Synthesis of difluoromethylene-containing 1,2,4-oxadiazole compounds via the reaction of 5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole with unsaturated compounds initiated by sodium dithionite

Article abstract of DOI:10.1055/s-2007-983705

5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole, synthesized by the iodination of the corresponding zinc reagent of 5-(bromodifluoromethyl)-3- phenyl-1,2,4-oxadiazole, reacted with various unsaturated compounds, such as alkenes, alkynes, pent-4-en-1-ols,

Full text of DOI:10.1055/s-2007-983705

1768
PAPER
Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
via the Reaction of 5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole with
Unsaturated Compounds Initiated by Sodium Dithionite
S
ynthesis of
Difluo
u
romethylene-Containin
y
g 1, 2,4-Oxad
a
iazole Com
n
pounds Yang,a Zhonghua Wang,a Xiang Fang,a Xianjin Yang,a Fanhong Wu,*a,b Yongjia Shena
a
Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Rd,
Shanghai 200237, P. R. of China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Rd,
Shanghai 200032, P. R. of China
b
Fax +86(21)64253074; E-mail: wfh@ecust.edu.cn
Received 28 February 2007; revised 13 April 2007
A convenient two-step synthesis of 5-(bromodifluoro-
methyl)-3-phenyl-1,2,4-oxadiazole (3) from benzonitrile
(1) was recently reported, via reaction with hydroxyl-
amine to give amidoximes 2, followed by condensation
Abstract: 5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole, syn-
thesized by the iodination of the corresponding zinc reagent of 5-
(bromodifluoromethyl)-3-phenyl-1,2,4-oxadiazole, reacted with
various unsaturated compounds, such as alkenes, alkynes, pent-4-
en-1-ols, and pent-4-enoic acids, in the presence of sodium dithion- with ethyl bromodifluoroacetate (Scheme 1).17
ite and sodium hydrogen carbonate in aqueous acetonitrile solution
The bromodifluoromethyl group of 3 could be converted
at ambient temperature to afford various difluoromethylenated
into a difluoroiodomethyl group by two methods (A and
1,2,4-oxadiazole-containing compounds, including g-butyrolac-
tones and tetrahydrofurans, in moderate yields.
B) (Scheme 1). In method A, 4 was obtained in 55% yield
via iodination of the zinc reagent of 3, which was generat-
ed by treatment of 3 with activated zinc powder in tetrahy-
drofuran. In method B, 3 was converted into 4 by a
halogen-exchange reaction; refluxing 3 in butanone for
five days in the presence of sodium iodide gave 4 in 30%
yield. Compared with method A, method B has the disad-
vantages of a long reaction time and unsatisfactory yield.
Key words: difluoromethylene, 1,2,4-oxadiazole, g-butyrolactone,
addition, cyclization
The selective introduction of the difluoromethylene moi-
ety into organic compound is of great importance, because
this group is believed to act in a similar fashion to the ox-
ygen of an ether.1 Difluoromethylene analogues, such as
amino acids,2 vitamin D3,3 and nucleotides,4 display dra-
matic changes and distinctive modifications in their bio-
logical activities. Fluorinated heterocyclic compounds
have attracted much attention among scientists for their
applications in medicine and agriculture.5 Compounds
bearing the 1,2,4-oxadiazole group have been shown to be
an enzyme inhibitor,6,7 an effective antimicrobial re-
agent,8 and a plant growth regulant,9 and the fluorinated
analogues of 1,2,4-oxadiazoles have been found to have
improved bioactivities compared to the corresponding
nonfluorinated compounds.10–14 However, much work has
been focused on the synthesis of trifluoromethyl or poly-
fluoroalkyl-substituted 1,2,4-oxadiazoles10–16 and limited
examples have been reported on the introduction of diflu-
oromethylenated 1,2,4-oxadiazoles.17 We are interested in
the synthesis of difluoromethylene-containing com-
pounds and we have previously described the synthesis of
g-lactones bearing a difluoromethylene group.18,19 In this
paper, we described the introduction of a difluoromethyl-
ene-containing 1,2,4-oxadiazole moiety into organic com-
pounds through the radical reaction of 5-
(difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole (4) with
various unsaturated substrates.
