Catalytic AgF-Initiated Intramolecular 1,3-Sulfonyl Migration of gem-Difluorovinyl Sulfonates to α,α-Difluoro-β-ketosulfones

Article abstract of DOI:10.1021/acs.orglett.0c03492

A 1,3-sulfonyl migration of difluorovinyl sulfonates initiated by a catalytic amount of silver fluoride is presented. α,α-Difluoro-β-ketosulfones were successfully prepared in excellent yields. This method features high chemoselectivity, good functional group tolerance, high atom economy, and mild, environmentally benign reaction conditions. Furthermore, mechanistic experiments indicate that this migration proceeds in an intermolecular pathway and the corresponding sulfinates are possible intermediates.

Full text of DOI:10.1021/acs.orglett.0c03492

pubs.acs.org/OrgLett
Letter
Catalytic AgF-Initiated Intramolecular 1,3-Sulfonyl Migration of
gem-Difluorovinyl Sulfonates to α,α-Difluoro-β-ketosulfones
Baojian Xiong, Lei Chen, Jie Xu, Haotian Sun, Xiong Li, Yue Li, and Zhong Lian*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03492
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A 1,3-sulfonyl migration of difluorovinyl sulfonates initiated by a catalytic
amount of silver fluoride is presented. α,α-Difluoro-β-ketosulfones were successfully
prepared in excellent yields. This method features high chemoselectivity, good functional
group tolerance, high atom economy, and mild, environmentally benign reaction
conditions. Furthermore, mechanistic experiments indicate that this migration proceeds
in an intermolecular pathway and the corresponding sulfinates are possible intermediates.
rganic sulfones have been widely used as protecting
groups or activating groups in organic synthesis, offering
O
substantial synthetic versatility,1 and thus play an important
role in synthetic chemistry. In particular, β-ketosulfone
derivatives have drawn considerable interest owing to the
presence of this moiety in broad biologically active compounds
or functional materials.2 Substantial efforts have been made on
the development for the synthesis of β-ketosulfone com-
pounds, such as acylation of alkyl sulfones,3 oxidation of β-
ketosulfides/β-hydroxysulfones,4 and alkylation of metallic aryl
sulfinates.5 However, these approaches require strong bases or
harsh reaction conditions along with poor functional group
tolerance. In recent years, radical sulfonylation has also been
developed as a useful approach to β-ketosulfone derivatives,
involving the addition of sulfonyl radicals to alkenes/alkynes,6
while external oxidants and a large excess amount of
sulfonylation reagents are generally required in these reports.
Recently, sulfonyl migrations have garnered significant
attention due to their potential applications in highly
functionalized heterocycles.7 Compared with the representa-
tive protocols described above, the synthesis of β-ketosulfone
derivatives via sulfonyl migrations is extremely rare: (1) In
2017, Li’s group reported a photoinduced rearrangement of
vinyl sulfonates to β-ketosulfones;8 (2) Feng et al. reported an
iridium-catalyzed visible-light-promoted sulfonyl migrations for
the construction of α-sulfonylated amides9 (Figure 1a).
On the other hand, the difluoromethyl moiety acting as an
exceptional structure in pharmaceuticals10 has received
increasing attention due to its unique physicochemical
properties.11 α-Functionalized fluorinated sulfones proved to
be of important value in organic synthesis12 and could be the
subject of a series of transformations.13 Therefore, developing
an efficient and practical protocol for the synthesis of
ketosulfone derivatives containing a difluoromethyl moiety is
of great significance. However, so far, there are few reports for
the preparation of these derivatives. The substitution of β-
ketosulfones with electrophilic fluorination reagents under
basic conditions provides a direct pathway to synthesize α,α-
Figure 1. Oxygen to carbon 1,3-sulfonyl migration and synthesis of α,
α-difluoro-β-ketosulfones.
Received: October 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03492
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
difluoro-β-ketosulfones, but this method generally suffers from
the monofluorinated products along with low yields of
difluorinated products and limited substrate scope.14 In
2009, Hu et al. reported nucleophilic fluoroalkylation of esters
to synthesize fluorinated β-ketosulfones.15 In 2020, Wu et al.
reported a photocatalyzed three-component sulfonylation of
aryldiazonium tetrafluoroborates with sodium metabisulfite
and 2,2-difluoro enol silyl ethers.16 Owing to the harsh
conditions and the poor accessibility of starting materials, these
approaches are confronted with limited functional group
tolerance (Figure 1b).
