Synthesis of 2,2-diaryl-1,1-difluoroethenes via Pd-catalyzed dehydrosulfonylative cross-coupling of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates with arylboronic acids

Article abstract of DOI:10.1016/j.tet.2018.04.054

By using PhSO₂CF₂H as the difluoromethylidene equivalent, a novel method for connecting aromatic aldehydes and arylboronic acids via consecutive reactions was developed to obtain structurally diverse 2,2-diaryl-1,1-difluoroethenes. The key step is the palladium-catalyzed dehydrosulfonylative cross-coupling of tosylates that are prepared from PhSO₂CF₂H, aromatic aldehydes and tosyl chloride. Mechanistic investigations showed that the reaction proceeds mainly through base-mediated dehydrosulfonylation followed by palladium-catalyzed C(sp²)-C(sp²) cross-coupling reaction.

Full text of DOI:10.1016/j.tet.2018.04.054

Accepted Manuscript
Synthesis of 2,2-diaryl-1,1-difluoroethenes via Pd-catalyzed dehydrosulfonylative
cross-coupling of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates with arylboronic
acids
Rui Zhang, Chuanfa Ni, Yanchuan Zhao, Jinbo Hu
PII:
S0040-4020(18)30443-5
10.1016/j.tet.2018.04.054
TET 29469
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 March 2018
Revised Date: 13 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Zhang R, Ni C, Zhao Y, Hu J, Synthesis of 2,2-diaryl-1,1-difluoroethenes via
Pd-catalyzed dehydrosulfonylative cross-coupling of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates
with arylboronic acids, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.054.
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ACCEPTED MANUSCRIPT
Synthesis of 2,2-diaryl-1,1-difluoroethenes via Pd-catalyzed
dehydrosulfonylative cross-coupling of
α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates with arylboronic
acids
Rui Zhang, Chuanfa Ni, Yanchuan Zhao, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032,
China
*Corresponding author. Tel.: +86 21 54925174; Fax: +86 21 64166128; E-mail:
jinbohu@sioc.ac.cn.
Dedicated to the memory of Sir Derek Barton for the 100th anniversary (1918-2018)
of his birth.
1

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Graphical Abstract
Abstract
By using PhSO2CF2H as the difluoromethylidene equivalent, a novel method for
connecting aromatic aldehydes and arylboronic acids via consecutive reactions was
developed to obtain structurally diverse 2,2-diaryl-1,1-difluoroethenes. The key step
is the palladium-catalyzed dehydrosulfonylative cross-coupling of tosylates that are
prepared from PhSO2CF2H, aromatic aldehydes and tosyl chloride. Mechanistic
investigations showed that the reaction proceeds mainly through base-mediated
dehydrosulfonylation followed by palladium-catalyzed C(sp2)-C(sp2) cross-coupling
reaction.
Keywords
1,1-Difluoroalkenes, Sulfone, Benzyl tosylate, Cross-coupling reaction, Palladium
catalysis.
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1. Introduction
1,1-Difluoroalkenes have attracted much attention in organic synthesis1,2 as well
as in pharmaceutical and agrochemical research3,4 due to their unique chemical and
biological properties.5 On one hand, 1,1-difluoroalkenes have been used as versatile
building blocks to deliver structurally diverse functionalized molecules, most of
which are otherwise difficult to efficiently prepare. On the other hand, the
difluoromethylidene group (=CF2) is regarded as the bioisostere of carbonyl group
and has been applied in the improvement of enzyme inhibitors.6 In these contexts,
many methods, including the difluoromethylidenation reactions, have been developed
to synthesize 1,1-difluoroalkenes.1 However, the methods that can deliver
1,1-diaryl-2,2-difluoroethenes are rare and usually suffer from limitations. The
Wittig-type gem-difluoroolefination of diaryl ketones7 and Barton−Kellogg-type
gem-difluoroolefination diaryl thioketones8 are of low efficiency and were
demonstrated with only very few examples. The Julia-Kocienski-type
gem-difluoroolefination of diaryl ketones9 and gem-difluoroolefination of diaryl diazo
compounds10 are synthetically useful, but the availability of the diaryl compounds can
impose restriction on their wide application. The metal-catalyzed cross-coupling
reactions of 2,2-difluoro-1-arylvinylstannane reagents,11 2,2-difluoro-1-arylvinylzinc
reagents,12 α-halo-β,β-difluorostyrenes12 and 2,2-difluoro-1-arylvinyl tosylates,13 also
involve the use of not readily-available coupling partners. Furthermore, the recently
disclosed Rh(I)-catalyzed defluorinative cross-coupling of trifluoromethylketone
N-tosylhydrazones and arylboronates affords 1,1-diaryl-2,2-difluoroethenes in
moderate yields.14
In the past decade, a series of fluorinated sulfones have been developed as
general fluoroalkylation reagents and widely used for the incorporation of various
fluoroalkyl groups into organic molecules by us and others.8,15,16 Difluoromethyl
sulfones are among the most versatile fluorinated sulfones and are capable of
incorporating
difluoromethyl
(-CF2H),
difluoromethylene
(-CF2-),
difluoromethylidene group (=CF2), as well as difluoro(sulfinato)methyl (-CF2SO2M)
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groups.15b,e The reaction of two molecules with difluoromethyl sulfones via
consecutive reactions is a unique synthetic method, which allows easy access to many
unsymmetrical gem-difluorinated compounds (Scheme 1a). This strategy has been
used for the synthesis of difluoromethylene-containing compounds (Scheme 1a, path
a);15 however, the synthesis of difluoromethylidiene-containing compounds, namely,
1,1-difluoroalkenes, by using similar strategy is still underdeveloped (Scheme 1a,
path b).
Scheme 1. The transformation of difluoromethyl sulfones and the synthesis of
1,1-difluoroalkenes.
