Air- and Light-Stable S-(Difluoromethyl)sulfonium Salts: C-Selective Electrophilic Difluoromethylation of β-Ketoesters and Malonates

Article abstract of DOI:10.1021/acs.orglett.8b03067

Air- and light-stable electrophilic difluoromethylating reagents, S-(difluoromethyl)-S-phenyl-S-(2,4,6-trialkoxyphenyl) sulfonium salts were successfully developed, and the introduction of intramolecular hydrogen bonds plays a crucial role for the stabilities and reactivities of these reagents. C-selective difluoromethylation of a broad range of β-ketoesters and malonates proceeded smoothly under mild reaction conditions to give good to excellent yields with excellent C/O regioselectivities.

Full text of DOI:10.1021/acs.orglett.8b03067

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Air- and Light-Stable S‑(Difluoromethyl)sulfonium Salts: C‑Selective
Electrophilic Difluoromethylation of β‑Ketoesters and Malonates
Sheng-Le Lu,∇,† Xin Li,∇,† Wen-Bing Qin,† Jian-Jian Liu,† Yi-Yong Huang,‡ Henry N. C. Wong,§
and Guo-Kai Liu*,†
†School of Pharmaceutical Sciences, Shenzhen University Health Science Center, 3688 Nanhai Ave., Shenzhen 518060, China
‡Department of Chemistry, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan
430070, China
§Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
S
* Supporting Information
ABSTRACT: Air- and light-stable electrophilic difluoromethylating reagents, S-(difluoromethyl)-S-phenyl-S-(2,4,6-trialkox-
yphenyl) sulfonium salts were successfully developed, and the introduction of intramolecular hydrogen bonds plays a crucial
role for the stabilities and reactivities of these reagents. C-selective difluoromethylation of a broad range of β-ketoesters and
malonates proceeded smoothly under mild reaction conditions to give good to excellent yields with excellent C/O
regioselectivities.
he difluoromethyl group (CF2H) is a key structural motif
Later on, the same group published difluoromethylation of
N-, S-, and P-nucleophiles with the Johnson-type difluor-
omethylating reagent (B in Figure 1),3b which was formed in
situ, because of its rapid decomposition. Xiao et al. reported a
modified S-(difluoromethyl)diarylsulfonium salt for O-difluor-
omethylation of 1,3-diketones.9 Recently, Akita has also
demonstrated another modified S-(difluoromethyl)-
diarylsulfonium salt for the amino-difluoromethylation of
aromatic alkenes in moderate yields via a radical pathway by
using visible-light photoredox catalysis.10 Hu and co-workers
synthesized the α-difluoromethyl sulfoximine (C in Figure 1)
as a difluorocarbene precursor for difluoromethylation of S-
and N-nucleophiles,3c along with limited scope of Csp-centered
nucleophiles. In 2016, the Shen group reported a difluor-
omethyl-(4-nitrophenyl)-bis(carbomethoxy) methylide sulfo-
nium ylide (D in Figure 1) as a direct electrophilic
difluoromethylating reagent for the difluoromethylation of
alcohols,3d whereas 2.0 equiv of alcohols was required.
T
in pharmaceuticals, agrochemicals, and materials.1 There-
fore, the introduction of a CF2H group into common organic
molecules represents a significant synthetic goal. Among all
existing strategies for the synthesis of difluoromethylated
compounds, the electrophilic approach is one of the most
powerful tools for incorporation of the CF2H unit into the
electron-rich sites of organic molecules. In past decades, many
difluorocarbene precursors have been developed.2,3c,5b,c
However, few direct electrophilic difluoromethylating reagents
were recorded (see Figure 1),3 although several functionalized
Figure 1. Electrophilic difluoromethylating reagents.
