Halotrifluoromethylation of 1,3-Enynes: Access to Tetrasubstituted Allenes

Article abstract of DOI:10.1021/acs.orglett.1c00449

A highly regioselective copper-catalyzed 1,4-chloro- and bromotrifluoromethylation of 1,3-enynes has been presented for the first time, which affords an efficient transformation to access halo- and CF3-containing tetrasubstituted allene derivatives with good to excellent yield. This protocol is practical and convenient, in which a wide range of functional groups are compatible. Applications of this method for the gram-scale preparation and late-stage functionalization of biologically active molecules are also demonstrated.

Full text of DOI:10.1021/acs.orglett.1c00449

pubs.acs.org/OrgLett
Letter
Halotrifluoromethylation of 1,3-Enynes: Access to Tetrasubstituted
Allenes
Jinfeng Huang, Yimin Jia, Xiangyu Li, Jianli Duan, Zhong-Xing Jiang, and Zhigang Yang*
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ABSTRACT: A highly regioselective copper-catalyzed 1,4-chloro-
and bromotrifluoromethylation of 1,3-enynes has been presented for
the first time, which affords an efficient transformation to access
halo- and CF3-containing tetrasubstituted allene derivatives with
good to excellent yield. This protocol is practical and convenient, in
which a wide range of functional groups are compatible.
Applications of this method for the gram-scale preparation and late-stage functionalization of biologically active molecules are
also demonstrated.
wing to the high electronegativity and small atomic
radius (similar to hydrogen) of fluorine, as well as the
C(sp2)−H trifluoromethylation of the alkenyl moiety, 1,2-
difunctionalization, or 3,4-difunctionalization of the alkenyl
and alkynyl moieties, respectively (Scheme 1a). Obviously, a
significant challenge for this process is to control the reaction
regioselectivity and promote the formation of more favored
O
high dissociation energy of C−F bond, fluorine-containing
compounds are widely applied in pharmaceuticals, agro-
chemicals, nuclear imaging, and materials science.1 In
particular, the trifluoromethyl group (CF3) has gained
significant interest in drug discovery, mainly because the CF3
unit can dramatically improve the lipophilicity, metabolic
stability of lead compounds, and ability to cross the blood−
brain barrier.2 Therefore, several highly effective approaches
for the direct incorporation of a CF3 motif into organic
molecules have been developed using nucleophilic, electro-
philic, and free-radical trifluoromethylation strategies.3
Scheme 1. Potential Side Reactions and 1,4-
Halotrifluoromethylation of 1,3-Enynes
Organic halogen has been identified as a versatile skeleton in
synthetic chemistry, which can be easily converted into
heteroatom functional groups (N, O, S, etc.), hydrocarbons,
alkenes, and hydrogen.4 Thus, it is of great value to construct
halogen-containing trifluoromethyl frameworks simultaneously
through a one-pot procedure. By the complementary use of
nucleophilic halide reagents and electrophilic CF3 reagents,
many elegant works have been well illustrated through a
difunctionalization strategy that allows convenient and efficient
access to the halogenated trifluoromethyl compounds.5−7 In
these reports, a variety of metal- or organocatalyzed systems
were proven to be efficient for the halotrifluoromethylation,
and their reactivity toward different multibond compounds,
such as alkenes,5 alkynes,5c,j,6 and other unsaturated com-
pounds,7 were investigated. In addition, for the terminal
alkenes or (hetero)arenes, a C(sp2)−H trifluoromethylation
may also occur.8 As a typical unsaturated compound, 1,3-
enynes were commonly used to construct valuable allenes.9 It
bears alkenyl and alkynyl residues, which could react with
electrophilic trifluoromethyl reagents independently. Thus,
when 1,3-enyne was employed as an unsaturated compound
for the halotrifluoromethylation, several potential side
reactions could occur, such as the competing premature
Received: February 5, 2021
Published: March 4, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00449
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2314−2319
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1,4-difunctionalization. Given the potential issues associated
with 1,4-halotrifluoromethylation of 1,3-enynes, their slow
progress is fairly understandable and a practical strategy has
not yet been successfully established. On the other hand,
allenes are not only versatile building blocks for natural
products, drug candidates, and materials but also key synthetic
intermediates frequently found in various organic trans-
formations.9 In continuation of our research program to
develop difunctionalized fluoroalkylation,5f,10 we herein report
an unprecedented 1,4-halotrifluoromethylation of 1,3-enynes
with a nucleophilic halide reagent (SOX2) and an electrophilic
CF3 reagent. This tandem reaction facilitates the construction
of halo- and CF3-containing tetrasubstituted allene derivatives
with high regioselectivity and excellent functional-group
tolerance.