NOH
CN
BrCF2COOEt
NH2OH⋅HCl, NaOH
C
NH2
Et3N, toluene,
reflux
EtOH–H2O, reflux
1
2
O
N
O
N
CF2Br
method A or B
N
CF2I
N
3
4
Scheme 1 Reagents and conditions: Method A: 1. Zn, HgCl2, THF,
N2, r.t.; 2. I2, 55%; Method B: butanone, NaI, reflux, 5 d, 30%.
The reaction of polyfluoroalkyl iodides with alkenes can
be effected by photolysis,20 electrolysis,21 free radical ini-
tiators,22 metal catalysts,23 and sulfur-oxy acid salts.24,25
We investigate the use of various initiators in the model
reaction of 4 with oct-1-ene (5b) (Table 1). In the pres-
ence of a metal (Cu, Zn, Mg, or Fe) the reaction of 4 with
5b in N,N-dimethylformamide or acetonitrile at 50 °C un-
der nitrogen for 5–10 hours went with 100% conversion
of 4, smoothly affording the corresponding adduct 6b in
moderate yields of 47–69% (Table 1, entries 1–4). When
2,2¢-azobis(isobutyronitrile) was used as the initiator, the
reaction was carried out at 50 °C without solvent for ten
hours with 76% conversion, giving the adduct 6b in 43%
SYNTHESIS 2007, No. 12, pp 1768–1778
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Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983705; Art ID: F04207SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
1769
Table 1 Reaction of 4 with 5b in the Presence of Various Initiators
O
N
O
N
n-Hex
initiator
+
CF2I
n-Hex
N
N
F
F
I
4
5b
6b
Entry
Initiator
Cu
Solvent
Temp (°C)
Time (h)
Conversiona of 4 (%)
Yielda (%)
1
2
3
4
5
6
MeCN
DMF
DMF
DMF
–
50
50
50
50
50
r.t.
10
10
10
5
100
100
100
100
76
69
47
56
65
44
78
Zn
Mg
Fe
AIBN
10
1
Na2S2O4/NaHCO3
MeCN–H2O 3:1
100
a Based on GC analysis.
H
RF
yield (Table 1, entry 5). However, when sodium dithionite
was employed, the reaction was complete within one hour
with 100% conversion of 4 in acetonitrile–water at room
temperature giving 6b in 78% yield (Table 1, entry 6).
RF
H
H
H
RFI
8'
RFI
8
The reaction of 4 with various alkenes in the presence of
sodium dithionite was performed (Scheme 2) and the de-
tailed results are summarized in Table 2. The addition of
4 to terminal alkenes 5a–f gave the corresponding adducts
6a–f at room temperature in 52–69% yields (Table 2, en-
tries 1–6). The reaction with internal alkenes also went
smoothly; upon reaction of 4 with cyclohexene (7), a mix-
ture of trans- and cis-isomers 8 in 1.26:1 ratio (based on
19F NMR) was obtained in 66% overall yield (Table 2, en-
try 11). As previously shown, the reaction proceeded by
trans and cis addition, since flipping of the ring 8 formed
at first to 8¢ may occur before transfer of the intermediate
radical with RFI 4 (Figure 1).26 In the case of cyclopentene
(9), only the trans-isomer 10 was detected (Table 2, entry
12). The NMR signal of the proton CHI exhibited a quar-
tet at d = 4.43 (J = 6.0 Hz) with coupling to adjacent
RFCH and CH2 that closely resembled those of the poly-
fluoroalkyl analogue characterized previously.26,27 Free
radical addition of 4 in the trans mode to cyclopentene
conformed to the pattern observed in reactions of this
type, since the cis-adduct would have considerable crowd-
ing of the bulky and electronegative RF and I groups.26,27
When diallyl ether 11 was used as the substrate, tetrahy-
