Free radical (phenylsulfonyl)difluoromethylation of alkynes with PhSO2CF2I reagent: stereoselective preparation of PhSO2CF2- and CF2H-substituted alkenes

Article abstract of DOI:10.1016/j.tet.2008.11.011

Stereoselective free radical (phenylsulfonyl)difluoromethylation of terminal alkynes with iododifluoromethyl phenyl sulfone (PhSO₂CF₂I) has been accomplished by using Et₃B/air as an initiator. The obtained PhSO₂

Full text of DOI:10.1016/j.tet.2008.11.011

Tetrahedron 65 (2009) 478–483
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Free radical (phenylsulfonyl)difluoromethylation of alkynes with PhSO2CF2I
reagent: stereoselective preparation of PhSO2CF2- and CF2H-substituted
alkenes
*
Ya Li, Huaifeng Li, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective free radical (phenylsulfonyl)difluoromethylation of terminal alkynes with iododi-
fluoromethyl phenyl sulfone (PhSO2CF2I) has been accomplished by using Et3B/air as an initiator. The
obtained PhSO2CF2-substituted vinyl iodides, which can be further subjected to Suzuki coupling and
Sonogashira coupling reactions, are useful precursors for the preparation of many structurally diverse
PhSO2CF2- and CF2H-substituted alkenes.
Received 6 September 2008
Received in revised form 4 November 2008
Accepted 6 November 2008
Available online 12 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Radical fluoroalkylation
(Phenylsulfonyl)difluoromethylation
Difluoromethyl
1. Introduction
a highly efficient radical (phenylsulfonyl)difluoromethylation of
terminal alkenes with iododifluoromethyl phenyl sulfone
Partially fluorinated organic compounds often exhibit an in-
crease in oxidative, hydrolytic, and thermal stabilities as compared
with their non-fluorinated counterparts, which can be attributed to
the high electronegativity, low polarizability, and the relative small
size of the fluorine atom.1–6 As a consequence, much effort has been
devoted to the studies on efficient synthesis of fluorinated bioactive
compounds. Among various fluorinated compounds, CF2H-con-
taining compounds are of particular interest, given the fact that by
the year 2005, thirty-nine difluoromethylated compounds had been
registered to be in the different developmental phases of the drug
discovery process.7
(PhSO2CF2I,1) byusing Et3B/airas an initiator.9 In this paper, wewish
to report our extended study on radical (phenylsulfonyl)-
difluoromethylation of alkynes using PhSO2CF2I reagent, which
serves as a good method for the stereoselective preparation of both
PhSO2CF2- and CF2H-substituted alkenes.
2. Results and discussion
Firstly, we used 1-hexyne (2a) as a model compound to examine
the radical addition reaction between iododifluoromethyl phenyl
sulfone (1) and an alkyne. As expected, the atom transfer reaction
Fluorination and fluoroalkylation are the two major methods to
prepare CF2H-containing compounds.3,4 Fluorination reagents, such
as SF4, DAST, TBAF, and BrF3, are frequently used to transform alde-
hydes or their derivatives into CF2H-containing compounds. In the
fluoroalkylation arena, chlorodifluoromethane and dibromodi-
fluoromethane, both of which are ozone depleting substances, are
often employed to construct the CF2H moiety. In our continuing
effort to develop difluoromethylation methodologies, we found that
PhSO2CF2H, PhSO2CF2SiMe3, and PhSO2CF2Br compounds are robust
nucleophilic difluoromethylation reagents.8 Recently, we disclosed
I
PhO2SF2C
nC4H9
E-3a, 77%
Et3B/air, CH2Cl2
-30 °C
+
PhSO2CF2I +
nC4H9
2a
NOE
I
1
H
PhO2SF2C
Z-3a, 9%
* Corresponding author. Tel.: þ86 21 54925174; fax: þ86 21 64166128.
E-mail address: jinbohu@mail.sioc.ac.cn (J. Hu).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.011

Y. Li et al. / Tetrahedron 65 (2009) 478–483
479
Table 1
Table 1, the free radical (phenylsulfonyl)difluoromethylation re-
action can tolerate many functional groups on the substrates 1b–1g,
such as hydroxyl, methoxy, acetyl, sulfonyl, and amide groups, giv-
ing satisfactory chemical yields of products. The E/Z isomeric ratio of
the products 3a–3g ranges from 2:1 to 9:1. It is worthwhile to
mention that the two isomers in entries 1, 4, 5, and 6 could be easily
separated by flash chromatography, while products 3b, 3c, and 3g
(entries2, 3, and7) wereobtainedin Z- andE-isomermixtures dueto
their similar polarities.
Products 3 can further undergo coupling reactions with nucleo-
philic reagents because of the existence of vinyl iodide function-
ality. Using compound E-3a as a model compound, we first tested
its Suzuki coupling reaction with boronic acids (Scheme 2). To our
delight, the coupling reaction of 3a with phenyl boronic acid (4a)
proceeded smoothly under typical coupling reaction conditions,
and the coupling product 5aa was isolated in 97% yield. Obvious
NOEs between the proton on the double bond and protons on the
substituted phenyl group indicated that the configuration of the
double bond was maintained intact during this coupling reaction.