Inspired by our previous work on the preparation of 2,2-difluoro-1-arylvinyl
benzoates from α-[difluoro(phenylsulfonyl)methyl]benzyl benzoates (Scheme 1b)17
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and Jeong’s work on the Suzuki- and Stille-type cross-coupling reactions of
2,2-difluoro-1-arylvinyl tosylates (Scheme 1c),13 we envisioned that
α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates could be used as alternative
precursors
2,2-diaryl-1,1-difluoroethenes. Herein, we report
dehydrosulfonylative cross-coupling reaction
of
2,2-difluoro-1-arylvinyl
tosylates
to
palladium-catalyzed
readily available
prepare
a
of
α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates with arylboronic acids (Scheme
1d). Since the base-mediated dehydrosulfonylative elimination reaction and the
subsequent palladium-catalyzed cross-coupling can proceed smoothly in one pot
without the isolation of the 2,2-difluoro-1-arylvinyl tosylate intermediates, this
synthetic method provides a very convenient approach to obtain structurally diverse
2,2-diaryl-1,1-difluoroethenes.
2. Results and discussion
Our
investigation
began
with
the
preparation
of
α-[difluoro(phenylsulfonyl)methyl]benzyl tosylate (1a) by an aldol-type reaction of
commercially available PhSO2CF2H and benzaldehyde followed by treatment with
tosyl chloride (Scheme 2). As previously described,18 the addition of PhSO2CF2H to
benzaldehyde could readily take place in THF in the presence of lithium
hexamethyldisilazide (LiHMDS) as the base and hexamethylphosphoric triamide
(HMPA) as an additive at –78 °C. We found that the further addition of tosyl chloride
to the reaction mixture at the same temperature could afford the desired benzyl
tosylate 1a in 85% yield. The same procedures are also applicable for the preparation
of other tosylates (1b-1i) from the corresponding aromatic aldehydes in good to
excellent isolated yields (Table 1). The electronic nature and steric hindrance of the
aryl substituent possess little influence on the reaction. Note that all the so-obtained
tosylates are crystalline solids and thus can be easily isolated and purified by
recrystallization. Compared with our previous observation that the reaction of
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α-[fluorobis(phenylsulfonyl)methyl]benzyl alcoholates with tosyl chloride failed to
give
the
desired
tosylates,19
the
ready
tosylation
of
α-[difluoro(phenylsulfonyl)methyl]benzyl alcoholates by tosyl chloride should be
attributed to their lower steric hindrance and higher thermal stability.
Scheme 2. Development of one-pot procedures for the synthesis of
α-[difluoro(phenylsulfonyl)methyl]benzyl tosylate 1a.
Table 1 Preparation of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates 1 a.
CF
2SO2Ph
CF
1) PhSO2 2H (1.0 equiv), LiHMDS (1.5 equiv)
THF/HMPA (10:1, v/v), 78 oC, 2 h
CHO
OTs
R
R
2) TsCl (1.5 equiv), 78 oC, 1 h
(1.5 equiv)
1
a Isolated yields after recrystallization.
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With α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates 1 in hand, we
investigated their dehydrosulfonylative cross-coupling reaction with arylboronic acids
under palladium catalysis to prepare 2,2-diaryl-1,1-difluoroethenes. The reaction
between tosylate 1a and phenylboronic acid (2a) was chosen as a model reaction to
test and then optimize the coupling reaction (Table 2). Typically, the reaction was
carried out with a loading of 4 mol% Pd2(dba)3 at 80 oC for 8 hours, a base was added
to promote the formation of the intermediate, 2,2-difluoro-1-phenylvinyl tosylate, and
the molar ratio of 1a, 2a, and the base was 1.5/1.0/3.0. When Cs2CO3 was used as the
base and Pd2(dba)3 was used as the catalyst, the reaction conducted in
1,2-dimethoxyethane (DME) afforded the desired coupling product 3a in 68% yield
(by 19F NMR). Screening of solvents showed that other solvents are inferior to DME
(Table 1, entries 2−5). The base effect is also significant: K2CO3 and t-BuOLi were
found to be less effective due to their weaker basicity than Cs2CO3, thus retarding the
dehydrosulfonylative elimination of 1a (Table 1, entries 6 and 7). The reaction
temperature also showed some influence on the reaction: the yield of 3a was
o
decreased to some extent when running the reaction at 100 oC or 60 C (Table 1,
entries 8 and 9). Importantly, it was found that the use of a phosphine ligand could
further improve the reaction, with P(o-tol)3 giving 3a in the highest yield (75%)
(Table 1, entries 10 and 11). Eventually, screening of the reactant ratio and catalyst
loading established the optimal reaction conditions as follows: 1.2 equiv of 1a, 1.0
equiv of 2a, 3.0 equiv of Cs2CO3, 4 mol% Pd2(dba)3 catalyst, 8 mol% P(o-tol)3 ligand,
DME solvent, 80 °C reaction temperature, and 8 h reaction time under N2 atmosphere
(Table 1, entry 12).
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Table 2 Screening of cross-coupling conditions a.
Entry
Ligand (mol%)
Base
Solvent
DME
Temp. (oC)
Yield (%)
1
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuOLi
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
80
80
80
80
80
80
80
100
60
80
80
80
68
34
2
—
DMF
b
3
—
DMSO
1,4-dioxane
NMP
—
4
—
16
5
—
19
6
—
DME
8
7
—
DME
0
8
—
DME
60
9
—
DME
48
10
P(o-tol)3 (18)
sPhos (18)
P(o-tol)3 (8)
DME
75
11
12c
a
DME
70
DME
75 (72)
Unless otherwise noted, all reactions were conducted according to the following conditions: 1a (0.3 mmol), 2a
(0.2 mmol), base (0.6 mmol), Pd2(dba)3 (0.008 mmol), ligand (0.036 mmol) in solvent (2.0 mL) at 60, 80, or 100
oC for 8 h. Yields were determined by 19F NMR spectroscopy analysis with PhSO2CF2H as an internal standard.
