Copper-Catalyzed Trifluoromethylation of Ynones Coupled with Dearomatizing Spirocyclization of Indoles: Access to CF3-Containing Spiro[cyclopentane-1,3′-indole]

Article abstract of DOI:10.1021/acs.orglett.0c01097

A one-pot protocol for the Cu(I)-catalyzed difunctionalization of indolyl ynones has been achieved via trifluoromethylation of alkyne followed by dearomatizing spirocyclization of indoles. This cascade process enables constructing diverse CF₃-c

Full text of DOI:10.1021/acs.orglett.0c01097

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Trifluoromethylation of Ynones Coupled with
Dearomatizing Spirocyclization of Indoles: Access to CF ‑Containing
3
Spiro[cyclopentane-1,3′-indole]
Chengwen Li, Li Xue, Jiaxin Zhou, Yilin Zhao, Guifang Han,* Jingli Hou, Yuguang Song,
and Yangping Liu*
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sı Supporting Information
ABSTRACT: A one-pot protocol for the Cu(I)-catalyzed difunctionalization of indolyl ynones has been achieved via
trifluoromethylation of alkyne followed by dearomatizing spirocyclization of indoles. This cascade process enables constructing
diverse CF -containing spiro[cyclopentane-1,3′-indole] scaffolds in moderate to excellent yields which have challenging quaternary
3
spirocyclic carbon and tetrasubstituted alkenes.
he spiroindolenines with a challenging quaternary
spirocyclic carbon are present as prominent substructures
tionalization of alkyne-tethered indoles can be facilely achieved
by intramolecular dearomatizing spirocyclization, catalyzed by
Lewis acids such as silver(I), copper(II), and trifluoroacetic
T
in bioactive natural products and pharmaceutically relevant
compounds that show antitumor, antiinfective, and antiproli-
5
acid (TFA). Comparatively, bifunctionalization of indolyl
1
ferative activities (Figure 1). As such, development of efficient
ynones is challenging and meaningful but with only a few
studies reported for this transformation. Van der Eycken
described a N-iodosuccinimide mediated intramolecularipso-
iodocyclization of indolyl ynones for the formation of
methods for direct construction of the spiroindolenine skeleton
2
is very valuable in synthetic chemistry. Among these methods,
the dearomatization of indole derivatives has received the most
attention since three-dimensional sophisticated spirocyclic
scaffolds can be conveniently obtained from aromatic starting
6
a
spiroindolenines. Unsworth and Taylor collaborated to
develop a palladium complex as both a π-acid and cross-
coupling catalyst that catalyzes a one-pot dearomatizing
spirocyclization/cross-coupling cascade reaction for the
3
4
materials, especially indolyl ynones. In general, monofunc-
6b
functionalized spirocycles. In the present study, we describe
Cu(I)-catalyzed difunctionalization of indolyl ynones via
trifluoromethylation of alkyne and dearomatizing spirocycliza-
tion of indoles.
Trifluoromethylation has been established as a critical
strategy in agrochemicals and medicinal chemistry to modulate
chemical and metabolic stability and increase their lip-
7
ophilicity, bioavailability, and protein-binding affinity. Thus,
a great deal of attention has been paid to develop selective,
Received: March 26, 2020
Figure 1. Representative bioactive molecules with spiroindolenine
motifs.
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01097
A
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8
efficient, and versatile trifluoromethylation methods. In
particular, transition-metal-catalyzed or mediated trifluorome-
thylations of alkynes based on a difunctionalization strategy
quaternary spirocyclic carbon and tetrasubstituted alkenes.
Herein, we report the synthesis of CF -containing spiro-
3
[cyclopentane-1,3′-indole] using the Cu(I)-catalyzed difunc-
tionalization of indolyl ynones in the presence of Togni’s
reagent.
9
−12
have undergone rapid development.
