Single C-F Transformations of o-Hydrosilyl Benzotrifluorides with Trityl Compounds as All-in-One Reagents

Article abstract of DOI:10.1021/acs.orglett.0c03529

A facile method to prepare difluoromethylenes, including α,α-difluorobenzyl chlorides, by single C-F transformations of benzotrifluorides is disclosed. The C-F cleavage followed by chlorination proceeded smoothly using trityl chloride through the generation of trityl cation as an activator and chloride anion as a nucleophile. Diverse difluoromethylenes such as difluorobenzyl ethers were efficiently prepared by virtue of the good versatility of the resulting chloro and fluorosilyl groups.

Full text of DOI:10.1021/acs.orglett.0c03529

pubs.acs.org/OrgLett
Letter
Single C−F Transformations of o‑Hydrosilyl Benzotrifluorides with
Trityl Compounds as All-in-One Reagents
Rika Idogawa, Youngchan Kim, Ken Shimomori, Takamitsu Hosoya, and Suguru Yoshida*
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ABSTRACT: A facile method to prepare difluoromethylenes, including α,α-
difluorobenzyl chlorides, by single C−F transformations of benzotrifluorides
is disclosed. The C−F cleavage followed by chlorination proceeded smoothly
using trityl chloride through the generation of trityl cation as an activator and
chloride anion as a nucleophile. Diverse difluoromethylenes such as
difluorobenzyl ethers were efficiently prepared by virtue of the good
versatility of the resulting chloro and fluorosilyl groups.
rganofluorines are of great significance in a broad range
of disciplines such as materials chemistry, pharmaceut-
O
ical sciences, and chemical biology.1 In particular, difluoro-
methylenes are attractive as bioactive compounds and organic
materials because of the properties affected by the introduction
of fluorine atoms.2−8 In spite of continuous efforts to develop
synthetic methods for difluoromethylenes, synthesizing a broad
range of difluoromethylenes is still challenging because of the
limitation of available building blocks and transformations.2−8
Herein we disclose a practical method for preparing α,α-
difluorobenzyl chlorides as versatile organofluorine building
blocks. This facile synthesis was achieved by single C−F
chlorination of o-hydrosilyl benzotrifluorides with trityl
chloride as an all-in-one reagent for generating trityl cation
as an activator and chloride anion as a nucleophile.
In contrast to benzyl halides as fundamental building blocks
in synthetic organic chemistry, transformations of α,α-
difluorobenzyl halides are still limited because of their poor
accessibility (Figure 1).8 Pioneering works by Yoshida and
coworkers in the 1990s showed potentially versatile trans-
formability of α,α-difluorobenzyl chlorides as electrophiles and
α,α-difluorobenzyl radical precursors, but the synthesis of α,α-
difluorobenzyl chlorides from arenes and bis-
(chlorodifluoroacetyl) peroxide was not easy (Figure 1A).8a
In 2020, Young and coworkers reported that single C−F
functionalization of benzotrifluorides could be achieved using a
frustrated Lewis pair from 2,4,6-triphenylpyridine and a
catalytic amount of tris(pentafluorophenyl)boron and follow-
ing treatment with nucleophiles, including chloride anion
(Figure 1B).6 We independently accomplished single C−F
transformations of benzotrifluorides assisted by activation of an
o-hydrosilyl group with a trityl cation in the presence of
nucleophiles such as allylsilanes.7a We also achieved the
synthesis of an o-fluorosilyl-substituted α,α-difluorobenzyl
chloride in moderate yield by treating an o-hydrosilyl
benzotrifluoride with trityl tetrafluoroborate and a diethyl
ether solution of hydrochloric acid.7a Recently, C−F thiolation
Figure 1. Background and plan of this study. (A) Conventional
methods. (B) Young’s work. (C) This work. (D) Working hypothesis
of this study.