drofuran derivative 12 was obtained as a mixture of trans-
and cis-isomers in 3.3:1 ratio, indicating a radical mecha-
nism (Table 2, entry 13).28
cis-isomer
trans-isomer
Figure 1
with coupling to the adjacent CF2CH=CHPh proton. The
signal of the CF2CH=CHPh proton was at d = 6.17 (q,
JH-H ª JH-F = 12.4 Hz) with coupling to the adjacent
CF2CH=CHPh and CF2CH=CHPh protons. This value of
J is consistent with the cis orientation of the two protons
attached to the double bond.30 When prop-2-yn-1-ol (15)
was used as the substrate, the reaction proceeded with a
prolonged reaction time (5–6 h) compared to alkenes and
with only 30% conversion of 15, giving a mixture of E/Z-
isomers in 1:2.45 ratio with the Z-isomer as the main
product (Table 2, entry 15).29 The ratio was determined on
the basis of 1H NMR. The signal of the
CF2CH=CICH2OH proton of the E-isomer (d = 7.10, t,
JH-F = 11.0 Hz) appeared at lower field than the Z-isomer
(d 6.76, t, JH-F = 13.1 Hz).31 The E- and Z-isomers were
easily separated by column chromatography in 5% and
15% yields, respectively (Table 2, entry 15).
F
F
F
F
O
N
O
N
Zn,
AcOH
N
N
5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole (4)
also showed high reactivity in the addition reaction with
phenylacetylene (13) under similar conditions, affording
adduct 14 as only the E-isomer in 90% yield (Table 2, en-
try 14).29 To determine the stereochemistry of 14, it was
reduced by zinc and acetic acid to give the Z-isomer 20
(Scheme 3). The NMR signal of the alkenyl proton
CF2CH=CHPh of 20 was at d = 7.11 (d, JH-H = 12.4 Hz)
H
H
H
I
(E)-14
(Z)-20
Scheme 3
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1770
X. Yang et al.
PAPER
O
N
O
N
R1
Na2S2O4
NaHCO3
CF2I
+
R1
N
N
F
F
I
4
5
6
I
O
O
N
N
Na2S2O4
NaHCO3
CF2I
+
N
N
F
F
major/minor = 1.26:1
4
7
8
I
O
N
O
N
Na2S2O4
NaHCO3
CF2I
+
N
N
F
F
only trans-isomer
4
9
10
O
N
O
N
I
CF2I
N
Na2S2O4
NaHCO3
+
N
F
F
O
O
major/minor = 3.3 :1
4
11
12
F
F
O
N
O
N
I
R1
Na2S2O4
NaHCO3
CF2I
R1
+
N
N
H
4
13: R1 = Ph
15: R1 = CH2OH
14: R1 = Ph only E-isomer
16: R1 = CH2OH E/Z = 1:2.45
Scheme 2
The reaction of 4 with pent-4-en-1-ols 5g–j gave the cor- termination of the stereochemistry was obtained by 1H–1H
responding adducts 6g–j (Table 2, entries 7–10). Treat- NOESY (Figure 2). For cis-17j, the apparent correlated
ment of 6g–j in N,N-dimethylformamide at 100 °C for peaks between H2 (d = 4.40–4.33) and H4 (d = 3.51–
three hours afforded tetrahydrofuran derivatives 17g–j in 3.44) showed a cis orientation of the two protons. For
90–94% yields (Scheme 4, Table 3). Cyclization of the trans-17i, the apparent correlated peaks between the pro-
adducts 6i and 6j gave a mixture of trans- and cis-isomers tons of the methyl group (d = 0.93) and H2 (d = 4.26–
in 1.60:1 and 1.74:1 ratios. Comparatively large chemical 4.18) showed that the methyl group and H2 were cis,
shift differences between the two protons at C3 (Dd = 1.05 which indicated trans orientation of H2 and H4. However,
for cis-17i, 0.80 for cis-17j) were indicative of the cis-iso- no correlated peaks were observed for the corresponding
mer; small differences (Dd = 0.0 for trans-17i, 0.11 for protons in trans-17j and cis-17i.