Isolated yield was given in the parentheses.
b Intractable mixture.
c 1a (0.24 mmol) and P(o-tol)3 (0.016 mmol) were used.
With the optimized conditions in hand, we first examined the substrate scope by
reacting tosylate 1a with different arylboronic acids 2 (Table 3). For ease of isolation
of the desired product, all reactions were performed on 0.5-mmol scale. Generally,
both electron-rich and electron-deficient arylboronic acids reacted smoothly to give
gem-difluoroolefins 3a-3i in moderate to good isolated yields (50–76%). The
oxidative homo-coupling was the major side reaction of arylboronic acids. Besides, it
was found that vigorous stirring was needed to promote the formation of products 3
due to the low solubility of Cs2CO3 in DME.
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Table 3 Scope of arylboronic acids a.
Pd2(dba)3 (4 mol%), P(o-tol)3
(8 mol%), Cs2CO3 (3.0 equiv)
CF2SO2Ph
CF2
Ar
+
OTs
Ar B(OH)2
DME, 80 oC, 8 h
2
1a
3
a Reaction conditions: 1a (0.6 mmol), 2 (0.5 mmol), Cs2CO3 (1.5 mmol), Pd2(dba)3 (0.02 mmol), P(o-tol)3 (0.04
mmol) in DME (5.0 mL) at 80 oC for 8 h. Isolated yields.
We then examined the reactions of various tosylates 1b-1i with phenylboronic
acid (2a). As shown in Table 4, the reaction is compatible with simple alkyl groups,
such as methyl, isopropyl, and tert-butyl, trifluoromethyl group, trifluoromethoxy
group, even 2-naphthyl substituent. However, both the arene substitution pattern and
the electron-donating ability of the substituent could significantly influence the
formation of the coupling products. In the cases of alkyl-substituted benzyl tosylates,
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the meta- and para-substituted ones could smoothly undergo the reaction to afford the
coupling products in moderate yields (Table 4, 3c, 3k, and 3l), while the
ortho-substituted ones failed to participate in the reaction due to the difficulty in
dehydrosulfonylation caused by the steric hindrance (Table 4, 3j). In the case where
methoxy-substituted benzyl tosylate was used, the cross-coupling reaction was
unsuccessful (Table 4, 3d). The failure of this reaction presumably arises from the
strong electron-donating destabilization of the carbanion of benzyl tosylate 1f, which
renders the deprotonation of 1f much more difficult.
Table 4 Scope of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates.
a
Reaction conditions: 1 (0.6 mmol), 2a (0.5 mmol), Cs2CO3 (1.5 mmol), Pd2(dba)3 (0.02 mmol), P(o-tol)3 (0.04
mmol) in DME (5.0 mL) at 80 C for 8 h. Isolated yields. Yields were determined by 19F NMR spectroscopy
o
b
analysis with PhOCF3 as an internal standard.
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To gain further insights into this palladium-catalyzed dehydrosulfonylative
cross-coupling reaction, we conducted the control experiment in the absence of the
palladium and monitored the progress of the reactions after 1 h with 19F NMR
spectroscopy (Scheme 3). In the absence of Pd2(dba)3/P(o-tol)3, the consumption of
tosylate 1a led to the formation 2,2-difluoro-1-phenylvinyl tosylate (4a) as the major
product (Scheme 3a); whereas in the presence of Pd2(dba)3/P(o-tol)3, in addition to the
coupling product 3a, the intermediate 4a was also observed in substantial amount
(Scheme 3b). Theses results suggested that 4a is a possible intermediate for the
generation of 3a. Moreover, tosylate 1a was consumed at the similar rate with or
without the catalyst, indicating that the dehydrosulfonylation of 1a to form 4a should
be a major pathway. In combination with previously reported coupling reaction of
isolated 2,2-difluoro-1-arylvinyl tosylates 4 with arylboronic acids,13b a proposed
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Scheme 3. Mechanism considerations. a Conversions and yields were determined by
19F NMR spectroscopy analysis with PhOCF3 as an internal standard.
mechanism of our present reaction is given in Scheme 3c, path a. First,
Cs2CO3-promoted dehydrosulfonylation of tosylate 1 gave 2,2-difluoro-1-arylvinyl
tosylate 4. Second, the palladium-catalyzed cross-coupling of 4 with arylboronic acids
affords 2,2-diaryl-1,1-difluoroethenes 3. Although the involvement of
palladium-catalyzed C(sp3)-C(sp2) coupling20 of 1 with arylboronic acids 2 to give
intermediate 5 followed by dehydrosulfonylation (Scheme 3c, path b) cannot be fully
ruled out at this stage, this pathway should not be the major one, if any, as we
observed that the dehydrosulfonylation of 1a was faster than the formation of 3a.
3. Conclusions
In summary, we report a new gem-difluoroolefination protocol for the synthesis of
2,2-diaryl-1,1-difluoroethenes from readily available PhSO2CF2H, aromatic aldehydes,
and arylboronic acids. The key step is the palladium-catalyzed dehydrosulfonylative
cross-coupling of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates that are derived
from PhSO2CF2H, aromatic aldehydes, and tosyl chloride. The dehydrosulfonylation
and coupling reaction are operated in one pot without the separation of the
intermediates, 2,2-difluoro-1-arylvinyl tosylates. This protocol not only represents a
novel synthetic application of PhSO2CF2H,15 it also provides an efficient approach to
prepare a series of 2,2-diaryl-1,1-difluoroethenes with varying structures from simple
starting materials.
4. Experimental section
4.1. General
Unless otherwise mentioned, solvents and reagents were purchased from commercial
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sources and used as received. The solvents MeCN and DMF were distilled over CaH2.