Received: October 23, 2020
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© XXXX American Chemical Society
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A

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of o-hydrosilyl benzotrifluorides was achieved using trityl
sulfides as all-in-one reagents to generate a trityl cation and
thiolate anions activated by ytterbium catalysis.7b Considering
the higher stability of chloride anion compared with thiolates,9
we envisioned that C−F chlorination of o-hydrosilyl
benzotrifluorides would take place with trityl chloride (1a)
through equilibrium generation of trityl cation and chloride
anion without any Lewis acid catalysis (Figure 1C).10 The
generation of trityl cation and chloride anion would trigger
hydride abstraction from benzotrifluoride 2 and fluoride
migration followed by nucleophilic attack of chloride anion
to difluorobenzyl cation II to provide difluorobenzyl chloride 3
(Figure 1D). Since the resulting chloro and fluorosilyl groups
can be transformed to various functional groups, a wide range
of difluoromethylenes can be synthesized from difluorobenzyl
chlorides 3.
As expected, C−F chlorination of o-hydrosilyl benzotri-
fluoride 2a with trityl chloride proceeded without any Lewis
acid catalysis (Table 1).11 We found that the desired o-
Table 1. Optimization of the Reaction Conditions
a
entry
solvent
yield (%)
88
83
62
0
1
2
3
CH2Cl2/HFIP (1:1 v/v)
CH2Cl2/HFIP (19:1 v/v)
CH2Cl2/HFIP (49:1 v/v)
CH2Cl2
4
5
6
HFIP
DMSO
50
0
7
DMF
0
8
CH3NO2
0
9
10
CH2Cl2/TFE (1:1)
PhCl/HFIP (1:1)
10
b
quant. (90 )
a
b
Yields based on 1H NMR analysis. The isolated yield for the
reaction conducted on a 3.0 mmol scale is shown in parentheses.
Figure 2. C−F transformations using trityl compounds. (A) Scope of
C−F transformations using trityl compounds. (B) Absorption spectra
of trityl compounds 1 in CH2Cl2/HFIP (1:1 v/v) at 50 μM (red line,
X = Cl; pink line, X = OTs; orange line, X = Br; green line, X = SCN;
blue line, X = N3; purple line, X = SAr). (C) Absorbance at 408 nm in
CH2Cl2/HFIP (100:0 to 0:100 v/v) at 50 μM. (D) Absorbance at
408 nm in PhCl/HFIP (100:0 to 0:100 v/v) at 50 μM. aData from ref
fluorosilyl-substituted difluorobenzyl chloride 3a was obtained
in good yield when benzotrifluoride 2a was treated with trityl
chloride dissolved in dichloromethane and 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP)12 (1:1 v/v) and that further C−F
transformations of 3a did not occur (entry 1). Decreasing the
amount of HFIP to 5 or 2 vol % slightly reduced the yield of 3a
(entries 2 and 3). On the other hand, no reaction proceeded in
the reaction without HFIP, similar to our previous reports
(entry 4).7 In addition, difluorobenzyl chloride 3a was
prepared in moderate yield when HFIP was solely used as a
solvent (entry 5). Difluorobenzyl chloride 3a was not obtained
when other polar solvents such as DMSO, DMF, and
nitromethane were used (entries 6−8). Furthermore, 2,2,2-
trifluoroethanol (TFE) instead of HFIP slightly facilitated C−
F chlorination (entry 9). Chlorobenzene instead of dichloro-
methane improved the efficiency (entry 10). The good
scalability was demonstrated by a gram-scale synthesis of 3a
in high yield.
b
c
9a. Data from ref 9b. Data from ref 9c.
in high yields without damaging methoxy, methoxycarbonyl,
and bromo groups. The yield of defluorochlorination product
3b was significantly improved from our previous result using
trityl tetrafluoroborate and hydrochloric acid.7a,13 It is
noteworthy that the selective C−F chlorination afforded
difluorobenzyl chlorides 3f and 3g having an unreacted
trifluoromethyl group in good yields. Not only chlorination
but also bromination, tosyloxylation, and thiocyanation
proceeded smoothly without any Lewis acid catalysis.14 It is
noteworthy that various transformations from C−F to C−Cl,
C−Br, C−OTs, and C−SCN were achieved by this simple
procedure using only trityl compounds.
