AIBN-initiated radical addition of gem-difluorinated alkyl iodides to alkynes and the Pd-catalyzed Sonogashira coupling reaction of E-phenyl difluoromethylene vinylic iodides with terminal alkynes

Article abstract of DOI:10.1016/j.tet.2007.07.087

The addition of gem-difluorinated alkyl iodides to alkynes initiated by AIBN neatly gave the corresponding difluoromethylene vinyl iodides among which the stereoselectivity of aromatic acetylenes was high. The further coupling reaction of E-phenyl difluor

Full text of DOI:10.1016/j.tet.2007.07.087

Tetrahedron 63 (2007) 10684–10692
AIBN-initiated radical addition of gem-difluorinated alkyl
iodides to alkynes and the Pd-catalyzed Sonogashira coupling
reaction of E-phenyl difluoromethylene vinylic iodides with
terminal alkynes
Xiang Fang,a Xueyan Yang,a Xianjin Yang,a,b Shenjie Mao,a Zhonghua Wang,a
Guorong Chena and Fanhong Wua,b,
*
aLaboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering,
East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received 14 May 2007; revised 23 July 2007; accepted 24 July 2007
Available online 31 July 2007
Abstract—The addition of gem-difluorinated alkyl iodides to alkynes initiated by AIBN neatly gave the corresponding difluoromethylene
vinyl iodides among which the stereoselectivity of aromatic acetylenes was high. The further coupling reaction of E-phenyl difluoromethylene
vinyl iodides with terminal alkynes in the presence of catalytic palladium afforded the substituted difluorinated enynes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
has been extensively investigated for the preparation of
perfluorinated vinyl iodides,7 few reports of difluoro-
methylene vinyl iodides have been documented. To the
best of our knowledge, only Chen described the addition
of diethyl iododifluoromethylphosphonate and difluoro-
diiodomethane derivatives to alkynes initiated by sodium
dithionate.8
Organofluorine compounds have been widely applied in
the areas of pharmaceuticals, agrochemicals, and other
fields due to their unique properties arising from altered
electron density, acidity or basicity, and hydrogen-bonding
capability.1 Indeed, recent reports have demonstrated that
the CF2 group has a steric profile similar to that of the
CH2 group, but since it has both a very different polarity
and a very different reactivity, it can be regarded as an
isopolar and isosteric replacement for oxygen.2 Some po-
tent antitumor agents, broad spectrum antibiotics, inhibi-
tors of HIV-1 reverse transcriptase, and potent inhibitors
of various proteolytic enzymes contain difluoromethylene
group.3
The importance of difluoromethylene vinylic iodides in
the synthesis of biologically active compounds prompted
us to explore new and convenient synthesis of the gem-di-
fluorinated alkyl iodide reagents. Iododifluoroacetate 1 has
been demonstrated to be a versatile gem-difluoromethyl-
ation reagent. Burton and Yang have developed a convenient
methodology for the preparation of iododifluoroacetate
from the commercially available bromodifluoroacetate.9
3-Phenyl-5-iododifluoromethyl-1,2,4-oxadiazole 2 bearing
1,2,4-oxadiazole moiety also could be prepared from
3-phenyl-5-bromodifluoro-1,2,4-oxadiazole using the same
method.10 Iododifluoromethyl phenyl thioether has been
prepared by the nucleophilic reaction of phenylthiol and
CF2I2 in a very low yield.11 Herein, a convenient and
efficient method for the synthesis of 3 has been achieved.
Bromodifluoromethyl phenyl thioether and its deriva-
tives12 have been readily converted to compounds 3 via the
halogen exchange process in the presence of sodium iodide
(Scheme 1).
Recently, much attention has been devoted to the synthe-
sis of vinylic iodides and their derivatives since they
emerged as highly valuable intermediates in a variety of
synthetic applications, such as in palladium-catalyzed So-
nogashira4 and other coupling reactions,5 particularly in
the synthesis of biologically active compounds.6 Although
the addition of perfluoroalkyl iodides to terminal alkynes
Keywords: Alkynes; Radical addition; Difluoromethylene vinylic iodides;
Sonogashira coupling.
* Corresponding author. Tel.: +86 21 64253530; e-mail: wfh@ecust.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.087

X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
10685
HgCl2
TG
I2
Unfortunately, the yields of propargyl alcohol and its deriv-
atives were very low. Under the same reaction conditions,
AIBN also initiated the addition of 1 to the internal alkyne
such as but-2-ynedioic acid dimethyl ester 4h (Scheme 2).
However, the adduct 5h was isolated in low yield (25%)
with no geometric selectivity (E/Z¼1:1).
+
ICF2CO2Et
1
BrCF2CO2Et Zn
BrZnCF2CO2Et
O
O
N
N
Zn/HgCl2
I2
CF2I
CF2Br
N
N
2
CF2CO2Et
NaI (excess)
acetone/DMF
I
AIBN
R
SCF2I
R
SCF2Br
R=H,Cl
ICF2CO2Et
+ MeOOC
COOMe
MeOOC
COOMe
3
1
4h
5h
Scheme 2.
Scheme 1.
The geometry of the double bond in 5 and 6 was established
by comparing the chemical shift of the vinylic protons,
which exhibited a typical triplets with coupling to the adja-
cent CF2 group. The alkenyl hydrogen of E-isomer appeared
2. Results and discussion
Among radical addition of perfluoroalkyl iodides to alkynes
initiated by UV light, AIBN, benzoyl peroxide, SmI2, Et3B,
Na2S2O4, etc.,13 Na2S2O4 is one of the most effective
methods for the preparation of fluorinated vinylic iodides.
However, when we treated iododifluoroacetate with phenyl-
ethyne in the presence of Na2S2O4/NaHCO3 in CH3CN/H2O
(1:1), DMF/H2O (1:1), or DMSO/H2O (1:1), 5a was formed
in only 16–24% yields. When 1,4-dioxane/H2O (1:1) was
used as solvent, the yield raised to 32%. When the mixture
was heated in copper powder at 60 ꢀC for 8 h, no adduct
was obtained. Fortunately, the addition of iododifluoroace-
tate to phenylethyne initiated by AIBN in the absence of sol-
vent at 65 ꢀC proceeded smoothly, and the addition reaction
was completed in 16 h and the E-isomer adduct 5a was iso-
lated in 85% yield. The scope of the reaction was studied by
the addition of iododifluoroacetate 1 and 3-phenyl-5-iodo-
difluoro-1,2,4-oxadiazole 2 to a variety of other terminal
alkynes. The results are summarized in Table 1. Unlike
perfluoroalkyl iodides,14 1 and 2 reacted with phenylethyne
4a to afford the corresponding adducts in good yields
(entries 1 and 8). Other functional groups, including alkyl,
ester, trimethylsilyl, on the alkynes gave moderate yields.
lower field than that of Z-isomer.15 The d 6.89 (JH–F
¼
1
11.9 Hz) and d 7.76 (JH–F¼11.4 Hz) chemical shifts on H
NMR spectra of 5b were assigned to E and Z isomers while
the d 6.92 (JH–F¼11.1 Hz) and d 7.37 (JH–F¼14.7 Hz) chem-
ical shifts on 1H NMR spectra of 5d were assigned to E and Z
isomers, respectively.