The solvents THF and toluene were distilled over sodium. Difluoromethyl phenyl
sulfone (PhSO2CF2H) was either prepared according to reported procedures21 or
1
19
purchased from J&K Scientific. All the melting points were uncorrected. H, F and
13C NMR spectra were recorded on a Bruker AM-300 NMR, VarianMercury-300, or
1
Agilent MR-400 NMR spectrometer. H NMR chemical shifts were determined
relative to internal (CH3)4Si (TMS) at δ 0.0 or to the signal of a residual protonated
solvent CDCl3 at δ 7.26. 19F NMR chemical shifts were determined relative to
external CFCl3 at δ 0.0. MS (EI-MS) were obtained on an Agilent 5975C gas
chromatography and HP5989A mass spectrometer. MS (ESI) were obtained on an
AGILENT1100 mass spectrometer. High-resolution mass data were recorded on a
Thermo Scientific LTQ FTICR mass spectrometer in the ESI mode.
4.2.
Typical
experimental
procedures
for
the
synthesis
of
α
-[difluoro(phenylsulfonyl)methyl]benzyl tosylates 1a–1i
Into a 250-mL three-necked round bottom flask equipped with a magnetic stir bar
were added benzaldehyde (7.959 g, 75.0 mmol, 1.5 equiv), difluoromethyl phenyl
sulfone (9.61 g, 50.0 mmol, 1.0 equiv), hexamethylphosphoramide (HMPA) (12.0
o
mL), and THF (120.0 mL). The mixture was cooled to –78 C with a dry ice-acetone
cold bath, and stirred at this temperature for 10 min. A solution of lithium
bis(trimethylsilyl)amide (1.0 M in THF, 75.0 mL, 75.0 mmol, 1.5 equiv) was added
o
dropwise at −78 C. The mixture was stirred at −78 °C for 2 hours, after which
p-toluenesulfonyl chloride (14.3 g, 75.0 mmol, 1.5 equiv) was added and then the
mixture was stirred at −78 °C for another 1 hour. The reaction was quenched by the
addition of a saturated aqueous solution of NH4Cl (40 mL). Ethyl acetate (EtOAc) (50
mL) were added to the reaction and the organic phase was separated. The aqueous
phase was extracted with EtOAc (2×50 mL) and the combined organic phases were
dried with MgSO4, filtered, and evaporated under vacuum. The residue was purified
by recrystallization from petroleum ether (PE)/EtOAc to afford the desired product 1a
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as a white solid (19.194 g, 85% yield).
4.2.1. 2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethyl 4-methylbenzenesulfonate (1a)
Performed on 50-mmol scale, 19.194 g, 85% yield. White solid, m.p. 112–114 oC; 1H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.62 (d,
J = 8.3 Hz, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.34 – 7.32 (m, 3H), 7.27 – 7.23 (m, 3H),
7.16 (d, J = 8.1 Hz, 2H), 6.17 (dd, J = 14.1, 9.5 Hz, 1H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 145.16 (s), 135.53 (s), 133.20 (s), 132.94 (s), 130.78 (s), 130.27 (s),
129.51 (s), 129.29 (s), 129.01 (s), 128.46 (s), 128.18 (s), 119.01 (dd, J = 298.8, 290.0
19
Hz), 77.37 (d, J = 20.2 Hz), 77.47 – 77.20 (m), 77.24 (d, J = 7.3 Hz), 21.62 (s); F
NMR (376 MHz, CDCl3) δ –107.54 (dd, J = 240.9, 9.4 Hz, 1F), –110.38 (dd, J =
240.9, 14.1 Hz, 1F); MS (ESI, m/z, %): 474.90 (M+Na+, 100.00); HRMS (ESI): Calcd.
For C21H18F2O5S2Na+: 475.0456; Found: 475.0452.
4.2.2. 2,2-Difluoro-2-(phenylsulfonyl)-1-(m-tolyl)ethyl 4-methylbenzenesulfonate (1b)
Performed on 50-mmol scale, 19.246 g, 82% yield. White solid, m.p. 115–118 oC; 1H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.9 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.61 –
7.54 (m, 4H), 7.16 – 7.11 (m, 5H), 7.04 (s, 1H), 6.12 (dd, J = 14.6, 9.1 Hz, 1H), 2.37
(s, 3H), 2.22 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 145.20 (s), 138.21 (s), 135.64 (s),
133.26 (s), 132.94 (s), 131.06 (s), 130.70 (s), 129.50 (s), 129.46 (s), 129.34 (s),
129.18 (s), 128.39 (s), 128.09 (s), 126.28 (s), 119.10 (dd, J = 298.7, 289.6 Hz), 77.52
19
(dd, J = 28.0, 20.3 Hz). 21.53 (s), 21.10 (s); F NMR (376 MHz, CDCl3) δ –107.28
(dd, J = 241.3, 9.1 Hz, 1F), –110.66 (dd, J = 241.3, 14.6 Hz, 1F); MS (ESI, m/z, %):
488.90 (M+Na+, 100.00); HRMS (ESI): Calcd. For C22H10F2O5S2Na+: 489.0612;
Found: 489.0619.
4.2.3. 2,2-Difluoro-2-(phenylsulfonyl)-1-(o-tolyl)ethyl 4-methylbenzenesulfonate (1c)
Performed on 50-mmol scale, 21.255 g, 91% yield. White solid, m.p. 138–139 oC. 1H
NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 2H), 7.73 (t, J = 7.5 Hz, 1H), 7.57 (t, J
14

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= 7.9 Hz, 4H), 7.25 (d, J = 6.6 Hz, 1H), 7.21 – 7.10 (m, 4H), 6.99 (t, J = 7.6 Hz, 1H),
13
6.53 (dd, J = 16.5, 6.9 Hz, 1H), 2.44 (s, 2H), 2.36 (s, 2H); C NMR (101 MHz,
CDCl3) δ 145.17 (s), 137.42 (s), 135.63 (s), 133.24 (s), 132.85 (s), 130.79 (s), 130.54
(s), 130.06 (s), 129.48 (s), 129.36 (s), 129.01 (s), 128.09 (s), 127.98 (s), 126.20 (s),
119.36 (dd, J = 299.9, 287.5 Hz), 73.12 (dd, J = 24.6, 15.1 Hz), 21.59 (s), 19.28 (s);
19F NMR (376 MHz, CDCl3) δ –106.89 (d, J = 247.2 Hz, 1F), –111.72 (d, J = 244.1
Hz, 1F) ; MS (ESI, m/z, %): 488.95 (M+Na+, 100.00); HRMS (ESI): Calcd. For
C22H10F2O5S2Na+: 489.0612; Found: 489.0617.