trans-17j) pointed to the trans configuration.32 Further de-
R2
O
R3
R3
R1
R1 R2
O
N
O
100 °C
N
OH
N
N
DMF, 3 h
I
F
F
F
F
6g–j
17g–j
Scheme 4
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Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
1771
Table 2 Addition Reaction of 4 with Various Alkenes or Alkynes Using Sodium Dithionite
Entry
Substrate
Alkene or alkyne
Product
6a
6b
6c
R1
Yielda (%)
1
5a
5b
5c
5d
5e
5f
H2C=CH(CH2)3Me
H2C=CH(CH2)5Me
H2C=CHCMe2CH2CO2Me
H2C=CHCH2CN
Bu
54
2
(CH2)5Me
68
3
CMe2CH2CO2Me
51
4
6d
6e
CH2CN
55
5
H2C=CHOAc
OAc
52
6
H2C=CHCH2OH
6f
CH2OH
69
7
5g
5h
5i
H2C=CH(CH2)2CH2OH
H2C=CHC(Me2)CH2CH2OH
H2C=CHCH2CH(Me)CH2OH
H2C=CHCH2CH(Ph)CH2OH
cyclohexene
6g
6h
6i
(CH2)2CH2OH
53
8
C(Me2)CH2CH2OH
52
9
CH2CH(Me)CH2OH
55
10
5j
6j
CH2CH(Ph)CH2OH
51
11
7
8
–
66
12
9
cyclopentene
10
12
14
16
–
65
13
11
13
15
(H2C=CHCH2)2O
HC≡CPh
–
49
14
Ph
90
15
HC≡CCH2OH
CH2OH
15 (Z), 5 (E)
a Isolated yield.
Table 3 Cyclization of the Adducts 6g–j
When pent-4-enoic acid (18a) or its derivatives 18b–j
were used as the substrates, g-butyrolactones 19 contain-
ing a difluoromethylenated l,2,4-oxadiazole group were
obtained (Scheme 5); these present an important kind of
compounds with high bioactivity.33 The reaction of 4 with
pent-4-enoic acids 18a–j proceeded smoothly in the pres-
ence of 1–1.2 equivalents of sodium hydroxide for 6–8
hours to give g-butyrolactones 19a–j (Table 4).
Entry
SubstrateR1
R2
H
R3
H
Product Yielda (%)
1
2
3
4
6g
6h
6i
H
17g
17h
17i
92
92
94
90
Me
H
Me
H
H
Me
Ph
6j
H
H
17j
The results showed that for 2-substituted pent-4-enoic ac-
a Isolated yields.
ids 18c–j, a mixture of cis/trans-isomers was formed.
1
Analysis of the crude product by H NMR spectroscopy
and integration of the signals attributed to H5 (–CHO–)
indicated that the cis/trans ratio ranged from 1.73:1 to
1:1.20 (Table 4, entries 3–10). Purification of the mixture
of cis/trans-isomers was easily achieved by silica gel
chromatography. Separation of the cis- or trans-isomer
from the mixture was difficult, but a pure sample of trans-
19c and cis-19c were eventually obtained. The stereo-
4
3
O
N
H
5
2
N
O1
F
F
H
NOE
cis-17j
1
chemistry of trans-19c and cis-19c was obtained by H–
1H NOESY. For trans-19c, the apparent correlated peaks
between the methyl protons (d = 1.32) and H5 (d = 4.96–
4.94) showed that H5 and the methyl group were cis,
which indicated a trans orientation of H3 and H5
(Figure 3). For cis-19c, the absence of the correlated
peaks between the methyl protons (d = 1.31) and H5
(d = 4.77–4.74) indicated a cis orientation of H3 and H5.