not improve when the reaction was performed in CH3CN or
dioxane (entries 6−7). Interestingly, when EtOAc was
employed as the solvent, the reaction system selectively
afforded the 1,4-halotrifluoromethylated product with a higher
yield (91%), while almost no C(sp2)−H trifluoromethylation
product 3a′ was detected (entry 8). Subsequently, other
commonly used copper salts, such as CuCl2, Cu2O, and CuI,
were also examined and the expected transformation also
occurred, but no superior reactivity was realized (entries 9−
11). To our surprise, PdCl2 could also drive the expected
reaction, although a lower yield was provided (entry 12). To
our delight, when 10 mol % of catalyst loading was employed,
the desired product 3a was obtained without obvious loss of
reactivity (entry 13). Finally, a reduction in the catalyst loading
to only 1 mol % along with a shorter reaction time (1 h) led to
3a in 82% yield (entry 14).
At the beginning of this study, 1,3-enyne 1a was used as a
model substrate to investigate reaction conditions (Table 1).
With the optimal reaction conditions developed (Table 1,
entry 14), we next studied the scope of 1,3-enynes derived
from different alkenyl moieties for this 1,4-difunctionalized
transformation, and the results are summarized in Scheme 2.
The reaction was performed on a 0.5 mmol scale and gave the
expected product 3a in slightly increased reactivity (95%). The
alkenyl moiety containing various substituents such as fluorine,
chlorine, and bromine at the aromatic ring’s para position
worked efficiently, resulting in tetrasubstituted allenes 3b−d in
80−87% yields. The alkenyl moiety bearing a methyl or
halogen substituent at the phenyl ring’s meta position tolerated
this trifluoromethylation and were transformed into the
expected products 3e−h in 77−92% yields. Likewise, the
alkenyl moiety with a sterically hindered ortho-substituted aryl
was well tolerated with the same reaction conditions, delivering
the targeted product 3i−l in 73−98% yields. A 1,3-enyne
bearing two substituents at the phenyl ring of the alkenyl
moiety was converted into the corresponding product 3m
efficiently. When fused ring-derived 1,3-enynes 1n,o (Ar = 1-
or 2-naphthyl) were subjected to this transformation, the
desired tetrasubstituted allenes were achieved in satisfactory
yields. To further benefit from the current method, the late-
stage halotrifluoromethylation of biologically active molecules
and natural products could be realized. 1,3-Enynes incorpo-
rated with L-menthol, polyethylene glycol (PEG), and propofol
were all suitable substrates, providing the corresponding
chlorotrifluoromethylated products 3p−s with good efficiency.
Even the 1,3-enyne-derived from complex natural product
vitamin E was also a suitable substrate. The desired
tetrasubstituted allene 3t was obtained as the sole adduct in
69% yield and 3:1 diastereoselectivity.
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
catalyst
solvent
3a (%)
3a′ (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
Cu2O
CuI
PdCl2
Cu(OAc)2
Cu(OAc)2
CH2Cl2
DMF
DMSO
THF
21
trace
trace
33
33
7
7
91
88
86
23
22
19
trace
trace
8
toluene
CH3CN
dioxane
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
6
trace
trace
trace
trace
trace
trace
trace
9
10
11
12
13
14
68
19
87
82
c
d
a
Reaction conditions: 1,3-enyne 1a (0.1 mmol), Togni’s reagent 2a
(1.5 equiv), SOCl2 (1.5 equiv), catalyst (20 mol %), solvent (1.0 mL),
b
rt, Ar, 12 h. Yields determined by 19F NMR spectroscopy using
c
trifluoromethylbenzene as an internal standard. Cu(OAc)2 (10 mol
%) was used. Cu(OAc)2 (1 mol %) was used; the reaction time was
d
1 h.