The direct carbotri-
fluoromethylation of alkynes was utilized to synthesize
complicated trifluoromethylated conjugated rings or spirocy-
clic compounds. For example, the Fu and Liu groups
independently demonstrated Cu-catalyzed aryltrifluoromethy-
First, we investigated the reaction of substrate 1a with
14
Togni’s reagent (2a) using CuI as catalyst at 37 °C under
1
9
argon atmosphere in DCM. F NMR results showed that
complicated products exist including the C2-trifluoromethy-
lated indolyl ynone 1b (20%) together with (bis)-
trifluoromethylated spiroindolenine 3b with challenging
quaternary spirocyclic carbon and tetrasubstituted alkene
(17%, Table 1, entry 1). The structures of 1b and 3b were
lation of alkynes for the synthesis of CF -containing hetero-
3
1
2g,h
cycles (Scheme 1a, b).
Comparatively, synthesis of
Scheme 1. Metal-Catalyzed Carbotrifluoromethylation of
Alkynes
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
CuI
CuBr
Togni’s reagent
solvent
yield (%) 3b
c
1
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
DCM
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
17
20
21
trace
trace
35
80 (78)
44
40
38
39
29
trace
77
trace
44
13
trace
c
2
c
3
CuCl
c
4
Cu(OAc)2
CuOTf
CuCl
CuCl
CuBr
c
5
d
d
d
d
,
,
,
,
f
f
f
f
6
7
8
9
1
1
1
1
1
1
1
1
1
e
CuI
d
d
d
d
d
d
d
d
d
,
f
,
f
,
f
,
f
,
f
,
f
,
f
,
f
,
f
0
1
2
3
4
5
6
7
8
CuCN
CuOTf
Cu(OAc)2
CuCl
CuCl
CuCl
CH CN
3
dioxane
EA
EtOH
DCE
CuCl
CuCl
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), catalyst (0.02
b
mmol), solvent (2 mL), 37 °C, 48 h, under Ar. The yield of the
compound 3b which was determined by F NMR analysis with
1
9
c
(
trifluoromethyl)benzene as an internal standard. 1a was used as a
d e
substrate. 1b was used as a substrate. The value in parentheses
f
indicates the isolated yield. Reaction temperature, 50 °C.
spirocyclic compounds containing C(vinyl)−CF3 is much
challenging. The spiroskelecton has a strong preference for an
intramolecular migration or ring-open reaction due to the large
ring strain and/or the driving force of rearomatization
determined by X-ray crystallographic analysis (see the
Supporting Information). The formation of the spiroindole-
nine 3b stimulated us to further investigate various copper
1
2b,c
(
Scheme 1d).
Accordingly, there is only one study
demonstrating the formation of the spiroskelecton compounds
catalysts including CuBr, CuCl, Cu(OAc) , and CuOTf.
2
through Cu(I)-catalyzed trifluoromethylation and dearomati-
Unfortunately, the yield of 3b was not improved, and 3a′
was separated as the main byproduct that does not bear a
trifluoromethyl group. Considering that the Togni’s reagent
(2a) will give o-iodobenzoic acid as the byproduct, the
substrates 1a are easily converted into hydrogenated analogues,
12l
zation cyclization tandem process of alkynes (Scheme 1c).
Recently, we found that Ag(I)-catalyzed cascade reaction of
the substituted indolyl ynones (1) with the Togni reagent (2a)
resulted in the formation of cyclopentaquinolinone instead of
the corresponding spiroindolenines possibly because the
spirocyclic compounds are unstable in the presence of Lewis
acid (i.e., Ag(I)) and underwent further ring expansion and
5
the spiroindolines (3a′), under acid conditions, Togni’s
reagent (2b) was used as the source of CF . Using 1a as the
3
substrate, unidentified byproducts were generated in this
reaction. Gratifyingly, using the C2-substituted compound 1b
as the substrate, the spiroindolenine 3b was obtained in 80%
yield (entry 7). Other copper catalysts including CuBr, CuI,
13
rearomatization (Scheme 1e). Theoretically, inhibiting the
rearrangement and rearomatization would be a good strategy
to obtain spiroindolenines (3), which have challenging
B
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Letter
2
CuCN, CuOTf, and Cu(OAc) were also tested (entries 8−
ynones (R ) was explored. It seems that the electronic effect of
the substituents has an influence on the reaction. The indolyl
ynones with electron-donating groups (1g−i) afforded the
desired products with high yields, while electron-withdrawing
groups (1j−m) resulted in the corresponding spiroskelecton
products (3j−m) with slightly lower efficiency. It is note-
worthy that a substrate with a thiophene-yl group attached to
the triple bond (1o) successfully provided the desired product
in 60% yield. The substrate with an alkyl group (1p) afforded
2
1
2), but the results were not improved. Evaluation of various
solvents (entries 13−17) revealed that the reaction was highly
dependent on the solvents: the use of acetonitrile gave a good
yield (entry 14), whereas in DMSO or 1,4-dioxane, none of the
desired product was detected. A control experiment revealed
that the copper catalyst was essential for the reaction (entry
1
8).