Et3B-initiated radical (phenylsulfonyl)difluoromethylation of terminal alkynes
Entry
Alkyne 2
Product 3
Isomeric Yielda
ratio (E/Z) (%)
I
C4H9
1
2
3
4
5
6
9:1
9:1
2:1
3:1
3:1
8:1
85
PhO2SF2C
C4H9
2a
3a
I
3
OH
67b
62b
62
PhO2SF2C
3OH
2b
3b
3c
I
OH
PhO2SF2C
PhO2SF2C
OH
2c
I
OCH3
OCH3
2d
3d
I
61
OAc
PhO2SF2C
PhO2SF2C
OAc
2e
3e
I
2
55
OTs
NOE
3OTs
2f
3f
O
N
O
O
3N
O
I
Pd(PPh3)4 (5 mol%)
I
H
+
2
PhB(OH)2
7
8:1
64b
K2CO3 (2.0 equiv.)
THF, 65 °C
97%
PhO2SF2C
PhO2SF2C
3a
C4H9
PhO2SF2C
C4H9
3g
2g
4a
5aa
a
Scheme 2.
The overall yield of Z- and E-isomer.
The Z- and E-isomer could not be separated by flash chromatography.
b
Using this optimized reaction condition, we studied the scope of
the coupling reaction of compound 3 with 4a, 4-chlorophenyl bo-
between 1 and 2a proceeded smoothly under the same conditions
for radical (phenylsulfonyl)difluoromethylation of terminal alkenes
with 1,9 that is, Et3B in hexane (1.0 mol/L) was added to a mixture of
1-hexyne (2a), PhSO2CF2I (1), and CH2Cl2 solvent at ꢀ30 ꢁC, and E-
3a and Z-3a product isomers were isolated in 77% and 9% yields,
respectively. The stereochemistry of the products was determined
on the basis of the relative strong NOEs between the proton on the
double bond and protons on aliphatic n-butyl group in product Z-3a
(Scheme 1).
ronic acid (4b), and a,b-unsaturated boronic acid (4c), respectively.
As shown in Table 2, the coupling reaction proceeded smoothly in
all cases, and the products 5 were obtained in good to excellent
yields. By using this method, we thus can obtain a variety of
structurally diverse PhSO2CF2-sustituted alkenes.
We also studied the Sonogashira coupling reaction between
compound 3 and terminal alkynes. Using NEt3 as both the base and
the solvent, we found that the Sonogashira coupling reaction pro-
ceeded readily, giving almost quantitative yield of products 6 (Table
3). We therefore extended this reaction to several functionalized
terminal alkynes. As shown in Table 3, it is apparent that the cou-
pling products 6 could be isolated in excellent yields in all cases.
By using this standard reaction condition, we extended this Et3B/
air-initiated radical (phenylsulfonyl)difluoromethylation reaction to
a variety of structurally diverse terminal alkynes 1b–1g. As shown in
Table 2
The Suzuki coupling reactions between compound 3 and boronic acids
Boronic acid
Product 5
Yielda (%)
Product 5
Yielda (%)
PhB(OH)2 4a
97
75
PhO2SF2C
OCH3
Cl
PhO2SF2C
C4H9
5aa
5da
Cl
p-ClC6H4B(OH)2 4b
85
75
85
79
PhO2SF2C
PhO2SF2C
C4H9
PhO2SF2C
PhO2SF2C
OCH3
5db
5ab
Ph
Ph
Ph
B(OH)2
C4H9
OCH3
4c
5dc
5ac
a
Isolated yield.

480
Y. Li et al. / Tetrahedron 65 (2009) 478–483
Table 3
reagent was prepared according to the previously reported pro-
cedures.9,16 1H NMR spectra were recorded on Bruker 300 or Mer-
cury 300 spectrometers with Me4Si as internal standard. 19F NMR
spectra were recorded on Bruker 300 or Mercury 300 spectrome-
ters with CFCl3 as external standard. 13C NMR spectra were recor-
ded on Avance 500 or DPX-400 spectrometers. Mass spectra were
obtained on a HP5989A spectrometer. High-resolution mass data
were recorded on a high-resolution mass spectrometer in the EI or
MALDI mode.
The coupling reaction of compound 3 with terminal alkynes
R'
I
PdCl2(PPh3)2 (2 mol%)
+
R'
PhO2SF2C
R
CuI (6 mol%), NEt3, rt
PhO2SF2C
R
3
6
Compound 3
Alkyne 2
Product 6
6aa
Yielda (%)
97
98
2a
4.2. Typical procedure of the radical addition of
iododifluoromethyl phenyl sulfone (1) with alkynes
6ab
Ph
I
2h
Et3B (1.0 mL, 1.0 mol in hexane) was added into a 10-mL Schlenk
flask containing iododifluoromethyl phenyl sulfone (1) (318 mg,
1.0 mmol) and 1-hexyne (2a) (164 mg, 2.0 mmol) in 4.0 mL of
CH2Cl2 at ꢀ30 ꢁC. Then a balloon filled with 100 mL of air was
connected to the reaction flask. The reaction mixture was stirred at
this temperature for 0.5 h. After removing of volatile solvents under
vacuum, the crude product was further purified by silica gel column
chromatography with ethyl acetate/petroleum ether (1: 10) to give
products E-3a (solid, 306 mg, 77% yield) and Z-3a (oil, 34 mg, 9%
yield).
O
PhO2SF2C
C4H9
6ac
6ad
91
96
N
3a
2g
O
OH
2b
6da
6db
93
94
2a
I
PhO2SF2C
3d
OCH3
Ph
2h
4.2.1. (E)-(1,1-Difluoro-3-iodohept-2-enylsulfonyl)benzene (E-3a)
White solid; mp 43–44 ꢁC; IR (film): 2928, 1625, 1581, 1450,
a
Isolated yield.