Based on a serendipitous discovery, we found a 1,3-sulfonyl
migration (from oxygen to carbon) of difluorovinyl sulfonates
to α,α-difluoro-β-ketosulfones initiated by a catalytic amount
of AgF (Figure 1c). Advantages of this method include high
atom-economy, broad substrate scope, excellent yields, and
mild reaction conditions. Notably, this method can be applied
to the facile preparation of derivatives of natural products and
bioactive compounds, which are challenging for the reported
methods.14−16
Our study began by evaluating the intramolecular migration
of 1a. As for the synthesis of the starting material 1a, there are
two reported methods to achieve it. One way is initiated from
commercially available benzaldehyde, treated with the
trifluoromethylation of aldehyde, sulfonylation of benzyl
alcohol and HF elimination under basic conditions to generate
1a.17 The alternative pathway to form 1a is the palladium-
catalyzed cross-coupling reaction between iodobenzene and
2,2-difluoro-1-(tributylstannyl)vinyl 4-methylbenzenesulfo-
nate.18 After screening with different fluoride sources, we
found that the corresponding product α,α-difluoro-β-ketosul-
fone (2a) could be isolated in an excellent yield (93% yield)
under the condition using AgF (10 mol %) as a reaction
promotor, MeCN as solvent at 60 °C (Table 1, entry 1). The
structure of 2a was confirmed by X-ray crystallography. Using
other fluoride sources such as CsF and KF resulted in lower
yields, and after 20 h part of the starting material (1a) was
recovered (entries 2 and 3). In addition, the use of LiF and
CuF2 afforded none of the desired product (entries 4 and 5).
Different solvents were tested, and we found that acetone,
DMF, and DMA led to slightly decreased yields (entries 7−9).
Replacing MeCN with DMSO led to a significantly decreased
yield of 2a (entry 10). The reaction carried out in DCE or
H2O did not work, and the starting material (1a) was
recovered (entries 11 and 12). Further investigation of the
reaction temperature indicated that half of 1a remained
unreacted after 20 h when decreasing the temperature to 40
°C (entry 13), while increasing the temperature to 80 °C
caused a slight decrease in the yield (entry 14). Control
experiments indicated AgF is essential for this transformation
(entry 15).
After establishing the optimized reaction conditions, we
turned to evaluate the substrate scope of this transformation.
Various substituted sulfonyl (Ar1 group) difluorostyrenes were
transformed smoothly. As shown in Scheme 1, the
difluorovinyl sulfones bearing a phenyl or an alkylbenzene
group afforded the sulfonyl migration products in excellent
yields (2b−2e). However, a lower yield was obtained for 2f
with a methyl group at the ortho position, which might be
caused by the hindrance effect. Naphthalene and biphenyl
derivatives delivered the desired products (2g−2i) in 80−96%
yields. Notably, the halide (fluoride, chloride, bromide, and
iodide) substituted substrates all led to clean formation of the
corresponding products in high yields (2j−2n, 73−98%).
Examination of electron-deficient substrates revealed that
ketone and ester moieties could be tolerated (2o−2p). In
addition, MeO- and Me2N-substituted difluorovinyl sulfones
(2q−2s) were obtained in 52−91% yields under the standard
conditions, and the substrate utilizing dihydrobenzofuran as a
substituent produced 2t in 90% yield.
a
Table 1. Optimization of the Reaction Conditions
Next, we studied the influence of the substitution of Ar2
group. Excellent yields were obtained when substrates
contained alkyl groups (2u−2w) as well as naphthalene and
biphenyl derivatives (2x−2y). Electron-rich substrates such as
difluorovinyl sulfones bearing a MeO, EtO, PhO, or morpho-
line group were found to be highly effective in this protocol
(2z−2ac). In addition, substrates (1ad−1ae) with an OTs or
OCF3 group were also well-tolerated. We then tested the
compatibility with unprotected phenol groups and obtained
2af in 77% yield. Interestingly, the ability to tolerate a diverse
set of aryl halides (2ag−2aj) left enough room for subsequent
manipulation. The presence of electron-poor groups also
appeared to be suitable substrate in this reaction (2ak−2ao),
although the CN group seemed less effective (2am).