With the optimized reaction conditions established (Table 1,
71% of the desired product (3p), while this is not the case for
entry 7), we next investigated the substrate scope for the
trifluoromethylation/dearomatizing spirocyclization reaction
using various indolyl ynones. The results are summarized in
Scheme 2. The use of 2-Ph indolyl ynone 1c under the
optimized reaction conditions led to the corresponding 3c in
high yields (88%). Similarly, the desired products 3d−3f were
obtained in moderate yields from the indolyl ynones with
bulky tert-butyl-substituted ynone 1q (to form 3q). Fur-
thermore, we studied the effect of the substituents on the
3
indole ring (R ). The substrates with either an electron-
withdrawing or electron-donating group at the C4- to C7-
positions of the indole ring were all tolerated. In particular, the
substrate with a 5-MeO group (1u) and substrates (1r−1t)
with a Me group at the 5-, 6-, or 7-position of the indole ring
were efficiently transformed into the corresponding spiroindo-
lenines 3u and 3r−3t, respectively, in moderate to high yields.
As for the electron-withdrawing substituents (e.g., Br, Cl and
F), the desired products (3v−3y) were obtained in moderate
yields. The steric hindrance at the C4-position (1w) was
unfavorable for the dearomatizing spirocyclization. Finally,
alcohol derivative 1z was also a suitable substrate which led to
spiroindolenine 3z in 43% yield with 1:1 dr under the standard
conditions.
1
substituents (R ) of 2-phenylacetylene, methyl, and iodo
groups. Then the effect of the substituents on the phenyl
Scheme 2. Substrate Scope of CuCl-Catalyzed Cascade
a
Reaction
We also investigated the synthetic versatility of the resulting
5c
spiro[cyclopentane-1,3′-indole] (Scheme 3). A large-scale
Scheme 3. Transformations of Spiro[cyclopentane-1,3′-
a
indole]
a
Reaction conditions: (a) 10% HCl (aq), THF, rt, 4 h; (b) 2-
mercaptoethanol, Et N, MeCN, rt, 22 h, under Ar; (c) ethynylben-
3
zene, Et N, PdCl (PPh ) , CuI, THF, rt, 12 h, under Ar; (e)
3
2
3 2
NaBH CN, TFA, EtOH, 1 h.
3
reaction was performed with the substrate 1f (600 mg, 1.56
mmol), and the corresponding product 3f was obtained in a
slightly lower yield (50% vs 62%). Then compound 3f was
hydrolyzed using aqueous HCl in THF to afford CF3-
containing spirocyclicoxindole 4f in almost quantitative yield.
Nucleophilic substitution of 3f with 2-mercaptoethanol led to
the formation of compound 5f in 90% yield, while the
Songashira reaction of 3f with ethynylbenzene led to 3d in
8
5% yield with the total yield of 53% in two steps from 1f,
higher than one step from 1d (24%). Reduction of 3e by
a
Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), CuCl (0.02
NaBH CN afforded the spiro[cyclopentane-1,3′-indoline] 6e
3
mmol), DCE (2 mL), 50 °C, 36−48 h, under Ar atmosphere.
with good stereoselectivity (dr >20:1) in excellent yield (95%).
C
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To obtain more insight into the reaction mechanism, we
performed several control experiments (Scheme 4). First,
Scheme 5. Proposed Reaction Mechanism
Scheme 4. Control Experiments
leads to the product 3 and the regeneration of the catalyst
Cu(I). The exact mechanism for this domino process still
remains unclear at present and deserves further detailed
studies.