In the case of phenylethynes 4a, 4e, and 4f (entries 1, 5, 6,
and 8), the adducts gave single isomer. As for the influence
of the substituent (R) in alkynes 4 on the geometric selectiv-
ity of the addition reactions, a possible explanation may be
given as follows: when the EtO2CCFꢁ2 adds to alkynes,
they would form vinyl intermediates B and C.16 Avinyl rad-
ical is known to have a low inversion barrier (6–9 kcal/mol),
and p-conjugated substituents such as phenyl groups are
usually thought to favor the linear form in order to ensure
a better orbital overlap for resonance.17 With such a linear
vinyl radical, we can assume that the steric hindrance be-
tween the CF2CO2Et group and electron donor was unfavor-
able for the formation of the E-isomer (C) leading to the
Z-isomer (B). Other substituents lead to a mixture of E and
Z isomers (Scheme 3).
Table 1. AIBN-initiated addition of iododifluoroacetate 1 and 3-phenyl-
5-iododifluoro-1,2,4-oxadiazole 2 to terminal alkynes 4
R
I
I
H
H
AIBN
+
R
I
R
CO2Et
CO2Et
ICF2CO2Et
AIBN
F
F
+
ICF2CO2Et
R
F
F
R
CF2CO2Et
5
1
4
CF2CO2Et
ICF2CO2Et
ICF2CO2Et
N
O
N
O
AIBN
I
H
H
R
H
CF2I +
Ph
R
R
N
+
N
R
C
CO2Et
R
CO2Et
Ph
CO2Et
F2
F
F
F
F
F
F
2
4
6
A
B
C
Entry Substance Alkyne 4
Product Yielda (%) E/Z ratiob
Scheme 3.
1
2
3
4
5
6
7
8
9
10
1
1
1
1
1
1
1
2
2
2
Ph (4a)
5a
5b
5c
5d
5e
85
30
38
35
11
13
Trace
95
79
100:0
3.2:1
4.2:1
1:2.3
100:0
100:0
COOMe (4b)
C4H9 (4c)
TMS (4d)
CH2OTs (4e)
CH2OCOPh (4f) 5f
CH2OH (4g)
Ph (4a)
C4H9 (4c)
CH2OH (4g)
Reduction of 2,2-difluoro-4-iodo-4-phenyl-but-3-enoic acid
ethyl ester 5a and 5-(1,1-difluoro-3-iodo-3-phenyl-allyl)-
3-phenyl-[1,2,4]oxadiazole 6a was achieved by acidic re-
duction with zinc according to the literature method18 and
the products 2,2-difluoro-4-phenyl-but-3-enoic acid ethyl
ester 7a and 5-(1,1-difluoro-3-phenyl-allyl)-3-phenyl-
[1,2,4]oxadiazole 7b were obtained in 70% and 80% yield,
respectively (Scheme 4). The products had Z-configuration
implying retention of stereochemistry during zinc reduction.
5g
6a
6c
6g
100:0
3:1
1:2.1
14
a
Isolated yield.
Determined by NMR spectra.
b

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X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
The determination of the configuration was based on the cou-
pling constant across the double bond on 1H NMR spectra. It
is well-known that in 1,2-substituted ethylenic compounds
adduct products 8 in 27% and 23% yields, respectively. In
the case of 4a (entries 1 and 2), the hydrolyzed products
were obtained in 85% and 76% yields through a long time
column chromatography on silica gel. In the case of elec-
tron-donating alkyl group and trimethylsilyl groups 4c and
4d (entries 5–8), intermediates 8 could convert to 9 easily
during column chromatography. The O]C–S moiety could
be identified by 13C NMR spectroscopy, which could reach
to d 185 ppm. The possible explanation was that when oxy-
gen, sulfur, and nitrogen in particular, adjacent to carbon–
fluorine bonds, it greatly increased the reactivity toward
nucleophiles.22
3
3
the Jtrans constant is always larger than the Jcis constant.
A doublet of triplet centered at 6.95 ppm (JH4–H3¼12.6 Hz,
JH4–F¼1.7 Hz) of 7a is observed for the H4 proton, which
1
shows the H NMR features described by Chen and Long
3
and Reglier et al.19 Similarly, the JH–H constant of 7b is
12.5 Hz, hence the configuration is ascertained as Z-isomer.
H4
Ph
I
H3
CF2CO2Et
Zn
HOAc/H2O
Ph
CF2CO2Et
Difluoromethylene vinylic iodides are valuable interme-
diates in a variety of synthetic applications. The Sonoga-
shira coupling reaction is one of the very useful methods
for the synthesis of fluorinated conjugated enynes. Under the
cocatalysis of PdCl2(PPh3)2 (2 mol %) and CuI (5 mol %),
the Sonogashira cross-coupling reaction of difluorometh-
ylene vinyl iodide 5a with phenylethyne was systematically
examined first, especially with bases and solvents. We found
that the base influenced the reaction drastically. When
1 equiv base (for example, Et3N and DABCO) was used,
the reaction did not occur or underwent very slowly
even at reflux (Table 3, entries 2, 3, and 9). In contrast,
the reactions were complicated while the base was exces-
sively used (Table 3, entries 1 and 5). Using 1.5 equiv of
1,4-diazabicyclo[2,2,2]octane (DABCO) as a base in THF,
the reaction proceeded very well to form difluorinated
enyne 10a in good yield (Table 3, entry 10). The results
are summarized in Table 3.
5a
7a
N
N
O
O
I
H
Zn
Ph
Ph
N
HOAc/H2O
N
Ph
C
Ph
C
F2
F2
6a
7b
Scheme 4.
Previous reports showed that halogen exchange reaction of
fluoroalkyl bromide in the presence of NaI usually pro-
ceeded easily in acetone20 or butanone.21 Unfortunately,
the reaction of bromodifluoromethyl phenyl thioether with
NaI did not occur when only acetone or butanone was
used as solvent. In DMF solution, bromodifluoromethyl
phenyl thioether was converted completely in several hours
into a complicated mixture with less than 10% of 3 formed.
When the reaction was carried out in the mixture of acetone
and DMF (4.4:1, v/v), it went on smoothly yielding 56% of
3a and 50% of 3b after fractional distillation.
The palladium/copper(I) iodide cocatalyzed coupling re-
action of difluoromethylene vinyl iodides 5a and 6a
with terminal alkynes 4 gave substituted difluorinated
enynes 10 and 11. The results are summarized in Table
4. Both aromatic (Table 4, entries 1 and 7) and aliphatic
acetylenes (Table 4, entries 2–5) worked well. The low
yields in entries 8 and 9 were due to incomplete reaction
even at reflux for 48 h. Another reason was that it was
difficult to isolate products by column chromatography
because the polarity of the product was similar to that
of the substrate.
Different from 5 and 6, adducts 8 prepared from iododifluo-
romethyl phenyl thioether analogues 3 and terminal alkynes
4 were not stable. The difluoromethylene moiety was hydro-
lyzed into carbonyl group in air or during column chromato-
graphy on silica gel except for strong electron-withdrawing
ester 4b. The detailed results are summarized in Table 2. In
the case of 4b (entries 3 and 4), a triplet of CF2 group was
observed on the 13C NMR spectra of the final products. How-
ever, the conversions of 3 were only 36% and 30% to give
Table 2. AIBN-initiated addition of iododifluoromethyl phenyl thioether 3 to terminal alkynes 4
I
I
ICF2S
AIBN
S
S
silica gel
R'
+
R
R
C
R
F2
R'
O
R'
3
4
8
9
Entry
R0
Alkyne 4
Conversiona (%)
Yield of 8b (%)
Yield of 9b (%)
E/Z ratioc
1
2
3
4
5
6
7
8
H (3a)
Cl (3b)
H (3a)
Cl (3b)
H (3a)
Cl (3b)
H (3a)
Cl (3b)
Ph (4a)
Ph (4a)
COOMe (4b)
COOMe (4b)
C4H9 (4c)
C4H9 (4c)
TMS (4d)
TMS (4d)
89
85
36
30
71
68
92
88
—
—
27 (8ba)
23 (8bb)
—
—
—
—
85 (9aa)
76 (9ab)
—
100:0
7.6:1
2.7:1
1.4:1
1:3.4
1:1.8
1:2.0
1:2.2
—
64 (9ca)
50 (9cb)
36 (9da)
31 (9db)
a
The conversion was determined by GC analysis.