1344, 1158, 1089, 997 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.98 (d,
J¼7.8 Hz, 2H), 7.75–7.80 (m, 1H), 7.60–7.65 (m, 2H), 6.42 (t,
Next, we attempted the reductive desulfonylation reaction of
compound 5 and 6 to obtain CF2H-substituted alkenes. Using an
environmentally friendly Mg/HOAc/NaOAc desulfonylation system
that was previously developed by our group,10 compounds 5ab and
5db can be easily transformed into CF2H-substituted alkenes
(Scheme 3). However, compounds 6 were totally destroyed when
subjected to the same conditions. It is worth noting that CF2H-
sustituted alkenes are useful precursors for synthesis of biologically
interesting compounds,11–15 and currently very few general
methods are available for their efficient synthesis.
J¼14.1 Hz, 1H), 2.65 (t, J¼7.5 Hz, 2H), 1.53–1.58 (m, 2H), 1.25–1.29
(m, 2H), 0.89 (t, J¼6.6 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.8
(d, J¼15.2 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d 135.5, 132.7, 130.8,
129.4, 125.4 (t, J¼6.4 Hz), 125.1 (t, J¼23.4 Hz), 120.1 (t, J¼285.0 Hz),
41.2 (t, J¼2.8 Hz), 32.3, 21.7, 13.8; ESI (m/z): 418 (MþNHþ4 ). Anal.
Calcd for C13H15F2IO2S: C, 39.01; H, 3.78. Found: C, 39.25; H, 3.76.
4.2.2. (Z)-(1,1-Difluoro-3-iodohept-2-enylsulfonyl)benzene (Z-3a)
Oily liquid; IR (film): 2959, 2933, 1633, 1584, 1449, 1346, 1166,
1091, 997 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
8.01 (d, J¼8.1 Hz, 2H),
7.74–7.77 (m, 1H), 7.62 (t, J¼7.8 Hz, 2H), 6.40 (t, J¼13.2 Hz, 1H), 2.69
Cl
Cl
(t, J¼7.2 Hz, 2H), 1.52–1.60 (m, 2H), 1.31–1.38 (m, 2H), 0.94 (t,
J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ98.6 (d, J¼13.0 Hz,
Mg, HOAc-NaOAc-H2O
DMF, rt
2F); 13C NMR (125 MHz, CDCl3):
d 135.4, 132.7, 130.9, 129.3, 120.4 (t,
PhO2SF2C
R
HF2C
R
J¼18.1 Hz), 119.0, 118.9 (t, J¼286.2 Hz), 48.4, 31.2, 21.2, 13.7; ESI
(m/z): 418 (MþNH4þ); HRMS (FTMS) calcd for C13H15F2IO2SNaþ
(MþNaþ): 422.9703, found: 422.9698.
R: -C4H9 (7ab, 65%)
R: -CH2OCH3 (7db, 52%)
R: -C4H9 (5ab)
R: -CH2OCH3 (5db)
Scheme 3.
4.2.3. (E)-6,6-Difluoro-4-iodo-6-(phenylsulfonyl)hex-4-
en-1-ol (3b)
3. Conclusion
White solid; mp 72–74 ꢁC (for a sample with isomeric ratio
E/Z¼9:1); IR (film): 3251, 1626, 1583, 1449, 1337, 1160, 1074,
In conclusion, we have successfully developed an efficient and
stereoselective radical (phenylsulfonyl)difluoromethylation of ter-
minal alkynes. By using Et3B/air as radical initiator, PhSO2CF2I can
add to a variety of alkynes to afford the corresponding products in
good yields and with moderate to good Z/E stereoselectivity. These
obtained PhSO2CF2-containing compounds, which can further un-
dergo Suzuki or Sonogashira coupling reactions, are highly useful
precursors for preparation of PhSO2CF2- and CF2H-substituted
alkenes.
1011 cmꢀ1. For E-isomer: 1H NMR (300 MHz, CDCl3):
d 7.99 (d,
J¼7.8 Hz, 2H), 7.76–7.81 (m, 1H), 7.61–7.66 (m, 2H), 6.47 (t,
J¼14.4 Hz, 1H), 3.69 (t, J¼6.0 Hz, 2H), 2.82 (t, J¼7.5 Hz, 2H), 1.83–
1.92 (m, 2H), 1.65 (t, J¼5.6 Hz, 1H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.6 (d, J¼15.2 Hz, 2F); 13C NMR (100 MHz, CDCl3):
d 135.5,
132.4, 130.7, 129.4, 125.7 (t, J¼24.4 Hz), 124.5 (t, J¼6.7 Hz), 120.0 (t,
J¼285.5 Hz), 61.0, 37.6 (d, J¼2.7 Hz), 33.2; ESI (m/z): 403 (Mþþ1),
425 (MþNaþ). Anal. Calcd for C12H13F2IO3S: C, 35.84; H, 3.26.
Found: C, 35.92; H, 3.30.