4.2.4.
2,2-Difluoro-1-(4-isopropylphenyl)-2-(phenylsulfonyl)ethyl
4-methylbenzenesulfonate (1d)
o
1
Performed on 20-mmol scale, 8.482 g, 86% yield. White solid, m.p. 130–131 C; H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.7 Hz, 2H), 7.71 (dd, J = 10.7, 4.3 Hz, 1H),
7.55 (t, J = 8.0 Hz, 4H), 7.19 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.05 (d, J =
8.2 Hz, 2H), 6.14 (dd, J = 14.6, 9.3 Hz, 1H), 2.84 (hept, J = 7.0 Hz, 1H), 2.34 (s, 3H),
13
1.19 (d, J = 6.9 Hz, 6H); C NMR (101 MHz, CDCl3) δ 151.29 (s), 144.94 (s),
135.58 (s), 133.38 (s), 133.00 (s), 130.70 (s), 129.42 (s), 129.31 (s), 129.11 (s), 128.07
(s), 126.51 (s), 119.16 (dd, J = 298.8, 289.5 Hz), 77.8 – 77.32 (m), 33.87 (s), 23.81 (s),
19
23.78 (s), 21.55 (s); F NMR (376 MHz, CDCl3) δ –107.31 (dd, J = 241.3, 9.3 Hz,
1F), –110.64 (dd, J = 241.4, 14.5 Hz, 1F); MS (ESI, m/z, %): 516.95 (M+Na+,
100.00); HRMS (ESI): Calcd. For C24H24F2O5S2Na+: 517.0925; Found: 517.0920.
4.2.5.
1-(4-(tert-Butyl)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl
4-methylbenzenesulfonate (1e)
o
1
Performed on 20-mmol scale, 8.397 g, 83% yield. White solid, m.p. 151–153 C; H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 2H), 7.73 – 7.69 (m, 1H), 7.57 – 7.53
(m, 4H), 7.19 (s, 4H), 7.10 (d, J = 8.1 Hz, 2H), 6.14 (dd, J = 14.8, 9.1 Hz, 1H), 2.34 (s,
13
3H), 1.26 (s, 9H); C NMR (101 MHz, CDCl3) δ 153.51 (s), 144.85 (s), 135.55 (s),
133.42 (s), 133.03 (s), 130.72 (s), 129.39 (s), 129.30 (s), 128.83 (s), 128.08 (s),
15

ACCEPTED MANUSCRIPT
125.35 (s), 119.16 (dd, J = 298.8, 289.2 Hz), 77.77 – 77.29 (m), 34.67 (s), 31.17 (s),
21.57 (s); 19F NMR (376 MHz, CDCl3) δ –107.12 (dd, J = 241.6, 9.1 Hz, 1F), –110.82
(dd, J = 241.7, 14.8 Hz, 1F); MS (ESI, m/z, %): 530.95 (M+Na+, 100.00); HRMS
(ESI): Calcd. For C25H26F2O5S2Na+: 531.1082; Found: 531.1079.
4.2.6.
2,2-Difluoro-1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethyl
4-methylbenzenesulfonate (1f)
o
1
Performed on 20-mmol scale, 8.403 g, 87% yield. White solid, m.p. 95–98 C; H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 2H), 7.72 – 7.70 (m, 1H), 7.66 – 7.64
(m, 2H), 7.59 – 7.55 (m, 2H), 7.31 – 7.24 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 6.83 –
13
6.77 (m, 3H), 3.83 (s, 3H), 2.36 (s, 3H); C NMR (101 MHz, CDCl3) δ 145.06 (s),
135.45 (s), 133.19 (s), 133.03 (s), 131.40 (s), 130.83 (s), 129.63 (s), 129.33 (s),
129.25 (s), 128.22 (s), 120.62 (s), 119.22 (dd, J = 298.8, 288.6 Hz), 118.38 (s), 110.70
(s), 70.29 (dd, J = 29.8, 20.2 Hz), 55.83 (s), 21.59 (s); 19F NMR (376 MHz, CDCl3) δ
–107.09 (dd, J = 243.2, 7.3 Hz, 1F), –111.54 (dd, J = 243.2, 16.1 Hz, 1F) ; MS (ESI,
m/z, %): 504.95 (M+Na+, 100.00); HRMS (ESI): Calcd. For C22H20F2O6S2Na+:
505.0562; Found: 505.0526.
4.2.7.