Isolated yield.
Determined by NMR spectra.
b
c

X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
10687
Table 3. Optimization of reaction conditions for the PdCl2(PPh3)2/CuI-cocatalyzed Sonogashira coupling reaction of 5a with phenylethyne
Ph
I
PdCl2(PPh3)2, CuI
Ph
+
Ph
CF2CO2Et
Ph
CF2CO2Et
10a
5a
Entry
Base
Solvent
Temp
Conversion (%)
Yielda (%)
1
2
3
4
5
6
7
8
Et3N
Et3N (1 equiv)
Et3N (1 equiv)
Et3N (1.5 equiv)
Et3N (4 equiv)
Pyridine (1.5 equiv)
Piperidine (4 equiv)
K2CO3 (1.5 equiv)
DABCO (1 equiv)
DABCO (1.5 equiv)
DABCO (1.5 equiv)
Et3N
THF
THF
CH3CN
CH3CN
CH3CN
THF
THF
THF
rt
Complicate
b
rt
Reflux
rt
rt
rt
rt
Reflux
rt
rt
rt
82c
100
63
46
Complicate
Complicate
d
100
83c
100
100
9
10
11
THF
CH3CN
86
75
a
Isolated yield.
No reaction occurred.
b
c
The conversion was determined by GC analysis.
Ph
O
d
The product was
.
N
Ph
C
F2
Table 4. PdCl2(PPh3)2/CuI-cocatalyzed Sonogashira coupling reaction of difluoromethylene vinylic iodides 5a and 6a with terminal alkyne 4
R
I
PdCl2(PPh3)2, CuI
DABCO/THF
+
R
Ph
CF2CO2Et
Ph
CF2CO2Et
10
5a
4
R
N
N
O
O
I
PdCl2(PPh3)2, CuI
DABCO/THF
Ph
Ph
+
R
N
N
Ph
C
Ph
C
F2
F2
6a
4
11
Entry
Substance
Alkyne
Product
Yield of 10 or 11a (%)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
6a
6a
6a
Ph (4a)
C4H9 (4c)
TMS (4d)
CH2OCOPh (4f)
C6H13 (4h)
t-C4H9 (4i)
Ph (4a)
10a
10b
10c
10d
10e
10f
11a
11b
11c
86
72
72
66
62
37b
72
C4H9 (4c)
TMS (4d)
31c
55c
a
Isolated yield.
The K2CO3 was used as base at reflux.
The substance does not react completely at reflux the conversion was 40% and 63%, respectively.
b
c
3. Conclusions
developed a facile method for the preparation of difluoro-
methylene enyenes via palladium-catalyzed cross-coupling
of difluoromethylene vinyl iodides with terminal alkynes.
In conclusion, we have developed a convenient procedure to
prepare difluoromethylene vinyl iodides. By utilizing AIBN
as an initiator, the difluoromethylene vinyl iodides were ob-
tained from gem-difluorinated alkyl iodides and the geomet-
ric selectivity of aromatic acetylenes was high. The adducts
8, except for strong electron-withdrawing ester 4b, were not
stable, therefore, the difluoromethylene moiety was hydro-
lyzed into carbonyl group on prolonged standing in air or
during column chromatography on silica gel. We have also
4. Experimental
4.1. General
Melting points were uncorrected. IR spectra were measured
on a Nicolet Magna IR-550 spectrometer. High-resolution

10688
X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
mass spectra were carried out on a Finnigan GC–MS-4021
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 6.40 (1H, t, JH–F
¼
1
spectrometer. H (500 MHz) and 13C (125.8 MHz) NMR
13.3 Hz), 4.34 (2H, q, J¼7.2 Hz), 2.61 (2H, t, J¼7.4 Hz),
1.59–1.49 (2H, m), 1.39–1.30 (5H, m), 0.93 (3H, t,
J¼7.3 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ98.69 (2F, d,
JH–F¼13.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.8 (t,
J¼34.4 Hz), 131.9 (t, J¼27.0 Hz), 120.2 (t, J¼7.5 Hz),
112.2 (t, J¼252.4 Hz), 63.9, 41.2, 32.6, 22.2, 14.6, 14.5.
spectra were recorded on a Bruker AC-500 spectrometer
with Me4Si as an internal standard. 19F NMR spectra were
obtained on a Bruker AC-500 (470 MHz) spectrometer in
CDCl3 with CFCl3 as an external standard, downfield shifts
being designated as negative. All chemical shifts (d) are ex-
pressed in parts per million, and coupling constants (J) are
given in hertz.
EIMS (m/z) 332 (M+, 3), 259 (29), 205 (81), 177 (100); IR
(cmꢂ1
C10H15F2IO2: 332.0085, found: 332.0079.
, KBr) 2961, 1769, 1631; HRMS calcd for
4.2. General procedure for the addition of
difluoromethylene iodides to terminal alkynes
4.2.4. 2,2-Difluoro-4-iodo-4-trimethylsilanyl-but-3-enoic
acid ethyl ester (5d). Light yellow liquid; E/Z¼1:2.3. Z-Iso-
1
Under nitrogen atmosphere, a mixture of difluoromethylene
iodides (5.0 mmol), alkyne 4 (6.0 mmol), and AIBN
(100 mg) was stirred at 65 ꢀC for 16 h. The reaction mixture
was directly purified by flash column chromatography (silica
gel, eluting with petroleum ether/ethyl acetate¼20:1) to
give 5.
mer: H NMR (CDCl3, 500 MHz) d 7.37 (1H, t, JH–F
¼
14.7 Hz), 4.34 (2H, q, J¼7.1 Hz), 1.36 (3H, t, J¼7.1 Hz),
0.32 (9H, s); 19F NMR (CDCl3, 470 MHz) d ꢂ98.57 (2F,
d, JH–F¼14.6 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.3
(t, J¼34.3 Hz), 144.4 (t, J¼25.9 Hz), 124.1 (t, J¼7.0 Hz),
112.4 (t, J¼252.1 Hz), 64.0, 14.5, 1.8.
4.2.1. 2,2-Difluoro-4-iodo-4-phenyl-but-3-enoic acid
ethyl ester (5a). Light yellow liquid; H NMR (CDCl3,
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 6.92 (1H, t, JH–F
¼
1
11.1 Hz), 4.36 (2H, q, J¼7.1 Hz), 1.36 (3H, t, J¼7.1 Hz),
0.24 (9H, s); 19F NMR (CDCl3, 470 MHz) d ꢂ99.82 (2F,
d, JH–F¼10.8 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.1
(t, J¼35.0 Hz), 139.0 (t, J¼29.0 Hz), 120.0, 112.9 (t,
J¼252.1 Hz), 63.9, 14.5, ꢂ1.3.
EIMS (m/z) 348 (M+, 3), 333 (10), 305 (27), 221 (75), 178
(100), 77 (31); IR (cmꢂ1, KBr) 2961, 1774, 848, 765;
HRMS calcd for C9H15F2IO2Si: 347.9854, found: 347.9855.