Inspired by the above halotrifluoromethylation reactions, we
turned our attention to the unique reactivity of 1,3-enynes and
performed the extensive exploration of this 1,4-difunctionalized
protocol by employing 1,3-enynes derived from different
alkynyl moieties. As displayed in Scheme 3, a wide range of
1,3-enynes were compatible with this transformation. The
electronical nature, positional change (para or meta), and steric
hindrance (ortho) of the phenyl ring did not have many
restrictions on the reaction efficiency; the expected adducts
5a−h were generated in satisfactory yields. When aliphatic
alkynes such as propyl, cyclopropyl, tert-butyl, and n-hexyl
were included in the 1,3-enynes and subjected to the standard
conditions, the reactions conducted smoothly to deliver the
corresponding products 5i−l in 75−86% yields. Indeed, the
alkynyl moiety containing a silyl group was also a suitable
substrate for the chlorotrifluoromethylation to afford the
At first, SOCl2 was selected as the nucleophilic halide reagent,
and Togni’s reagent11 (2a) was chosen as the electrophilic CF3
source in the presence of a copper catalyst. When the reaction
was carried out in CH2Cl2 at room temperature under an argon
atmosphere for 12 h, the corresponding tetrasubstituted allene
3a was obtained in 21% yield with an almost equal amount of
byproduct 3a′ (Table 1, entry 1). Encouraged by this
preliminary result, various solvents were then investigated. It
was found that the solvent plays a crucial role in the
regioselectivity and reactivity of the reaction. Polar solvents
including DMF and DMSO only provided C(sp2)−H
trifluoromethylated product 3a′, albeit in poor yields (entries
2 and 3). In contrast, when THF or toluene was employed as
the solvent, only the expected 1,4-halotrifluoromethylation
occurred, affording 3a as the sole product in slightly increased
yields (entries 4 and 5). The yield and the regioselectivity did
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Scheme 2. Scope with Respect to the Alkenyl Moiety of 1,3-
enynes
Scheme 3. Scope with Respect to the Alkynyl Moiety of 1,3-
Enynes
a
a
a
Reaction conditions: 1,3-enyne 4 (0.5 mmol), Togni’s reagent 2a
(1.5 equiv), SOCl2 (1.5 equiv), Cu(OAc)2 (1 mol %), EtOAc (5.0
b
mL), rt, Ar, 1 h; yields are isolated yields. CH2Cl2 was used as
c
solvent, and TMSBr was used as bromine source. Diastereoselectivity
was determined by HPLC analysis of the crude product.
delivering the corresponding allene 3a without reactivity loss
while still maintaining an 81% isolated yield (Scheme 4a).
To demonstrate the utility of these transformations, further
derivatizations of the halotrifluoromethylation product were
investigated (Scheme 4b). Under basic conditions and the use
of Pd(PPh3)2Cl2 as a catalyst, a coupling reaction between 3a
and phenylboronic acid could occur in a mixture solvent of
dioxane and H2O, resulting in the formation of triphenyl-
substituted allene 6 in 85% yield. The chloro group of the
allene undergoes a nucleophilic attack by KSCN to generate
expected thiocyanate 7 with 60% yield. Treatment of 3a with
potassium phthalimide in DMF resulted in the elimination of
the chloro group, delivering the double bond migration
product 3a′ in good yield (71%) and geometric selectivity
(Z-alkene). Also, the chloro group could be readily removed
via a reduction with zinc powder in acetic acid, and the
reduced product 8 was detected in 59% yield.
a
Reaction conditions: 1,3-enyne 1 (0.5 mmol), Togni’s reagent 2a
(1.5 equiv), SOCl2 (1.5 equiv), Cu(OAc)2 (1 mol %), EtOAc (5.0
mL), rt, Ar, 1 h; yields are isolated yields. Diastereoselectivity was
determined by HPLC analysis of the crude product.
b
expected product 5m in 84% yield. Noticeably, when TMSBr
was employed as a bromine source instead of SOCl2, the
resulting brominated adduct 5n was obtained in 50% yield.
When an internal 1,3-enyne 4o was investigated, the
corresponding product 5o was obtained in 89% yield and
good regioselectivity. Finally, the structure of trifluoromethy-
lated tetrasubstituted allene 5c was unambiguously confirmed
by an X-ray crystallographic analysis.