A broad range of fluorosilyl-substituted difluoromethylenes
3b−j were successfully prepared by C−F functionalizations
with trityl compounds (Figure 2A). For example, difluor-
obenzyl chlorides 3b−e were prepared from benzotrifluorides
The generation of trityl cation from trityl compounds 1a and
1d−f was confirmed by absorption spectra in dichloromethane
B
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and HFIP, while a small concentration of trityl cation was
generated from trityl thiolate 1b or trityl azide 1c (Figure 2B).
The cleavabilities of trityl compounds to generate trityl cation
and the corresponding counteranions were attributed to the
stability of the counteranions, which were clearly shown by pKa
values of the conjugate acids.9 The concentration of trityl
cation was increased by increasing the amount of HFIP, and
trityl cation was not detected when only dichloromethane or
chlorobenzene was used (Figure 2C,D).
The C−F chlorination and C−Si bromination sequence
enabled us to prepare a wide variety of o-bromo-substituted
difluorobenzyl chlorides (Figure 3B). For example, not only o-
bromo-α,α-difluorobenzyl chloride (7b) but also 4-anisyl- and
4-(methoxycarbonyl)phenyl-substituted difluorobenzyl chlor-
ides 7c and 7d were efficiently prepared from 3b−d,
respectively. We also synthesized heteroaromatic-substituted
difluorobenzyl chlorides 7e and 7f by C−F chlorination and
C−Si bromination of o-hydrosilyl-substituted benzotrifluorides
in two steps. Electron-deficient 2,5-dibromo-α,α-difluoroben-
zyl chloride (7g) was successfully prepared in good yield. It is
noteworthy that we accomplished the synthesis of difluor-
obenzyl chlorides 7h and 7i bearing a trifluoromethyl group
keeping the difluoromethylene group intact. These results
clearly indicated an advantage of this study since the facile
synthesis of α,α-difluorobenzyl chlorides having a trans-
formable o-bromo group was a challenging issue in the
previous C−F transformations.5,6 Additionally, the preparation
of α-fluorobenzyl chloride 11 was also achieved via C−F
chlorination of the difluoromethyl group of 9 and subsequent
C−Si bromination (Figure 3C).5c,17
Various ortho-functionalized difluorobenzyl chlorides were
synthesized by transformations of the fluorosilyl group (Figure
3A). Indeed, we succeeded in the synthesis of difluorobenzyl
The good transformability of the chloro group enabled the
synthesis of a wide range of difluorobenzyl ethers from
alcohols under basic conditions (Figure 4A). Such ethers are
difficult to prepare by conventional methods because of the
Figure 3. C−F chlorination and C−Si transformations. (A) C−Si
transformations of 3a. (B) Synthesis of o-bromo-substituted
difluorobenzyl chlorides 7. (C) C−F chlorination and C−Si
bromination of 9.
chlorides 4−8 by protonation with wet tetrabutylammonium
fluoride, arylation by palladium-catalyzed Hiyama cross-
coupling with aryl iodide,15 and halogenations with N-
halosuccimides.16 These results clearly show that the single
defluorochlorination of the trifluoromethyl group and
subsequent C−Si transformations based on the good reactivity
of the fluorosilyl group can be used to prepare a broad range of
ortho-substituted difluorobenzyl chlorides.
Figure 4. Transformations of the chloro group. (A) Synthesis of
various difluorobenzyl ethers 12. (B) Radical addition using 7a. aSmI2
was added in two portions. See the Supporting Information for details.
C
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limited accessibility of difluorobenzyl chlorides.8h Indeed,
heating difluorobenzyl chloride 7a possessing a bulky bromo
group at the ortho position with phenol in the presence of
cesium carbonate in DMSO furnished difluorobenzyl ether 12a
in high yield, and no side product formed by C−F cleavage was
observed.18 Difluorobenzyl ethers 12b and 12c were also
prepared from 4- and 2-methoxyphenol, respectively. We also
succeeded in the synthesis of difluorobenzyl ether 12d in
moderate yield leaving the ester moiety untouched. It is
noteworthy that O-benzylation proceeded selectively to
provide 12e when difluorobenzyl chloride 7a was treated
with 2-pyridone, and the N-benzylation product was not
detected. Unfortunately, cyclohexyl difluorobenzyl ether 12f
was not detected in the reaction of 7a with cyclohexanol.
