Palladium-Catalyzed Ring-Opening Coupling of gem-Difluorocyclopropanes for the Construction of 2-Fluoroallylic Sulfones

Article abstract of DOI:10.1021/acs.joc.9b01897

A Pd-catalyzed ring-opening sulfonylation of gem-difluorocyclopropanes is reported. This protocol involves C-C bond cleavage, β-F elimination, and allylic coupling to form corresponding 2-fluoroallylic sulfones efficiently with Z-selectivity. Different substrates bearing diverse functional groups are tolerated. Moreover, this method is successfully used for the late-stage derivation of several bioactive molecules.

Full text of DOI:10.1021/acs.joc.9b01897

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Article
Palladium-Catalyzed Ring-Opening Coupling of gem-
Difluorocyclopropanes for the Construction of 2-Fluoroallylic Sulfones
Jiabin Ni, Bekzod Nishonov, Azizbek Pardaev, and Ao Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01897 • Publication Date (Web): 20 Sep 2019
Downloaded from pubs.acs.org on September 21, 2019
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Palladium-Catalyzed Ring-Opening Coupling of
gem-Difluorocyclopropanes for the Construction of
2-Fluoroallylic Sulfones
Jiabin Ni,†,‡ Bekzod Nishonov,†,‡ Azizbek Pardaev,†,‡ and Ao Zhang*,†,‡,#
†CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese
Academy of Sciences, Shanghai 201203, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
#School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
F F
Pd
SO2Ar
R
F
R
ArSO2Na

Ring-opening/-F elimination
Broad substrate scope
Z-Selectivity
Late-stage functionalization
ABSTRACT: A Pd-catalyzed ring-opening sulfonylation of gem-difluorocyclopropanes is reported. This
protocol involves C-C bond cleavage, β-F elimination and allylic coupling to form corresponding
2-fluoroallylic sulfones efficiently with Z-selectivity. Different substrates bearing diverse functional groups
are tolerated. Moreover, this method is successfully used for the late-stage derivation of several bioactive
molecules
.
INTRODUCTION
In the past few decades, organic fluorine chemistry has significantly flourished owing to its wide
applications in drug discovery and material science1. The introduction of fluorine atoms can provide
potentials to improve the polarity, lipophilicity and metabolic stability of certain drug molecules1.
Among the fluorine-containing molecules, monofluoroalkenes have attracted significant intetests in
medicinal chemistry,2 especially as amide bond isosteres or mimic of enols3. They can also be
viewed as fluorinated synthons for further derivations4. Thus, the wide utility of monofluoroalkenes
has spurred substantial advances in the development of new methodologies for their synthesis5.
Scheme 1. Previous Reports on Transition-metal-catalyzed Ring-opening Reactions of
gem-Difluorocyclopropanes
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Previous work
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Transition-metal
R
FG
F
a)
R
F
F
cat. Pd
FG= N, O, C
(Fu Group)
cat. Ni
FG= H
9
(Gade Group)
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(limited functional groups)
R
b)
cat. Ag
TMSO
F
Ar2
Ar1
Ar1H, Ar2H
R
F
F
(substrates are difficult to prepare)
Recently, structurally unique gem-difluorocyclopropanes were successfully synthesized,6 providing an
attractive option to access high value fluorinated compounds by transition-metal-catalyzed ring-opening
strategy.7-9 Fu and coworkers9a,b firstly reported the Pd-catalyzed ring-opening couplings of
gem-difluorocyclopropanes with N-, O-, or C-nucleophilics to form 2-fluoroallylic products in high
regioselectivity. Later, Gade and coworkers9c reported the nickel complex-induced C-F bond activation of
gem-difluorocyclopropanes via a radical mechanism (Scheme 1a). In addition, the Ag-catalyzed
ring-opening diarylation of gem-difluorocyclopropanes containing an O-substituent was realized by Wang
group9d (Scheme 1b). Despite the achievements in the formation of monofluoroalkenes from ring-opening of
gem-difluorocyclopropanes, the current approaches still suffer from limited functional groups that can be
introduced, together with narrow substrate scope and applications. Therefore, development of new protocols
that allow for introduction of diverse functional groups on the fluoroalkenes is highly anticipated.
Scheme 2. Outline of Our Work
a) Important fluorinated-allylic scaffold
F F
O
O
H2N
S
S
O
O
F
F
Br
Liquid crystal
SSAO/VAP-1 inhibitor
b) This work
R
F
F
R
SO2Ar
Pd
F
Ring-opening/ -F elimination

Broad substrate scope
Z-selectivity
Late-stage functionalization
In view of the important significance of sulfonyl compounds in drugs, agrochemicals and
materials10,11 (Scheme 2a), and the potential for further functionalization at the adjacent carbon due
to the sulfonyl group's strong electron-withdrawing nature, we decided to develop a new and
versatile method to incorporate a sulfonyl group onto the 2-fluoroallylic scaffold through the
ring-opening coupling of gem-difluorocyclopropanes with sodium arylsulfinates under palladium
catalysis (Scheme 2b).
RESULTS AND DISCUSSION
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Table 1. Reaction Optimizationa
5
6
F F
O
S
7
8
9
[Pd] (10 mol%), ligand (10 mol%)
+
O
PhSO2Na
F
Base (1.5 equiv.), solvent, N2, 100 oC
2a
10
11
12
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1a
3a
entry [Pd]
ligand
base
Additive
solvent
PhMe
1,4-dioxane
DCE
yield[%]b
Trace
N.R.
63%
N.R.
N.R.
56%
31%
60%
49%
14%
28%
21%
22%
N.R.
46%
N.R.
Trace
82%
N.R.
1
Pd(TFA)2
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
S-Phos
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
/
2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
PdCl2
/
3
/
4
/
DMF
DMSO
DCE
5
/
6
/
7
/
DCE
8
Pd(dba)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
/
DCE
9
/
DCE
10
11
12
13
14
15c
16d
17d
18d
19
tBu-X-Phos K3PO4
/
DCE
XantPhos
dppf
K3PO4
K3PO4
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
/
DCE
/
DCE
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
/
DCE
/
DCE
H2O
nBu4NI
nBu4NBF4 DCE
nBu4NPF6 DCE
nBu4NPF6
DCE
DCE
Pd(TFA)2 X-Phos
/
X-Phos
DCE
aReaction conditions: 1a (0.10 mmol), 2a (0.20 mmol), [Pd] (0.010 mmol), ligand (0.010 mmol), base (0.15
o
b
c
d
mmol), solvent (1.0 ml), 100 C, N2, 16h. Isolated yield. H2O (10 μL). Quaternary ammonium salt (20
mol%).
Initially, we commenced our reaction with 2-(2,2-difluorocyclopropyl)naphthalene (1a) and sodium
benzenesulfinate (2a) as the model substrates under Pd(TFA)2/X-Phos/K3PO4 reaction system (Table 1).