In sharp contrast to the extensively investigated electrophilic
trifluoromethylation reactions, the electrophilic difluoromethy-
lation is still quite underdeveloped, possibly because of the lack
of suitable electrophilic difluoromethylating reagents for
transferring a CF2H group to a wide variety of nucleophiles,
particularly C-nucleophiles. For example, compared to the
electrohilic difluoromethylating reagents were reported.4−8
Prakash and co-workers first disclosed that an S-difluorometh-
yl-S-phenyl-S-(2,3,4,5-tetramethylphenyl) sulfonium reagent
(see A in Figure 1) is effective for transferring a CF2H
group into various N-, S-, and P-nucleophiles.3a However, A is
a very unstable semisolid and is not suitable for the
difluoromethylation of carbon nucleophiles and phenols.
Received: September 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03067
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
exclusively C-regioselective trifluoromethylation of β-ketoest-
ers,11 difluoromethylation of β-ketoesters normally gave poor
to moderate C/O regioselectivities, as reported by the Shibata
group (see Schemes 1a and 1b).5b,12 During preparation of this
Table 1. Design and Synthesis of Bench-Stable Electrophilic
Difluoromethylating Reagents (1)
a
Scheme 1. Regioselective Electrophilic Difluoromethylation
of β-Ketoesters
1
R
R′
X
yield (%)
1a
1b
1c
1d
1e
H
H
H
p-Br
p-MeO
Me
Et
Me
Me
Me
BF4
BF4
PF6
BF4
BF4
86
66
82
55
82
b
a
b
For details, see the Supporting Information. Proceeded at −20 °C.
even after keeping it on the bench for six months at ambient
temperature.
With these bench-stable reagents in hand, their reactivities
were initially evaluated by difluoromethylation of β-ketoesters
(see Table 2), and methyl tetralone carboxylate 2aa was
employed as a model substrate. The reaction proceeded
smoothly at room temperature in THF by using NaH as a base.
Interestingly, the C−CF2H product 3aa was predominantly
a
Table 2. Survey of Reaction Conditions
manuscript, the same group described another protocol
affording an enhanced C/O regioselectivity (see Scheme
1c).13 Therefore, the development of more-stable, more-
reactive, and more-versatile electrophilic difluoromethylating
reagents is still highly in demand. Herein, we disclose new
difluoromethylating reagents, namely S-difluoromethyl-S-phe-
nyl-S-(2,4,6-trialkoxyphenyl) sulfonium salts 1. They have
proven to be very stable and are capable of transferring a CF2H
group into the tertiary carbon center of β-ketoesters and
malonates in good to excellent yields with excellent C/O
regioselectivities (see Scheme 1d).
3aa/4aa
entry
1
base (equiv)
solvent
THF
THF
THF
yield (%)
ratio
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
NaH (1.2)
Et3N (1.2)
DBU (1.2)
Cs2CO3 (1.2) THF
KOH (1.2)
LiOH (1.2)
56
NR
NR
28
26
54
40
45
43
46
59
67
68
72
88
74
83
95:5
88:12
80:20
95:5
85:15
90:10
86:14
87:13
95:5
94:6
94:6
94:6
94:6
THF
THF
THF
THF
THF
THF
THF
THF
The investigation commenced with the design and synthesis
of new electrophilic difluoromethylating reagents. At present,
the existing electrophilic difluoromethylating reagents have
many drawbacks, such as instability, unsatisfactory reactivity,
and relatively hard-acid character, leading to limited substrate
scope. The principal task is to solve the stability problem of the
reagents, which probably results from the acidity and high
1b NaH (1.2)
1c NaH (1.2)
1d NaH (1.2)
9
10
11
12
1e
1a
1a
1a
1a
1a
1a
1a
1a
1a
NaH (1.2)
NaH (1.5)
NaH (2.2)
NaH (2.2)
NaH (2.2)
NaH (2.2)
NaH (2.2)
NaH (2.2)
NaH (2.2)
LiOH (2.2)
b
13
THF
+
electrophilicity of the CF2H moiety. Apart from introducing
14
15
16
17
18
19
CH3CN
toluene
p-xylene
chlorobenzene
fluorobenzene
fluorobenzene
electron-donating groups, we thought that we could modulate
its acidity and electropositivity via an intramolecular hydrogen
bond at the +CF2H unit. With this in mind, reagents 1
containing a 2,4,6-trialkoxyphenyl group were designed, and
readily synthesized from difluoromethylsulfoxides and 1,3,5-
trialkoxybenzenes in good yields (66%−86%) as a white
crystalline powder in up to 20-g scale (see Table 1). The
nonclassical intramolecular hydrogen bond between the H
atom in the CF2H unit and the O atom in the ortho-methoxy
substituent of the aryl moiety were confirmed by a single-
crystal X-ray crystallographic analysis. Compound 1a was
found to be very stable, and no decomposition was observed
95:5
97:3
97:3
97:3
c
93(86)
94(87)
c
a
Reaction conditions (unless otherwise specified): 2aa (0.1 mmol),
base, 1a (1.2 mmol, 1.2 equiv), fluorobenzene (1.0 mL), rt, 20 min.