Furthermore, we turned our attention to investigate the
scope of substrates with a range of heterocycles, and high
yields were obtained for the derivatives containing indole,
quinoline, and thiophene moieties (2ap−2at).
Encouraged by these results, we intended to extend this
approach to small complex molecules containing natural
products or druglike scaffolds. L-(−)-Menthol derivative
worked efficiently, giving 2au in 80% yield. Substrates derived
from amino acids such as L-phenylalanine and D-proline could
be transformed with high efficiency in this protocol (2av−
2ax). The utility of the method was also demonstrated by a
late-stage functionalization of tocopherol, fructose, and
pregnenolone derivatives (2ay−2aaa) in good yields. These
b
b
deviation from the standard
conditions
yield of 2a
recovery for 1a
entry
(%)
(%)
c
1
2
3
4
5
6
7
8
none
CsF instead of AgF
KF instead of AgF
96 (93)
nd
46
29
94
95
nd
nd
nd
nd
11
99
97
50
nd
98
42
65
0
LiF instead of AgF
CuF2 instead of AgF
NMP instead of MeCN
acetone instead of MeCN
DMF instead of MeCN
DMA instead of MeCN
DMSO instead of MeCN
DCE instead of MeCN
H2O instead of MeCN
40 °C instead of 60 °C
80 °C instead of 60 °C
no AgF
0
93
94
89
90
73
0
9
10
11
12
13
14
15
0
43
91
0
a
Reaction conditions: 1a (62.0 mg, 0.2 mmol), AgF (2.5 mg, 10 mol
b
%), MeCN (0.5 mL), 60 °C, 20 h. Yields were determined by 19F
NMR analysis using benzotrifluoride as the internal standard.
c
Isolated yield in the parentheses.
B
https://dx.doi.org/10.1021/acs.orglett.0c03492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Substrate Scope of α,α-Difluoro-β-ketosulfones*
*
a
b
Standard conditions: difluorovinyl tosylates (0.2 mmol), AgF (2.5 mg, 10 mol %), MeCN (0.5 mL), 60 °C, 20 h. 80 °C instead of 60 °C. AgF
(20 mol %) was used.
C
https://dx.doi.org/10.1021/acs.orglett.0c03492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
results highlight that this protocol is potential for the late-stage
modification of complex molecules and provide an approach to
access valuable molecules in pharmaceutical chemistry.
Furthermore, the practicability of this method has also been
demonstrated in a gram-scale reaction, and α,α-difluoro-β-
ketosulfone (2a) could be obtained in 90% yield (Scheme 2-
1).
products (2a, 2r, 2ad, and 2aab) were formed in similar yields
(52%, 38%, 43%, and 47%). This result provided the evidence
for the migration of sulfonyl group via an intermolecular
process.
Accordingly, aryl sulfinate may be produced during the
reaction. Controlled experiments of 1b with a catalytic amount
of sodium p-toluenesulfinate under the standard conditions
yielded the crossover products 2a and 2b in 8% and 87% yield,
respectively, which strongly indicated aryl sulfinate was
involved in this transformation (Scheme 2-5a). This
assumption was further enhanced by the fact that 1b could
react with 1.0 equiv of sodium p-toluenesulfinate to produce 2a
and 2b in 46% and 42% yields, respectively (Scheme 2-5b).
Furthermore, we found that a similar result could be achieved
when using a catalytic amount of sodium p-toluenesulfinate in
the absence of AgF, indicating AgF only played a role in
producing the corresponding p-toluenesulfinate (Scheme 2-
5c). Finally, we found that the side product 3 did not react
with sodium p-toluenesulfinate to afford the desired compound
2a (Scheme 2-6).
Scheme 2. Gram-Scale Reaction and Preliminary
Mechanistic Studies
On the basis of the controlled experiments above, a plausible
mechanism is presented for this 1,3-sulfonyl migration. First,
silver fluoride reacts with difluorovinyl sulfonates (A) to
produce the side product (trifluoromethyl)acetophenone (B)
and the corresponding aryl sulfinate (C).20 Subsequently,
nucleophilic attack of the formed intermediate C occurs on the
highly electron-deficient carbon of gem-difluorostyrenes to
form the desired product α,α-difluoro-β-ketosulfones (D).
Meanwhile, the formed aryl sulfinate takes part in the next
cycle (Figure 2).
Figure 2. Proposed mechanism of the transformation.