After examination of various solvents, the desired product 2-fluoroallylic sulfone 3a was obtained in 63%
yield using DCE as the solvent (entry 1-5). The structure of 3a and its Z-configuration were confirmed by its
crystal structure (Scheme 3)12. Then a number of palladium catalysts were screened and Pd(TFA)2 remains
the optimal (entries 6-8). Subsequently, different phosphine ligands such as monodentate ligands (S-Phos
t
and Bu-X-Phos) and bidentate ligands (XantPhos and dppf) were screened, but no improvements were
observed (entries 9-12). Switching the bases led to inferior results (entries 13-14). Further, addition of H2O
was found unable to improve the yield (entry 15). Moreover, a phase transfer catalyst (nBu4NX) was added
to enhance the solubility of PhSO2Na in DCE (entries 16-18). Gratifyingly, 10 mol% of nBu4NPF6 promoted
the substrate transformation and the product was obtained in 82% isolated yield . It is of note that no
conversion occurred in the absence of palladium catalyst (entry 19). Collectively, the reaction conditions in
entry 18 is selected as the optimal and standard conditions for further investigation.
Scheme 3. Sulfonylation Reactions with Sodium Arylsulfinatesa
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F
F
O
5
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7
8
Pd(TFA)2 (10 mol%), X-Phos (10 mol%)
S
+
Ar
ArSO2Na
2
O
F
K3PO4 (1.5 equiv.), nBu4NPF6 (20 mol%),
DCE, N2, 100 oC, 16h
1a
F
3
9
3b, X= Me, 78%;
3c, X= iPr, 73%;
3d, X= tBu, 70%;
3e, X= OMe, 76%;
3f, X= F, 69%;
O
S
10
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O
S
O
O
F
3a 82% (71%b)
X
CCDC 1910759
3g, X=CF3, 55%;
3h, X= COOMe, 59%;
3i, X= Ac, 47%;
O
O
S
O
F
O
S
S
O
Me
O
F
3l 47%
F
MeO
3k 81%
OMe
Me
3j 45%
Me
O
Me
O
O
S
S
O
S
CF3
F
3o N.R.
O
F
O
F
3m 60%
3n 42%
aReaction conditions: 1a (0.10 mmol), 2 (0.20 mmol), Pd(TFA)2 (0.010 mmol), X-phos (0.010 mmol),
K3PO4 (0.15 mmol), nBu4NPF6 (0.020 mmol), DCE (1.0 mL), 100 °C, N2, 16 h. Yield of isolation. b1 mmol
scale.
Next, the substrate scope with respect to various sodium arylsulfinates was explored, and the results are
shown in Scheme 3. Generally, the reactions proceeded smoothly (3b-n). Aryl sulfinates bearing
electron-donating (Me, iPr, tBu, MeO) or electron-withdrawing groups (F, CF3, COOMe, Ac) at
para-position offered the corresponding products 3b-i in 47-78% yields. It is worth noting that the
disubstituted sodium arylsulfinates were also compatible, and the yields of 3j and 3k were 45% and 81%,
respectively. Moreover, sodium arylsulfinates with a methyl substituent either at the meta or the
ortho-position were found compatible as well, affording the corresponding product 3l or 3m in moderate
yields. The bulky naphthylsulfinate was also tolerant, giving the product 3n in an acceptable yield.
Unfortunately, no desired product (3o) was obtained when alkyl sulfinate salt CF3SO2Na was used as the
coupling partner under the standard conditions.
Further, we surveyed the scope of the reaction using various substituted gem-difluorocyclopropane
substrates (Scheme 4). It was found that the gem-difluorocyclopropanes with diverse electronic or
steric para-substituents were well suited under the standard conditions. Both electron-donating
t
groups such as Me, Bu, OMe, OBn, (4a-d) as well as the electron-withdrawing groups such as F,
CN, OAc, COOMe (4e-h) on arenes were well tolerated in the reaction. Notably, the survival of the
chloro substituent on the phenyl (4i) during this transformation provided further synthetic potential.
Gratifyingly, (difluorocyclopropyl)benzene equipped with 2,5-disubstituted methyl also gave the
expected product 4j in 73% yield. Moreover, pyrene substrate participated in the reaction as well,
providing product 4k in 41% yield.
Scheme 4. Sulfonylation Reactions with gem-Difluorocyclopropanesa
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F
F
O
5
6
7
8
Pd(TFA)2 (10 mol%), X-Phos (10 mol%)
S
+
Ph
PhSO2Na
2a
R
R
O
F
K3PO4 (1.5 equiv.), nBu4NPF6 (20 mol%),
DCE, N2, 100 oC, 16h
1
4
9
O
S
10
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4a, X= Me, 63%;
4b, X= tBu, 76%;
4c, X= OMe, 63%;
4d, X= OBn, 61%;
O
S
4e, X= F, 69%;
4f, X= CN, 35%;
4g, X= OAc, 48%;
4h, X= COOEt, 59%
O
F
O
F
F
X
4i 61%
Cl
Me
Me
O
O
Me
H
O
S
S
O
H
H
O
F
F
O
S
4j 73%
4k 41%
O
From esterone
4l 66%
Late-stage functionalization of bioactive molecules
O
Me
O
O
H
H
F
O
O
S
O
H
F
O
O
O
S
O
From clofibrate
4n 44%
From esterone
4m 65%
O
O
O
O
O
F
O
S
O
O
O
O
S
O
O
O
O
F
O
From fenofibrate
4o 42%
From diacetone-D-glucose
4p 34%
aReaction conditions: 1 (0.10 mmol), 2a (0.20 mmol), Pd(TFA)2 (0.010 mmol), X-phos (0.010
n
mmol), K3PO4 (0.15 mmol), Bu4NPF6 (0.020 mmol), DCE (1.0 mL), 100 °C, N2, 16 h. Yield of
isolation.
To further illustrate the value of this palladium-catalyzed ring-opening coupling protocol, we
proceed to conduct the reaction with pharmaceutically useful substrates. Appealingly, the bioactive
molecules equipped with the 2-fluoroallylic sulfone scaffold, including esterone derivatives (4l-m),
cholesterol-lowering drug clofibrate and fenofibrate derivatives 4n and 4o, as well as
diacetone-d-glucose derivative (4p), were obtained under the standard reaction conditions in yields
up to 66%. Since these derivatives are not easily prepared through previously reported methods, the
current protocol provides a valuable tool for late-stage functionalization of bioactive molecules in
drug discovery.
Scheme 5. Mechanistic Studies
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F F
O
5
6
7
8
Standard conditions
S
Ph
+
PhSO2Na
2a
O
a)
F
Radical scavenger
3a
1a
9
Radical scavenger
Isolated yield of 3a
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None
82%
55%
74%
57%
TEMPO (1 equiv)
1,1-Diphenylethylene (1 equiv)
BQ (1 equiv)
Standard conditions
b)
+
PhSO2Na
N.R.
2a
Subsequently, radical scavenger experiments were conducted to investigate the reaction
mechanism (Scheme 5a). The addition of radical scavenger, including TEMPO,
a
1,1-diphenylethylene or 1,4-benzoquinone (BQ) under the standard reaction condition, failed to
significantly suppress the reaction, suggesting a radical pathway is not involved9a. Further, in the
case of 2-cyclopropylnaphthalene as the substrate, the ring-opening coupling reaction did not occur,
pointing out the importance of the gem-difluoro moiety on the palladium-catalyzed ring-opening of
cyclopropane (Scheme 5b).
On the basis of the above investigations and the previous reported ring-opening reactions9 of
gem-difluorocyclopropanes, a plausible mechanism for production of the current sulfonated
2-fluoroallyl derivatives is shown in Scheme 6. First, the transformation is started by the oxidative
insertion of Pd(0) to cyclopropane C-C bond (para to gem-difluoro) due to “the fluorine effect” 13,
thus forming a cyclopalladium species I. A β-fluoro elimination then occurs to form the
2-fluorinated π-allyl palladium intermediate II. Subsequent nucleophilic attack14 of sodium
arylsulfinates followed by decomplexation of palladium species affords the corresponding
2-fluoroallylic products.