Furthermore, various difluorobenzyl chlorides participated in
the difluorobenzyl ether synthesis. For instance, 4-methox-
yphenyl-substituted difluorobenzyl ether 12g was efficiently
synthesized by O-benzylation of phenol. In addition,
methoxycarbonyl-substituted difluorobenzyl ether 12h was
prepared, albeit in low yield. O-Benzylation of phenol allowed
for the preparation of difluorobenzyl ethers 12i and 12j
possessing heteroaromatic rings. We also accomplished the
synthesis of electron-deficient difluorobenzyl ethers 12k−m
having bromo- and trifluoromethyl groups. The difluorobenzyl
ether synthesis would be useful in pharmaceutical sciences and
agrochemistry since a broad range of benzyl ethers are
bioactive compounds and replacing hydrogen atoms with
fluorines has gained attention as a means to modulate the
properties such as bioactivity, lipophilicity, and stability toward
oxidation.
AUTHOR INFORMATION
Corresponding Author
■
Suguru Yoshida − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Chiyoda-ku, Tokyo 101-
0062, Japan; orcid.org/0000-0001-5888-9330; Email: s-
yoshida.cb@tmd.ac.jp
Authors
Rika Idogawa − Laboratory of Chemical Bioscience, Institute
of Biomaterials and Bioengineering, Tokyo Medical and
Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062,
Japan
Youngchan Kim − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Chiyoda-ku, Tokyo 101-
0062, Japan
Ken Shimomori − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Chiyoda-ku, Tokyo 101-
0062, Japan
Takamitsu Hosoya − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Chiyoda-ku, Tokyo 101-
0062, Japan; orcid.org/0000-0002-7270-351X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03529
Notes
Samarium-mediated reductive radical addition between
difluorobenzyl chloride 7a and styrene (13) realized further
C−C bond formation through difluorobenzyl radical III
(Figure 4B). Indeed, treatment of 7a and 13 with samarium
iodide in the presence of HMPA and TMEDA in methanol
afforded difluoromethylene 14 in good yield without C−F
cleavage or damage to the bromo group.8d Thus, the significant
versatility of difluorobenzyl chlorides allowed us to synthesize a
wide range of organofluorines by not only substitution
reactions but also radical reactions.
In summary, we have developed an efficient method for the
synthesis of α,α-difluorobenzyl chlorides through single C−F
chlorination of benzotrifluorides with trityl chloride assisted by
an o-hydrosilyl group. Equilibrium generation of trityl cation
and chloride anion from trityl chloride facilitated the efficient
C−F chlorination leaving the difluoromethylene group intact,
whereas it is not easy to prepare difluoromethylenes by
previously reported defluorohalogenation methods.10 The
good transformabilities of the chloro and fluorosilyl groups
realized the synthesis of diverse difluorobenzyl ethers having a
transformable o-bromo group. Further studies to expand
synthesizable organofluorines involving the development of
synthetic methods for o-hydrosilyl-substituted benzotrifluor-
ides are ongoing in our group.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Yuki Sakata at Tokyo Medical and
Dental University for HRMS analyses. This work was
supported by JSPS KAKENHI Grants JP19K05451 (C;
S.Y.), JP18H02104 (B; T.H.), and JP18H04386 (Middle
Molecular Strategy; T.H.); the Naito Foundation (S.Y.); the
Japan Agency for Medical Research and Development
(AMED) under Grant JP20am0101098 (Platform Project for
Supporting Drug Discovery and Life Science Research,
BINDS); the Cooperative Research Project of the Research
Center for Biomedical Engineering; and the Research Program
of “Five-Star Alliance” in “Network Joint Research Center for
Materials and Devices”. HRMS analyses were performed using
research equipment shared in MEXT Project for Promoting
Public Utilization of Advanced Research Infrastructure
(Program for Supporting Introduction of the New Sharing
System), Grant JPMXS0422300120.