Chlorinated allenes are highly useful intermediates and
versatile building blocks in organic synthesis. This halotri-
fluoromethylation could easily be carried out on a gram scale,
showing the potential opportunity for further applications.
Under the standard reaction conditions, 1,3-enyne 1a (0.82 g)
reacted smoothly with Togni’s reagent 2a and SOCl2,
Several control experiments were performed to gain more
mechanistic insight into the process (Scheme 5). When 2,6-di-
tert-butyl-4-methylphenol (BHT) was added as a radical
inhibitor, the chlorotrifluoromethylation was partly prohibited
(Scheme 5a). Furthermore, the reaction was almost sup-
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a
tion of 1,3-enynes has been proposed in Scheme 6. Initially, an
Scheme 4. Scale up and Derivatization Experiments
electrophilic trifluoromethyl radical (•CF3) was generated from
Scheme 6. Plausible Mechanism
a
Reaction conditions: (i) Pd(PPh3)2Cl2, Cs2CO3, PhB(OH)2,
dioxane/H2O, rt; (ii) KSCN, acetone/H2O, rt; (iii) potassium
phthalimide, DMF, 45 °C (oil bath); (iv) Zn, AcOH, Ar, rt.
Togni’s reagent 2a via a single-electron-transfer (SET) caused
by the copper(II) complex with concomitant formation of
copper(III) species. The radical (•CF3) would then be
captured by the 1,3-enyne 1a to furnish the trifluoromethylated
allenyl radical intermediate A. The CF3-allenyl radical species
combined with another Cu(II) and SOCl2 to give a CF3-
allenyl-Cu(III)Cl2 species B, which would then undergo
reductive elimination to produce the final product 3a and
released Cu(I). Finally, the copper(I) species serves as the real
catalyst to recycle the reaction.
Scheme 5. Control Experiments
In conclusion, we have developed the first copper-mediated
1,4-halotrifluoromethylation of 1,3-enynes with an electrophilic
trifluoromethylating reagent and a nucleophilic halide reagent
(SOX2), an approach that previously presented a formidable
challenge.5−7 Various halo- and CF3-containing tetrasubsti-
tuted allenes were formed with high yield and regioselectivity,
which can be easily converted into some valuable molecules.
This process is readily scaled up, and diverse transformations
of 1,3-enynes are being pursued for the late-stage derivatization
of biologically relevant compounds. Further development of
other kinds of 1,4-difunctionalization of 1,3-enynes involving
fluorine chemistry is presently underway in this laboratory.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00449.
pressed, and no expected product 3a was observed in the
presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
Scheme 5b). Next, compound 9 was subjected to the standard
reaction conditions as a radical clock instead of 1,3-enyne 1a,
and the reaction proceeded smoothly to produce the ring-
opened product 10 in 85% yield (Scheme 5c). These
experimental results reveal that these transformations proceed-
ing through the free-radical pathway would be expected for the
classical electrophilic trifluoromethylation process. In addition,
a similar yield of 3a was also observed when CuOAc was
employed as the catalyst instead of Cu(OAc)2 (Scheme 5d).
On the basis of the previous observations and previous
literature data,5−7 a mechanism for the halotrifluoromethyla-
Experimental procedures, screening of reaction con-
1
ditions, characterization data, and copies of H, 13C,
19FNMR (PDF)
Accession Codes
CCDC 2054394 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Letter
Wiley-Blackwell: Chichester, 2009. (c) Meanwell, N. A. Fluorine and
Fluorinated Motifs in the Design and Application of Bioisosteres for
Drug Design. J. Med. Chem. 2018, 61, 5822−5880. (d) Mei, H.; Han,
J.; Fustero, S.; Medio-Simon, M.; Sedgwick, D. M.; Santi, C.;
Ruzziconi, R.; Soloshonok, V. A. Fluorine-Containing Drugs
Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25, 11797−
11819.
AUTHOR INFORMATION
Corresponding Author
■
Zhigang Yang − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan 430071,
China; orcid.org/0000-0002-4857-4850;
(3) (a) Ma, J.-A.; Cahard, D. Strategies for nucleophilic, electro-
philic, and radical trifluoromethylations. J. Fluorine Chem. 2007, 128,
975−996. (b) Ma, J.-A.; Cahard, D. Asymmetric Fluorination,
Trifluoromethylation, and Perfluoroalkylation Reactions. Chem. Rev.