Scheme 6. The Proposed Mechanism
F F
Pd(0)
F
Ar
Pd
F
Oxidative addition
Ar
I
-F elimination

F
Coupling
F
Ar
FG
Ar
FG= ArSO2
Pd F
II
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In summary, a palladium-catalyzed ring-opening coupling of gem-difluorocyclopropanes with a
range of sodium arylsulfinates is developed. The 2-fluoroallylic sulfones are obtained in moderate to
good yields with Z-selectivity. This method features good compatibility with broad substrates and
substituents. Furthermore, this protocol is successfully applied to late-stage diversification of a class
of bioactive compounds, which may be useful in drug discovery.
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EXPERIMENTAL SECTION
All solvents and commercially chemicals were purchased from Adamas-beta, J&K, Alfa Aesar, TCI or
Energy Chemicals, and used without further purifications. The reaction products were purified by column
chromatography or PTLC. 1H and 13C NMR spectra were measured using CDCl3 as the solvent. Mass spectra
were conducted at the EI or ESI-TOF mode. The melting points were measured by a melting point apparatus
and were uncorrected. The reaction reagents ArSO2Na were synthesized according to the previous report.15
Synthetic procedure for gem-difluorocyclopropanes 19a. A 25 ml sealed tube was added with
anhydrous NaI (0.220 g, 20 mol%), 5 ml of THF as solvent, and an appropriate alkene (7.34 mmol, 1.0 equiv)
under N2. TMSCF3 (2.72 ml, 2.50 equiv) was then added. The mixture was warmed to 65 oC in oil bath and
stirred for 4 h. The solvents were removed under reduced pressure. The residue was isolated through column
chromatography to afford corresponding product 1.
o
1
1-(Benzyloxy)-4-(2,2-difluorocyclopropyl)benzene (1e). White solid, mp 53-54 C. H NMR (400 MHz,
CDCl3) δ 7.45 – 7.35 (m, 4H), 7.32 (t, J = 7.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H),
5.04 (s, 2H), 2.69 (td, J = 12.5, 8.2 Hz, 1H), 1.82 – 1.69 (m, 1H), 1.58 – 1.49 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 158.0, 136.9, 129.2, 128.6, 128.0, 127.4, 125.9, 114.9, 112.7 (dd, J = 286.7, 284.6 Hz), 70.0, 26.5
(t, J = 11.5 Hz), 16.9 (t, J = 10.5 Hz); Ms (EI): m/z = 260 [M]+; HRMS (EI): m/z [M]+ Calcd for C16H14F2O,
260.1007; Found, 260.1010.
4-(2,2-Difluorocyclopropyl)phenyl acetate (1h). Colorless liquid, 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J
= 8.4 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 2.74 (td, J = 12.5, 8.2 Hz, 1H), 2.29 (s, 3H), 1.88 – 1.77 (m, 1H),
1.63 – 1.53 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 169.4, 149.8, 131.3, 129.1, 121.6, 112.4 (dd, J = 287.2,
284.6 Hz), 26.6 (t, J = 11.5 Hz), 21.1, 17.3 (t, J = 10.6 Hz); Ms (EI): m/z = 212 [M]+; HRMS (EI): m/z [M]+
Calcd for C11H10F2O2, 212.0643; Found, 212.0641.
1-(2,2-Difluorocyclopropyl)pyrene (1l). White solid, mp 96-97 oC. 1H NMR (400 MHz, CDCl3) δ 8.31 (d,
J = 9.2 Hz, 1H), 8.19 – 8.12 (m, 3H), 8.09 (d, J = 7.9 Hz, 1H), 8.04 – 7.96 (m, 3H), 7.87 (d, J = 7.9 Hz, 1H),
3.36 (td, J = 12.3, 8.4 Hz, 1H), 2.15 – 2.05 (m, 1H), 1.93 – 1.84 (m, 1H); 13C NMR (126 MHz, CDCl3) δ
131.3, 130.9, 130.8, 130.7, 128.1, 127.5, 127.3, 127.1, 126.03, 126.00, 125.32, 125.30, 124.7, 124.6, 124.5,
123.4, 113.1 (dd, J = 285.8, 284.1 Hz), 25.6 (t, J = 11.4 Hz), 16.8 (t, J = 10.7 Hz); Ms (EI): m/z = 278 [M]+;
HRMS (EI): m/z [M]+ Calcd for C19H12F2, 278.0902; Found, 278.0900.
(8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-
o
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3-yl 4-(2,2-difluorocyclopropyl)benzoate (1n). White solid, mp 176-177 C. H NMR (400 MHz, CDCl3) δ
8.15 (d, J = 8.4 Hz, 2H), 7.38 – 7.32 (m, 3H), 7.01 – 6.96 (m, 1H), 6.94 (s, 1H), 2.99 – 2.91 (m, 2H), 2.83 (td,
J = 12.2, 8.2 Hz, 1H), 2.52 (dd, J = 18.8, 8.6 Hz, 1H), 2.43 (d, J = 16.7 Hz, 1H), 2.33 (s, 1H), 2.15 (dt, J =
22.6, 6.4 Hz, 1H), 2.10 – 1.87 (m, 4H), 1.77 – 1.69 (m, 1H), 1.66 – 1.45 (m, 6H), 0.93 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 220.7, 165.1, 148.8, 139.7, 138.1, 137.5, 130.3, 128.5, 128.1, 126.5, 121.7, 118.8,
112.2 (dd, J = 288.3, 284.8 Hz), 50.5, 47.9, 44.2, 38.0, 35.8, 31.6, 29.4, 27.3 (t, J = 11.6 Hz), 26.4, 25.8, 21.6,
17.6 (t, J = 10.5 Hz), 13.8; Ms (EI): m/z = 450 [M]+; HRMS (EI): m/z [M]+ Calcd for C28H28F2O3, 450.2001;
Found, 450.2001.
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Ethyl 2-(4-(2,2-difluorocyclopropyl)phenoxy)-2-methylpropanoate (1o). Colorless liquid, H NMR (400
MHz, CDCl3) δ 7.09 (d, J = 8.7 Hz, 2H), 6.83 – 6.76 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.75 – 2.62 (m, 1H),
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1.83 – 1.72 (m, 1H), 1.59 (s, 6H), 1.56 – 1.49 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3)
δ 174.2, 154.6, 128.8, 127.2, 119.1, 112.6 (dd, J = 287.2, 284.8 Hz), 79.2, 61.4, 26.5 (t, J = 11.5 Hz), 25.3,
17.1 (t, J = 10.5 Hz), 14.0; Ms (EI): m/z = 284 [M]+; HRMS (EI): m/z [M]+ Calcd for C15H18F2O3, 284.1219;
Found, 284.1232.