Yields and the ratio of 3aa/4aa were determined by 19F NMR
spectroscopy with p-chlorofluorobenzene as an internal standard.
b
c
The reaction was allowed to proceed at 0 °C. Yields of isolated
products are given in parentheses.
B
DOI: 10.1021/acs.orglett.8b03067
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Organic Letters
Letter
obtained in 56% yield with only a trace of O-CF2H product
4aa, as can be substantiated by 19F NMR spectral analysis
(entry 1 in Table 2). Encouraged by this result, we further
examined a variety of common bases, including Et3N, DBU,
Cs2CO3, and KOH. The organic bases were ineffective for this
reaction (entries 2 and 3 in Table 2), while KOH and Cs2CO3
gave lower yields and poor C/O regioselectivities (entries 4
and 5 in Table 2). LiOH was also identified as a potentially
appropriate base (entry 6 in Table 2). The screening of
reagents 1b−1e did not give better results (entries 7−10 in
Table 2). The yields were slightly improved to 59% and 67%
with a similar level of C/O regioselectivity when 1.5 and 2.2
equiv of NaH were used, respectively (see entries 11 and 12 in
Table 2). Decreasing the reaction temperature to 0 °C did not
obviously improve the yield and C/O regioselectivity (see
entry 13 in Table 2). The yield was dramatically increased to
88% without any loss of C/O regioselectivity, using toluene as
a solvent (entry 15 in Table 2). Screening of other arene
solvents indicated that fluorobenzene was the best choice,
affording 93% yield with a C/O ratio of 97:3 (entry 18 in Table
2). The use of LiOH instead of NaH gave a similar result
(94%, 97:3 C/O regioselectivity) (see entry 19 in Table 2).
Under the optimized reaction conditions (entries 18 and 19
in Table 2), the scope of β-ketoesters 2 (Scheme 2) was
explored. A broad range of tetralone and indanone carboxylates
were smoothly transferred into the corresponding C-selective
CF2H products 3aa−3an, 3ba−3bn containing a quaternary
carbon center in good to excellent yields (up to 87%). Notably,
this reaction was not sensitive to the electronic nature and
position of the substituents on the phenyl ring of the methyl
carboxylates (3aa−3aj, 3ba−3bi). Moreover, a wide variety of
alkyl indanone and tetralone carboxylates also readily under-
went a reaction to furnish 3bj−3bn and 3ak and 3al in high
yields (up to 84%) with high C/O regioselectivies (up to 97:3).