To gain more insight about this transformation, we carried
out several control experiments. First, adding a stoichiometric
amount of AgF led to the yield of 2a being reduced to 50%,
and the side product trifluoro-1-phenylethanone (3) was
isolated in 39% yield (Scheme 2-2). Second, the stoichiometric
reactions with p-toluenesulfonyl fluoride or naphthalene-2-
sulfonyl fluoride under the standard conditions only afforded
trace amounts of 3 and 2b in similar yields, while the crossover
products (2a and 2h) were not observed (Scheme 2-3). These
results firmly rule out the transformation proceeding via the
difluoroalkyl anion attacking sulfonyl group pathway.19 Next, a
crossover experiment was performed in order to confirm
whether this reaction proceeded in an intermolecular or
intramolecular fashion (Scheme 2-4). The experiment was
conducted by applying an equivalent amount of 1r and 1ad to
the standard conditions. It was found that four crossover
In summary, we have discovered a 1,3-sulfonyl migration of
difluorovinyl sulfonates to α,α-difluoro-β-ketosulfones initiated
by catalytic amount of silver fluoride. This method features
very broad functional group tolerance, high atom economy,
and mild, environmentally benign reaction conditions. A series
of α,α-difluoro-β-ketosulfones could be produced in excellent
yields. Finally, mechanistic investigations indicated that this
intramolecular migration proceeded in an intermolecular
manner and the corresponding sulfinates are possible
intermediates.
D
https://dx.doi.org/10.1021/acs.orglett.0c03492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
ASSOCIATED CONTENT
REFERENCES
■
■
(1) (a) Simpkins, N. S. Meldola Lecture. New stereoselective
sı
* Supporting Information
reactions in organic synthesis. Chem. Soc. Rev. 1990, 19, 335−354.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03492.
̈
́
(b) Backvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M. The Use of
Sulfonyl 1,3-Dienes in Organic Synthesis. Chem. Rev. 1998, 98, 2291−
2312. (c) Back, T. G.; Clary, K. N.; Gao, D. Cycloadditions and
Cyclizations of Acetylenic, Allenic, and Conjugated Dienyl Sulfones.
Chem. Rev. 2010, 110, 4498−4553. (d) Fang, Y.; Luo, Z.; Xu, X.
Recent advances in the synthesis of vinyl sulfones. RSC Adv. 2016, 6,
59661−59676.
Experimental procedures along with characterization
data and copies of 1H, 13C and 19F NMR spectra (PDF)
Accession Codes
(2) (a) Swenson, R. E.; Sowin, T. J.; Zhang, H. Q. Synthesis of
Substituted Quinolines Using the Dianion Addition of N-Boc-anilines
and α-Tolylsulfonyl-α,β-unsaturated Ketones. J. Org. Chem. 2002, 67,
9182−9185. (b) Xiang, J.; Ipek, M.; Suri, V.; Massefski, W.; Pan, N.;
Ge, Y.; Tam, M.; Xing, Y.; Tobin, J. F.; Xu, X.; Tam, S. Synthesis and
biological evaluation of sulfonamidooxazoles and β-keto sulfones:
selective inhibitors of 11β-hydroxysteroid dehydrogenase type I.
Bioorg. Med. Chem. Lett. 2005, 15, 2865−2869. (c) Curti, C.; Laget,
M.; Ortiz Carle, A.; Gellis, A.; Vanelle, P. Rapid synthesis of sulfone
derivatives as potential anti-infectious agents. Eur. J. Med. Chem. 2007,
42, 880−884. (d) Huang, X.; Xue, J. A Novel Multicomponent
Reaction of Arynes, β-Keto Sulfones, and Michael-Type Acceptors: A
Direct Synthesis of Polysubstituted Naphthols and Naphthalenes. J.
Org. Chem. 2007, 72, 3965−3968. (e) Xiang, J.; Ipek, M.; Suri, V.;
Tam, M.; Xing, Y.; Huang, N.; Zhang, Y.; Tobin, J.; Mansour, T. S.;
McKew, J. β-Keto sulfones as inhibitors of 11β-hydroxysteroid
dehydrogenase type I and the mechanism of action. Bioorg. Med.
Chem. 2007, 15, 4396−4405. (f) Yang, H.; Carter, R. G.; Zakharov, L.