Isopropyl 2-(4-(4-(2,2-difluorocyclopropyl)benzoyl)phenoxy)-2-methylpropanoate (1p). White solid, mp
50-51 oC. 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 10.0, 8.7 Hz, 4H), 7.32 (d, J = 8.2 Hz, 2H), 6.86 (d, J
= 8.9 Hz, 2H), 5.09 (dt, J = 12.6, 6.3 Hz, 1H), 2.82 (td, J = 12.2, 8.3 Hz, 1H), 1.96 – 1.85 (m, 1H), 1.76 –
1.68 (m, 1H), 1.66 (s, 6H), 1.20 (d, J = 6.3 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 194.9, 173.1, 159.5,
138.0, 136.9, 131.9, 130.5, 129.9, 127.7, 117.1, 112.2 (dd, J = 287.8, 284.3 Hz), 79.3, 69.3, 27.2 (t, J = 11.5
Hz), 25.3, 21.4, 17.4 (t, J = 10.5 Hz); Ms (EI): m/z = 402 [M]+; HRMS (EI): m/z [M]+ Calcd for C23H24F2O4,
402.1637; Found, 402.1637.
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(3aS,5S,6R,6aS)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-y
l 4-(2,2-difluorocyclopropyl)benzoate (1q). White solid, mp 93-94 oC. 1H NMR (400 MHz, CDCl3) δ 7.99 (d,
J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 5.95 (d, J = 3.6 Hz, 1H), 5.49 (d, J = 2.6 Hz, 1H), 4.62 (d, J = 3.7
Hz, 1H), 4.39 – 4.30 (m, 2H), 4.14 – 4.06 (m, 2H), 2.80 (td, J = 12.2, 8.2 Hz, 1H), 1.96 – 1.85 (m, 1H), 1.74
– 1.65 (m, 1H), 1.56 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.8,
139.7, 129.9, 128.4, 128.1, 112.4, 112.1 (dd, J = 288.4, 284.6 Hz), 109.4, 105.1, 83.4, 80.0, 76.7, 72.6, 67.3,
27.3 (t, J = 11.5 Hz), 26.8, 26.7, 26.2, 25.2, 17.6 (t, J = 10.6 Hz); Ms (ESI): m/z = 463.4 [M+Na]+; HRMS
(ESI): m/z [M+Na]+ Calcd for C22H26F2O7Na, 463.1539; Found, 463.1548.
General procedure for 2-fluoroallylic sulfones. A dry 10 mL sealed tube was added with
gem-difluorocyclopropane 1 (0.10 mmol), ArSO2Na 2a (0.20 mmol), Pd(TFA)2 (3.3 mg, 0.010 mmol),
X-phos (4.8 mg, 0.010 mmol), K3PO4 (31.8 mg, 0.15 mmol), nBu4NPF6 (7.7 mg, 0.020 mmol), and DCE (1.0
mL) under N2. The reaction was stirred for 16 h at 100 oC in oil bath. The mixture was cooled, diluted with
DCM, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was
purified by PTLC to afford corresponding product 3 or 4.
(Z)-2-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)naphthalene (3a). White solid, yield: 82% (26.7 mg);
mp 116-117 oC. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.4, 1.2 Hz, 2H), 7.83 (s, 1H), 7.81 – 7.75 (m,
3H), 7.71 – 7.65 (m, 1H), 7.59 – 7.51 (m, 3H), 7.50 – 7.44 (m, 2H), 5.77 (d, J = 37.1 Hz, 1H), 4.12 (d, J =
18.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 148.4 (d, J = 266.1 Hz), 138.1, 134.2, 133.2, 132.9, 129.4 (d, J
= 3.6 Hz), 129.3, 128.6, 128.4 (d, J = 7.6 Hz), 128.2, 128.2, 127.6, 126.5, 126.4, 126.2 (d, J = 7.7 Hz), 114.5
(d, J = 6.6 Hz), 61.1 (d, J = 29.6 Hz); Ms (ESI): m/z = 349.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C19H15FO2SNa, 349.0699; Found, 349.0675.
(Z)-2-(2-Fluoro-3-tosylprop-1-en-1-yl)naphthalene (3b). Pale yellow solid, yield: 78% (26.5 mg); mp
136-137 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.74 (m, 6H), 7.54 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 6.1,
3.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.79 (d, J = 37.1 Hz, 1H), 4.10 (d, J = 18.7 Hz, 2H), 2.44 (s, 3H); 13
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NMR (126 MHz, CDCl3) δ 148.6 (d, J = 266.0 Hz), 145.3, 135.2, 133.2, 132.8, 129.9, 129.5 (d, J = 3.5 Hz),
128.6, 128.4 (d, J = 7.6 Hz), 128.2, 128.1, 127.6, 126.5, 126.4, 126.2 (d, J = 7.7 Hz), 114.3 (d, J = 6.6 Hz),
61.2 (d, J = 29.6 Hz), 21.7; Ms (ESI): m/z = 363.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C20H17FO2SNa, 363.0825; Found, 363.0831.
(Z)-2-(2-Fluoro-3-((4-isopropylphenyl)sulfonyl)prop-1-en-1-yl)naphthalene (3c). White solid, yield: 73%
(27.0 mg); mp143-144 oC. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.83 – 7.76 (m, 4H), 7.54
(dd, J = 8.6, 1.6 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.40 (d, J = 8.3 Hz, 2H), 5.75 (d, J = 37.1 Hz, 1H), 4.11 (d, J
= 18.7 Hz, 2H), 3.00 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 156.0,
148.6 (d, J = 266.4 Hz), 135.4, 133.2, 132.8, 129.6 (d, J = 3.6 Hz), 128.8, 128.4, (d, J = 7.6 Hz), 128.2,
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128.1, 127.6, 127.4, 126.5, 126.4, 126.2 (d, J = 7.6 Hz), 114.4 (d, J = 6.7 Hz), 61.2 (d, J = 29.5 Hz), 34.3,
23.6; Ms (ESI): m/z = 391.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C22H21FO2SNa, 391.1138;
Found, 391.1143.
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(Z)-2-(3-((4-(tert-Butyl)phenyl)sulfonyl)-2-fluoroprop-1-en-1-yl)naphthalene (3d). White solid, yield:
70% (26.7 mg); mp 153-154 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.6 Hz, 2H), 7.83 – 7.76 (m, 4H),
7.59 – 7.52 (m, 3H), 7.48 (dd, J = 6.3, 3.1 Hz, 2H), 5.74 (d, J = 37.1 Hz, 1H), 4.11 (d, J = 18.7 Hz, 2H), 1.35
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 158.3, 148.6 (d, J = 266.4 Hz), 135.1, 133.2, 132.8, 129.6 (d, J = 3.5
Hz), 128.5, 128.4 (d, J = 7.6 Hz), 128.2, 128.1, 127.6, 126.5, 126.4, 126.3, 126.2, 114.4 (d, J = 6.7 Hz), 61.2
(d, J = 29.5 Hz), 35.3, 31.0; Ms (ESI): m/z = 405.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C23H23FO2SNa, 405.1295; Found, 405.1305.
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(Z)-2-(2-Fluoro-3-((4-methoxyphenyl)sulfonyl)prop-1-en-1-yl)naphthalene (3e). White solid, yield: 76%
(27.0 mg); mp 163-164 oC. 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.83 (m, 3H), 7.82 – 7.75 (m, 3H), 7.55 (dd,
J = 8.6, 1.5 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.00 (d, J = 9.0 Hz, 2H), 5.78 (d, J = 37.2 Hz, 1H), 4.10 (d, J =
18.8 Hz, 2H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.1, 148.8 (d, J = 266.0 Hz), 133.2, 132.8,
130.8, 129.6, 129.6 (d, J = 3.5 Hz), 128.4 (d, J = 7.7 Hz), 128.2, 128.1, 127.6, 126.5, 126.4, 126.2 (d, J = 7.7
Hz), 114.4, 114.2 (d, J = 6.7 Hz), 61.2 (d, J = 29.4 Hz), 55.7; Ms (ESI): m/z = 379.1 [M+Na]+; HRMS (ESI):
m/z [M+Na]+ Calcd for C20H17FO3SNa, 379.0775; Found, 379.0781.