H
4
3
O
N
CH3
5
2
N
O
F
F
H
1
NOE
trans-17i
1
Figure 2
The H NMR spectra of trans-19d–j and cis-19d–j were
similar to those of trans-19c and cis-19c. The differences
of the chemical shifts between the two protons on C3 in
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

1772
X. Yang et al.
PAPER
R1
F
R2 R3
O
N
O
R3
R1
N
Na2S2O4
+
CF2I
N
N
O
CO2H
O
F
R2
NaHCO3,
NaOH
4
18a–j
19a–j
Scheme 5
Table 4 Fluoroalkylation–Lactonization of 4 with Pent-4-enoic Acids 18
Entry
Substrate
18a
R1
H
R2
H
R3
Product
19a
19b
19c
Yielda (%)
Ratio cis/trans b
–
1
2
H
52
50
46
46.
48
59
62
8
18b
18c
Me
H
Me
H
Me
–
3
Me
1.06:1
1.23:1
1.36:1
1.37:1
1.73:1
1.39:1
1.63:1
1:1.20
4
18d
18e
H
H
Et
19d
19e
5
H
H
Pr
6
18f
H
H
Bu
19f
7
18g
H
H
i-Bu
19g
19h
19i
8
18h
18i
H
H
Bn
9
H
H
Ph
34
49
10
18j
H
H
4-MeOC6H4CONH
19j
a Isolated yields.
b Based on 1H NMR.
cis-19c–j were relatively larger compared to those in the involve the addition of 4 to the double bond of pent-4-eno-
trans-isomer.34
ic acids 18a–j and followed by intramolecular SN2 reac-
tion of the adducts.36
All products exhibited a typical AB pattern signal in the
19F NMR spectrum.35 For example, the 19F NMR of cis- In conclusion, 5-(difluoroiodomethyl)-3-phenyl-1,2,4-
19c exhibited two doublets of multiplets at d = –96.25 and oxadiazole (4) was prepared by treatment of 3 with acti-
–99.64. The lower field signal was a doublet of doublet of vated zinc powder in tetrahydrofuran followed by an iodi-
doublets with J = 282.3, 19.3, 11.8 Hz. The higher field nation reaction. The reaction of 4 with different alkenes,
signal was also a doublet of doublet of doublets with alkynes, pent-4-en-1-ols, or pent-4-enoic acids initiated
J = 282.3, 19.3, 15.5 Hz. In some cases, the lower or high- by sodium dithionite was realized. As a result, various di-
er field signal exhibited a doublet of triplets. For example, fluoromethylenated 1,2,4-oxadiazole containing deriva-
both the two signals of 6b and 6c were a doublet of trip- tives, such as g-butyrolactones and tetrahydrofuran
lets. In 19F NMR of 6f, the higher field signal was a dou- derivatives, were obtained in moderate yields, which pro-
blet of triplets with J = 277.6, 16.5 Hz.
vided a convenient method for the introduction of the di-
fluoromethylene-containing 1,2,4-oxadiazole moiety into
organic compounds.
We presume that the mechanism of the addition of 4 to
alkenes is similar to the reaction of polyfluoroalkyl iodide
with alkenes, which involves a single electron-transfer
process.25 The formation of g-butyrolactones 19a–j may
IR spectra were measured on a Nicolet Magna IR-550 spectrometer.
HRMS were carried out on a Finnigan GC-MS-4021 spectrometer.
NMR spectra were recorded in CDCl3 soln at 20 °C on a Bruker
AC-500 spectrometer operating at 500 MHz (1H), 125.8 MHz (13C),
and 470.5 MHz (19F). Chemical shifts (d) are given relative to TMS
for 1H and 13C NMR, and relative to CFCl3 for 19F NMR. Column
chromatography was performed by using silica gel H, particle size
20–30 mm. Melting points are uncorrected.