2,2-Difluoro-2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethyl
4-methylbenzenesulfonate (1g)
o
1
Performed on 20-mmol scale, 7.721 g, 74% yield. White solid, m.p. 140–143 C; H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 2H), 7.77 – 7.73 (m, 1H), 7.62 – 7.57
(m, 4H), 7.48 (q, J = 8.4 Hz, 4H), 7.16 (d, J = 8.1 Hz, 2H), 6.21 (dd, J = 13.7, 9.4 Hz,
13
1H), 2.37 (s, 3H); C NMR (101 MHz, CDCl3) δ 145.63 (s), 135.78 (s), 133.55 (s),
132.86 (s), 132.83 (q, J = 32.89 Hz), 132.61 (s), 130.80 (s), 129.62 (s), 129.47 (s),
129.41 (s), 128.18 (s), 125.39 (q, J = 3.7 Hz), 123.56 (q, J = 272.4 Hz), 118.75 (dd, J
19
= 299.3, 290.3 Hz), 76.39 (dd, J = 27.6, 20.9 Hz), 21.53 (s); F NMR (376 MHz,
CDCl3) δ –63.06 (s, 3F), –107.85 (dd, J = 241.7, 9.4 Hz, 1F), –110.39 (dd, J = 241.7,
13.7 Hz, 1F) ; MS (ESI, m/z, %): 542.90 (M+Na+, 100.00); HRMS (ESI): Calcd. For
16

ACCEPTED MANUSCRIPT
C22H17F5O5S2Na+: 543.0330; Found: 543.0342.
4.2.8.
2,2-Difluoro-2-(phenylsulfonyl)-1-(4-(trifluoromethoxy)phenyl)ethyl
4-methylbenzenesulfonate (1h)
o
1
Performed on 20-mmol scale, 8.797 g, 83% yield. White solid, m.p. 105–108 C; H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.58 (t, J
= 8.1 Hz, 4H), 7.36 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz,
13
2H), 6.18 (dd, J = 13.6, 9.7 Hz, 1H), 2.36 (s, 3H); C NMR (101 MHz, CDCl3) δ
150.48 (s), 145.55 (s), 135.73 (s), 133.05 (s), 132.71 (s), 130.78 (s), 130.71 (s),
129.57 (s), 129.38 (s), 128.23 (d, J = 2.1 Hz), 128.11 (s), 120.74 (s), 120.26 (q, J =
258.0 Hz), 118.82 (dd, J = 298.6, 290.5 Hz), 76.42 (dd, J = 27.5, 20.7 Hz), 21.50 (s);
19F NMR (376 MHz, CDCl3) δ –58.34 (s, 3F), –108.54 (dd, J = 241.2, 9.6 Hz, 1F), –
110.88 (dd, J = 241.4, 13.6 Hz, 1F) ; MS (ESI, m/z, %): 558.90 (M+Na+, 100.00);
HRMS (ESI): Calcd. For C22H17F5O6S2Na+: 559.0279; Found: 559.0264.
4.2.9.
2,2-Difluoro-1-(naphthalen-2-yl)-2-(phenylsulfonyl)ethyl
4-methylbenzenesulfonate (1i)
o
1
Performed on 20-mmol scale, 8.332 g, 83% yield. White solid, m.p. 145–147 C; H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 2H), 7.80 – 7.64 (m, 5H), 7.60 – 7.46
(m, 6H), 7.37 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 6.32 (dd, J = 14.1, 9.6 Hz,
13
1H), 2.18 (s, 3H); C NMR (101 MHz, CDCl3) δ 145.24 (s), 135.56 (s), 133.89 (s),
133.21 (s), 132.91 (s), 132.47 (s), 130.76 (s), 129.87 (s), 129.38 (s), 129.28 (s),
128.48 (s), 128.35 (s), 128.10 (s), 127.64 (s), 127.42 (s), 126.64 (s), 125.01 (s), 119.23
(dd, J = 298.8, 290.2 Hz), 77.68 (d, J = 20.4, 7.2 Hz), 21.39 (s); 19F NMR (376 MHz,
CDCl3) δ –107.51 (dd, J = 241.2, 9.6 Hz, 1F), –110.19 (dd, J = 241.2, 14.1 Hz, 1F) ;
MS (ESI, m/z, %): 524.90 (M+Na+, 100.00); HRMS (ESI): Calcd. For
C25H10F2O5S2Na+: 525.0612; Found: 525.0603.
4.3.
Typical
experimental
procedures
for
the
synthesis
of
17

ACCEPTED MANUSCRIPT
2,2-diaryl-1,1-difluoroethenes 3a–3l
Under the N2 atmosphere, DME (5.0 mL) was added into an oven-dried 20-mL
Schlenk tube containing tosylate 1a (270.2 mg, 0.6 mmol, 1.0 equiv), phenylboronic
acid (2a) (60.9 mg, 0.5 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0)
(Pd2(dba)3) (18.4 mg, 0.02 mmol, 4 mol%), tri(o-tolyl)phosphine (12.2 mg, 0.04
mmol, 8 mol%), Cs2CO3 (489.0 mg, 1.5 mmol, 3.0 equiv) and a magnetic stir bar. The
mixture were heated to 80 oC and stirred vigorously for 8 hours. After the addition of
petroleum ether (PE) (10 mL), the mixture was filtered through Celite layer. The
filtrate was concentrated under vacuum and purified by flash column chromatography
(silica gel; petroleum ether/diethyl ether, 5:1, v/v) to give the desired product 3a as
colorless oil (77.6 mg, 72% yield).