2008, 108, PR1−PR43. (c) Tomashenko, O. A.; Grushin, V. V.
Aromatic Trifluoromethylation with Metal Complexes. Chem. Rev.
2011, 111, 4475−4521. (d) Furuya, T.; Kamlet, A. S.; Ritter, T.
Catalysis for fluorination and Trifluoromethylation. Nature 2011, 473,
470−477. (e) Studer, A. A “Renaissance” in Radical Trifluoromethy-
lation. Angew. Chem., Int. Ed. 2012, 51, 8950−8958. (f) Egami, H.;
Sodeoka, M. Trifluoromethylation of Alkenes with Concomitant
Introduction of Additional Functional Groups. Angew. Chem., Int. Ed.
2014, 53, 8294−8308. (g) Merino, E.; Nevado, C. Addition of CF3
across unsaturated moieties: a powerful functionalization tool. Chem.
Email: zgyang@whu.edu.cn
Authors
Jinfeng Huang − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China
Yimin Jia − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China
Xiangyu Li − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China
Jianli Duan − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China
Soc. Rev. 2014, 43, 6598−6608. (h) Charpentier, J.; Fruh, N.; Togni,
̈
A. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine
Reagents. Chem. Rev. 2015, 115, 650−682. (i) Liu, X.; Xu, C.; Wang,
M.; Liu, Q. Trifluoromethyltrimethylsilane: Nucleophilic Trifluor-
omethylation and Beyond. Chem. Rev. 2015, 115, 683−730. (j) Yang,
X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in Catalytic
Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation,
and Trifluoromethylthiolation Reactions. Chem. Rev. 2015, 115, 826−
870. (k) Bos, M.; Poisson, T.; Pannecoucke, X.; Charette, A. B.;
Jubault, P. Recent Progress Toward the Synthesis of Trifluoromethyl-
and Difluoromethyl-Substituted Cyclopropanes. Chem. - Eur. J. 2017,
23, 4950−4961. (l) Zhang, C. Recent Developments in Trifluor-
omethylation or Difluoroalkylation by Use of Difluorinated
Phosphonium Salts. Adv. Synth. Catal. 2017, 359, 372−383.
(m) Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed Radical Relay
for Asymmetric Radical Transformations. Acc. Chem. Res. 2018, 51,
2036−2046. (n) Bhaskaran, R. P.; Babu, B. P. Progress in
Electrochemical Trifluoromethylation Reactions. Adv. Synth. Catal.
2020, 362, 5219−5237. (o) Ogawa, Y.; Tokunaga, E.; Kobayashi, O.;
Hirai, K.; Shibata, N. Current Contributions of Organofluorine
Compounds to the Agrochemical Industry. iScience 2020, 23, 101467.
(4) (a) Smith, M. B.; March, J. Advanced Organic Chemistry:
Reactions, Mechanism and Structure; Wiley-VCH, 2001. (b) Rønnest,
M. H.; Raab, M. S.; Anderhub, S.; Boesen, S.; Krämer, A.; Larsen, T.
O.; Clausen, M. H. Disparate SAR Data of Griseofulvin Analogues for
the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and
MDA-MB-231 Cancer Cells. J. Med. Chem. 2012, 55, 652−660.
(c) Hiszpanski, A. M.; Saathoff, J. D.; Shaw, L.; Wang, H.; Kraya, L.;
Zhong-Xing Jiang − Hubei Province Engineering and
Technology Research Center for Fluorinated
Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan
University, Wuhan 430071, China; orcid.org/0000-
0003-2601-4366
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00449
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for financial support from the National Key
Research and Development Program of China (Grant No.
2018YFA0704000) and the National Natural Science
Foundation of China (Grant No. 22077098). We are grateful
to Dr. Guofu Qiu in the School of Pharmaceutical Sciences at
Wuhan University for the NMR analysis.
Luttich, F.; Brady, M. A.; Chabinyc, M. L.; Kahn, A.; Clancy, P.; Loo,
̈
REFERENCES
Y.-L. Halogenation of a Nonplanar Molecular Semiconductor to Tune
Energy Levels and Bandgaps for Electron Transport. Chem. Mater.