N. Enantioselective Total Synthesis of Lycopodine. J. Am. Chem. Soc.
2008, 130, 9238−9239. (g) Eweas, A. F.; Allam, G.; Abuelsaad, A. S.
A.; ALGhamdi, A. H.; Maghrabi, I. A. Design, synthesis, anti-
schistosomal activity and molecular docking of novel 8-hydroxyquino-
line-5-sufonyl 1,4-diazepine derivatives. Bioorg. Chem. 2013, 46, 17−
25. (h) Petrov, K. G.; Zhang, Y.-M.; Carter, M.; Cockerill, G. S.;
Dickerson, S.; Gauthier, C. A.; Guo, Y.; Mook, R. A., Jr.; Rusnak, D.
W.; Walker, A. L.; Wood, E. R.; Lackey, K. E. Optimization and SAR
for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-
furanylquinazoline series. Bioorg. Med. Chem. Lett. 2006, 16, 4686−
4691.
CCDC 2022858 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.
AUTHOR INFORMATION
■
Corresponding Author
Zhong Lian − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, West China
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China; orcid.org/0000-
0003-2533-3066; Email: lianzhong@scu.edu.cn
Authors
Baojian Xiong − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, West China
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
Lei Chen − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital and
West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
Jie Xu − Department of Dermatology, State Key Laboratory of
Biotherapy and Cancer Center, West China Hospital and
West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
Haotian Sun − Department of Dermatology, State Key
Laboratory of Biotherapy and Cancer Center, West China
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
Xiong Li − Department of Dermatology, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital and
West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
Yue Li − Department of Dermatology, State Key Laboratory of
Biotherapy and Cancer Center, West China Hospital and
West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
(3) (a) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. Efficient
Conversion of Sulfones into β-Keto Sulfones by N-Acylbenzotriazoles.
J. Org. Chem. 2003, 68, 1443−1446. (b) Katritzky, A. R.; Abdel-
Fattah, A. A. A.; Vakulenko, A. V.; Tao, H. N-Sulfonylbenzotriazoles
as Advantageous Reagents for C-Sulfonylation. J. Org. Chem. 2005, 70,
9191−9197.
(4) (a) Nielsen, M.; Jacobsen, C. B.; Paixao, M. W.; Holub, N.;
̃
Jørgensen, K. A. Asymmetric Organocatalytic Formal Alkynylation
and Alkenylation of α,β-Unsaturated Aldehydes. J. Am. Chem. Soc.
2009, 131, 10581−10586. (b) Zweifel, T.; Nielsen, M.; Overgaard, J.;
Jacobsen, C. B.; Jørgensen, K. A. Practical Synthesis of β-Carbonyl
Phennyltetrazolesulfones and Investigations of Their Reactivities in
Organocatalysis. Eur. J. Org. Chem. 2011, 2011, 47−52. (c) Singh, A.
K.; Chawla, R.; Keshari, T.; Yadav, V. K.; Yadav, L. D. S. Aerobic
oxysulfonylation of alkenes using thiophenols: an efficient one-pot
route to β-ketosulfones. Org. Biomol. Chem. 2014, 12, 8550−8554.
(5) (a) Xie, Y.-Y.; Chen, Z.-C. Hypervalent iodine in synthesis. 66.
one pot preparation of β-keto sulfones by reaction of ketones,
[Hydroxy(Tosyloxy)Iodo] benzene, andsodium sulfonates. Synth.
Commun. 2001, 31, 3145−3149.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03492
(6) (a) Wei, W.; Liu, C.-L.; Yang, D.-S.; Wen, J.-W.; You, J.-M.; Suo,
Y.-R.; Wang, H. Copper-catalyzed direct oxysulfonylation of alkenes
with dioxygen and sulfonylhydrazides leading to β-ketosulfones.
Chem. Commun. 2013, 49, 10239−10241. (b) Jiang, Y.; Loh, T.-P.
Catalytic and direct methyl sulfonylation of alkenes and alkynes using
a methyl sulfonyl radical generated from a DMSO, dioxygen and
copper system. Chem. Sci. 2014, 5, 4939−4943. (c) Wang, H.; Lu, Q.;
Qian, C.; Liu, C.; Liu, W.; Chen, K.; Lei, A. Solvent-Enabled Radical
Selectivities: Controlled Syntheses of Sulfoxides and Sulfides. Angew.