500 MHz) d 7.31 (5H, s), 6.72 (1H, t, JH–F¼10.9 Hz),
3.97 (2H, q, J¼7.2 Hz), 1.19 (3H, t, J¼7.2 Hz); 19F
NMR (CDCl3, 470 MHz) d ꢂ94.92 (2F, d, JH–F
¼
10.8 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.2 (t,
J¼33.3 Hz), 141.4, 133.7 (t, J¼28.4 Hz), 130.1, 128.7,
128.4, 111.5 (t, J¼250.3 Hz), 109.4 (t, J¼10.1 Hz),
63.8, 14.3; EIMS (m/z) 352 (M+, 1) 279 (15), 225 (37),
197 (52), 169 (100), 102 (29), 91 (46); IR (cmꢂ1, KBr)
2984, 1772, 1630, 697; HRMS calcd for C12H11F2IO2:
351.9772, found: 351.9771.
4.2.5. 2,2-Difluoro-4-iodo-5-(toluene-4-sulfonyloxy)-
pent-3-enoic acid ethyl ester (5e). Light yellow liquid; 1H
NMR (CDCl3, 500 MHz) d 7.73 (2H, d, J¼8.3 Hz), 7.31
4.2.2. 4,4-Difluoro-2-iodo-pent-2-enedioic acid 5-ethyl
ester 1-methyl ester (5b). Light yellow liquid; E/Z¼3.2:1.
(2H, d, J¼8.1 Hz), 6.64 (1H, tt, JH–F¼11.5 Hz, JH–H¼
Z-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.76 (1H, t, JH–F
¼
1.7 Hz), 4.62–4.60 (2H, m), 4.27 (2H, q, J¼7.1 Hz), 2.39
(3H, s), 1.28 (3H, t, J¼7.1 Hz); 19F NMR (470 MHz,
CDCl3) d ꢂ100.42 (2F, dt, JH–F¼9.4, 2.4 Hz); 13C NMR
(125.8 MHz, CDCl3) d 161.0 (t, J¼33.7 Hz), 144.7, 131.4,
129.1, 128.5 (t, J¼29.4 Hz), 127.0, 110.4 (t, J¼249.8 Hz),
100.4 (t, J¼8.7 Hz), 74.4, 62.5, 20.7, 12.9; EIMS (m/z)
460 (M+, 1), 333 (86), 305 (27), 155 (100), 91 (65); IR
(cmꢂ1, KBr) 3047, 2985, 1771, 1369, 1177, 667; HRMS
calcd for C14H15F2IO5S: 459.9653, found: 459.9650.
11.4 Hz), 4.40 (2H, q, J¼7.1 Hz), 3.90 (3H, s), 1.38 (3H, t,
J¼7.1 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ101.45 (2F,
d, JH–F¼9.4 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.0,
162.1 (t, J¼33.3 Hz), 142.3 (t, J¼29.9 Hz), 112.3 (t,
J¼249.4 Hz), 99.4 (t, J¼9.6 Hz), 64.4, 55.1, 14.5.
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 6.89 (1H, t, JH–F
¼
11.9 Hz), 4.35 (2H, q, J¼7.1 Hz), 3.81 (3H, s), 1.36 (3H, t,
J¼7.1 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ98.92 (2F, d,
JH–F¼14.1 Hz); 13C NMR (CDCl3, 125.8 MHz) d 164.4,
162.6 (t, J¼33.3 Hz), 141.1 (t, J¼29.8 Hz), 111.5 (t,
J¼250.8 Hz), 95.1 (t, J¼9.6 Hz), 64.0, 54.3, 14.5.
4.2.6. Benzoic acid 4-ethoxycarbonyl-4,4-difluoro-2-
iodo-but-2-enyl ester (5f). White solid; mp 124–125 ꢀC;
1H NMR (CDCl3, 500 MHz) d 8.10 (2H, d, J¼8.1 Hz),
7.60 (1H, t, J¼7.4 Hz), 7.47 (2H, t, J¼7.7 Hz), 6.71 (1H,
t, JH–F¼13.3 Hz), 5.13 (2H, s), 4.36 (2H, q, J¼7.1 Hz),
1.35 (3H, t, J¼7.1 Hz); 19F NMR (470 MHz, CDCl3)
d ꢂ98.61 (2F, d, JH–F¼13.2 Hz); 13C NMR (125.8 MHz,
EIMS (m/z) 334 (M+, 8), 262 (100), 207 (12); IR (cmꢂ1
,
KBr) 2986, 2957, 1777, 1738, 1625, 773; HRMS calcd for
C8H9F2IO4: 333.9514, found: 333.9514.
CDCl3)
d
166.0, 163.4 (t, J¼33.8 Hz), 135.0 (t,
4.2.3. 2,2-Difluoro-4-iodo-oct-3-enoic acid ethyl ester
(5c). Colorless liquid; E/Z¼4.2:1. Z-Isomer: 1H NMR
(CDCl3, 500 MHz) d 6.38 (1H, t, JH–F¼12.9 Hz), 4.36
(2H, q, J¼7.1 Hz), 2.61 (2H, t, J¼7.4 Hz), 1.59–1.49 (2H,
m), 1.39–1.30 (5H, m), 0.93 (3H, t, J¼7.3 Hz); 19F NMR
(CDCl3, 470 MHz) d ꢂ98.81 (2F, d, JH–F¼11.3 Hz); 13C
NMR (CDCl3, 125.8 MHz) d 163.2 (t, J¼34.4 Hz), 128.8
(t, J¼29.6 Hz), 115.5 (t, J¼9.7 Hz), 112.7 (t, J¼
247.7 Hz), 63.8, 47.1, 31.6, 21.8, 14.5, 14.4.
J¼27.9 Hz), 134.1, 130.6, 130.0, 129.2, 112.2 (t,
J¼253.2 Hz), 110.7 (t, J¼7.4 Hz), 66.3, 64.4, 14.5; EIMS
(m/z) 410 (M+, 1), 283 (100), 255 (28), 105 (86), 77 (15);
IR (cmꢂ1, KBr) 3064, 2985, 1769, 1729, 1635, 712;
HRMS calcd for C14H13F2IO4: 409.9827, found: 409.9833.
4.2.7. 4,4-Difluoro-2-iodo-3-methoxycarbonyl-pent-2-
enedioic acid 5-ethyl ester 1-methyl ester (5h). Light yel-
1
low liquid; E/Z¼1:1; H NMR (CDCl3, 500 MHz) d 4.40

X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
10689
(4H, q, J¼7.2 Hz), 3.90–3.81 (12H, m), 1.38 (3H, t,
J¼7.2 Hz), 1.36 (3H, t, J¼7.2 Hz); 19F NMR (CDCl3,
470 MHz) d ꢂ99.51 (2F, s), ꢂ101.51 (2F, s); 13C NMR
(CDCl3, 125.8 MHz) d 165.0, 164.9, 162.8, 162.0, 161.1
(t, J¼33.0 Hz), 160.9 (t, J¼32.7 Hz), 138.3 (t,
J¼26.0 Hz), 137.2 (t, J¼26.2 Hz), 110.9 (t, J¼255.4 Hz),
110.4 (t, J¼255.9 Hz), 101.0 (t, J¼5.2 Hz), 98.5 (t,
J¼6.0 Hz), 63.9, 63.7, 54.0, 53.8, 53.3, 53.2, 13.8, 13.8;
d, JH–F¼10.8 Hz); 13C NMR (CDCl3, 125.8 MHz)
d 169.9 (t, J¼35.9 Hz), 167.9, 130.9, 128.1, 126.6, 124.7
(t, J¼29.6 Hz), 124.5, 114.2 (t, J¼8.6 Hz), 111.3 (t,
J¼242.6 Hz), 70.7.