4. Experiment sections
4.1. General
4.2.4. (E)-4,4-Difluoro-2-iodo-4-(phenylsulfonyl)but-2-en-1-ol (3c)
White solid; mp 67–70 ꢁC (for a sample with isomeric ratio
E/Z¼2:1); IR (film): 3420, 1631, 1581, 1451, 1330, 1163, 1009,
682 cmꢀ1. For E-isomer: 1H NMR (300 MHz, CDCl3):
d 7.99 (d,
Unless otherwise mentioned, solvents and reagents were pur-
chased from commercial sources and used as received. PhSO2CF2I
J¼8.4 Hz, 2H), 7.77–7.84 (m, 1H), 7.64–7.68 (m, 2H), 6.56 (t,
J¼13.8 Hz, 1H), 4.45 (s, 2H), 2.65 (s, 1H); 19F NMR (282 MHz, CDCl3):

Y. Li et al. / Tetrahedron 65 (2009) 478–483
481
d
ꢀ95.2 (d, J¼13.5 Hz, 2F); ESI (m/z): 392 (MþNHþ4 ). Anal. Calcd for
(282 MHz, CDCl3);
CDCl3): d 159.2, 140.7, 135.1, 133.4, 130.8, 129.2, 128.9, 128.5, 126.6,
d
ꢀ95.3 (d, J¼15.5 Hz, 2F); 13C NMR (125 MHz,
C10H9F2IO3S: C, 32.10; H, 2.42. Found: C, 32.15; H, 2.42.
121.8 (t, J¼282.2 Hz), 112.1 (t, J¼22.2 Hz), 31.2, 31.0, 22.6, 53.7; ESI
(m/z): 368 (MþNH4þ); HRMS (EI) calcd for C13H15F2þ (MþꢀPhSO2):
209.1142, found: 209.1154.
4.2.5. (E)-(1,1-Difluoro-3-iodo-4-methoxybut-2-
enylsulfonyl)benzene (3d)
Oily liquid; IR (film): 2932, 1624, 1583, 1449, 1345, 1166, 1100,
1010 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
8.00 (d, J¼7.8 Hz, 2H),
7.78–7.83 (m, 1H), 7.62–7.68 (m, 2H), 6.69 (t, J¼14.1 Hz, 1H), 4.20 (s,
2H), 3.34 (s, 3H); 19F NMR (282 MHz, CDCl3):
ꢀ96.0 (d, J¼13.3 Hz,
2F); 13C NMR (75 MHz, CDCl3):
135.7, 132.3, 1130.8, 129.5, 127.6 (t,
4.3.2. (E)-1-Chloro-4-(1,1-difluoro-1-(phenylsulfonyl)hept-2-en-3-
yl)benzene (5ab)
White solid; mp 69–71 ꢁC; IR (film): 2963, 1906, 1636, 1591,
d
1492, 1449, 1334, 1214, 1161, 1089 cmꢀ1
;
1H NMR (300 MHz,
d
J¼24.6 Hz), 123.1 (t, J¼6.6 Hz), 119.9 (t, J¼285.0 Hz); ESI (m/z): 389
(Mþþ1); HRMS (MALDI) calcd for C11H11F2IO3SNaþ (MþNaþ):
410.9328, found: 410.9334.
CDCl3):
2H), 7.34 (s, 4H), 5.75 (t, J¼15.3 Hz, 1H), 2.73 (s, 2H), 1.29 (s, 4H),
0.83 (s, 3H); 19F NMR (282 MHz, CDCl3):
ꢀ95.4 (d, J¼16.3 Hz,
2F); 13C NMR (100 MHz, CDCl3):
157.9 (t, J¼5.7 Hz), 139.1, 135.1,
d
8.03 (d, J¼7.5 Hz, 2H), 7.74–7.79 (m, 1H), 7.60–7.65 (m,
d
d
4.2.6. (E)-4,4-Difluoro-2-iodo-4-(phenylsulfonyl)but-2-enyl
acetate (3e)
135.0, 133.2, 130.7, 129.2, 128.7, 128.0, 121.7 (t, J¼282.3 Hz), 112.6
(t, J¼22.4 Hz), 31.2, 30.9, 22.6, 13.7; ESI (m/z): 385 (Mþþ1), 402
(MþNHþ4 ). Anal Calcd for C19H19ClF2O2S: C, 59.29; H, 4.98.
Found: C, 59.31; H, 4.94.
White solid; mp 69–70 ꢁC; IR (film): 3100, 2933, 1732, 1630,
1452, 1337, 1241, 1161 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 8.00 (d,
J¼7.5 Hz, 2H), 7.80 (t, J¼7.2 Hz, 1H), 7.62–7.67 (m, 2H), 6.69 (t,
J¼14.1 Hz, 1H), 4.93 (s, 2H), 2.16 (s, 3H); 19F NMR (282 MHz, CDCl3):
4.3.3. ((1E,3E)-3-(2,2-Difluoro-2-(phenylsulfonyl)ethylidene)hept-
1-enyl)benzene (5ac)
d
ꢀ96.5 (d, J¼15.0 Hz, 2F); 13C NMR (125 MHz, CDCl3):
d 169.6,
135.7, 132.2, 130.9, 129.5, 128.3 (t, J¼24.7 Hz), 119.8 (t, J¼285.2 Hz),
116.0 (t, J¼6.5 Hz), 65.4 (t, J¼4.2 Hz), 20.8; ESI (m/z): 417 (Mþþ1),
434 (MþNHþ4 ). Anal. Calcd for C12H11F2IO4S: C, 34.63; H, 2.66.
Found: C, 34.82; H, 2.48.