The heterocycloketoesters 2am and 2an were also compatible,
providing 3am and 3an in 86% and 53% yields, respectively,
with a C/O regioselectivity of 97:3. β-Ketoesters containing
cycloheptanone and cyclooctanone moieties proved to be
suitable in this reaction, offering 3c, 3e, and 3f in 84%, 85%,
and 68% yields, respectively, with high C/O regioselectivities
(up to >99:1). Benzyl 2-oxocyclopentanecarboxylate 2d was
also converted to 3d in 56% yield with a C/O regioselectivity
of 95:5. Remarkably, the usually less-reactive acyclic β-
ketoesters 2g−2l were also tolerated, producing C-CF2H
products 3g−3l in good yields (60%−70%) without any
influence on the C/O-regioselectivities. The current process
was readily scalable, as demonstrated by the gram-scale
synthesis of 3aa (85% yield) under the standard reaction
conditions.
Scheme 2. Electrophilic C-Selective Difluoromethylation of
β-Ketoesters and Malonates
a
a
Reaction conditions (unless otherwise specified): 2 or 5 (0.2 mmol,
1.0 equiv), base (2.2 mmol, 2.2 equiv), 1a (1.2 mmol, 1.2 equiv),
fluorobenzene (2.0 mL), rt, 20 min. Yields are for the isolated C-
selective products 3 or 6, and C/O-regioisomeric ratio was
In order to highlight the synthetic utility of this process,
some pharmaceutically important heterocyclic compounds 3p
and 3q were delivered in 83% and 95% yields, respectively,
with distinguished C/O regioselectivities (>99:1), and 3m, 3n
and 3o were obtained in yields of 72%, 72%, and 73%,
respectively, with high C/O regioselectivities (up to 96:4).
Further applications of 1a in a direct C-difluoromethylation for
malonates were also evaluated under the standard conditions.
A variety of monoaryl and arylalkyl-substituted malonates 5a−
5j were successfully transferred to the corresponding C-CF2H
products 6a−6j bearing a quaternary carbon center in high to
excellent yields (72%−94%). Notably, malonates exhibited
much more predominant C/O regioselectivities than β-
b
determined by 19F NMR spectroscopy. LiOH was used as a base.
cNaH was used as a base. dGram-scale synthesis of 3aa. Me = methyl,
Et = ethyl, i-Pr = i-propyl, Bn = benzyl, Ph = phenyl.
ketoesters, and all selected cases showed C/O regioselectivities
of >99:1.
Although the reason for such excellent C/O regioselectivity
is still unclear in the difluoromethyaltion of β-ketoesters and
malonates, the intramolecular hydrogen bond and electron-
donating effect of the 2,4,6-trialkoxyphenyl group in reagents 1
should play a key role in decreasing the electrophilicity of the
sulfonium salts, which may render reagent 1 to become a soft
C
DOI: 10.1021/acs.orglett.8b03067
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electrophilic difluoromethylating reagent, therefore orientating
its reactivity toward C-nucleophiles to achieve a high C/O
regioselectivity. Moreover, the substituents in the aryl sulfoxide
can also adjust the reactivity of the final reagents.
Scheme 4. Control Experiments and Plausible Reaction
Mechanism for the Difluoromethylation of β-Ketoesters by
1a
In addition, the asymmetric difluoromethylation of β-
ketoesters was also surveyed. No enantioselectivity and low
yields were obtained under the same and modified conditions
as that of asymmetric trifluoromethylation by Gade et al. (with
Cu II/ligands; for details, see Table S2 in the Supporting
Information (SI)). Furthermore, cinchona alkaloids were
employed for this asymmetric transformation. After exhaustive
optimization, no satisfactory enantiomeric excess (ee) was
achieved (up to 26% ee; for details, see Table S3 in the SI).
Therefore, the asymmetric difluoromethylation of β-ketoesters
remains challenging, and further investigation is required.