Chem., Int. Ed. 2016, 55, 1094−1097. (d) Yang, D.; Huang, B.; Wei,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation (21901168), “1000-Youth Talents Plan”, and
Sichuan University.
E
https://dx.doi.org/10.1021/acs.orglett.0c03492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
W.; Li, J.; Liu, Y.; Ding, J.; Sun, P.; Wang, H. Visible-light initiated
direct oxysulfonylation of alkenes with sulfinic acids leading to β-
ketosulfones. Green Chem. 2016, 18, 5630−5634. (e) Shao, A.; Gao,
M.; Chen, S.; Wang, T.; Lei, A. CO/O2 assisted oxidative carbon−
carbon and carbon−heteroatom bond cleavage for the synthesis of
oxosulfonates from DMSO and olefins. Chem. Sci. 2017, 8, 2175−
2178. (f) Lu, Q.-Q.; Zhang, J.; Zhao, G.-L.; Qi, Y.; Wang, H.-M.; Lei,
A.-W. Dioxygen-Triggered Oxidative Radical Reaction: Direct
Aerobic Difunctionalization of Terminal Alkynes toward β-Keto
Sulfones. J. Am. Chem. Soc. 2013, 135, 11481−11484. (g) Handa, S.;
Fennewald, J. C.; Lipshutz, B. H. Aerobic Oxidation in Nanomicelles
of Aryl Alkynes, in Water at Room Temperature. Angew. Chem., Int.
Ed. 2014, 53, 3432−3435. (h) Wang, H.; Wang, G.; Lu, Q.; Chiang,
C.-W.; Peng, P.; Zhou, J.; Lei, A. Catalyst-Free Difunctionalization of
Activated Alkenes in Water: Efficient Synthesis of β-Keto Sulfides and
Sulfones. Chem. - Eur. J. 2016, 22, 14489−14493.
(14) (a) Loghmani-Khouzani, H.; oorheravi, M. R.; Sadeghi, M. M.
M.; Caggiano, L.; Jackson, R. F. W. α-Fluorination of β-ketosulfones
by Selectfluor F−TEDA−BF4. Tetrahedron 2008, 64, 7419−7425.
(b) Vints, I.; Gatenyo, J.; Rozen, S. Mono and difluorination of
centers α to sulfonates and phosphonates using AcOF. J. Fluorine
Chem. 2013, 146, 66−69.
(15) Ni, C.; Zhang, L.; Hu, J. Synthesis of Fluorinated β-
Ketosulfones and gem-Disulfones by Nucleophilic Fluoroalkylation
of Esters and Sulfinates with Di- and Monofluoromethyl Sulfones. J.
Org. Chem. 2009, 74, 3767−3771.
(16) He, F.-S.; Yao, Y.; Xie, W.; Wu, J. Photoredox-catalyzed
sulfonylation of difluoroenoxysilanes with the insertion of sulfur
dioxide. Chem. Commun. 2020, 56, 9469−9472.
(17) Zhang, H.; Zhou, C.-B.; Chen, Q.-Y.; Xiao, J.-C.; Hong, R.
Monofluorovinyl Tosylate: A Useful Building Block for the Synthesis
of Terminal Vinyl Monofluorides via Suzuki-Miyaura Coupling. Org.
Lett. 2011, 13, 560−563.
(18) Han, S. Y.; Jeong, I. H. Efficient Synthesis of 2,2-Diaryl-1,1-
difluoroethenes via Consecutive Cross-Coupling Reactions of 2,2-
Difluoro-1-tributylstannylethenyl p-Toluenesulfonate. Org. Lett. 2010,
12, 5518−5521.
(19) Gao, X.; Cheng, R.; Xiao, Y.-L.; Wan, X.-L.; Zhang, X. Copper-
Catalyzed Highly Enantioselective Difluoroalkylation of Secondary
Propargyl Sulfonates with Difluoroenoxysilanes. Chem. 2019, 5,
2987−2999.
(20) The reaction was quenched by adding concd HCl, and the
corresponding sulfinic acid was detected by LC−MS. For the
experimental details, see the Supporting Information.
(7) Flynn, A. J.; Ford, A.; Maguire, A. R. Synthetic and mechanistic
aspects of sulfonyl migrations. Org. Biomol. Chem. 2020, 18, 2549−
2610.