White solid; mp 90–91 ꢁC; IR (film): 1609, 1448, 1338, 1217,
1160, 1077, 995 cmꢀ1
; d 8.02 (d,
1H NMR (300 MHz, CDCl3):
J¼7.2 Hz, 2H), 7.73–7.78 (m, 1H), 7.60–7.65 (m, 2H), 7.42–7.48 (m,
2H), 7.27–7.39 (m, 3H), 6.87 (t, J¼16.5 Hz, 1H), 6.73 (d, J¼16.5 Hz,
1H), 5.70 (t, J¼16.2 Hz, 1H), 2.54–2.59 (m, 2H), 1.37–1.54 (m, 4H),
4.2.7. (E)-6,6-Difluoro-4-iodo-6-(phenylsulfonyl)hex-4-enyl 4-
methylbenzenesulfonate (3f)
0.93 (t, J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ94.4 (d,
J¼16.3 Hz, 2F); 13C NMR (100 MHz, CDCl3):
d
154.9 (t, J¼5.4 Hz),
White solid; mp 73–74 ꢁC; IR (film): 3070,1625,1581,1447,1362,
136.1, 135.0, 133.4, 130.7, 129.8, 129.2, 128.7, 127.0, 122.1 (t,
J¼282.0 Hz), 113.0 (t, J¼22.1 Hz), 32.3, 28.1, 23.0, 13.8; ESI (m/z):
399 (MþNaþ). Anal. Calcd for C21H22F2O2S: C, 67.00; H, 5.89.
Found: C, 66.93; H, 5.85.
1343, 1176, 1164, 1077 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.96 (d,
J¼7.5 Hz, 2H), 7.78 (d, J¼8.4 Hz, 3H), 7.61–7.66 (m, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 6.44 (t, J¼13.8 Hz, 1H), 4.07 (t, J¼6.0 Hz, 2H), 2.74 (t,
J¼7.5 Hz, 2H), 2.43 (s, 3H), 1.89–1.98 (m, 2H); 19F NMR (282 MHz,
CDCl3):
d
ꢀ96.4 (d, J¼14.1 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d 144.9,
4.3.4. (Z)-(4,4-Difluoro-1-methoxy-4-(phenylsulfonyl)but-2-en-2-
yl)benzene (5da)
135.7, 132.9, 132.4, 130.8, 129.9 129.5, 127.8 (d, J¼8.1 Hz), 126.5 (t,
J¼25.3 Hz), 122.0 (t, J¼7.1 Hz), 119.9 (t, J¼287.5 Hz), 68.7, 37.7 (d,
J¼2.3 Hz), 29.5, 21.6; ESI (m/z): 557 (Mþþ1), 574 (MþNH4þ). Anal.
Calcd for C19H19F2IO5S2: C, 41.02; H, 3.44. Found: C, 41.21; H, 3.59.
White solid; mp 45–47 ꢁC; IR (film): 1643, 1447, 1374, 1342, 1211,
1166, 1087, 1012 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 8.04 (d,
J¼7.8 Hz, 2H), 7.76–7.81 (m, 1H), 7.62–7.67 (m, 2H), 7.49–7.51 (m,
2H), 7.38–7.40 (m, 3H), 5.98 (t, J¼15.6 Hz, 1H), 4.60 (s, 2H), 3.21 (s,
4.2.8. (E)-2-(6,6-Difluoro-4-iodo-6-(phenylsulfonyl)hex-4-
enyl)isoindoline-1,3-dione (3g)
3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ94.3 (d, J¼15.8 Hz, 2F); 13C NMR
White solid; mp 127–129 ꢁC (for a sample with isomeric ratio
E/Z¼8:1). IR (film): 3059, 1769, 1712, 1622, 1451, 1397, 1336,
(100 MHz, CDCl3):
d
154.2 (t, J¼5.8 Hz), 138.3, 135.3, 133.0, 130.8,
129.4, 129.3, 128.5, 127.1, 121.3 (t, J¼282.1 Hz), 68.3 (t, J¼3.6 Hz),
58.0; ESI (m/z): 356 (MþNHþ4 ), 361 (MþNaþ). Anal. Calcd for
C17H16F2O3S: C, 60.34; H, 4.77. Found: C, 60.35; H, 4.71.
1161 cmꢀ1. For E-isomer: 1H NMR (300 MHz, CDCl3):
d 7.84–7.88 (m,
4H), 7.72–7.77 (m, 3H), 7.26–7.60 (m, 2H), 6.45 (t, J¼14.1 Hz, 1H),
3.74 (t, J¼6.9 Hz, 2H), 2.74–2.79 (m, 2H),1.99–2.01 (m, 2H); 19F NMR
4.3.5. (Z)-1-Chloro-4-(4,4-difluoro-1-methoxy-4-(phenylsulfonyl)-
but-2-en-2-yl)benzene (5db)
(282 MHz, CDCl3):
d
ꢀ95.7 (d, J¼13.8 Hz, 2F); ESI (m/z): 532
(Mþþ1),
549
(MþNHþ4 );
HRMS
(MALDI)
calcd
for
White solid; mp 68–69 ꢁC; IR (film): 1644, 1491, 1448, 1372,
C20H16F2INO4SNaþ (MþNaþ): 553.9700, found: 553.9705.