4.3.1. (2,2-Difluoroethene-1,1-diyl)dibenzene (3a)
Prepared from 1a (0.6 mmol) and phenylboronic acid (2a) (0.5 mmol), 77.6 mg, 72%
1
19
yield. Colorless oil; H NMR (400 MHz, CDCl3) δ 7.39 – 7.26 (m, 9H); F NMR
(376 MHz, CDCl3) δ –87.80 (s, 2F); MS (ESI, m/z, %): 238.95 (M+Na+, 100.00). The
characterization data are in consistence with previous report.14
4.3.2. 1-(2,2-Difluoro-1-phenylvinyl)-4-methylbenzene (3b)
Prepared from 1a (0.6 mmol) and p-tolylboronic acid (2b) (0.5 mmol), 74.5 mg, 76%
yield. Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.22 (m, 9H), 7.15 (s, 4H),
2.36 (s, 3H); 19F NMR (376 MHz, CDCl3) δ –88.10 (d, J = 34.0 Hz, 1F), –88.30 (d, J
= 34.1 Hz, 1F); MS (ESI, m/z, %): 253.00 (M+Na+, 100.00). The characterization
data are in consistence with previous report.14
4.3.3. 1-(2,2-Difluoro-1-phenylvinyl)-3-methylbenzene (3c)
Method A, prepared from 1a (0.6 mmol) and m-tolylboronic acid (2c) (0.5 mmol),
53.7 mg, 61% yield; Method B, prepared from 1b (0.6 mmol) and phenylboronic acid
1
(2a) (0.5 mmol), 62.5 mg, 71% yield. Colorless oil; H NMR (400 MHz, CDCl3) δ
18

ACCEPTED MANUSCRIPT
7.39 – 7.19 (m, 6H), 7.15 – 7.03 (m, 3H), 2.33 (s, 3H); 19F NMR (376 MHz, CDCl3) δ
–87.79 (d, J = 32.9 Hz, 1F), –88.14 (d, J = 32.8 Hz, 1F); MS (ESI, m/z, %): 253.0
(M+Na+, 100.00). The characterization data are in consistence with previous report.14
4.3.4. 1-(2,2-Difluoro-1-phenylvinyl)-4-methoxybenzene (3d)
Prepared from 1a (0.6 mmol) and 4-methoxyphenylboronic acid (2d) (0.5 mmol),
67.8 mg, 64% yield. Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.22 (m, 5H),
7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 3.81 (s, 1H), 3.81 (s, 3H); 19F NMR
(376 MHz, CDCl3) δ –88.73 (d, J = 34.9 Hz, 1F), –88.91 (d, J = 34.9 Hz, 1F); MS
(ESI, m/z, %): 269.0 (M+Na+, 100.00). The characterization data are in consistence
with previous report.14
4.3.5. (4-(2,2-Difluoro-1-phenylvinyl)phenyl)(methyl)sulfane (3e)
Prepared from 1a (0.6 mmol) and 4-(methylthio)phenylboronic acid (2e) (0.5 mmol),
66.1 mg, 58% yield. Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.21 (m, 7H),
19
7.17 (d, J = 8.4 Hz, 2H), 2.48 (s, 3H); F NMR (376 MHz, CDCl3) δ –87.67 (d, J =
32.4 Hz, 1F), –87.77 (d, J = 32.4 Hz, 1F); MS (ESI, m/z, %): 284.95 (M+Na+,
100.00) . The characterization data are in consistence with previous report.8b
4.3.6. 1-(2,2-Difluoro-1-phenylvinyl)-3-methoxybenzene (3f)
Prepared from 1a (0.6 mmol) and 3-methoxyphenylboronic acid (2f) (0.5 mmol), 58.3
mg, 55% yield. Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.24 (m, 6H), 6.86
19
– 6.81 (m, 3H), 3.77 (s, 3H); F NMR (376 MHz, CDCl3) δ –87.09 (d, J = 31.8 Hz,
1F), –87.56 (d, J = 31.7 Hz, 1F); MS (ESI, m/z, %): 268.95 (M+Na+, 100.00). The
characterization data are in consistence with previous report.8b
4.3.7. 1-(2,2-Difluoro-1-phenylvinyl)-4-(trifluoromethyl)benzene (3g)
Method A, prepared from 1a (0.6 mmol) and 4-(trifluoromethyl)phenylboronic acid
(2g) (0.5 mmol), 62.4 mg, 50% yield; Method B, prepared from 1g (0.6 mmol) and
19

ACCEPTED MANUSCRIPT
phenylboronic acid (2a) (0.5 mmol), 91.1 mg, 73% yield. Colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.38 – 7.29 (m, 5H),7.23 (dd, J = 8.1, 7.0 Hz,
19
2H); F NMR (376 MHz, CDCl3) δ –62.74 (s, 3F), –85.74 (d, J = 28.1 Hz, 1F),
-86.47 (d, J = 28.1 Hz, 1F); MS (ESI, m/z, %): 322.95 (M+Na+, 100.00). The
characterization data are in consistence with previous report.9a
4.3.8. 1-(2,2-Difluoro-1-phenylvinyl)-4-(trifluoromethoxy)benzene (3h)
Method A, prepared from 1a (0.6 mmol) and 4-(trifluoromethoxy)phenylboronic acid
(2h) (0.5 mmol), 85.1 mg, 64% yield; Method B, prepared from 1h (0.6 mmol) and
phenylboronic acid (2a) (0.5 mmol), 86.2 mg, 65% yield. Colorless oil; 1H NMR (400
19
MHz, CDCl3) δ 7.39 – 7.24 (m, 7H), 7.19 (d, J = 8.1 Hz, 2H); F NMR (376 MHz,
CDCl3) δ –57.86 (s), –86.88 (d, J = 30.7 Hz, 1F), –87.33 (d, J = 30.7 Hz, 1F); MS
(ESI, m/z, %): 322.95 (M+Na+, 100.00). The characterization data are in consistence
with previous report.9a
4.3.9. 2-(2,2-Difluoro-1-phenylvinyl)naphthalene (3i)
Method A, prepared from 1a (0.6 mmol) and 2-naphthylboronic acid (2i) (0.5 mmol),
81.2 mg, 70% yield; Method B, prepared from 1i (0.6 mmol) and phenylboronic acid
1
(2a) (0.5 mmol), 84.7 mg, 73% yield. Colorless oil; H NMR (400 MHz, CDCl3) δ
19