2015, 27, 1892−1900. (d) China, H.; Kumar, R.; Kikushima, K.;
Dohi, T. Halogen-Induced Controllable Cyclizations as Diverse
Heterocycle Synthetic Strategy. Molecules 2020, 25, 6007.
■
(1) (a) Uneyama, K. Organofluorine Chemistry; Wiley-Blackwell:
New Delhi, 2006. (b) Mu
̈
ller, K.; Faeh, C.; Diederich, F. Fluorine in
Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−
1886. (c) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, Germany,
2013. (d) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing
herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16−29.
(5) (a) Kamigata, N.; Fukushima, T.; Yoshida, M. Reaction of
trifluoromethanesulphonyl chloride with alkenes catalysed by a
ruthenium(II) complex. J. Chem. Soc., Chem. Commun. 1989, 1559−
1560. (b) Oh, S. H.; Malpani, Y. R.; Ha, N.; Jung, Y.-S.; Han, S. B.
Vicinal Difunctionalization of Alkenes: Chlorotrifluoromethylation
with CF3SO2Cl by Photoredox Catalysis. Org. Lett. 2014, 16, 1310−
1313. (c) Xu, T.; Cheung, C. W.; Hu, X. Iron-Catalyzed 1,2-Addition
of Perfluoroalkyl Iodides to Alkynes and Alkenes. Angew. Chem., Int.
Ed. 2014, 53, 4910−4914. (d) Tang, X. J.; Dolbier, W. R. Efficient
Cu-catalyzed Atom Transfer Radical Addition Reactions of Fluo-
roalkylsulfonyl Chlorides with Electron-deficient Alkenes Induced by
Visible Light. Angew. Chem., Int. Ed. 2015, 54, 4246−4249. (e) Bagal,
D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B. M.;
Reiser, O. Trifluoromethylchlorosulfonylation of Alkenes: Evidence
(e) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
̃
Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-
Containing Pharmaceuticals, Compounds Currently in Phase II−III
Clinical Trials of Major Pharmaceutical Companies: New Structural
Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518.
(f) Moschner, J.; Stulberg, V.; Fernandes, R.; Huhmann, S.; Leppkes,
J.; Koksch, B. Approaches to Obtaining Fluorinated α-Amino Acids.
Chem. Rev. 2019, 119, 10718−10801.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
(b) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
2318
https://dx.doi.org/10.1021/acs.orglett.1c00449
Org. Lett. 2021, 23, 2314−2319

Organic Letters
pubs.acs.org/OrgLett
Letter
for an Inner-Sphere Mechanism by a Copper Phenanthroline
Photoredox Catalyst. Angew. Chem., Int. Ed. 2015, 54, 6999−7002.
(f) Fu, M.; Chen, L.; Jiang, Y.; Jiang, Z.-X.; Yang, Z. Copper-
Catalyzed Intermolecular Chloro- and Bromotrifluoromethylation of
Alkenes. Org. Lett. 2016, 18, 348−351. (g) Fang, J.; Wang, Z.-K.; Wu,
S.-W.; Shen, W.-G.; Ao, G.-Z.; Liu, F. Photoredox-catalysed chloro-,
bromo- and trifluoromethylthio-trifluoromethylation of unactivated
alkenes with sodium triflinate. Chem. Commun. 2017, 53, 7638−7641.
(h) Ye, K.-Y.; Pombar, G.; Fu, N.; Sauer, G. S.; Keresztes, I.; Lin, S.
Anodically Coupled Electrolysis for the Heterodifunctionalization of
Alkenes. J. Am. Chem. Soc. 2018, 140, 2438−2441. (i) Shang, X.-J.;
Liu, D.; Liu, Z.-Q. A NaSO2CF3/NaBrO3-mediated bromotrifluor-
omethylation of enyne via free-radical cascade processes. Org. Chem.
Front. 2018, 5, 2856−2859. (j) Rawner, T.; Lutsker, E.; Kaiser, C. A.;
Reiser, O. The Different Faces of Photoredox Catalysts: Visible-Light-
Mediated Atom Transfer Radical Addition (ATRA) Reactions of
Perfluoroalkyl Iodides with Styrenes and Phenylacetylenes. ACS Catal.
2018, 8, 3950−3956. (k) Ye, K.-Y.; Song, Z.; Sauer, G. S.; Harenberg,
J. H.; Fu, N.; Lin, S. Synthesis of Chlorotrifluoromethylated
Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization. Chem.