1345, 1214, 1165, 1086 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 8.03 (d,
J¼7.5 Hz, 2H), 7.76–7.81 (m, 1H), 7.62–7.68 (m, 2H), 7.35–7.45 (m,
4.3. Typical procedure of the Suzuki reactions of compounds
(3) with boronic acids
4H), 5.97 (t, J¼15.6 Hz, 1H), 4.58 (s, 2H), 3.27 (s, 3H); 19F NMR
(282 MHz, CDCl3):
CDCl3):
128.7, 128.5, 121.2 (t, J¼282.3 Hz), 115.4 (t, J¼23.8 Hz), 68.2 (t,
J¼3.7 Hz), 58.0; EI (m/z %): 231 (MþꢀPhSO2). Anal. Calcd for
C17H15ClF2O3S: C, 54.77; H, 4.06. Found: C, 54.74; H, 4.04.
d
ꢀ94.3 (d, J¼16.3 Hz, 2F); 13C NMR (100 MHz,
d
150.3 (t, J¼5.8 Hz), 136.7, 135.5, 135.4, 132.9, 130.8, 129.3,
A mixture of E-3a (160 mg, 0.4 mmol), phenyl boronic acid (4a)
(60 mg, 0.48 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K2CO3
(111 mg, 0.8 mmol) was stirred in THF at 65 ꢁC under N2 atmo-
sphere for 8 h. The mixture was filtered and the filtrate was con-
centrated under reduced pressure. The residue was purified by
flash column chromatography with ethyl acetate/petroleum ether
(1:30) to afford 5aa (136 mg, 97%).
4.3.6. ((1E,3Z)-5,5-Difluoro-3-(methoxymethyl)-5-(phenylsul-
fonyl)penta-1,3-dienyl)benzene (5dc)
White solid; mp 111–113 ꢁC; IR (film): 1628, 1450, 1336, 1216,
4.3.1. (E)-(1,1-Difluor-1-(phenylsulfonyl)hept-2-en-3-yl)benzene
(5aa)
1160, 1086, 993 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 8.02 (d,
J¼7.2 Hz, 2H), 7.75–7.80 (m, 1H), 7.61–7.66 (m, 2H), 7.46–7.50 (m,
2H), 7.25–7.39 (m, 3H), 7.16 (d, J¼15.6 Hz, 1H), 6.79 (d, J¼15.6 Hz,
1H), 5.90 (t, J¼15.9 Hz, 1H), 4.45 (s, 2H), 3.36 (s, 3H); 19F NMR
Oily liquid; IR (film): 2959, 1636, 1584, 1448, 1342, 1220, 1166,
1076 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
8.03 (d, J¼7.2 Hz, 2H),
7.73–7.78 (m, 1H), 7.60–7.65 (m, 2H), 7.37 (s, 5H), 5.75 (t, J¼15.6 Hz,
(282 MHz, CDCl3):
CDCl3):
d
ꢀ93.5 (d, J¼16.6 Hz, 2F); 13C NMR (75 MHz,
1H), 2.73 (s, 2H), 1.29–1.30 (m, 4H), 0.83–0.85 (m, 3H); 19F NMR
d
150.3 (t, J¼6.1 Hz), 136.2, 135.6 (t, J¼1.6 Hz), 135.4, 133.0,

482
Y. Li et al. / Tetrahedron 65 (2009) 478–483
130.8, 129.4, 128.88, 128.80, 127.5 (d, J¼1.5 Hz), 127.2, 121.6 (t,
J¼283.4 Hz), 115.3 (t, J¼23.1 Hz), 67.0 (t, J¼3.4 Hz), 57.9; ESI (m/z):
382 (MþNHþ4 ). Anal. Calcd for C19H18F2O3S: C, 62.64; H, 4.98.
Found: C, 62.60; H, 5.18.
95.2, 81.1 (d, J¼3.3 Hz), 61.4, 32.7 (t, J¼2.6 Hz), 31.1, 30.7, 22.3, 15.9,
13.8; ESI (m/z): 357 (Mþþ1), 374 (MþNHþ4 ), 379 (MþNaþ). Anal.
Calcd for C18H22F2O3S: C, 60.47; H, 6.41. Found: C, 60.47; H, 6.42.
4.4.5. (Z)-(1,1-Difluoro-3-(methoxymethyl)non-2-en-4-ynylsul-
fonyl)benzene (6da)
4.4. Typical procedure of the Sonogashira coupling reactions
of compounds (3) with alkynes
Oily liquid; IR (film): 2961, 2222, 1622, 1450, 1345, 1166, 1097,
1000 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
7.80 (d, J¼8.1 Hz, 2H),
7.74–7.79 (m, 1H), 6.28 (t, J¼7.5 Hz, 2H), 5.97 (t, J¼14.4 Hz, 1H), 4.19
(s, 2H), 3.37 (s, 3H), 2.39 (t, J¼6.9 Hz, 2H), 1.39–1.65 (m, 4H), 0.92 (t,
Under N2 atmosphere, a mixture of E-3a (120 mg, 0.3 mmol), 1-
hexyne (2a) (30 mg, 0.36 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol),
and NEt3 (2.0 mL) was stirred at room temperature for about
10 min. The mixture was filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by flash column
chromatography with ethyl acetate/petroleum ether (1:30) to af-
ford 6aa (103 mg, 97%).
J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.8 (d, J¼16.1 Hz,
2F); ESI (m/z): 365 (MþþNa); HRMS (FTMS) calcd for
C17H20F2O3SNaþ (MþþNa): 365.0993, found: 365.1002.