(Z)-2-(2-Fluoro-3-((4-fluorophenyl)sulfonyl)prop-1-en-1-yl)naphthalene (3f). Yellow solid, yield: 69%
(23.7 mg); mp 126-127 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 8.7, 5.0 Hz, 2H), 7.86 – 7.77 (m, 4H),
7.54 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 6.2, 3.2 Hz, 2H), 7.27 – 7.21 (m, 2H), 5.82 (d, J = 37.2 Hz, 1H), 4.13
(d, J = 18.6 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 166.2 (d, J = 257.8 Hz), 148.3 (d, J = 265.7 Hz), 134.2
(d, J = 3.0 Hz), 133.2, 132.9, 131.6 (d, J = 9.7 Hz), 129.3 (d, J = 3.5 Hz), 128.5 (d, J = 7.7 Hz), 128.2 (d, J =
5.9 Hz), 127.6, 126.6, 126.5, 126.2 (d, J = 7.8 Hz), 116.8, 116.6, 114.7 (d, J = 6.6 Hz), 61.3 (d, J = 29.6 Hz);
Ms (ESI): m/z = 367.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C19H14F2O2SNa, 367.0575; Found,
367.0578.
(Z)-2-(2-Fluoro-3-((4-(trifluoromethyl)phenyl)sulfonyl)prop-1-en-1-yl)naphthalene (3g). Yellow solid,
yield: 55% (21.7 mg); mp 133-134 oC. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.2 Hz, 2H), 7.87 – 7.82
(m, 3H), 7.81 – 7.77 (m, 3H), 7.53 (dd, J = 8.6, 1.5 Hz, 1H), 7.51 – 7.46 (m, 2H), 5.84 (d, J = 37.1 Hz, 1H),
4.17 (d, J = 18.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 147.8 (d, J = 265.6 Hz), 141.7, 135.9 (q, J = 33.3
Hz), 133.2, 133.0, 129.3, 129.1 (d, J = 3.8 Hz), 128.6 (d, J = 7.6 Hz), 128.3, 128.2, 127.6, 126.7, 126.5,
126.4 (q, J = 3.6 Hz), 126.1 (d, J = 7.7 Hz), 123.0 (q, J = 273.8 Hz), 115.0 (d, J = 6.4 Hz), 61.2 (d, J = 29.9
Hz); Ms (ESI): m/z = 417.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C20H14F4O2SNa, 417.0543;
Found, 417.0550.
Methyl (Z)-4-((2-fluoro-3-(naphthalen-2-yl)allyl)sulfonyl)benzoate (3h). White solid, yield: 59% (22.5
mg); mp 127-128 oC. 1H NMR (400 MHz, CDCl3) δ 8.24 – 8.20 (m, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.83 (s,
1H), 7.81 – 7.76 (m, 3H), 7.52 (dd, J = 8.6, 1.6 Hz, 1H), 7.50 – 7.44 (m, 2H), 5.83 (d, J = 37.2 Hz, 1H), 4.16
(d, J = 18.6 Hz, 2H), 3.96 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.4, 148.0 (d, J = 265.7 Hz), 142.0,
135.3, 133.2, 133.0, 130.4, 129.3 (d, J = 3.4 Hz), 128.8, 128.6 (d, J = 7.6 Hz), 128.3, 128.2, 127.6, 126.7,
126.5, 126.2 (d, J = 7.7 Hz), 114.9 (d, J = 6.6 Hz), 61.2 (d, J = 29.9 Hz), 52.8; Ms (ESI): m/z = 407.1
[M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C21H17FO4SNa, 407.0724; Found, 407.0728.
(Z)-1-(4-((2-Fluoro-3-(naphthalen-2-yl)allyl)sulfonyl)phenyl)ethan-1-one (3i). White solid, yield: 47%
(17.2 mg); mp 166-167 oC. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H),
7.84 – 7.76 (m, 4H), 7.55 – 7.45 (m, 3H), 5.84 (d, J = 37.2 Hz, 1H), 4.16 (d, J = 18.6 Hz, 2H), 2.65 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 196.6, 148.0 (d, J = 265.7 Hz), 141.9, 141.2, 133.2, 132.9, 129.2 (d, J = 3.6
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Hz), 129.1, 129.0, 128.5 (d, J = 7.6 Hz), 128.3, 128.2, 127.6, 126.7, 126.5, 126.1 (d, J = 7.7 Hz), 114.9 (d, J
= 6.6 Hz), 61.1 (d, J = 29.7 Hz), 26.9; Ms (ESI): m/z = 391.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd
for C21H17FO3SNa, 391.0775; Found, 391.07855.
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(Z)-2-(3-((3,5-Dimethylphenyl)sulfonyl)-2-fluoroprop-1-en-1-yl)naphthalene (3j). White solid, yield: 45%
(15.9 mg); mp 106-107 oC. 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.82 – 7.76 (m, 3H), 7.58 – 7.52 (m,
3H), 7.50 – 7.44 (m, 2H), 7.28 (s, 1H), 5.78 (d, J = 37.0 Hz, 1H), 4.09 (d, J = 18.7 Hz, 2H), 2.35 (s, 6H); 13
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NMR (126 MHz, CDCl3) δ 148.6 (d, J = 266.2 Hz), 139.4, 137.9, 135.9, 133.3, 132.9, 129.6 (d, J = 3.4 Hz),
128.4 (d, J = 7.6 Hz), 128.2, 128.1, 127.6, 126.5, 126.4, 126.3 (d, J = 7.6 Hz), 126.1, 114.4 (d, J = 6.7 Hz),
61.2 (d, J = 29.4 Hz), 21.2; Ms (ESI): m/z = 377.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C21H19FO2SNa, 377.0982; Found, 377.0982.
(Z)-2-(3-((2,4-Dimethoxyphenyl)sulfonyl)-2-fluoroprop-1-en-1-yl)naphthalene (3k). Colorless oil, yield:
81% (31.3 mg); mp 129-130 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.79 –
7.71 (m, 3H), 7.53 (dd, J = 8.6, 1.5 Hz, 1H), 7.48 – 7.40 (m, 2H), 6.57 – 6.51 (m, 2H), 5.84 (d, J = 37.2 Hz,
1H), 4.34 (d, J = 19.0 Hz, 2H), 4.00 (s, 3H), 3.85 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.9, 159.0, 149.2
(d, J = 266.2 Hz), 133.2, 132.9, 132.7, 129.8 (d, J = 3.4 Hz), 128.2 (d, J = 7.7 Hz), 128.1, 128.0, 127.5,
126.4, 126.3, 126.2, 118.5, 113.8 (d, J = 6.8 Hz), 104.8, 99.5, 59.2 (d, J = 29.2 Hz), 56.4, 55.7; Ms (ESI):
m/z = 409.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C21H19FO4SNa, 409.0880; Found, 409.0886.