In summary, we have developed an operationally simple,
highly efficient copper-catalyzed cascade reaction which
involves trifluoromethylation of alkynes and dearomatizing
spirocyclization of indoles. The use of Cu(I)/Togni reagent 2b
instead of Ag(I)/Togni reagent 2a prevents the Lewis acid
induced rearomatization of the spiroindolenines. This
methodology enables regiospecific construction of trifluor-
omethylated spiro[cyclopentane-1,3′-indole] scaffolds contain-
ing quaternary spirocyclic carbon and tetrasubstituted alkenes
under mild conditions in good to excellent yields.
radical-trapping experiments were conducted by employing
2
,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). In the pres-
19
1
3
ence of 200 mol % of TEMPO, F NMR spectroscopy showed
that the reaction was inhibited and the radical-trapping
product TEMPO-CF was obtained in 60% yield. In addition,
3
the reaction of spirocycle 3c′ and Togni’s reagent (2b) could
not afford the corresponding product 3c under standard
conditions with almost complete recovery of 3c′, implying that
the spirocycle 3c′ was not the active intermediate.
Furthermore, indole 1b proved to be inactive for this
transformation in the absence of Togni’s reagent (2b)
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01097.
(Scheme 4c), but Cu(II) with 2-iodobenzoic acid converted
compound 1a into spiroindolines 3a′ in 90% yield (Scheme
5a,b
Detailed experimental procedures characterization data,
4
d). These results suggest that unlike Ag(I)
and Cu(II),
1
19
X-ray structure of 1b, 3b and the copies of H, F and
CuCl as a weak Lewis acid is not able to induce intramolecular
dearomatizing spirocyclization under the standard conditions.
On the basis of the above control experiments and
1
3
C NMR spectra (PDF)
Accession Codes
12
previously reported results, two plausible mechanisms for
this cascade reaction are proposed (Scheme 5). For the first
mechanism, the Togni’s reagent (2b) is first activated by Cu(I)
by means of a single-electron transfer to generate highly
reactive CF3 radical and Cu(II). Then CF3 radical
CCDC 1955808 and 1955810 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
regioselectively attacks aryl ynones 1 at the α-position to
2
form a C(sp )−CF bond together with the generation of
3
benzylcarbon-centered radical I. Subsequently, the carbon-
centered radical I undergoes 5-exo dearomatizing cyclization
onto the electron-rich C-3 position of the indole to give the
spirocyclic intermediate II, rather than a 6-endo cyclization
leading to the carbazol-3-one. The radical II is then oxidized
by Cu(II) to iminium ion III. Finally, the deprotonation of the
iminium ion III is transformed into the desired product 3. On
the other hand, the Cu-mediated electrophilic spirocyclization
may be also feasible. Coordination of Cu(II) with a triple bond
of ynones promotes spirocyclization of compound 1 to give the
AUTHOR INFORMATION
Corresponding Authors
■
Guifang Han − Tianjin Key Laboratory on Technologies
Enabling Development of Clinical Therapeutics and Diagnostics,
School of Pharmacy, Tianjin Medical University, Tianjin
300070, P.R. China; Email: hanguifang@tmu.edu.cn
Yangping Liu − Tianjin Key Laboratory on Technologies
Enabling Development of Clinical Therapeutics and Diagnostics,
School of Pharmacy, Tianjin Medical University, Tianjin
300070, P.R. China; orcid.org/0000-0001-5455-3602;
Email: liuyangping@tmu.edu.cn
15
intermediate complex V, which further reacts with CF radical
3
to afford the intermediate VI. Reductive elimination of VI
D
https://dx.doi.org/10.1021/acs.orglett.0c01097
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Authors
pubs.acs.org/OrgLett
Letter
405−425. (i) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem.
Soc. 2010, 132, 11418−1419.
Chengwen Li − Tianjin Key Laboratory on Technologies
Enabling Development of Clinical Therapeutics and
Diagnostics, School of Pharmacy, Tianjin Medical University,
Tianjin 300070, P.R. China
Li Xue − Tianjin Key Laboratory on Technologies Enabling
Development of Clinical Therapeutics and Diagnostics, School
of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R.