4.4.6. (Z)-(5,5-Difluoro-3-(methoxymethyl)-5-(phenylsulfonyl)-
pent-3-en-1-ynyl)benzene (6db)
White solid; mp 62–64 ꢁC; IR (film): 1693, 1596, 1356, 1265,
4.4.1. (E)-(3-Butyl-1,1-difluoronon-2-en-4-ynylsulfonyl)benzene
(6aa)
1168, 1029, 924, 858 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 8.02 (d,
J¼7.8 Hz, 2H), 7.75–7.80 (m, 1H), 7.61–7.69 (m, 2H), 7.49–7.52 (m,
Oily liquid; IR (film): 2959, 2223, 1620, 1449, 1345, 1217, 1166,
1092, 998 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
8.00 (d, J¼7.5 Hz, 2H),
2H), 7.33–7.36 (m, 3H), 6.16 (t, J¼15.6 Hz, 1H), 4.32 (s, 2H), 3.43 (s,
3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.5 (d, J¼15.2 Hz, 2F); 13C NMR
7.76 (t, J¼7.5 Hz, 1H), 7.59–7.64 (m, 2H), 5.80 (t, J¼15.6 Hz, 1H), 2.36
(t, J¼7.2 Hz, 4H), 1.25–1.60 (m, 8H), 0.86–0.97 (m, 6H); 19F NMR
(100 MHz, CDCl3):
d
138.3 (t, J¼6.2 Hz), 135.4, 132.8, 132.0, 130.8,
ꢀ95.5 (d, J¼16.1 Hz, 2F); 13C NMR (75 MHz,
129.39, 129.30, 128.3, 121.9, 120.98 (t, J¼282.3 Hz), 120.91 (t,
J¼24.1 Hz), 96.0, 87.1, 69.3 (t, J¼4.0 Hz), 58.5; ESI (m/z): 363
(Mþþ1), 380 (MþNHþ4 ). Anal. Calcd for C19H16F2O3S: C, 62.97; H,
4.45. Found: C, 63.18; H, 4.39.
(282 MHz, CDCl3):
CDCl3):
J¼283.4 Hz), 117.5 (t, J¼22.8 Hz), 96.4 (t, J¼1.3 Hz), 80.7 (d,
J¼2.1 Hz), 32.8 (t, J¼2.5 Hz), 30.7 (t, J¼2.5 Hz), 30.4, 22.3, 21.9, 19.1,
13.8, 13.5; ESI (m/z): 355 (Mþþ1), 372 (MþNHþ4 ). Anal. Calcd for
C19H24F2O2S: C, 64.38; H, 6.82. Found: C, 64.62; H, 6.80.
d
d
142.1 (t, J¼6.1 Hz), 135.1, 133.3, 130.8, 129.2, 121.4 (t,
4.5. Typical procedure for magnesium-mediated
desulfonylation
4.4.2. (E)-(3-(2,2-Difluoro-2(phenylsulfonyl)ethylidene)hept-1-
ynyl)benzene (6ab)
Into
a 10-mL flask containing compound 5aa (196 mg,
0.51 mmol) in 8.0 mL DMF at room temperature was added 4 mL of
HOAc/NaOAc (1:1) buffer solution (8 mol/L). Magnesium turnings
(184 mg, 7.6 mmol) were added in portions. The reaction mixture
was stirred at room temperature for 5 h followed by adding 15 mL
of water. The solution mixture was extracted with Et2O (20 mLꢂ3),
and the combined organic phase was dried over MgSO4. After the
removal of ethyl ether, the crude product was purified by silica gel
column chromatography using petroleum as eluent to give product
7aa (liquid, 81 mg, 65%).
Oily liquid; IR (film): 2211, 1618, 1490, 1449, 1338, 1164, 1097,
998, 759 cmꢀ1; 1H NMR (300 MHz, CDCl3):
7.74–7.79 (m, 1H), 7.60–7.65 (m, 2H), 7.46 (s, 2H), 7.36 (s, 3H), 6.00
d
8.02 (d, J¼7.8 Hz, 2H),
(t, J¼15.0 Hz, 1H), 2.46–2.49 (m, 2H), 1.59–1.68 (m, 2H), 1.35–1.43
(m, 2H), 0.94 (t, J¼6.9 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.7
(d, J¼16.6 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d 141.4, 135.4, 133.3,
131.9, 130.9, 129.4, 129.2, 128.5, 122.2, 121.4 (t, J¼283.9 Hz), 118.8 (t,
J¼23.6 Hz), 94.5, 89.1 (d, J¼3.0 Hz), 32.6 (t, J¼2.7 Hz), 30.9, 22.5,
14.0; ESI (m/z): 392 (MþNHþ4 ). Anal. Calcd for C21H20F2O2S: C,
67.36; H, 5.38. Found: C, 67.33; H, 5.45.