EIMS (m/z) 378 (M+, 3), 251 (54), 145 (100), 77 (57); IR
(cmꢂ1, KBr) 3439, 3037, 1650, 1066, 755, 691; HRMS calcd
for C12H9F2IN2O2: 377.9677, found: 377.9676.
EIMS (m/z) 392 (M+, 5), 288 (100), 265 (19); IR (cmꢂ1
,
KBr) 2957, 1779, 1741, 1613, 1259, 772; HRMS calcd for
C10H11F2IO6: 391.9568, found: 391.9568.
4.3. General procedure for the reduction of difluoro-
methylene vinylic iodides
4.2.8. 5-(1,1-Difluoro-3-iodo-3-phenyl-allyl)-3-phenyl-
[1,2,4]oxadiazole (6a). Colorless liquid; H NMR (CDCl3,
A mixture of 5a (1.0 mmol), AcOH (0.5 mL), water
(0.5 mL), and freshly activated zinc powder (75 mg,
1.2 mmol) was stirred at room temperature. After comple-
tion of the reaction, the mixture was diluted with water
(5 mL), extracted with CHCl3 (5 mLꢃ2), and dried with
MgSO4. Column chromatography gave 7a in 80% yield.
1
500 MHz) d 7.95–7.93 (2H, m), 7.54–7.45 (3H, m), 7.22–
7.11 (5H, m), 7.01 (1H, t, JH–F¼9.9 Hz); 19F NMR
(CDCl3, 470 MHz) d ꢂ87.4 (2F, d, JH–F¼9.9 Hz); 13C
NMR (CDCl3, 125.8 MHz) d 172.3 (t, J¼35.2 Hz), 170.2,
142.0, 134.7 (t, J¼29.0 Hz), 133.4, 131.1, 130.6, 129.8,
129.3, 129.0, 127.2, 112.8 (t, J¼244.4 Hz), 112.4 (t,
J¼10.1 Hz); EIMS (m/z) 424 (M+, 4), 297 (3), 269 (100),
167 (28), 77 (5); IR (cmꢂ1, KBr) 3059, 1629, 1445, 756,
697; HRMS calcd for C17H11F2IN2O: 423.9884, found:
423.9876.
4.3.1. 5-(1,1-Difluoro-3-phenyl-allyl)-3-phenyl-[1,2,4]oxa-
diazole (7b). Colorless liquid; 1H NMR (CDCl3, 500 MHz)
d 7.98–7.96 (2H, m), 7.51–7.42 (3H, m), 7.29–7.17 (5H,
m), 7.11 (1H, d, JH–H¼12.5 Hz), 6.17 (1H, q, J¼12.5 Hz);
19F NMR (CDCl3, 470 MHz) d ꢂ87.3 (2F, d, JH–F
¼
12.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 172.2 (t,
J¼35.6 Hz), 169.2, 141.1 (t, J¼8.2 Hz), 134.5, 132.3,
129.5, 129.4, 129.3, 128.8, 128.2, 126.3, 122.4 (t,
J¼27.5 Hz), 112.9 (t, J¼244.4 Hz); EIMS (m/z) 298 (M+,
79), 195 (35), 133 (100), 103 (58), 77 (25); IR (cmꢂ1, KBr)
3062, 1648, 1446, 759, 695; HRMS calcd for
C17H12F2N2O: 298.0918, found: 298.0919.
4.2.9. 5-(1,1-Difluoro-3-iodo-hept-2-enyl)-3-phenyl-
[1,2,4]oxadiazole (6c). Colorless liquid; E/Z¼3:1. E-Iso-
1
mer: H NMR (CDCl3, 500 MHz) d 8.12–8.09 (2H, m),
7.55–7.48 (3H, m), 6.73 (1H, t, JH–F¼12.8 Hz), 2.65 (2H,
t, J¼7.5 Hz), 1.58–1.51 (2H, m), 1.37–1.29 (2H, m), 0.90
(3H, t, J¼7.4 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ89.9
(2F, d, JH–F¼12.7 Hz); 13C NMR (CDCl3, 125.8 MHz)
d 171.3 (t, J¼36.4 Hz), 168.9, 131.9, 130.9 (t, J¼26.7 Hz),
129.0, 127.7, 125.5, 121.3 (t, J¼7.2 Hz), 111.6 (t,
J¼246.1 Hz), 40.9, 32.0, 21.6, 13.8.
Z-Isomer: 1H NMR (CDCl3, 500 MHz) d 8.14–8.10 (2H, m),
7.57–7.48 (3H, m), 6.68 (1H, t, JH–F¼10.9 Hz), 2.66 (2H, t,
J¼7.2 Hz), 1.60–1.53 (2H, m), 1.40–1.30 (2H, m), 0.95 (3H,
t, J¼7.4 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ90.6 (2F, d,
JH–F¼10.3 Hz); 13C NMR (CDCl3, 125.8 MHz) d 171.0
(t, J¼35.9 Hz), 168.9, 131.8, 129.0, 127.7, 127.6 (t,
J¼29.9 Hz), 125.8, 118.0 (t, J¼9.7 Hz), 112.2 (t,
J¼241.7 Hz), 46.7, 31.1, 21.2, 13.7.
4.4. General procedure for the preparation of 3
The mixture of bromodifluoromethyl phenyl thioether
(0.126 mol), NaI (57 g, 0.38 mol), acetone (88 mL), and
DMF (20 mL) was stirred at reflux for a week. After evapo-
ration of acetone, water (60 mL) was added. The mixture
was extracted with ethyl ether (3ꢃ50 mL). The organic layer
was combined and washed with saturated Na2SO3 and brine.
After removal of the solvent, the residue underwent frac-
tional distillation to give a pale yellow oil 3a in 56% yield
(bp 70–72 ꢀC/1 mmHg) and 3b in 50% yield (bp 80–
84 ꢀC/1 mmHg).
EIMS (m/z) 404 (M+, 2), 322 (30), 277 (11), 195 (100), 145
(37), 77 (16); IR (cmꢂ1, KBr) 3066, 2960, 1632, 1446, 755,
692; HRMS calcd for C15H15F2IN2O: 404.0197, found:
404.0197.
4.5. General procedure for the addition of iododifluoro-
methyl phenyl thioether and derivative 3 to terminal
alkynes
Under nitrogen atmosphere, a mixture of iododifluoromethyl
phenyl thioether and derivative 3 (5.0 mmol), alkyne 4
(6.0 mmol) and AIBN (100 mg) were stirred at 65 ꢀC for
24 h. The reaction mixture was dissolved in CH2Cl2
(20 mL), and then silica gel (200–300 mesh) was added.
The solvent was evaporated to dryness and the powder was
exposed to air overnight, and then purified by flash column
chromatography (silica gel, eluting with petroleum ether/
ethyl acetate¼100:1).
4.2.10. 4,4-Difluoro-2-iodo-4-(3-phenyl-[1,2,4]oxadiazol-
5-yl)-but-2-en-1-ol (6g). Colorless liquid; E/Z¼1:2.1. E-
1
Isomer: H NMR (CDCl3, 500 MHz) d 8.01–7.98 (2H, m),
7.51–7.42 (3H, m), 6.76 (1H, t, JH–F¼12.9 Hz), 4.39 (2H,
d, J¼5.5 Hz), 2.49 (1H, t, J¼6.8 Hz); 19F NMR (CDCl3,
470 MHz) d ꢂ88.63 (2F, d, JH–F¼13.2 Hz); 13C NMR
(CDCl3, 125.8 MHz) d 170.0 (t, J¼36.1 Hz), 167.8, 131.0,
130.8 (t, J¼28.2 Hz), 128.1, 126.6, 124.3, 118.6 (t,
J¼7.5 Hz), 110.4 (t, J¼245.8 Hz), 65.2.