China
Jiaxin Zhou − Tianjin Key Laboratory on Technologies Enabling
Development of Clinical Therapeutics and Diagnostics, School
of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R.
China
Yilin Zhao − Tianjin Key Laboratory on Technologies Enabling
Development of Clinical Therapeutics and Diagnostics, School
of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R.
China
(
1
(
4) Naj
1244.
5) (a) James, M. J.; Cuthbertson, J. D.; O’Brien, P.; Taylor, R. J. K.;
́
era, C.; Sydnes, L. S.; Yus, M. Chem. Rev. 2019, 119, 11110−
Unsworth, W. P. Angew. Chem., Int. Ed. 2015, 54, 7640−7643.
(b) Clarke, A. K.; James, M. J.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Angew. Chem., Int. Ed. 2016, 55, 13798−13802.
(c) Liddon, J. T. R.; Clarke, A. K.; Taylor, R. J. K.; Unsworth, W. P.
Org. Lett. 2016, 18, 6328−6331. (d) Liddon, J. T. R.; James, M. J.;
Clarke, A. K.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Chem. -
Eur. J. 2016, 22, 8777−8780. (e) Fedoseev, P.; Van der Eycken, E.
Chem. Commun. 2017, 53, 7732−7735.
(6) (a) Fedoseev, P.; Coppola, G.; Ojeda, G. M.; Van der Eycken, E.
K. Chem. Commun. 2018, 54, 3625−3628. (b) Ho, H. E.; Stephens, T.
C.; Payne, T. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. ACS
Catal. 2019, 9, 504−510. (c) Ho, H. E.; Pagano, A.; Rossi-Ashton, J.
A.; Donald, J. R.; Epton, R. G.; Churchill, J. C.; James, M. J.; O’Brien,
P.; Taylor, R. J. K.; Unsworth, W. P. Chem. Sci. 2020, 11, 1353.
Jingli Hou − Tianjin Key Laboratory on Technologies Enabling
Development of Clinical Therapeutics and Diagnostics, School
of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R.
China; orcid.org/0000-0003-2001-5878
Yuguang Song − Tianjin Key Laboratory on Technologies
Enabling Development of Clinical Therapeutics and
Diagnostics, School of Pharmacy, Tianjin Medical University,
Tianjin 300070, P.R. China
(7) (a) Mu
1886. (b) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822−5880.
c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. J. Med. Chem. 2015, 58, 8315−8359. (d) Wang, J.; Sanchez-
Rosello, M.; Acena, J. L.; Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432−2506.
e) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422−518.
f) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
̈
ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−
(
́
́
̃
(
̃
(
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01097
Wiley-Blackwell: Chichester, 2009. (g) Kirsch, P. Modern Fluoro
organic Chemistry: Synthesis Reactivity, Applications; Wiley-VCH:
Weinheim, 2004. (h) Shimizu, M.; Hiyama, T. Angew. Chem., Int.
Ed. 2005, 44, 214−231. (i) Schlosser, M. Angew. Chem., Int. Ed. 2006,
Notes
45, 5432−5446. (j) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.;
The authors declare no competing financial interest.
Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496−3508.
(
8) (a) Zheng, Y.; Ma, J. A. Adv. Synth. Catal. 2010, 352, 2745−
2750. (b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
475−4521. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011,
ACKNOWLEDGMENTS
■
4
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21603163, 21572161,
473, 470−477. (d) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950−
8958. (e) Koike, T.; Akita, M. Chem. 2018, 4, 409−437. (f) Ni, C.;
Hu, J. Chem. Soc. Rev. 2016, 45, 5441−5454. (g) Alonso, C.; de
Marigorta, E. M.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115,
3
1500684, 31971174, and 21871210), the Science &
Technology Projects of Tianjin (Nos. 18JCQNJC76100 and
8JCYBJC95300), and Tianjin Municipal 13th five-year plan
1
(
847−1935.
9) For selected recent examples of oxytrifluoromethylation
reactions of CC bonds, see: (a) Janson, P. G.; Ghoneim, I.;
Ilchenko, N. O.; Szabo,
1
(
Tianjin Medical University Talent Project).