The synthetic application of the C-CF2H product 3aa was
further demonstrated (see Scheme 3). Thus, compounds 7 and
Scheme 3. Synthetic Utilization of 3aa
8 were obtained via LiAlH4 and Et3SiH/TFA reduction in 73%
and 75% yields, respectively. Most importantly, the highly
efficient cyclization of 3aa and hydrazine offered fused-
heterocyclic molecule 9 in 75% yield, which is of potential
pharmaceutical interest.14
Mechanistically, both direct nucleophilic substitution and
difluorocarbene pathways are possible during the difluorome-
thylation of 2 with 1. To gain insight into the reaction
mechanism, some control experiments were performed (see
Scheme 4). The use of a deuterium-labeled reagent [D]-1a
gave a higher yield of nondeuterated product 3aa than
deuterated product [D]-3aa (Scheme 4a). In addition, when
tetramethylethylene was injected into the reaction system of
2aa and 1a (see Scheme 4b), difluorocarbene intermediate was
trapped to form 3,3-difluoro-1,1,2,2,-tetramethylcyclopropane
in 30% yield. Furthermore, no deuterated product was
detected when deuterated toluene was used as solvent (see
Scheme 4c). These results clearly suggest that the difluor-
ocarbene pathway of the capturing proton from substrate 2 to
produce nondeuterated product is predominant (see Pathway
A in Scheme 4d). The proposed mechanism starts with the
deprotonation of 2 by a base to generate a nucleophile (Nu−),
1. An intramolecular hydrogen bond interaction and electronic
effect are both essential in the design of 1. When 1 were
allowed to react with a wide variety of β-ketoesters and
malonates, C-CF2H products bearing quaternary carbon
centers were predominantly accessed in good to excellent
yields (up to 95%, and a C/O ratio of >99:1) under mild
reaction conditions. Control experiments revealed that this
difluoromethylation reaction mainly involves a difluorocarbene
intermediate. Further investigations of reagents 1 toward other
types of nucleophiles are underway in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03067.
−
which combines with CF2 to afford an anion (Nu-CF2 ). A
difluorocarbene intermediate can be formed in situ from 1 and
a base, or Nu-CF2− (see pathway B in Scheme 4d). Finally, the
anion Nu-CF2− abstracts a proton from substrate 2, along with
the production of a new Nu− (see pathway A in Scheme 4d),
or captures a proton from reagent 1 (see pathway B in Scheme
4d) to give the target compound. However, the direct
nucleophilic attack pathway could not be completely ruled
out (see pathway C in Scheme 4d).
Detailed experimental procedures, characterization data,
1H, 13C, 19F NMR spectra, and HRMS (PDF)
Accession Codes
CCDC 1860007 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.
In conclusion, we have successfully obtained bench-stable
and easy-to-handle electrophilic difluoromethylating reagents
D
DOI: 10.1021/acs.orglett.8b03067
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
F.; Hu, J. Org. Lett. 2009, 11, 2109. (d) Zhu, J.; Liu, Y.; Shen, Q.
Angew. Chem., Int. Ed. 2016, 55, 9050.
(4) Zhang, C.; Cao, H.; Wang, Z.; Zhang, C.; Chen, Q.; Xiao, J.
Synlett 2010, 2010, 1089.
(5) (a) Liu, G.; Mori, S.; Wang, X.; Noritake, S.; Tokunaga, E.;
Shibata, N. New J. Chem. 2012, 36, 1769. (b) Liu, G.; Wang, X.; Lu,
X.; Xu, X.-H.; Tokunaga, E.; Shibata, N. ChemistryOpen 2012, 1, 227.
(c) Liu, G.; Wang, X.; Xu, X.-H.; Lu, X.; Tokunaga, E.; Tsuzuki, S.;
Shibata, N. Org. Lett. 2013, 15, 1044.
(6) (a) Zhang, W.; Zhu, J.; Hu, J. Tetrahedron Lett. 2008, 49, 5006.
(b) He, Z.; Luo, T.; Hu, M.; Cao, Y.; Hu, J. Angew. Chem., Int. Ed.
2012, 51, 3944. (c) He, Z.; Hu, M.; Luo, T.; Li, L.; Hu, J. Angew.