- Eur. J. 2018, 24, 12274−12279. (l) Xu, C.; Huang, W.; Zhang, R.;
Gao, C.; Li, Y.; Wang, M. Trifluoromethylations of Alkenes Using
PhICF3Cl as Bifunctional Reagent. J. Org. Chem. 2019, 84, 14209−
14216. (m) Ouyang, Y.; Tong, C.-L.; Xu, X.-H.; Qing, F.-L. Copper
and Zinc Copromoted Bromo(chloro)trifluoromethylation of Alkenes
and Alkynes with Trifluoromethanesulfonic Anhydride. Org. Lett.
2021, 23, 346−350.
(6) (a) Hang, Z.; Li, Z.; Liu, Z.-Q. Iodotrifluoromethylation of
Alkenes and Alkynes with Sodium Trifluoromethanesulfinate and
Iodine Pentoxide. Org. Lett. 2014, 16, 3648−3651. (b) Iqbal, N.;
Jung, J.; Park, S.; Cho, E. J. Controlled Trifluoromethylation
Reactions of Alkynes through Visible-Light Photoredox Catalysis.
Angew. Chem., Int. Ed. 2014, 53, 539−542. (c) Zhang, S. L.; Wan, H.
X.; Bie, W. F. syn-Fluoro- and -Oxy-trifluoromethylation of
Arylacetylenes. Org. Lett. 2017, 19, 6372−6375. (d) Han, H. S.;
Lee, Y. J.; Jung, Y.-S.; Han, S. B. Stereoselective Photoredox-Catalyzed
Chlorotrifluoromethylation of Alkynes: Synthesis of Tetrasubstituted
Alkenes. Org. Lett. 2017, 19, 1962−1965. (e) Wu, G.; Wangelin, A. J.
V. Stereoselective cobalt-catalyzed halofluoroalkylation of alkynes.
Chem. Sci. 2018, 9, 1795−1802. (f) Zhang, S.-L.; Dong, J.-J.
Hydrogen-Bonding-Assisted α-F Elimination from Cu−CF3 for in
Situ Generation of R3N·HF Reagents: Reaction Design and
Applications. Org. Lett. 2019, 21, 6893−6896. (g) Lee, W.; Lee, Y.;
Yoo, M.; Han, S. B.; Kim, H. J. Photoredox-catalyzed halotrifluor-
omethylations of alkynes with triethylammonium halides: synthesis of
tetrasubstituted alkenes containing CF3 and halogens. Org. Chem.
Front. 2020, 7, 3209−3214.
(d) Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. A
General Synthesis of Fluoroalkylated Alkenes by Palladium-Catalyzed
Heck-Type Reaction of Fluoroalkyl Bromides. Angew. Chem., Int. Ed.
2015, 54, 1270−1274. (e) Beatty, J. W.; Douglas, J. J.; Cole, K. P.;
Stephenson, C. R. J. A scalable and operationally simple radical
Trifluoromethylation. Nat. Commun. 2015, 6, 7919−7924. (f) Straa-
thof, N. J. W.; Cramer, S. E.; Hessel, V.; Noël, T. Practical
Photocatalytic Trifluoromethylation and Hydrotrifluoromethylation
of Styrenes in Batch and Flow. Angew. Chem., Int. Ed. 2016, 55,
15549−15553. (g) Wang, X.; Zhao, S.; Liu, J.; Zhu, D.; Guo, M.;
Tang, X.; Wang, G. Copper-Catalyzed C−H Difluoroalkylations and
Perfluoroalkylations of Alkenes and (Hetero)arenes. Org. Lett. 2017,
19, 4187−4190. (h) Guerrero, I.; Correa, A. Cu-Catalyzed Site-
Selective C(sp2)−H Radical Trifluoromethylation of Tryptophan-
Containing Peptides. Org. Lett. 2020, 22, 1754−1759.
(9) (a) Hoffmann-Röder, A.; Krause, N. Synthesis and Properties of
Allenic Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed.
2004, 43, 1196−1216. (b) Ma, S. Some Typical Advances in the
Synthetic Applications of Allenes. Chem. Rev. 2005, 105, 2829−2871.