(Z)-2-(2-Fluoro-3-(m-tolylsulfonyl)prop-1-en-1-yl)naphthalene (3l). White solid, yield: 47% (17.0 mg);
mp 117-118 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.72 (m, 6H), 7.54 (d, J = 8.6 Hz, 1H), 7.51 – 7.40 (m,
4H), 5.78 (d, J = 37.0 Hz, 1H), 4.11 (d, J = 18.7 Hz, 2H), 2.41 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 148.5
(d, J = 266.1 Hz), 139.6, 138.0, 135.0, 133.2, 132.9, 129.5 (d, J = 3.6 Hz), 129.1, 128.9, 128.4 (d, J = 7.6
Hz), 128.2, 128.1, 127.6, 126.5, 126.4, 126.2 (d, J = 7.6 Hz), 125.7, 114.4 (d, J = 6.7 Hz), 61.1 (d, J = 29.6
Hz), 21.2; Ms (ESI): m/z = 363.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C20H17FO2SNa, 363.0825;
Found, 363.0835.
(Z)-2-(2-Fluoro-3-(o-tolylsulfonyl)prop-1-en-1-yl)naphthalene (3m). White solid, yield: 60% (20.4 mg);
mp 113-114 oC. 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.13, 1.2 Hz, 1H), 7.83 – 7.72 (m, 4H), 7.56 –
7.43 (m, 4H), 7.35 (t, J = 7.2 Hz, 2H), 5.79 (d, J = 37.1 Hz, 1H), 4.15 (d, J = 18.9 Hz, 2H), 2.74 (s, 3H); 13
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NMR (126 MHz, CDCl3) δ 148.4 (d, J = 266.0 Hz), 138.6, 136.3, 134.2, 133.2, 132.8, 132.7, 130.9, 129.5 (d,
J = 3.4 Hz), 128.4 (d, J = 7.7 Hz), 128.2, 128.1, 127.6, 126.7, 126.5, 126.3, 126.2 (d, J = 7.7 Hz), 114.4 (d, J
= 6.7 Hz), 60.5 (d, J = 29.4 Hz), 20.5; Ms (ESI): m/z = 363.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd
for C20H17FO2SNa, 363.0825; Found, 363.0834.
(Z)-1-((2-Fluoro-3-(naphthalen-2-yl)allyl)sulfonyl)naphthalene (3n). Colorless oil, yield: 42% (15.8 mg);
mp 138-139 oC. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 8.4 Hz, 1H), 8.34 (dd, J = 7.4, 1.1 Hz, 1H), 8.16
(d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.79 – 7.68 (m, 5H), 7.66 – 7.61 (m, 1H), 7.60 – 7.53 (m, 1H),
7.48 – 7.40 (m, 3H), 5.66 (d, J = 36.9 Hz, 1H), 4.31 (d, J = 18.8 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ
148.3 (d, J = 266.5 Hz), 135.7, 134.1, 133.3, 133.1, 132.8, 131.6, 129.4 (d, J = 3.4 Hz), 129.3, 129.1, 129.0,
128.4 (d, J = 7.6 Hz), 128.2, 128.0, 127.5, 127.1, 126.5, 126.3, 126.2 (d, J = 7.7 Hz), 124.4, 123.9, 114.5 (d,
J = 6.6 Hz), 60.7 (d, J = 29.5 Hz); Ms (ESI): m/z = 399.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C23H17FO2SNa, 399.0825; Found, 399.0831.
(Z)-1-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)-4-methylbenzene (4a). White solid, yield: 63% (18.3
mg); mp 139-140 oC. 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.89 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J
= 7.9 Hz, 2H), 7.30 – 7.26 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.58 (d, J = 37.3 Hz, 1H), 4.06 (d, J = 18.7 Hz,
2H), 2.34 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 147.6 (d, J = 264.3 Hz), 138.2 (d, J = 2.1 Hz), 138.1, 134.1,
129.2, 129.2, 129.1 (d, J = 3.6 Hz), 128.8 (d, J = 7.4 Hz), 128.6, 114.3 (d, J = 6.9 Hz), 61.1 (d, J = 29.6 Hz),
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21.3; Ms (ESI): m/z = 313.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C16H15FO2SNa, 313.0669;
Found, 313.0675.
(Z)-1-(tert-butyl)-4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzene (4b). White solid, yield: 76%
(25.2 mg); mp 112-113 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.4 Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H),
7.57 (t, J = 7.8 Hz, 2H), 7.37 – 7.30 (m, 4H), 5.60 (d, J = 37.4 Hz, 1H), 4.07 (d, J = 18.6 Hz, 2H), 1.31 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 151.4 (d, J = 2.1 Hz), 147.7 (d, J = 264.5 Hz), 138.1, 134.1, 129.2,
129.1 (d, J = 3.2 Hz), 128.6, 128.6, 125.5, 114.2 (d, J = 6.9 Hz), 61.1 (d, J = 29.7 Hz), 34.6, 31.2; Ms (ESI):
m/z = 355.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C19H21FO2SNa, 355.1138; Found, 355.1148.
(Z)-1-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)-4-methoxybenzene (4c). White solid, yield: 63% (19.3
mg); mp 120-121 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.89 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J
= 7.9 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.56 (d, J = 37.5 Hz, 1H), 4.06 (d, J = 18.7
Hz, 2H), 3.81 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.4 (d, J = 3.0 Hz), 146.7 (d, J =262.8 Hz), 138.2,
134.1, 130.2 (d, J = 7.7 Hz), 129.2, 128.6, 124.6 (d, J = 3.4 Hz), 113.9, 113.9, 61.1 (d, J = 29.7 Hz), 55.2;
Ms (ESI): m/z = 329.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C16H15FO3SNa, 329.0681; Found,
329.0630.
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(Z)-1-(Benzyloxy)-4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzene (4d). White solid, yield: 61%
(23.3 mg); mp 148-149 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.88 (m, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.56
(t, J = 7.8 Hz, 2H), 7.44 – 7.36 (m, 4H), 7.33 (d, J = 8.8 Hz, 3H), 6.91 (d, J = 8.8 Hz, 2H), 5.55 (d, J = 37.4
Hz, 1H), 5.06 (s, 2H), 4.05 (d, J = 18.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 158.6 (d, J = 2.9 Hz), 146.8
(d, J = 263.0 Hz), 138.2, 136.7, 134.1, 130.3 (d, J = 7.7 Hz), 129.2, 128.6, 128.0, 127.4, 124.9 (d, J = 3.5
Hz), 114.9, 113.9 (d, J = 7.1 Hz), 70.0, 61.1 (d, J = 29.7 Hz); Ms (ESI): m/z = 405.1 [M+Na]+; HRMS (ESI):
m/z [M+Na]+ Calcd for C22H19FO3SNa, 405.0931; Found, 405.0942.
(Z)-1-Fluoro-4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzene (4e). White solid, yield: 69% (20.3
mg); mp 104-105 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.90 (m, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.58 (t, J
= 7.9 Hz, 2H), 7.37 (dd, J = 8.6, 5.5 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 5.61 (d, J = 36.8 Hz, 1H), 4.07 (d, J =
18.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 162.3 (dd, J = 249.4, 3.3 Hz), 147.9 (dd, J = 264.9, 2.3 Hz),
138.1, 134.2, 130.6 (t, J = 8.0 Hz), 129.3, 128.6, 128.1 (t, J = 3.3 Hz), 115.6 (d, J = 21.7 Hz), 113.3 (d, J =
6.9 Hz), 60.9 (d, J = 29.5 Hz); Ms (ESI): m/z = 317.0 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for
C15H12F2O2SNa, 317.0418; Found, 317.0422.