Z-Isomer: 1H NMR (CDCl3, 500 MHz) d 8.04–8.00 (2H, m),
7.48–7.40 (3H, m), 7.10 (1H, t, JH–F¼11.2 Hz), 4.30 (2H, s),
2.74 (1H, s); 19F NMR (CDCl3, 470 MHz) d ꢂ91.14 (2F,
4.5.1. 3-Iodo-3-phenyl-thioacrylic acid S-phenyl ester
(9aa). Yellow solid; mp 130–131 ꢀC; 1H NMR (CDCl3,
500 MHz) d 7.37–7.27 (10H, m), 7.15 (1H, s); 13C NMR
(CDCl3, 125.8 MHz) d 185.8, 142.6, 137.9, 135.1, 130.3,

10690
X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
130.2, 129.9, 128.7, 128.6, 127.8, 117.3; EIMS (m/z) 366
(M+, 0.2), 257 (100), 129 (12), 102 (36); IR (cmꢂ1, KBr)
3051, 1689, 1577. Anal. Calcd for C15H11IOS: C, 49.20;
H, 3.03. Found: C, 49.36; H, 2.96.
(CDCl3, 500 MHz) d 7.42 (5H, s), 6.97 (1H, s), 3.05 (2H,
t, J¼7.5 Hz), 1.56–1.49 (2H, m), 1.37–1.29 (2H, m), 0.89
(3H, t, J¼7.3 Hz); 13C NMR (CDCl3, 125.8 MHz) d 186.0,
136.8, 135.2, 130.3, 129.9, 129.9, 118.9, 42.9, 32.6, 22.3,
14.5.
4.5.2. 3-Iodo-3-phenyl-thioacrylic acid S-(4-chloro-phen-
yl) ester (9ab). Yellow solid; mp 103–104 ꢀC; E/Z¼7.6:1. Z-
7.08 (1H, s); 13C NMR (CDCl3, 125.8 MHz) d 186.0,
143.9, 136.8, 136.4, 131.5, 131.2, 130.2, 129.7, 129.2,
126.1, 114.0.
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.42 (5H, s), 6.78
(1H, s), 2.69 (2H, t, J¼7.4 Hz), 1.62–1.56 (2H, m), 1.37–
1.29 (2H, m), 0.94 (3H, t, J¼7.4 Hz); 13C NMR (CDCl3,
125.8 MHz) d 186.0, 136.8, 135.2, 130.2, 130.0, 128.0,
118.8, 48.4, 32.1, 22.1, 14.5.
1
Isomer: H NMR (CDCl3, 500 MHz) d 7.42–7.22 (9H, m),
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.42–7.22 (9H, m),
7.14 (1H, s); 13C NMR (CDCl3, 125.8 MHz) d 185.1, 142.5,
137.5, 136.7, 136.3, 130.4, 130.1, 128.7, 128.5, 126.2, 118.1.
EIMS (m/z) 346 (M+, 1), 237 (100), 219 (3), 109 (11); IR
(cmꢂ1, KBr) 2957, 1689, 1584, 745; HRMS calcd for
C13H15IOS: 345.9888, found: 345.9887.
EIMS (m/z) 400 (M+, 0.1), 257 (100), 102 (41); IR (cmꢂ1
KBr) 3050, 1691, 1570, 1092. Anal. Calcd for C15H10ClIOS:
C, 44.97; H, 2.52. Found: C, 45.39; H, 2.36.
,
4.5.6. 3-Iodo-hept-2-enethioic acid S-(4-chloro-phenyl)
1
ester (9cb). Light yellow liquid; E/Z¼1:1.8. Z-Isomer: H
NMR (CDCl3, 500 MHz) d 7.40–7.36 (4H, m), 6.95 (1H,
s), 3.05 (2H, t, J¼7.5 Hz), 1.55–1.47 (2H, m), 1.37–1.29
(2H, m), 0.89 (3H, t, J¼7.4 Hz); 13C NMR (CDCl3,
125.8 MHz) d 185.3, 136.7, 136.3, 130.1, 129.8, 126.4,
119.8, 42.9, 32.5, 22.3, 14.5.
4.5.3. 4,4-Difluoro-2-iodo-4-phenylsulfanyl-but-2-enoic
acid methyl ester (8ba). Light yellow liquid; E/Z¼2.7:1.
1
Z-Isomer: H NMR (CDCl3, 500 MHz) d 7.67–7.44 (5H,
m), 7.56 (1H, t, JH–F¼10.4 Hz), 3.85 (3H, s); 19F NMR
(CDCl3, 470 MHz) d ꢂ71.84 (2F, d, JH–F¼10.8 Hz); 13C
NMR (CDCl3, 125.8 MHz) d 163.6, 143.5 (t, J¼30.1 Hz),
137.5, 131.1, 129.9, 128.2, 125.4 (t, J¼279.5 Hz), 97.5,
55.0.
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.35–7.32 (4H, m),
6.78 (1H, s), 2.70 (2H, t, J¼7.4 Hz), 1.61–1.55 (2H, m),
1.37–1.29 (2H, m), 0.94 (3H, t, J¼7.4 Hz); 13C NMR
(CDCl3, 125.8 MHz) d 185.2, 136.6, 136.4, 130.9, 130.1,
126.3, 119.8, 48.5, 32.1, 21.9, 14.4.
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.61–7.37 (5H, m),
6.49 (1H, t, JH–F¼10.7 Hz), 3.78 (3H, s); 19F NMR (CDCl3,
470 MHz) d ꢂ71.79 (2F, d, JH–F¼10.8 Hz); 13C NMR
(CDCl3, 125.8 MHz) d 165.8, 137.5 (t, J¼27.9 Hz), 137.4,
131.0, 129.9, 126.2, 125.6 (t, J¼279.5 Hz), 91.5 (t,
J¼6.1 Hz), 53.9.
EIMS (m/z) 370 (M+, 8), 261 (100), 243 (32), 223 (28), 134
(6), 109 (18); IR (cmꢂ1, KBr) 2952, 1737, 751; HRMS calcd
for C11H9F2IO2S: 369.9336, found: 369.9336.
EIMS (m/z) 382 (M+2+, 1), 380 (M+, 2), 237 (100), 145 (5),
143 (16); IR (cmꢂ1, KBr) 2958, 1691, 1584, 746; HRMS
calcd for C13H14ClIOS: 379.9499, found: 379.9480.
4.5.7. 3-Iodo-3-trimethylsilanyl-thioacrylic acid S-phen-
yl ester (9da). Light yellow liquid; E/Z¼1:2. Z-Isomer: 1H
NMR (CDCl3, 500 MHz) d 7.66 (1H, s), 7.22 (5H, s), 0.08
(9H, s); 13C NMR (CDCl3, 125.8 MHz) d 187.4, 150.2,
134.9, 130.3, 130.0, 130.0, 127.8, 1.4.
4.5.4. 4-(4-Chloro-phenylsulfanyl)-4,4-difluoro-2-iodo-
but-2-enoic acid methyl ester (8bb). Light yellow liquid;
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.26 (5H, s), 7.10
(1H, s), 0.06 (9H, s); 13C NMR (CDCl3, 125.8 MHz) d 186.2,
139.4, 135.1, 133.2, 130.3, 127.8, 123.3, ꢂ0.9.