7.83 – 7.72 (m, 4H), 7.48 – 7.46 (m, 2H), 7.34 – 7.29 (m, 6H); F NMR (376 MHz,
CDCl3) δ –87.35 (d, J = 31.5 Hz, 1F), –87.56 (d, J = 31.5 Hz, 1F); MS (ESI, m/z, %):
289.0 (M+Na+, 100.00). The characterization data are in consistence with previous
report.9a
4.3.10. 1-(2,2-Difluoro-1-phenylvinyl)-4-isopropylbenzene (3k)
Prepared from 1d (0.6 mmol) and phenylboronic acid (2a) (0.5 mmol), 83.8 mg, 65%
1
yield. Colorless oil; H NMR (400 MHz, CDCl3) δ 7.36 – 7.26 (m, 5H), 7.21 – 7.16
19
(m, 4H), 2.91 (hept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H); F NMR (376 MHz,
CDCl3) δ –88.23 (d, J = 2.8 Hz, 2F); MS (ESI, m/z, %): 281.0 (M+Na+, 100.00). The
20

ACCEPTED MANUSCRIPT
characterization data are in consistence with previous report.9a
4.3.11. 1-(tert-Butyl)-4-(2,2-difluoro-1-phenylvinyl)benzene (3l)
Prepared from 1e (0.6 mmol) and phenylboronic acid (2a) (0.5 mmol), 84.3 mg, 62%
1
yield. Colorless oil; H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m, 4H), 7.30 – 7.26
(m, 3H), 7.19 (d, J = 8.1 Hz, 2H), 1.32 (s, 2H); 19F NMR (376 MHz, CDCl3) δ –88.02
(d, J = 33.4 Hz, 1F), –88.20 (d, J = 33.4 Hz, 1F); MS (ESI, m/z, %): 295.0 (M+Na+,
100.00). The characterization data are in consistence with previous report.14
Acknowledgments
Support of our work by the National Basic Research Program of China
(2015CB931900), the National Key Research and Development Program of China
(2016YFB0101200), the National Natural Science Foundation of China (21632009,
21472221, 21421002, and 21372246), the Key Programs of the Chinese Academy of
Sciences (KGZD-EW-T08), the Key Research Program of Frontier Sciences of CAS
(QYZDJ-SSW-SLH049), and the Shanghai Academic Research Leader Program
(15XD1504400) is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary
data
related
to
this
article
can
be
found
at
https://doi.org/10.1016/j.tet.2018.xx.xxx.
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14. Zhang Z, Yu W, Zhou Q, Li T, Zhang Y, Wang J. Chin J Chem. 2016;34:473.
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15. For reviews, see: (a) Ni C, Hu J. Chem Soc Rev. 2016;45:5441;
(b) Ni C, Hu M, Hu J. Chem Rev. 2015;115:765;
(c) Zhang W, Ni C, Hu J. Top Curr Chem. 2012;308, 25;
(d) Ni C, Hu J. Synlett. 2011; 770;
(e) Hu J. J Fluorine Chem. 2009;130:1130;
(f) Hu J, Zhang W, Wang F. Chem Commun. 2009;7465;
(g) Prakash GKS, Hu J. Acc Chem Res. 2007;40:921;
(h) Liu Q, Ni C, Hu J. Natl Sci Rev. 2017;4:303.
16. For selected recent examples, see: (a) Rong J.; Deng L.; Tan P.; Ni C.; Gu Y.; Hu J.
Angew Chem Int Ed. 2016;55:2743;
(b) Rong J.; Ni C.; Wang Y.; Kuang C.; Gu Y.; Hu J. Acta Chim Sinica.
2017;75:105;
(c) Miao W, Zhao Y, Ni C, Gao B, Zhang W, Hu J. J Am Chem Soc. 2018;140:880;
(d) Merchant RR, Edwards JT, Qin T, Kruszyk MM, Bi C, Che G, Bao D-H, Qiao
W, Sun L, Collins MR, Fadeyi OO, Gallego GM, Mousseau JJ, Nuhant P, Baran
PS. Science. 2018; DOI: 10.1126/science.aar7335;
(e) Miao W, Ni C, Zhao Y, Hu J. Org Lett. 2016;18:2766;
(f) Xiao P, Rong J, Ni C, Guo J, Li X, Chen D, Hu J. Org Lett. 2016;18:5912;
(g) Li X, Zhao J-W, Hu M, Chen D, Ni C, Wang L, Hu, J. Chem Commun.
2016;52:3657;
(h) Zhao Y, Jiang F, Hu J. J Am Chem Soc. 2015;137:5199;
(i) Zhao Y, Ni C, Jiang F, Gao B, Shen X, Hu J. ACS Catalysis. 2013;3:631;
(j) Zhao Y, Gao B, Ni C, Hu J. Org Lett. 2012;14:6080;
(k) Su Y-M, Feng G-S, Wang Z-Y, Lan Q, Wang X-S. Angew Chem Int Ed.
2015;54:6003;
(l) Zhao Y, Gao B, Hu J. J Am Chem Soc. 2012;134:5790;
(m) Prakash GKS, Ni C, Wang F, Hu J, Olah GA. Angew Chem Int Ed.
2011;50:2559;
(n) Prakash GKS, Ni C, Wang F, Zhang Z, Haiges R, Olah GA. Angew Chem Int
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Ed. 2013;52:10835;
(o) He Z, Luo T, Hu M, Cao Y, Hu J. Angew Chem Int Ed. 2012;51:3944;
(p) Shen X, Zhang L, Zhao Y, Zhu L, Li G, Hu J. Angew Chem Int Ed.
2011;50:2588.
17. Zhang L, Li Y, Hu J. J Fluorine Chem. 2007;128:755.
18. Prakash GKS, Hu J, Wang Y, Olah GA. Eur J Org Chem. 2005;2218.
19. Shen X, Ni C, Hu J. Chin J Chem. 2013;31:878.
20. Brambilla M, Tredwell M. Angew Chem Int Ed. 2017;56:11981.
21. (a) Hine J, Porter JJ. J Am Chem Soc. 1960;82:6178;
(b) Langlois BR. J Fluorine Chem. 1988;41:247;
(c) Wang X, Liu G, Xu X-H, Shibata N, Tokunaga E, Shibata N. Angew Chem Int
Ed. 2014;53:1827.
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