(Z)-4-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzonitrile (4f). White solid, yield: 35% (10.6 mg);
mp 124-125 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 8.3, 1.0 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.64 –
7.56 (m, 4H), 7.49 (d, J = 8.4 Hz, 2H), 5.72 (d, J = 36.0 Hz, 1H), 4.10 (d, J = 18.8 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 150.7 (d, J = 270.9 Hz), 138.1, 136.3 (d, J = 3.5 Hz), 134.4, 132.3, 129.4, 129.2 (d, J = 8.1
Hz), 128.5, 118.5, 112.9 (d, J = 6.3 Hz), 111.6 (d, J = 2.9 Hz), 60.8 (d, J = 29.1 Hz); Ms (ESI): m/z = 302.3
[M+H]+; HRMS (ESI): m/z [M+Na]+ Calcd for C16H12FNO2SNa, 324.0465; Found, 324.0472.
(Z)-4-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)phenyl acetate (4g). White solid, yield: 48% (16.0 mg);
mp 106-107 oC. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.57 (t, J =
7.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 5.61 (d, J = 36.8 Hz, 1H), 4.07 (d, J = 18.7
Hz, 2H), 2.30 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.3, 150.3, 148.3 (d, J = 266.0 Hz), 138.0, 134.2,
130.0, 129.9, 129.7 (d, J = 3.4 Hz), 129.3, 128.6, 121.8, 113.4 (d, J = 6.9 Hz), 61.0 (d, J = 29.6 Hz), 21.1;
Ms (ESI): m/z = 357.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C17H15FO4SNa, 357.0567; Found,
357.0578.
Ethyl (Z)-4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzoate (4h). White solid, yield: 59% (20.5 mg);
mp 108-109 oC. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 7.4 Hz, 2H), 7.70 (t, J =
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7.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 5.69 (d, J = 36.5 Hz, 1H), 4.37 (q, J = 7.1 Hz,
2H), 4.10 (d, J = 18.7 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 166.1, 149.7 (d, J =
269.1 Hz), 138.0, 136.2 (d, J = 3.5 Hz), 134.3, 129.9 (d, J = 2.3 Hz), 129.7, 129.3, 128.6 (d, J = 7.9 Hz),
128.5, 113.6 (d, J = 6.6 Hz), 61.0, 60.0 (d, J = 29.2 Hz), 14.3; Ms (ESI): m/z = 371.2 [M+Na]+; HRMS (ESI):
m/z [M+H]+ Calcd for C18H18FO4S, 349.0904; Found, 349.0913.
(Z)-1-Chloro-3-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzene (4i). Pale yellow oil, yield: 61% (18.9
mg); mp 101-102 oC. 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.91 (m, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.58 (t, J
= 7.8 Hz, 2H), 7.39 (s, 1H), 7.26 – 7.23 (m, 3H), 5.60 (d, J = 36.3 Hz, 1H), 4.07 (d, J = 18.7 Hz, 2H); 13C
NMR (126 MHz, CDCl3) δ 149.2 (d, J = 267.6 Hz), 138.1, 134.5, 134.3, 133.6 (d, J = 3.4 Hz), 129.8, 129.3,
128.7 (d, J = 8.4 Hz), 128.6, 128.3 (d, J = 2.1 Hz), 126.9 (d, J = 7.2 Hz), 113.2 (d, J = 6.6 Hz), 61.9 (d, J =
29.4 Hz) ； Ms (ESI): m/z = 333.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ Calcd for C15H12ClFO2SNa,
333.0123; Found, 333.0129.
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(Z)-2-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)-1,4-dimethylbenzene (4j). White solid, yield: 73%
(22.3 mg); mp 76-77 oC. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2, 1.6 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H),
7.58 (t, J = 7.7 Hz, 2H), 7.31 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.72 (d, J = 36.3 Hz,
1H), 4.10 (d, J = 18.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 147.9 (d, J = 264.7
Hz), 138.1, 135.4, 134.2, 132.9, 130.2 (d, J = 2.6 Hz), 130.0, 129.7 (d, J = 9.8 Hz), 129.3, 129.0, 128.7,
112.0 (d, J = 7.7 Hz), 61.0 (d, J = 30.0 Hz), 21.0, 19.4; Ms (ESI): m/z = 327.2 [M+Na]+; HRMS (ESI): m/z
[M+Na]+ Calcd for C17H17FO2SNa, 327.0825; Found, 327.0834.
(Z)-1-(2-Fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)pyrene (4k). White solid, yield: 41% (16.3 mg); mp
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156-157 C. H NMR (400 MHz, CDCl3) δ 8.22 – 8.00 (m, 10H), 7.96 (d, J = 9.2 Hz, 1H), 7.71 (t, J = 7.5
Hz, 1H), 7.59 (t, J = 7.7 Hz, 2H), 6.58 (d, J = 35.1 Hz, 1H), 4.30 (d, J = 18.3 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 148.9 (d, J = 265.7 Hz), 138.1, 134.3, 131.3, 131.2, 130.7, 129.4, 128.7, 128.5, 128.0, 127.9, 127.3,
127.1 (d, J = 8.9 Hz), 126.1, 125.7, 125.4, 124.7, 124.6, 123.0, 111.8 (d, J = 8.1 Hz), 61.2 (d, J = 29.9 Hz);
Ms (ESI): m/z = 423.1 [M+Na]+; HRMS (ESI): m/z [M+H]+ Calcd for C25H18FO2S, 401.1006; Found,
401.1013.
(8R,9S,13S,14S)-3-((Z)-2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)-13-methyl-6,7,8,9,11,12,13,14,15,16-
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decahydro-17H-cyclopenta[a]phenanthren-17-one (4l). White solid, yield: 66% (30.0 mg); mp 199-200 C.
1H NMR (400 MHz, CDCl3) δ 7.97 – 7.89 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.24 (d,
J = 8.0 Hz, 1H), 7.16 (d, J = 9.1 Hz, 2H), 5.56 (d, J = 37.4 Hz, 1H), 4.06 (d, J = 18.6 Hz, 2H), 2.88 (dd, J =
8.9, 4.0 Hz, 2H), 2.51 (dd, J = 18.7, 8.6 Hz, 1H), 2.44 – 2.36 (m, 1H), 2.33 – 2.23 (m, 1H), 2.20 – 2.11 (m,
1H), 2.10 – 1.99 (m, 2H), 1.98 – 1.92 (m, 1H), 1.68 – 1.57 (m, 2H), 1.54 (d, J = 5.3 Hz, 1H), 1.52 – 1.40 (m,
3H), 0.90 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 220.7, 147.8 (d, J = 264.7 Hz), 140.1 (d, J = 2.1 Hz), 138.1,
136.7, 134.1, 129.5 (d, J = 3.3 Hz), 129.4 (d, J = 7.3 Hz), 129.2, 128.6, 126.3 (d, J = 7.4 Hz), 125.5, 114.1 (d,
J = 6.9 Hz), 61.0 (d, J = 29.6 Hz), 50.4, 47.9, 44.4, 38.0, 35.8, 31.5, 29.3, 26.4, 25.6, 21.5, 13.8；Ms (ESI):
m/z = 475.2 [M+Na]+; HRMS (ESI): m/z [M+H]+ Calcd for C27H30FO3S, 453.1894; Found, 453.1905.