́
K. J. Org. Lett. 2012, 14, 2882−2885.
b) Maji, A.; Hazra, A.; Maiti, D. Org. Lett. 2014, 16, 4524−4527.
c) Tomita, R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2015, 54,
2923−12927. (d) Malpani, Y. R.; Biswas, B. K.; Han, H. S.; Jung, Y.-
REFERENCES
(
(
1
■
(
1) (a) Liu, X.-Y.; Qin, Y. Acc. Chem. Res. 2019, 52, 1877−1891.
(
b) O’Connor, S. E.; Maresh, J. Nat. Prod. Rep. 2006, 23, 532−547.
S.; Han, S. B. Org. Lett. 2018, 20, 1693−1697. (e) Han, H. S.; Oh, E.
H.; Jung, Y.-S.; Han, S. B. Org. Lett. 2018, 20, 1698−1702. (f) Wang,
X.; Studer, A. Org. Lett. 2017, 19, 2977−2980.
(
c) Park, H. B.; Kim, Y.-J.; Lee, J. K.; Lee, K. R.; Kwon, H. C. Org.
Lett. 2012, 14, 5002−5005. (d) Zhang, Z.; Xie, S.; Cheng, B.; Zhai,
H.-B.; Li, Y. J. Am. Chem. Soc. 2019, 141, 7147−7154. (e) Zhi, M.;
Gan, Z.; Ma, R.; Cui, H.; Li, E.-Q.; Duan, Z.; Mathey, F. Org. Lett.
(10) For selected recent examples of aminotrifluoromethylation
2
(
019, 21, 3210−3213.
reactions of CC bonds, see: (a) Ge, G.-C.; Huang, X.-J.; Ding, C.-
H.; Wang, S.-L.; Dai, L.-X.; Hou, X.-L. Chem. Commun. 2014, 50,
3048−3051. (b) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G. Angew.
Chem., Int. Ed. 2015, 54, 9356−9360. (c) Xiang, Y.; Kuang, Y.; Wu, J.
Org. Chem. Front. 2016, 3, 901−905. (d) Wang, Q.; He, L.; Li, K. K.;
Tsui, G. C. Org. Lett. 2017, 19, 658−661.
2) (a) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P.
Chem. - Eur. J. 2016, 22, 2856−2881. (b) Wu, Q.-F.; He, H.; Liu, W.-
B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418−11419. (c) Wu, Q.-
F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680−1683.
(
d) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47,
2
558−2573.
3) For a book, see: (a) Asymmetric Dearomatization Reactions; You,
S.-L., Ed.; Wiley-VCH: Weinheim, 2016. For selected reviews, see:
b) Bariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V. Chem. Soc.
Rev. 2018, 47, 3831−3848. (c) Zheng, C.; You, S.-L. Nat. Prod. Rep.
(11) For selected recent examples of halotrifluoromethylation
reactions of CC bonds, see: (a) Wallentin, C.-J.; Nguyen, J. D.;
Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134,
8875−8884. (b) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem.,
Int. Ed. 2014, 53, 539−542. (c) Hang, Z.; Li, Z.; Liu, Z.-Q. Org. Lett.
2014, 16, 3648−3651. (d) Zhang, S.-L.; Wan, H.-X.; Bie, W.-F. Org.
Lett. 2017, 19, 6372−6375. (e) Zhang, S.-L.; Dong, J.-J. Org. Lett.
2019, 21, 6893−6896.
(
(
2
019, 36, 1589−1605. (d) Saya, J. M.; Ruijter, E.; Orru, R. V. A.
Chem. - Eur. J. 2019, 25, 8916−8935. (e) Roche, S. P.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2011, 50, 4068−4093. (f) Zhuo, C.-X.; Zhang,
W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662−12686.
(12) For selected recent examples of carbotrifluoromethylation
reactions of CC bonds, see: (a) Janson, P. G.; Ghoneim, I.;
Ilchenko, N. O.; Szabo, K. J. Org. Lett. 2012, 14, 2882−2885.