EIMS (m/z) 362 (M+, 4), 347 (13), 253 (100), 235 (15), 109
(20); IR (cmꢂ1, KBr) 2954, 1682, 1539, 843, 746; HRMS
calcd for C12H15IOSSi: 361.9658, found: 361.9654.
1
E/Z¼1.4:1. Z-Isomer: H NMR (CDCl3, 500 MHz) d 7.58
(2H, d, J¼8.3 Hz), 7.38 (2H, d, J¼8.3 Hz), 7.56 (1H, t,
JH–F¼10.5 Hz), 3.87 (3H, s); 19F NMR (CDCl3, 470 MHz)
d ꢂ71.7 (2F, d, JH–F¼10.8 Hz); 13C NMR (CDCl3,
125.8 MHz) d 163.5, 143.1 (t, J¼29.9 Hz), 138.7, 137.9,
130.2, 130.0, 125.2 (t, J¼280.1 Hz), 98.0, 55.0.
4.5.8. 3-Iodo-3-trimethylsilanyl-thioacrylic acid S-(4-
chloro-phenyl) ester (9db). Light yellow liquid; E/Z¼
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.52 (2H, d,
1
J¼8.4 Hz), 7.38 (2H, d, J¼8.3 Hz), 6.50 (1H, t, JH–F
¼
1:2.2. Z-Isomer: H NMR (CDCl3, 500 MHz) d 7.85 (1H,
10.7 Hz), 3.79 (3H, s); 19F NMR (CDCl3, 470 MHz)
d ꢂ71.7 (2F, d, JH–F¼10.8 Hz); 13C NMR (CDCl3,
125.8 MHz) d 165.7, 138.6, 137.8, 137.2 (t, J¼27.9 Hz),
130.2, 130.0, 125.4 (t, J¼280.1 Hz), 92.0 (t, J¼6.1 Hz),
54.0.
s), 7.41–7.38 (4H, m), 0.27 (9H, s); 13C NMR (CDCl3,
125.8 MHz) d 187.3, 149.9, 136.3, 136.2, 130.3, 130.2,
126.3, 1.3.
E-Isomer: 1H NMR (CDCl3, 500 MHz) d 7.35–7.33 (4H, m),
7.29 (1H, s), 0.26 (9H, s); 13C NMR (CDCl3, 125.8 MHz)
d 185.8, 139.1, 136.8, 136.2, 134.2, 126.3, 124.3, 1.3.
EIMS (m/z) 406 (M+2+, 7), 404 (M+, 18), 279 (12), 277 (32),
261 (100); IR (cmꢂ1, KBr) 2953, 1736, 1093, 745; HRMS
calcd for C11H8ClF2IO2S: 403.8946, found: 403.8946.
EIMS (m/z) 398 (M+2+, 1), 396 (M+, 2), 383 (5), 381 (11),
253 (100) 145 (7), 143 (18); IR (cmꢂ1, KBr) 2955, 1685,
1539, 844, 759; HRMS calcd for C12H14ClIOSSi:
395.9268, found: 395.9265.
4.5.5. 3-Iodo-hept-2-enethioic acid S-phenyl ester (9ca).
Light yellow liquid; E/Z¼1:3.4. Z-Isomer: 1H NMR

X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
10691
4.6. General procedure for the cross-coupling of 5a and
6a with terminal alkyne 4
(M+, 16), 311 (7), 253 (13), 105 (100), 77 (10); IR (cmꢂ1
,
KBr) 3300, 3063, 2928, 2855, 1772, 1727, 1621, 777, 713;
HRMS calcd for C22H18F2O4: 384.1173, found: 384.1174.
Under nitrogen atmosphere, a mixture of 5a (0.5 mmol), al-
kyne 4 (0.8 mmol), PdCl2(PPh3)2 (2 mol %), CuI (5 mol %),
and DABCO (0.75 mmol) was stirred in THF at room tem-
perature overnight. The reaction mixture was extracted
with ethyl ether (2ꢃ20 mL), which was washed with water
(2ꢃ10 mL) and dried over anhydrous Na2SO4. Evaporation
of the solvent gave a residue, which was purified by flash
column chromatography (silica gel, eluting with petroleum
ether/ethyl acetate¼50:1) to give 10.
4.6.5. 2,2-Difluoro-4-phenyl-dodec-3-en-5-ynoic acid eth-
yl ester (10e). Red liquid; H NMR (CDCl3, 500 MHz)
1
d 7.38–7.32 (5H, m), 6.17 (1H, t, JH–F¼12.3 Hz), 3.88
(2H, q, J¼7.2 Hz), 2.34 (2H, t, J¼7.2 Hz), 1.57–1.51 (2H,
m), 1.42–1.25 (6H, m), 1.12 (3H, t, J¼7.2 Hz), 0.88 (3H,
t, J¼7.0 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ92.5 (2F, d,
JH–F¼12.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.7 (t,
J¼33.5 Hz), 136.9, 135.0 (t, J¼10.1 Hz), 129.6, 129.2,
128.7, 126.5 (t, J¼28.2 Hz), 112.7 (t, J¼245.1 Hz), 96.5,
81.6, 63.5, 31.9, 29.2, 29.0, 23.2, 20.2, 14.7, 14.3; EIMS
4.6.1. 2,2-Difluoro-4,6-diphenyl-hex-3-en-5-ynoic acid
ethyl ester (10a). Red liquid; 1H NMR (CDCl3, 500 MHz)
d 7.48–7.30 (10H, m), 6.35 (1H, t, JH–F¼12.3 Hz), 3.92
(2H, q, J¼7.2 Hz), 1.14 (3H, t, J¼7.2 Hz); 19F NMR
(CDCl3, 470 MHz) d ꢂ92.9 (2F, d, JH–F¼12.2 Hz); 13C
NMR (CDCl3, 125.8 MHz) d 163.5 (t, J¼33.6 Hz), 136.2,
134.4 (t, J¼10.0 Hz), 132.5, 129.8, 129.7, 129.4, 129.1,
128.9, 127.5 (t, J¼28.0 Hz), 122.8, 112.6 (t, J¼245.6 Hz),
94.3, 89.8, 63.6, 14.3; EIMS (m/z) 326 (M+, 20), 253
(100), 127 (27); IR (cmꢂ1, KBr) 3059, 2985, 2205, 1772,
1617, 757, 693; HRMS calcd for C20H16F2O2: 326.1118,
found: 326.1109.
(m/z) 334 (M+, 11), 261 (100), 127 (16), 91(9); IR (cmꢂ1
,
KBr) 2930, 2858, 2219, 1773, 1618, 699; HRMS calcd for
C20H24F2O2: 334.1744, found: 334.1744.
