970. Dai, L.; Xia, Z.-H.;
Gao, Y.-Y.; Gao, Z.-H.; Ye, S. Angew. Chem., Int. Ed. 2019, 58, 18124.
(p) Song, R.; Chi, Y. R. Angew. Chem., Int. Ed. 2019, 58, 8628−8630.
(13) (a) Gelat, F.; Patra, A.; Pannecoucke, X.; Biju, A. T.; Poisson, T.;
Besset, T. Org. Lett. 2018, 20, 3897−3901. (b) Yang, W.; Ma, D.; Zhou,
Y.; Dong, X.; Lin, Z.; Sun, J. Angew. Chem., Int. Ed. 2018, 57, 12097. Li,
J.-L.; Liu, Y.-Q.; Zou, W.-L.; Zeng, R.; Zhang, X.; Liu, Y.; Han, B.; He,
Y.; Leng, H.-J.; Li, Q.-Z. Angew. Chem., Int. Ed. 2019, DOI: 10.1002/
anie.201912450.
(2) (a) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525−616.
(b) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E.
J. J. Med. Chem. 1973, 16, 1207−1216. (c) Hansch, C.; Leo, A.; Taft, R.
Chem. Rev. 1991, 91, 165−195. (d) Nie, J.; Guo, H.-C.; Cahard, D.; Ma,
J.-A. Chem. Rev. 2011, 111, 455−529. (e) Tomashenko, O. A.; Grushin,
V. V. Chem. Rev. 2011, 111, 4475−4521.
(3) (a) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115,
̈
650−682. (b) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765−825.
(c) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731−
764. (d) Lee, K.; Silverio, D. L.; Torker, S.; Robbins, D. W.; Haeffner,
F.; Van der Mei, F. W.; Hoveyda, A. H. Nat. Chem. 2016, 8, 768.
(e) Tian, Y.; Chen, S.; Gu, Q.-S.; Lin, J.-S.; Liu, X.-Y. Tetrahedron Lett.
2018, 59, 203−215.
(4) (a) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.;
Shiro, M.; Shibata, N. Org. Lett. 2011, 13, 3972−3975. (b) Parsons, A.
T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120−9123.
(c) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J.
Am. Chem. Soc. 2011, 133, 16410−16413. (d) 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. (e) Shimizu, R.; Egami, H.; Hamashima, Y.;
Sodeoka, M. Angew. Chem., Int. Ed. 2012, 51, 4577−4580. (f) Ambler,
B. R.; Altman, R. A. Org. Lett. 2013, 15, 5578−5581. (g) Iqbal, N.; Jung,
J.; Park, S.; Cho, E. J. Angew. Chem., Int. Ed. 2014, 53, 539−542. (h) Li,
D
DOI: 10.1021/acs.orglett.9b04203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) (a) Ishii, T.; Kakeno, Y.; Nagao, K.; Ohmiya, H. J. Am. Chem. Soc.
2019, 141, 3854−3858. (b) Ishii, T.; Ota, K.; Nagao, K.; Ohmiya, H. J.
Am. Chem. Soc. 2019, 141, 14073−14077.
(15) (a) Nakanishi, I.; Itoh, S. Chem. Commun. 1997, 1927−1928.
(b) Nakanishi, I.; Itoh, S.; Suenobu, T.; Inoue, H.; Fukuzumi, S. Chem.
Lett. 1997, 26, 707−708. (c) Nakanishi, I.; Itoh, S.; Suenobu, T.;
Fukuzumi, S. Angew. Chem., Int. Ed. 1998, 37, 992−994. (d) Nakanishi,
I.; Itoh, S.; Fukuzumi, S. Chem. - Eur. J. 1999, 5, 2810−2818.
(16) (a) Li, F.; Wu, Z.; Wang, J. Angew. Chem., Int. Ed. 2014, 54, 656−
659. (b) Wu, Z.; Li, F.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 1629−
1633. (c) Wu, J.; Zhao, C.; Wang, J. J. Am. Chem. Soc. 2016, 138, 4706−
4709. (d) Zhao, C.; Li, F.; Wang, J. Angew. Chem., Int. Ed. 2016, 55,
1820−1824. (e) Peng, Q.; Guo, D.; Bie, J.; Wang, J. Angew. Chem., Int.
Ed. 2018, 57, 3767−3771. (f) Zhao, C.; Guo, D.; Munkerup, K.; Huang,
K.-W.; Li, F.; Wang, J. Nat. Commun. 2018, 9, 611. (g) Yang, G.; Guo,
D.; Meng, D.; Wang, J. Nat. Commun. 2019, 10, 3062.
E
DOI: 10.1021/acs.orglett.9b04203
Org. Lett. XXXX, XXX, XXX−XXX