4.5.1. (E)-1-Chloro-4-(1,1-difluorohept-2-en-3-yl)benzene (7ab)
4.4.3. (E)-2-(6-(2,2-Difluoro-2-(phenylsulfonyl)ethylidene)dec-4-
ynyl)isoindoline-1,3-dione (6ac)
Liquid; IR (film): 2960, 1654, 1593, 1493, 1405, 1380, 1141, 1070,
1014 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.28–7.35 (m, 4H), 6.48 (td,
White solid; mp 70–72 ꢁC; IR (film): 2933, 1771, 1709, 1623,
J¼56.1, 6.9 Hz, 1H), 5.71–5.80 (m, 1H), 2.53–2.58 (m, 2H), 1.25–1.36
1398, 1337, 1170 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.98 (d,
(m, 4H), 0.86 (t, J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ109.2
(dd, J¼55.2, 9.6 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d 149.4 (t,
J¼7.8 Hz, 2H), 7.81–7.85 (m, 2H), 7.69–7.78 (m, 3H), 7.59–7.64 (m,
2H), 5.68 (t, J¼15.3 Hz, 1H), 3.78–3.83 (m, 2H), 2.45 (t, J¼6.6 Hz,
2H), 2.69 (t, J¼6.6 Hz, 2H), 1.95–2.02 (m, 2H), 1.43–1.50 (m, 2H),
1.27–1.34 (m, 2H), 0.89 (t, J¼7.5 Hz, 3H); 19F NMR (282 MHz,
J¼12.5 Hz), 138.8, 134.3, 128.7, 127.8, 120.9 (t, J¼26.0 Hz), 112.4 (t,
J¼230.7 Hz), 30.7, 30.2, 22.4, 13.7; EI (m/z %): 244 (Mþ, 2.7), 202
(100.0). Anal. Calcd for C13H15ClF2: C, 63.81; H, 6.18. Found: C,
63.97; H, 6.28.
CDCl3):
d
ꢀ95.2 (d, J¼15.5 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d
168.3, 141.6 (t, J¼5.8 Hz), 135.2, 134.0, 133.2, 132.0, 130.7, 129.2,
4.5.2. (Z)-1-Chloro-4-(4,4-difluoro-1-methoxybut-2-en-2-yl)-
benzene (7db)
123.2, 121.2 (t, J¼285.0 Hz), 118.0 (t, J¼22.5 Hz), 94.5, 81.2 (d,
J¼3.8 Hz), 37.2, 32.6, 30.6, 27.1, 22.3, 17.3, 13.8; ESI (m/z): 508
(MþNaþ). Anal. Calcd for C26H25F2NO4S: C, 64.32; H, 5.17; N, 2.88.
Found: C, 64.31; H, 5.26; N, 2.76.
Liquid; IR (film): 2963, 1657, 1594, 1493, 1410, 1261, 1094, 1015,
800 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.32–7.38 (m, 4H), 6.71 (td,
J¼56.4, 6.9 Hz, 1H), 5.91–5.99 (m, 1H), 4.38 (s, 2H), 3.37 (s, 3H); 19F
NMR (282 MHz, CDCl3):
d
ꢀ109.8 (dd, J¼56.1, 9.8 Hz, 2F); 13C NMR
4.4.4. (E)-6-(2,2-Difluoro-2-(phenylsulfonyl)ethylidene)dec-4-yn-
1-ol (6ad)
(100 MHz, CDCl3):
d
144.4 (t, J¼12.0 Hz), 137.1, 134.8, 128.7, 127.9,
Oily liquid; IR (film): 3396, 2957, 2223, 1620, 1449, 1337, 1165,
123.9 (t, J¼26.6 Hz), 111.7 (t, J¼230.1 Hz), 69.9, 58.3; EI (m/z %): 232
(Mþ, 4.3), 202 (36.4), 45 (100.0); HRMS (EI) calcd for C11H11F2ClO:
232.0466, found: 232.0461.
1091, 999 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
8.00 (d, J¼7.8 Hz, 2H),
7.73–7.78 (m, 1H), 7.62 (t, J¼7.8 Hz, 2H), 5.82 (t, J¼15.6 Hz, 1H), 3.76
(t, J¼6.0 Hz, 2H), 2.47–2.51 (m, 2H), 2.33–2.38 (m, 2H), 1.77–1.86
(m, 2H), 1.67 (d, J¼3.6 Hz, 1H), 1.48–1.58 (m, 2H), 1.25–1.39 (m, 2H),
Acknowledgements
0.90 (t, J¼7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
ꢀ95.2 (d,
J¼15.2 Hz, 2F); 13C NMR (75 MHz, CDCl3):
d
141.9 (t, J¼6.3 Hz),
We thank the National Natural Science Foundation of China
(20502029, 20772144, 20825209), Shanghai Rising-Star Program
135.2, 133.1, 130.7, 129.2, 121.3 (t, J¼283.3 Hz), 117.9 (t, J¼23.5 Hz),

Y. Li et al. / Tetrahedron 65 (2009) 478–483
483
2. Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley:
New York, NY, 1991.
(06QA14063), and the Chinese Academy of Sciences (Hundreds-
Talent Program and Knowledge Innovation Program) for financial
support.
3. Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006.
4. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
5. Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004.
6. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786.
7. Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. J. Comb. Chem. 2007, 9, 920–923.
8. Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921–930 and the references
cited therein.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.011.
9. Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem. 2007, 72, 5824–5827.
10. Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273–8277.
11. Konno, T.; Kitazume, T. Chem. Commun. 1996, 2227–2228.
12. Tellier, F.; Sauvetre, R. J. Fluorine Chem. 1996, 76, 181–185.
13. Furuya, T.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2005, 126, 721–725.
14. Xiao, L.; Kitazume, T. Tetrahedron: Asymmetry 1997, 8, 3597–3601.
15. Konno, T.; Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 2000, 41, 8467–8472.
16. Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2004, 6, 4315–4317.
References and notes
1. Organofluorine Compounds in Medicinal Chemistry and Biomedicinal Applications;
Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.