4.6.6. 2,2-Difluoro-7,7-dimethyl-4-phenyl-oct-3-en-5-
ynoic acid ethyl ester (10f). Red liquid; 1H NMR (CDCl3,
500 MHz) d 7.39–7.31 (5H, m), 6.16 (1H, t, JH–F
¼
12.3 Hz), 3.87 (2H, q, J¼7.2 Hz), 1.25 (9H, s), 1.10 (3H, t,
J¼7.2 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ92.1 (2F, d,
JH–F¼12.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.6 (t,
J¼33.6 Hz), 136.9, 135.0 (t, J¼10.3 Hz), 129.6, 129.2,
128.7, 126.4 (t, J¼28.4 Hz), 112.7 (t, J¼244.9 Hz), 104.0,
80.2, 63.5, 31.3, 28.7, 14.3; EIMS (m/z) 306 (M+, 19), 233
4.6.2. 2,2-Difluoro-4-phenyl-dec-3-en-5-ynoic acid ethyl
ester (10b). Red liquid; 1H NMR (CDCl3, 500 MHz)
d 7.38–7.32 (5H, m), 6.17 (1H, t, JH–F¼12.3 Hz), 3.88
(2H, q, J¼7.2 Hz), 2.35 (2H, t, J¼7.1 Hz), 1.56–1.49 (2H,
m), 1.45–1.38 (2H, m), 1.11 (3H, t, J¼7.2 Hz), 0.91 (3H,
t, J¼7.3 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ92.4 (2F, d,
JH–F¼12.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 164.7 (t,
J¼33.6 Hz), 137.8, 136.0 (t, J¼10.1 Hz), 130.6, 130.2,
129.7, 127.6 (t, J¼28.2 Hz), 113.7 (t, J¼245.0 Hz), 97.4,
82.6, 64.5, 32.1, 23.7, 20.8, 15.3, 15.2; EIMS (m/z) 306
(M+, 10), 233 (100), 127 (10), 91 (3); IR (cmꢂ1, KBr)
3059, 2960, 2872, 2219, 1772, 1619, 776, 699; HRMS calcd
for C18H20F2O2: 306.1431, found: 306.1428.
(100), 218 (21), 203 (10), 127 (13), 91 (6); IR (cmꢂ1
,
KBr) 2970, 2869, 2217, 1774, 1618, 761, 700; HRMS calcd
for C18H20F2O2: 306.1431, found: 306.1431.
4.6.7. 5-(1,1-Difluoro-3,5-diphenyl-pent-2-en-4-ynyl)-3-
phenyl-[1,2,4]oxadiazole (11a). Light red liquid; 1H NMR
(CDCl3, 500 MHz) d 7.97–7.93 (2H, m), 7.52–7.44 (5H,
m), 7.37–7.32 (5H, m), 7.25–7.18 (3H, m), 6.63 (1H, t,
JH–F¼11.5 Hz); 19F NMR (CDCl3, 470 MHz) d ꢂ85.4 (2F,
d, JH–F¼11.8 Hz); 13C NMR (CDCl3, 125.8 MHz) d 171.8
(t, J¼35.5 Hz), 169.2, 136.3 (t, J¼9.6 Hz), 135.8, 132.5,
132.3, 129.9, 129.8, 129.5, 129.1, 128.9, 128.8, 128.2,
127.1 (t, J¼28.1 Hz), 126.3, 122.6, 112.7 (t, J¼240.5 Hz),
95.7, 89.4; EIMS (m/z) 398 (M+, 5), 298 (10), 269 (100),
167 (51), 77 (16); IR (cmꢂ1, KBr) 3060, 2205, 1600,
1445, 757, 692; HRMS calcd for C25H16F2N2O: 398.1231,
found: 398.1230.
4.6.3. 2,2-Difluoro-4-phenyl-6-trimethylsilanyl-hex-3-en-
5-ynoic acid ethyl ester (10c). Red liquid; 1H NMR (CDCl3,
500 MHz) d 7.40–7.33 (5H, m), 6.29 (1H, t, JH–F¼12.2 Hz),
3.89 (2H, q, J¼7.2 Hz), 1.11 (3H, t, J¼7.2 Hz), 0.20 (9H, s);
19F NMR (CDCl3, 470 MHz) d ꢂ92.9 (2F, d, JH–F
¼
12.2 Hz); 13C NMR (CDCl3, 125.8 MHz) d 163.4 (t,
J¼33.5 Hz), 135.9, 134.2 (t, J¼9.9 Hz), 129.8, 129.3,
128.8, 128.4 (t, J¼28.2 Hz), 112.4 (t, J¼245.4 Hz), 104.8,
100.0, 63.6, 14.3, 0.3; EIMS (m/z) 322 (M+, 13), 307 (9),
249 (100), 152 (22), 77 (6); IR (cmꢂ1, KBr) 3060, 2962,
2151, 1774, 1615, 761, 699; HRMS calcd for C17H20F2O2Si:
322.1201, found: 322.1200.
4.6.8. 5-(1,1-Difluoro-3-phenyl-non-2-en-4-ynyl)-3-phen-
yl-[1,2,4]oxadiazole (11b). Light red liquid; 1H NMR
(CDCl3, 500 MHz) d 7.94–7.91 (2H, m), 7.53–7.42 (3H,
m), 7.28–7.10 (5H, m), 6.46 (1H, t, JH–F¼11.5 Hz), 2.36
(2H, t, J¼7.1 Hz), 1.56–1.48 (2H, m), 1.45–1.38 (2H, m),
0.91 (3H, t, J¼7.4 Hz); 19F NMR (CDCl3, 470 MHz)
d ꢂ85.2 (2F, d, JH–F¼11.8 Hz); 13C NMR (CDCl3,
125.8 MHz) d 171.9 (t, J¼35.2 Hz), 169.1, 136.9 (t,
J¼9.6 Hz), 136.4, 132.2, 130.1, 129.5, 128.7, 127.9, 126.3
(t, J¼28.1 Hz), 112.8 (t, J¼240.0 Hz), 98.0, 81.3, 31.0,
22.6, 19.9, 14.2; EIMS (m/z) 378 (M+, 8), 269 (100), 167
(45), 77 (25); IR (cmꢂ1, KBr) 3061, 2219, 1600, 1446,
757, 696.
4.6.4. Benzoic acid 6-ethoxycarbonyl-6,6-difluoro-4-
phenyl-hex-4-en-2-ynyl ester (10d). Light yellow liquid;
1H NMR (CDCl3, 500 MHz) d 8.07 (2H, d, J¼8.3 Hz),
7.60–7.34 (8H, m), 6.31 (1H, t, JH–F¼12.1 Hz), 5.08 (2H,
s), 3.90 (2H, q, J¼7.2 Hz), 1.12 (3H, t, J¼7.2 Hz); 19F
NMR (CDCl3, 470 MHz) d ꢂ93.4 (2F, d, JH–F¼11.8 Hz);
13C NMR (CDCl3, 125.8 MHz) d 166.4, 163.3 (t,
J¼33.6 Hz), 135.5, 134.1 (t, J¼6.6 Hz), 133.3 (t, J¼
9.9 Hz), 130.5, 130.0, 129.2, 129.1, 128.9, 112.3 (t,
J¼245.7 Hz), 88.0, 86.7, 63.7, 53.5, 14.2; EIMS (m/z) 384
4.6.9. 5-(1,1-Difluoro-3-phenyl-5-trimethylsilanyl-pent-
2-en-4-ynyl)-3-phenyl-[1,2,4]oxadiazole (11c). Light red
1
liquid; H NMR (CDCl3, 500 MHz) d 7.93–7.90 (2H, m),
7.50–7.41 (3H, m), 7.28–7.11 (5H, m), 6.56 (1H, t,

10692
X. Fang et al. / Tetrahedron 63 (2007) 10684–10692
JH–F¼11.5 Hz), 0.19 (9H, s); 19F NMR (CDCl3, 470 MHz)
d ꢂ85.7 (2F, d, JH–F¼11.8 Hz); 13C NMR (CDCl3,
125.8 MHz) d 171.6 (t, J¼35.4 Hz), 169.2, 136.1 (t,
J¼9.6 Hz), 135.5, 132.3, 129.7, 129.5, 128.8, 128.2, 126.2,
112.6 (t, J¼240.5 Hz), 104.3, 101.6, 0.3; EIMS (m/z) 394
(M+, 1), 269 (100), 167 (37), 77 (17); IR (cmꢂ1, KBr)
3062, 1601, 1446, 757, 697.
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Acknowledgements
This research work was supported by the National Natural
Science Foundation of China (Grant No. 20672034).
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