Chem., Int. Ed. 2012, 51, 11545.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gkliu@szu.edu.cn.
ORCID
Yi-Yong Huang: 0000-0001-6209-8304
Henry N. C. Wong: 0000-0002-3763-3085
Guo-Kai Liu: 0000-0001-7617-4267
Author Contributions
∇These authors contributed equally.
Notes
(7) Wang, X.; Liu, G.; Xu, X.-H.; Shibata, N.; Tokunaga, E.; Shibata,
N. Angew. Chem., Int. Ed. 2014, 53, 1827.
The authors declare no competing financial interest.
́
(8) (a) Urban, C.; Mace, Y.; Cadoret, F.; Blazejewski, J. C.; Magnier,
E. Adv. Synth. Catal. 2010, 352, 2805. (b) Urban, C.; Cadoret, F.;
ACKNOWLEDGMENTS
Blazejewski, J. C.; Magnier, E. Eur. J. Org. Chem. 2011, 2011, 4862.
■
́
(c) Mace, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2012, 2479.
This research was financially supported by the Science and
Technology Foundation of Shenzhen, Shenzhen Science and
T e c h n o l o g y I n n o v a t i o n C o m m i t t e e ( N o s .
JCYJ20160308110354332, JCYJ20170818143001461), and
the Natural Science Foundation of Guangdong Province
(No. 2015A030310285). We thank Prof. Yu-Dong Yang
(Sichuan University) for helpful discussions.
(9) Yue, C.-B.; Lin, J.-H.; Cai, J.; Zhang, C.-P.; Zhao, G.; Xiao, J.-C.;
Li, H. RSC Adv. 2016, 6, 35705.
(10) Noto, N.; Koike, T.; Akita, M. Chem. Sci. 2017, 8, 6375.
(11) For α-carbon trifluoromethylation of β-ketoesters, see:
(a) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156.
(b) Ma, J.-A.; Cahard, D. J. Org. Chem. 2003, 68, 8726.
(c) Eisenberger, P.; Gischig, S.; Togni, A. Chem. - Eur. J. 2006, 12,
2579. (d) Petrik, V.; Cahard, D. Tetrahedron Lett. 2007, 48, 3327.
(e) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007,
46, 754. (f) Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro,
M. Eur. J. Org. Chem. 2008, 2008, 3465. (g) Noritake, S.; Shibata, N.;
Nomura, Y.; Huang, Y.; Matsnev, A.; Nakamura, S.; Toru, T.; Cahard,
D. Org. Biomol. Chem. 2009, 7, 3599. (h) Matsnev, A.; Noritake, S.;
Nomura, Y.; Tokunaga, E.; Nakamura, S.; Shibata, N. Angew. Chem.,
Int. Ed. 2010, 49, 572. (i) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. J.
Am. Chem. Soc. 2012, 134, 10769. (j) Le, T.-N.; Kolodziej, E.; Diter,
REFERENCES
■
́
́
(1) (a) Perez, R. A.; Sanchez-Brunete, C.; Miguel, E.; Tadeo, J. L. J.
Agric. Food Chem. 1998, 46, 1864. (b) Mu
̈
ller, K.; Faeh, C.; Diederich,
F. Science 2007, 317, 1881. (c) Jeschke, P.; Baston, E.; Leroux, F. R.
Mini-Rev. Med. Chem. 2007, 7, 1027 and references therein .
(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (e) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (f) Ojima, I.