REFERENCES
■
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320.
(b) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.
2015, 58, 8315.
ASSOCIATED CONTENT
■
(2) Hiyama, T.; Yamamoto, H. Organofluorine Building Blocks. In
Organofluorine Compounds; Yamamoto, H., Ed.; Springer: Berlin,
2000; pp 77−118.
(3) For recent selected examples of difluoromethylene synthesis, see:
(a) Fuchibe, K.; Oki, R.; Hatta, H.; Ichikawa, J. Single C−F Bond
Activation of the CF3 Group with a Lewis Acid: CF3−Cyclopropanes
as Versatile 4,4−Difluorohomoallylating Agents. Chem. - Eur. J. 2018,
24, 17932. (b) Komoda, K.; Iwamoto, R.; Kasumi, M.; Amii, H.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03529.
Experimental procedures and characterization data for
new compounds, including NMR spectra (PDF)
D
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Copper-Promoted Cross-Coupling Reactions for the Synthesis of
Aryl(difluoromethyl)phosphonates Using Trimethylsilyl-
(difluoromethyl)phosphonate. Molecules 2018, 23, 3292. (c) Kawa-
mura, S.; Henderson, C. J.; Aoki, Y.; Sekine, D.; Kobayashi, S.;
Sodeoka, M. Reactivity and properties of bis(chlorodifluoroacetyl)
peroxide generated in situ from chlorodifluoroacetic anhydride for
chlorodifluoromethylation reactions. Chem. Commun. 2018, 54,
11276. (d) Zeng, X.; Yan, W.; Zacate, S. B.; Chao, T.-H.; Sun, X.;
Cao, Z.; Bradford, K. G. E.; Paeth, M.; Tyndall, S. B.; Yang, K.; Kuo,
T.-C.; Cheng, M.-J.; Liu, W. Copper-Catalyzed Decarboxylative
Difluoromethylation. J. Am. Chem. Soc. 2019, 141, 11398. (e) Hisano,
N.; Kimura, D.; Mori, K. Synthesis of Seven-membered Ring
Containing Difluoromethylene Unit by Sc(OTf)3-catalyzed Activation
of Single C−F Bond in CF3 Group. Chem. Lett. 2019, 48, 771.
(f) Meyer, C. F.; Hell, S. M.; Misale, A.; Trabanco, A. A.; Gouverneur,
V. Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid.
Angew. Chem., Int. Ed. 2019, 58, 8829. (g) Tang, L.; Liu, Z.-Y.; She,
W.; Feng, C. Selective single C−F bond arylation of trifluoromethy-
lalkene derivatives. Chem. Sci. 2019, 10, 8701. (h) Miller, E.; Kim, S.;
Gibson, K.; Derrick, J. S.; Toste, F. D. Regio- and Enantioselective
Bromocyclization of Difluoroalkenes as a Strategy to Access
Tetrasubstituted Difluoromethylene-Containing Stereocenters. J.
Am. Chem. Soc. 2020, 142, 8946. (i) Jiang, X.; Meyer, D.; Baran,
omethylaromatics with Unactivated Alkenes. J. Am. Chem. Soc. 2018,
140, 163. (g) Vogt, D. B.; Seath, C. P.; Wang, H.; Jui, N. T. Selective
C−F Functionalization of Unactivated Trifluoromethylarenes. J. Am.
Chem. Soc. 2019, 141, 13203. (h) Luo, C.; Bandar, J. S. Selective
Defluoroallylation of Trifluoromethylarenes. J. Am. Chem. Soc. 2019,
141, 14120.
(6) Mandal, D.; Gupta, R.; Jaiswal, A. K.; Young, R. D. Frustrated
Lewis-Pair-Meditated Selective Single Fluoride Substitution in
Trifluoromethyl Groups. J. Am. Chem. Soc. 2020, 142, 2572.