(c) Yu, S.; Ma, S. How easy are the syntheses of allenes? Chem.
Commun. 2011, 47, 5384−5418. (d) Aubert, C.; Fensterbank, L.;
Garcia, P.; Malacria, M.; Simonneau, A. Transition Metal Catalyzed
Cycloisomerizations of 1,n-Allenynes and -Allenenes. Chem. Rev.
2011, 111, 1954−1993. (e) Yu, S.; Ma, S. Allenes in Catalytic
Asymmetric Synthesis and Natural Product Syntheses. Angew. Chem.,
Int. Ed. 2012, 51, 3074−3112. (f) Ye, J.; Ma, S. Conquering three-
carbon axial chirality of allenes. Org. Chem. Front. 2014, 1, 1210−
1224. (g) Ye, J.; Ma, S. Palladium-Catalyzed Cyclization Reactions of
Allenes in the Presence of Unsaturated Carbon−Carbon Bonds. Acc.
Chem. Res. 2014, 47, 989−1000. (h) Chu, W.-D.; Zhang, Y.; Wang, J.
Recent advances in catalytic asymmetric synthesis of allenes. Catal.
Sci. Technol. 2017, 7, 4570−4579.
(10) (a) Zheng, Y.; Jia, Y.; Yuan, Y.; Jiang, Z.-X.; Yang, Z. F−-Free
Deoxyhydrotrifluoromethylation of α-Keto Esters with
−
Ph3P+CF2CO2 : Synthesis of α−CF3-Substituted Esters. J. Org.
Chem. 2020, 85, 10913−10923. (b) Wang, N.; Jia, Y.; Qin, H.;
Jiang, Z.-X.; Yang, Z. Chlorotrifluoromethylthiolation of Sulfur Ylides
for the Formation of Tetrasubstituted Trifluoromethylthiolated
Alkenes. Org. Lett. 2020, 22, 7378−7382. (c) Qin, H.; Jia, Y.;
Wang, N.; Jiang, Z.-X.; Yang, Z. Practical and regioselective
halotrifluoromethylthiolation of sulfur ylides. Chem. Commun. 2020,
56, 8265−8268.
(11) Eisenberger, P.; Gischig, S.; Togni, A. Novel 10-I-3 Hypervalent
Iodine-Based Compounds for Electrophilic Trifluoromethylation.
Chem. - Eur. J. 2006, 12, 2579−2586.
(7) (a) Shono, T.; Kise, N.; Oka, H. Electroreductive coupling of
halofluoro compounds with aldehydes. Tetrahedron Lett. 1991, 32,
6567−6570. (b) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.;
Maiti, D. Oxidative Trifluoromethylation of Unactivated Olefins: An
Efficient and Practical Synthesis of α-Trifluoromethyl-Substituted
Ketones. Angew. Chem., Int. Ed. 2013, 52, 9747−9750. (c) Li, L.;
Chen, Q.-Y.; Guo, Y. Synthesis of α-Trifluoromethyl Ketones via the
Cu-Catalyzed Trifluoromethylation of Silyl Enol Ethers Using an
Electrophilic Trifluoromethylating Agent. J. Org. Chem. 2014, 79,
5145−5152. (d) Jiang, X.; Meyer, D.; Baran, D.; González, M. A. C.;
Szabó, K. J. Trifluoromethylthiolation, Trifluoromethylation, and
Arylation Reactions of Difluoro Enol Silyl Ethers. J. Org. Chem. 2020,
85, 8311−8319.
(8) (a) Feng, C.; Loh, T.-P. Copper-catalyzed olefinic trifluor-
omethylation of enamides at room temperature. Chem. Sci. 2012, 3,
3458−3462. (b) Feng, C.; Loh, T.-P. Directing-Group-Assisted
Copper-Catalyzed Olefinic Trifluoromethylation of Electron-Defi-
cient Alkenes. Angew. Chem., Int. Ed. 2013, 52, 12414−12417. (c) Lin,
Q.-Y.; Xu, X.-H.; Qing, F.-L. Chemo-, Regio-, and Stereoselective
Trifluoromethylation of Styrenes via Visible Light-Driven Single-
Electron Transfer (SET) and Triplet−Triplet Energy Transfer
(TTET) Processes. J. Org. Chem. 2014, 79, 10434−10446.
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