(8) Xie, L.; Zhen, X.; Huang, S.; Su, X.; Lin, M.; Li, Y. Photoinduced
rearrangement of vinyl tosylates to β-ketosulfones. Green Chem. 2017,
19, 3530−3534.
(9) Wang, L.; Lu, C.; Yue, Y.; Feng, C. Visible-Light-Promoted Oxo-
Sulfonylation of Ynamides with Sulfonic Acids. Org. Lett. 2019, 21,
3514−3517.
́
́
(10) (a) Begue, J.-P.; Bonnet-Delpon, D. Recent advances (1995−
2005) in fluorinated pharmaceuticals based on natural products. J.
Fluorine Chem. 2006, 127, 992−1012. (b) Cerqueira, N. M. F. S. A.;
Fernandes, P. A.; Ramos, M. J. Chem. - Eur. J. 2007, 13, 8507−8515.
(c) Teague, S. J. Learning lessons from drugs that have recently
entered the market. Drug Discovery Today 2011, 16, 398−411.
(11) (a) Meanwell, N. A. Fluorine and Fluorinated Motifs in the
Design and Application of Bioisosteres for Drug Design. J. Med. Chem.
2018, 61, 5822−5880. (b) Kirsch, P. Modern Fluoroorganic Chemistry:
Synthesis, Reactivity, Applications; Wiley-VCH Verlag, 2004.
(12) Prakash, G. K. S.; Hu, J. Selective Fluoroalkylations with
Fluorinated Sulfones, Sulfoxides, and Sulfides. Acc. Chem. Res. 2007,
40, 921−930.
(13) (a) Ni, C.; Li, Y.; Hu, J. Nucleophilic Fluoroalkylation of
Epoxides with Fluorinated Sulfones. J. Org. Chem. 2006, 71, 6829−
6833. (b) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.;
Nakamura, S.; Toru, T. Fluorobis(phenylsulfonyl)methane: A
Fluoromethide Equivalent and Palladium-Catalyzed. Angew. Chem.,
Int. Ed. 2006, 45, 4973−4977. (c) Prakash, G. K. S.; Chacko, S.;
Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Stereoselective
Monofluoromethylation of Primary and Secondary Alcohols by Using
a Fluorocarbon Nucleophile in a Mitsunobu Reaction. Angew. Chem.,
Int. Ed. 2007, 46, 4933−4936. (d) Mizuta, S.; Shibata, N.; Goto, Y.;
Furukawa, T.; Nakamura, S.; Toru, T. Cinchona Alkaloid-Catalyzed
Enantioselective Monofluoromethylation Reaction Based on
Fluorobis(phenylsulfonyl)methane Chemistry Combined with a
Mannich-type Reaction. J. Am. Chem. Soc. 2007, 129, 6394−6395.
(e) Ni, C.; Zhang, L.; Hu, J. Nucleophilic Fluoroalkylation of α,β-
Enones, Arynes, and Activated Alkynes with Fluorinated Sulfones:
Probing the Hard/Soft Nature of Fluorinated Carbanions. J. Org.
Chem. 2008, 73, 5699−5713. (f) Furukawa, T.; Shibata, N.; Mizuta,
S.; Nakamura, S.; Toru, T.; Shiro, M. Catalytic Enantioselective
Michael Addition of 1-Fluorobis(phenylsulfonyl)methane to α,β-
Unsaturated Ketones Catalyzed by Cinchona Alkaloids. Angew. Chem.,
́
Int. Ed. 2008, 47, 8051−8054. (g) Sanz-Marco, A.; GarcIa-Ortiz, A.;
́
Blay, G.; Fernandez, I.; Pedro, J. R. Highly Enantioselective
Copper(I)-Catalyzed Conjugate Addition of Terminal Alkynes to
1,1-Difluoro-1-(phenylsulfonyl)-3-en-2-ones: New Ester/Amide Sur-
rogates in Asymmetric Catalysis. Chem. - Eur. J. 2014, 20, 668−672.
(h) Ye, W.; Zhang, L.; Ni, C.; Ronga, J.; Hu, J. Stereoselective [3 + 2]
cycloaddition of N-tert-butanesulfinyl imines to arynes facilitated by a
removable PhSO2CF2 group: synthesis and transformation of cyclic
sulfoximines. Chem. Commun. 2014, 50, 10596−10599.
F
https://dx.doi.org/10.1021/acs.orglett.0c03492
Org. Lett. XXXX, XXX, XXX−XXX