(7) (a) Yoshida, S.; Shimomori, K.; Kim, Y.; Hosoya, T. Single C−F
Bond Cleavage of Trifluoromethylarenes with an ortho-Silyl Group.
Angew. Chem., Int. Ed. 2016, 55, 10406. (b) Kim, Y.; Kanemoto, K.;
Shimomori, K.; Hosoya, T.; Yoshida, S. Functionalization of a Single
C−F Bond of Trifluoromethylarenes Assisted by an ortho-Silyl Group
Using a Trityl-Based All-in-One Reagent with Ytterbium Triflate
Catalyst. Chem. - Eur. J. 2020, 26, 6136.
(8) (a) Yoshida, M.; Morinaga, Y.; Ueda, M.; Kamigata, N.; Iyoda,
M. Convenient preparation of (chlorodifluoromethyl)arenes. Useful
precursors for aryldifluoromethyl radicals. Chem. Lett. 1992, 21, 227.
(b) Yoshida, M.; Morinaga, Y.; Iyoda, M. Convenient preparation of
difluoromethylene-functionalized compounds from chlorodifluoro-
acetic acid. J. Fluorine Chem. 1994, 68, 33. (c) Yoshida, M.; Suzuki,
D.; Iyoda, M. Reductive conversion of chlorodifluoromethylbenzene
with samarium(II) diiodide. Chem. Lett. 1994, 23, 2357. (d) Yoshida,
M.; Morishima, A.; Suzuki, D.; Iyoda, M.; Aoki, K.; Ikuta, S. One-
electron reductive cleavage of the C−Cl bond of ArCF2Cl: convenient
route for the synthesis of ArCF2 derivatives. Bull. Chem. Soc. Jpn.
1996, 69, 2019. (e) Yoshida, M.; Suzuki, D.; Iyoda, M. Nucleophilic
introduction of fluorinated alkyl groups into aldehydes and ketones
using the corresponding alkyl halide with samarium(II) iodide. J.
Chem. Soc., Perkin Trans. 1 1997, 1, 643. (f) Dolbier, W. R., Jr.; Duan,
J.-X.; Roche, A. J. A Novel, Non-High-Dilution Method for
Preparation of 1,1,2,2,9,9,10,10-Octafluoro[2.2]paracyclophane. Org.
Lett. 2000, 2, 1867. (g) Guidotti, J.; Metz, F.; Tordeux, M.;
Wakselman, C. Preparation of (phenyldifluoromethyl)- and (phenox-
ydifluoromethyl)-silanes by magnesium-promoted carbon-chlorine
bond activation. Synlett 2004, 1759. (h) Guidotti, J.; Schanen, V.;
Tordeux, M.; Wakselman, C. Reactions of (chlorodifluoromethyl)-
benzene and (chlorodifluoromethoxy)benzene with nucleophilic
reagents. J. Fluorine Chem. 2005, 126, 443.
́
́
́
D.; Cortes Gonzalez, M. A.; Szabo, K. J. Trifluoromethylthiolation,
Trifluoromethylation, and Arylation Reactions of Difluoro Enol Silyl
Ethers. J. Org. Chem. 2020, 85, 8311. (j) Liao, L.; An, R.; Li, H.; Xu,
Y.; Wu, J.-J.; Zhao, X. Catalytic Access to Functionalized Allylic gem-
Difluorides via Fluorinative Meyer−Schuster-Like Rearrangement.