Fluorine in Medicinal Chemistry and Chemical Biology; Blackwell:
Oxford, U.K., 2009. (g) Meanwell, N. A. J. Med. Chem. 2011, 54,
2529. (h) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications, 2nd Edition; Wiley−VCH: Weinheim,
́
P.; Pegot, B.; Bournaud, C.; Toffano, M.; Guilot, R.; Vo-Thanh, G.;
Magnier, E. Chimia 2014, 68, 410. (k) Liu, Y.; Shao, X.; Zhang, P.;
Lu, L.; Shen, Q. Org. Lett. 2015, 17, 2752. (l) Saidalimu, I.; Tokunaga,
́
E.; Shibata, N. ACS Catal. 2015, 5, 4668. (m) WoZniak, Ł.; Murphy,
́
́
Germany, 2013. (i) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del
̃
J. J.; Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 5678. (n) Umemoto,
T.; Zhang, B.; Zhu, T.; Zhou, X.; Zhang, P.; Hu, S.; Li, Y. J. Org.
Chem. 2017, 82, 7708.
(12) Yang, Y.; Lu, X.; Liu, G.; Tokunaga, E.; Tsuzuki, S.; Shibata, N.
ChemistryOpen 2012, 1, 221.
(13) Wang, J.; Tokunaga, E.; Shibata, N. Chem. Commun. 2018, 54,
8881.
Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2014, 114, 2432. (j) New Fluorinated Carbons:
Fundamentals and Applications; Boltalina, O. V., Nakajima, T., Eds.;
Elsevier: Amsterdam, 2016. (k) Zafrani, Y.; Yeffet, D.; Sod-Moriah,
G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. J.
Med. Chem. 2017, 60, 797.
(2) For difluorocarbene reagents, see: (a) Birchall, J. M.; Cross, G.
E.; Haszeldine, R. N. Proc. Chem. Soc. London 1960, 81. (b) Wheaton,
G. A.; Burton, D. J. J. Fluorine Chem. 1976, 8, 97. (c) Chen, Q.; Zhu,
S. Sci. Sin., Ser. B (Engl. Ed.) 1986, 30, 561. (d) Chen, Q.; Wu, S. J.
Org. Chem. 1989, 54, 3023. (e) Tian, F.; Kruger, V.; Bautista, O.;
Duan, J.-X.; Li, A.-R.; Dolbier, W. R., Jr.; Chen, Q.-Y. Org. Lett. 2000,
2, 563. (f) Zhang, L.; Zheng, J.; Hu, J. J. Org. Chem. 2006, 71, 9845.
(g) Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J.
Chem. Commun. 2007, 5149. (h) Zafrani, Y.; Sod-Moriah, G.; Segall,
Y. Tetrahedron 2009, 65, 5278. (i) Oshiro, K.; Morimoto, Y.; Amii, H.
Synthesis 2010, 2010, 2080. (j) Wang, F.; Zhang, W.; Zhu, J.; Li, H.;
Huang, K.-W.; Hu, J. Chem. Commun. 2011, 47, 2411. (k) Wang, F.;
Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.;
Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 2011, 50, 7153.
(l) Wang, F.; Huang, W.; Hu, J. Chin. J. Chem. 2011, 29, 2717.
(m) Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 2092.
(n) Thomoson, C. S.; Dolbier, W. R., Jr. J. Org. Chem. 2013, 78, 8904.
(o) Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Chem. - Eur. J. 2013, 19,
15261. (p) Feng, Z.; Min, Q.-Q.; Fu, X.-P.; An, L.; Zhang, X. Nat.
Chem. 2017, 9, 918.
(14) (a) Brullo, C.; Rocca, M.; Fossa, P.; Cichero, E.; Barocelli, E.;
Ballabeni, V.; Flammini, L.; Giorgio, C.; Saccani, F.; Domenichini, G.;
Bruno, O. Bioorg. Med. Chem. Lett. 2012, 22, 1125. (b) Mawdsley, E.
A.; Berlin, K. D.; Chesnut, R. W.; Durham, N N. J. Med. Chem. 1976,
19, 239.
(3) For direct electrophilic difluoromethylating reagents, see:
(a) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863. (b) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.;
Olah, G. A. J. Fluorine Chem. 2011, 132, 792. (c) Zhang, W.; Wang,
E
DOI: 10.1021/acs.orglett.8b03067
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