(
2
g) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47,
558−2573. (h) Huang, G.; Yin, B. Adv. Synth. Catal. 2019, 361,
E
https://dx.doi.org/10.1021/acs.orglett.0c01097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(
b) Gao, P.; Shen, Y.-W.; Fang, R.; Hao, X.-H.; Qiu, Z.-H.; Yang, F.;
Yan, X.-B.; Wang, Q.; Gong, X.-J.; Liu, X.-Y.; Liang, Y.-M. Angew.
Chem., Int. Ed. 2014, 53, 7629−7633. (c) Chen, S.; Li, D. Y.; Jiang, L.
L.; Liu, K.; Liu, P. N. Org. Lett. 2017, 19, 2014−2017. (d) Iqbal, N.;
Jung, J.; Park, S.; Cho, E. J. Angew. Chem., Int. Ed. 2014, 53, 539−542.
(
4
e) Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int. Ed. 2014, 53,
910−4914. (f) Ge, G.-C.; Huang, X.-J.; Ding, C.-H.; Wan, S.-L.; Dai,
L.-X.; Hou, X.-L. Chem. Commun. 2014, 50, 3048−3051. (g) Xu, J.;
Wang, Y.; Gong, T.; Xiao, B.; Fu, Y. Chem. Commun. 2014, 50,
1
2
2915−12918. (h) Wang, Y.; Jiang, M.; Liu, J. Chem. - Eur. J. 2014,
0, 15315−15319. (i) Xiong, Y.-P.; Wu, M.-Y.; Zhang, X.-Y.; Ma, C.-
L.; Huang, L.; Zhao, L.-J.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16,
1
4
000−1003. (j) Li, Y.; Lu, Y.; Qiu, G.; Ding, Q. Org. Lett. 2014, 16,
240−4243. (k) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G. Angew.
Chem., Int. Ed. 2015, 54, 9356−9360. (l) Hua, H. L.; He, Y. T.; Qiu,
Y. F.; Li, Y. X.; Song, B.; Gao, P.; Song, X. R.; Guo, D. H.; Liu, X. Y.;
Liang, Y. M. Chem. - Eur. J. 2015, 21, 1468−1473. (m) Li, Y.; Xiang,
Y.; Li, Z.; Wu, J. Org. Chem. Front. 2016, 3, 1493−1497. (n) Huang,
L.; Ye, L.; Li, X.-H.; Li, Z.-L.; Lin, J.-S.; Liu, X.-Y. Org. Lett. 2016, 18,
5
284−5287. (o) Wang, Q.; He, L.; Li, K. K.; Tsui, G. C. Org. Lett.
2
017, 19, 658−661. (p) Zhang, Y.; Guo, D.; Ye, S.; Liu, Z.; Zhu, G.
Org. Lett. 2017, 19, 1302−1305. (q) Li, J.; Lei, Y.; Yu, Y.; Qin, C.; Fu,
Y.; Li, H.; Wang, W. Org. Lett. 2017, 19, 6052−6055. (r) Guo, S.;
AbuSalim, D. I.; Cook, S. P. Angew. Chem., Int. Ed. 2019, 58, 11704−
1
1708.
(
13) Han, G.; Xue, L.; Zhao, L.; Zhu, T.; Hou, J.; Song, Y.; Liu, Y.
Adv. Synth. Catal. 2019, 361, 678−682.
14) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem. - Eur. J. 2006,
k, V.; Pietrasiak, E.; Schwenk, R.; Togni,
(
1
2, 2579−2586. (b) Matouse
̌
A. J. Org. Chem. 2013, 78, 6763−6768. (c) Fiederling, N.; Haller, J.;
Schramm, H. Org. Process Res. Dev. 2013, 17, 318−319.
(
15) (a) Han, G.; Wang, Q.; Chen, L.; Liu, Y.; Wang, Q. Adv. Synth.
Catal. 2016, 358, 561−566. (b) Ibarra-Rivera, T. R.; Gam
́
ez-
Montano, R.; Miranda, L. D. Chem. Commun. 2007, 3485−3487.
̃
F
https://dx.doi.org/10.1021/acs.orglett.0c01097
Org. Lett. XXXX, XXX, XXX−XXX