Angew. Chem., Int. Ed. 2020, 59, 11010. (k) Xie, Q.; Zhu, Z.; Li, L.;
Ni, C.; Hu, J. Controllable double CF2-insertion into sp2 C−Cu bond
using TMSCF3: a facile access to tetrafluoroethylene-bridged
structures. Chem. Sci. 2020, 11, 276. (l) Cloutier, M.; Mamone, M.;
Paquin, J.-F. Drastic fluorine effect: complete reversal of the selectivity
in the Au-catalyzed hydroalkoxylation reaction of fluorinated
haloalkynes. Chem. Commun. 2020, 56, 5969. (m) Kadri, H.; Taher,
T. E.; Xu, Q.; Sharif, M.; Ashby, E.; Bryan, R. T.; Willcox, B. E.;
Mehellou, Y. Aryloxy Diester Phosphonamidate Prodrugs of
Phosphoantigens (ProPAgens) as Potent Activators of Vγ9/Vδ2 T-
Cell Immune Responses. J. Med. Chem. 2020, 63, 11258. (n) Wang,
W.; Wang, P.; Zhang, Q.; Du, P.; Zhang, J.; Deng, H.; Jiang, H.
Construction of S-CF2/ O-CF2 bonds via inter/intramolecular radical
nucleophilic substitution reaction. Tetrahedron 2020, 76, 131477.
(o) Tarui, A.; Ueo, M.; Morikawa, M.; Tsuta, M.; Iwasaki, S.;
Morishita, N.; Karuo, Y.; Sato, K.; Kawai, K.; Omote, M. One-Pot
Ring-Opening Peptide Synthesis Using α,α-Difluoro-β-Lactams.
Synthesis 2020, 52, 3657. (p) Kikushima, K.; Etou, Y.; Kamura, R.;
Takeda, I.; Ito, H.; Ohashi, M.; Ogoshi, S. Direct Transformation of
Tetrafluoroethylene to Trifluorovinylzinc via sp2 C−F Bond
Activation. Org. Lett. 2020, 22, 8167.
(9) (a) Johnson, E. C. B.; Kent, S. B. H. Insights into the Mechanism
and Catalysis of the Native Chemical Ligation Reaction. J. Am. Chem.
́
Soc. 2006, 128, 6640. (b) Bjerrum, J.; Schwarzenbach, G.; Sillen, L.
G.; Stability Constants; Chemical Society: London, 1958. (c) Smith,
M. B. March’s Advanced Organic Chemistry, 7th ed.; John Wiley &
Sons: Hoboken, NJ, 2012; pp 312−346.
̈
(10) (a) Traff, A. M.; Janjetovic, M.; Ta, L.; Hilmersson, G. Selective
C−F Bond Activation: Substitution of Unactivated Alkyl Fluorides
using YbI3. Angew. Chem., Int. Ed. 2013, 52, 12073. (b) Mizukami, Y.;
Song, Z.; Takahashi, T. Halogen Exchange Reaction of Aliphatic
Fluorine Compounds with Organic Halides as Halogen Source. Org.
(4) (a) Jaroschik, F. Picking One out of Three: Selective Single C−F
Activation in Trifluoromethyl Groups. Chem. - Eur. J. 2018, 24,
14572. (b) Hamel, J.-D.; Paquin, J.-F. Activation of C−F bonds α to
C−C multiple bonds. Chem. Commun. 2018, 54, 10224.
̈
Lett. 2015, 17, 5942. (c) Janjetovic, M.; Ekebergh, A.; Traff, A. M.;
Hilmersson, G. Catalytic Iodination of the Aliphatic C−F Bond by
YbI3(THF)3: Mechanistic Insight and Synthetic Utility. Org. Lett.
2016, 18, 2804. (d) Goh, K. K. K.; Sinha, A.; Fraser, C.; Young, R. D.
Catalytic halodefluorination of aliphatic carbon−fluorine bonds. RSC
Adv. 2016, 6, 42708. (e) Jaiswal, A. K.; Prasad, P. K.; Young, R. D.
Nucleophilic Substitution of Aliphatic Fluorides via PseudohalideIn-
termediates. Chem. - Eur. J. 2019, 25, 6290. (f) Liu, Z.; Tu, X.-S.; Guo,
L.-T.; Wang, X.-C. Aluminum-catalyzed tunable halodefluorination of
trifluoromethyl- and difluoroalkyl-substituted olefins. Chem. Sci. 2020,
11, 11548.