(8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-
3-yl 4-((Z)-2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzoate (4m). White solid, yield: 65% (37.2 mg); mp
166-167 oC. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 7.98 – 7.92 (m, 2H), 7.71 (t, J = 7.5 Hz,
1H), 7.59 (t, J = 7.7 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 8.5, 2.4 Hz,
1H), 6.94 (d, J = 2.2 Hz, 1H), 5.74 (d, J = 36.4 Hz, 1H), 4.11 (d, J = 18.6 Hz, 2H), 2.97 – 2.91 (m, 2H), 2.52
(dd, J = 18.9, 8.6 Hz, 1H), 2.47 – 2.38 (m, 1H), 2.36 – 2.26 (m, 1H), 2.21 – 1.95 (m, 4H), 1.70 – 1.58 (m,
3H), 1.57 – 1.49 (m, 3H), 0.93 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 220.8, 164.9, 150.1 (d, J = 269.6 Hz),
148.7, 138.1, 138.1, 137.5, 136.9 (d, J = 3.4 Hz), 134.4, 130.3, 129.3, 129.0 (d, J = 2.3 Hz), 128.8 (d, J = 7.8
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Hz), 128.5, 126.5, 121.6, 118.8, 113.5 (d, J = 6.4 Hz), 60.9 (d, J = 29.2 Hz), 50.4, 47.9, 44.1, 38.0, 35.8, 31.5,
29.4, 26.3, 25.7, 21.6, 13.8; Ms (ESI): m/z = 595.2 [M+Na]+; HRMS (ESI): m/z [M+H]+ Calcd for
C34H34FO5S, 573.2105; Found, 573.2108.
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Ethyl (Z)-2-(4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)phenoxy)-2-methylpropanoate (4n). Colorless
oil, yield: 44% (17.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H),
7.56 (t, J = 7.7 Hz, 2H), 7.29 (s, 1H), 7.26 (s, 1H), 6.76 (d, J = 8.6 Hz, 2H), 5.56 (d, J = 37.4 Hz, 1H), 4.23
(q, J = 7.1 Hz, 2H), 4.05 (d, J = 18.7 Hz, 2H), 1.60 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 174.0, 155.4 (d, J = 3.2 Hz), 147.0 (d, J = 263.5 Hz), 138.2, 134.1, 129.9 (d, J = 7.6 Hz), 129.2,
128.6, 125.7 (d, J = 3.4 Hz), 118.6, 113.8 (d, J = 6.9 Hz), 79.1, 61.5, 61.0 (d, J = 29.6 Hz), 25.3, 14.0; Ms
(ESI): m/z = 429.1 [M+Na]+; HRMS (ESI): m/z [M+H]+ Calcd for C21H24FO5S, 407.1323; Found, 407.1326.
Isopropyl (Z)-2-(4-(4-(2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzoyl)phenoxy)-2-methylpropanoate
(4o). Colorless oil, yield: 42% (22.0 mg). 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.93 (m, 2H), 7.77 – 7.69 (m,
5H), 7.59 (t, J = 7.7 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 5.72 (d, J = 36.6 Hz, 1H),
5.09 (hept, J = 6.2 Hz, 1H), 4.11 (d, J = 18.7 Hz, 2H), 1.66 (s, 6H), 1.21 (d, J = 6.3 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 194.7, 173.1, 159.6, 149.7 (d, J = 268.9 Hz), 138.1, 137.5 (d, J = 2.3 Hz), 135.4 (d, J = 3.4
Hz), 134.3, 132.0, 130.4, 130.0, 129.3, 128.6, 128.5, 117.2, 113.6 (d, J = 6.6 Hz), 79.4, 69.3, 61.0 (d, J =
29.2 Hz), 25.3, 21.5; Ms (ESI): m/z = 547.1 [M+Na]+; HRMS (ESI): m/z [M+H]+ Calcd for C29H30FO6S,
525.1742; Found, 525.1752.
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(3aS,5S,6R,6aS)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-
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yl 4-((Z)-2-fluoro-3-(phenylsulfonyl)prop-1-en-1-yl)benzoate (4p). Colorless oil, yield: 34% (19.0 mg). H
NMR (400 MHz, CDCl3) δ 8.00 – 7.92 (m, 4H), 7.71 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.47 (d, J
= 8.5 Hz, 2H), 5.95 (d, J = 3.7 Hz, 1H), 5.72 (d, J = 36.4 Hz, 1H), 5.49 (d, J = 2.5 Hz, 1H), 4.63 (d, J = 3.7
Hz, 1H), 4.38 – 4.30 (m, 2H), 4.15 – 4.06 (m, 4H), 1.56 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); 13
C
NMR (126 MHz, CDCl3) δ 164.7, 150.1 (d, J = 269.8 Hz), 138.1, 136.8 (d, J = 3.4 Hz), 134.4, 129.9, 129.3,
128.811 (d, J = 7.8 Hz), 128.810 (d, J = 2.5 Hz), 128.5, 113.4 (d, J = 6.3 Hz), 112.4, 109.4, 105.1, 83.3, 79.9,
76.7, 72.5, 67.2, 60.9 (d, J = 29.1 Hz), 26.8, 26.7, 26.2, 25.2; Ms (ESI): m/z = 585.2 [M+Na]+; HRMS (ESI):
m/z [M+Na]+ Calcd for C28H31FO9SNa, 585.1565; Found, 585.1570.
Preparation of 3a at 1 mmol-scale. To a dry 25 mL sealed tube with a magnetic stirrer,
2-(2,2-difluorocyclopropyl)naphthalene 1a (204 mg), PhSO2Na 2a (328 mg), Pd(TFA)2 (33.2 mg), X-phos
n
(47.6 mg), K3PO4 (318 mg), Bu4NPF6 (77 mg), and DCE (4.0 mL) were added under N2. The mixture was
o
warmed to 100 C in oil bath and stirred for 16 h. The reaction was cooled and diluted with DCM. After
filtration, the filtrate was concentrated under reduced pressure. The residue was purified through column
chromatography (eluent: EA/PE=1:4~1:2), to afford 3a (230 mg) in 71% yield.
Mechanic experiments (Scheme 5a). To
a
dry 10 mL sealed tube, was added
2-(2,2-difluorocyclopropyl)naphthalene 1a (20.4 mg), PhSO2Na 2a (32.8 mg), Pd(TFA)2 (3.3 mg), X-phos
n
(4.8 mg), Bu4NPF6 (7.7 mg), K3PO4 (31.8 mg), and DCE (1.0 mL) under N2. TEMPO (15.6 mg) or
o
1,1-diphenylethylene (18 mg) or BQ (22 mg) was then added2. The mixture was warmed to 100 C in oil
bath and stirred for 16 h. A similar work-up provided the corresponding product 3a.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H NMR and 13C NMR spectra for new compounds and X-ray crystallography data for compound 3a.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
* Email: aozhang@simm.ac.cn
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We appreciate the support from National Program on Key Basic Research Project of China (Grant
2015CB910603-004), and the Chinese National NSF (Grants 81430080, 81773565).
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