(5) (a) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. A New C−F
Bond-Cleavage Route for the Synthesis of Octafluoro[2.2]-
paracyclophane. J. Org. Chem. 2001, 66, 7216. (b) Dang, H.;
Whittaker, A. M.; Lalic, G. Catalytic activation of a single C−F bond
in trifluoromethyl arenes. Chem. Sci. 2016, 7, 505. (c) Mallov, I.;
Ruddy, A. J.; Zhu, H.; Grimme, S.; Stephan, D. W. C−F Bond
Activation by Silylium Cation/Phosphine Frustrated Lewis Pairs:
Mono-Hydrodefluorination of PhCF3, PhCF2H, and Ph2CF2. Chem. -
Eur. J. 2017, 23, 17692. (d) Munoz, S. B.; Ni, C.; Zhang, Z.; Wang, F.;
Shao, N.; Mathew, T.; Olah, G. A.; Prakash, G. K. S. Selective Late-
Stage Hydrodefluorination of Trifluoromethylarenes: A Facile Access
(11) See the Supporting Information for further examinations to
optimize the reaction conditions.
to Difluoromethylarenes. Eur. J. Org. Chem. 2017, 2322. (e) Chen, K.;
(12) (a) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T.
Fluorine-Directed Nazarov Cyclizations: A Controlled Synthesis of
Cross-Conjugated 2-Cyclopenten-1-ones. J. Org. Chem. 1995, 60,
3
̈
Berg, N.; Gschwind, R.; Konig, B. Selective Single C(sp )−F Bond
Cleavage in Trifluoromethylarenes: Merging Visible-Light Catalysis
with Lewis Acid Activation. J. Am. Chem. Soc. 2017, 139, 18444.
(f) Wang, H.; Jui, N. T. Catalytic Defluoroalkylation of Trifluor-
́
́
2320. (b) Begue, J.-P.; Bonnet-Delpon, D.; Crousse, B. Fluorinated
Alcohols: A New Medium for Selective and Clean Reaction. Synlett
E
https://dx.doi.org/10.1021/acs.orglett.0c03529
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2004, 18. (c) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66,
5775.
(13) The good efficiency of the defluorochlorination using trityl
chloride might be derived from the proximity effect of the nucleophile
as a counteranion and the mild conditions avoiding the presence of
strong Brønsted acid.
(14) Defluorochlorination product 3a was more stable than
defluorobromination product 3h, showing a clear advantage as a
synthetic intermediate.
(15) (a) Hatanaka, Y.; Hiyama, T. Alkenylfluorosilanes as widely
applicable substrates for the palladium-catalyzed coupling of
alkenylsilane/fluoride reagents with alkenyl iodides. J. Org. Chem.
1989, 54, 268. (b) Sore, H. F.; Galloway, W. R. J. D.; Spring, D. R.
Palladium-catalysed cross-coupling of organosilicon reagents. Chem.
Soc. Rev. 2012, 41, 1845. (c) Hirabayashi, K.; Kawashima, J.;
Nishihara, Y.; Mori, A.; Hiyama, T. A New Transformation of
Silanols. Palladium-Catalyzed Cross-Coupling with Organic Halides
in the Presence of Silver(I) Oxide. Org. Lett. 1999, 1, 299.
(16) Su, B.; Hartwig, J. F. Ir-Catalyzed Enantioselective, Intra-
molecular Silylation of Methyl C−H Bonds. J. Am. Chem. Soc. 2017,
139, 12137.
(17) Mandal, D.; Gupta, R.; Young, R. D. Selective Monode-
fluorination and Wittig Functionalization of gem-Difluoromethyl
Groups to Generate Monofluoroalkenes. J. Am. Chem. Soc. 2018,
140, 10682.
(18) Ikeda, M.; Matsuzawa, T.; Morita, T.; Hosoya, T.; Yoshida, S.
Synthesis of Diverse Aromatic Ketones through C−F Cleavage of
Trifluoromethyl Group. Chem. - Eur. J. 2020, 26, 12333.
F
https://dx.doi.org/10.1021/acs.orglett.0c03529
Org. Lett. XXXX, XXX, XXX−XXX