NOE
H3C
H
4
F
H
F
3
2
O
N
N
O
5
O1
5-(Difluoroiodomethyl)-3-phenyl-1,2,4-oxadiazole (4)
Procedure A: Under N2, to a suspension of activated Zn powder (2.1
g, 33 mmol), THF (60 mL), and HgCl2 (800 mg) was added drop-
trans-19c
Figure 3
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Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
1773
wise a soln of 3 (8.0 g, 29 mmol) in THF (40 mL) over 30 min. The
mixture was stirred for 4 h and then I2 (12.0 g, 47 mmol) was added
and the mixture was stirred for 20 h. Et2O (30 mL) was added and
the ether soln was washed consecutively with sat. Na2SO3,
NaHCO3, and H2O and dried (anhyd Na2SO4), and the solvent was
removed to give an oil. This was subjected to column chromatogra-
phy (PE–EtOAc, 150:1) to give pure 4; yield: 55%.
19F NMR (470.5 MHz, CDCl3): d = –95.61 (dt, JF-F = 277.6 Hz,
JH-F = 14.1 Hz, 1 F), –100.66 (dt, JF-F = 277.6 Hz, JH-F = 16.5 Hz,
1 F).
HRMS: m/z [M]+ calcd for C17H21F2IN2O: 434.0667; found:
434.0710.
Methyl 6,6-Difluoro-4-iodo-3,3-dimethyl-6-(3-phenyl-1,2,4-
oxadiazol-5-yl)hexanoate (6c)
IR (film): 3067, 1598, 1424, 1130, 1090 cm–1.
Pale-yellow oil.
IR (film): 3068, 1736, 1211, 1169, 1145, 755, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–8.11 (m, 2 H), 7.58–7.50 (m,
3 H).
13C NMR (125.8 MHz, CDCl3): d = 172.7 (t, J = 30.3 Hz), 169.6,
132.9, 132.8, 128.5, 125.9, 81.3 (t, J = 311.7 Hz).
19F NMR (470.5 MHz, CDCl3): d = –49.84 (s, 2 F).
HRMS: m/z [M]+ calcd for C9H5F2IN2O: 321.9415; found:
321.9429.
1H NMR (500 MHz, CDCl3): d = 8.13–7.49 (m, 5 H), 4.59–4.57 (m,
1 H), 3.66 (s, 3 H), 3.28–3.21 (m, 1 H), 3.18–3.09 (m, 1 H), 2.60 (d,
J = 5.0 Hz, 1 H), 2.43 (d, J = 5.0 Hz, 1 H), 1.26 (s, 3 H), 1.20 (s, 3
H).
13C NMR (125.8 MHz, CDCl3): d = 172.1, 171.7 (t, J = 33.8 Hz),
169.4, 132.5, 129.7, 128.3, 126.3, 116.1 (t, J = 245.0 Hz), 52.2,
46.0, 43.8 (t, J = 23.9 Hz), 38.6, 35.2, 26.2, 24.9.
19F NMR (470.5 MHz, CDCl3): d = –95.72 (dt, JF-F = 277.6 Hz,
JH-F = 14.1 Hz, 1 F), –102.09 (dt, JF-F = 277.6 Hz, JH-F = 16.5 Hz,
1 F).
Procedure B: A mixture of 3 (2.75 g, 10 mmol), NaI (6.00 g, 40
mmol), and butanone (50 mL) was refluxed for 5 d. After removal
of the solvent, 2 M sodium sulfite (10 mL) was added and the soln
was extracted with Et2O (3 × 50 mL). The combined organic ex-
tracts were washed with H2O and dried (anhyd Na2SO4) and the sol-
vent was removed to give an oil. Pure 4 was obtained after column
chromatography; yield: 30%.
HRMS: m/z [M]+ calcd for C17H19F2IN2O3: 464.0409; found:
464.0411.
5-(1,1-Difluoro-3-iodoalkyl)- and 5-(1,1-Difluoro-3-iodoalk-2-
enyl)-3-phenyl-1,2,4-oxadiazoles 6a–j, 8, 10, 12, 14, 16; General
Procedure
5,5-Difluoro-3-iodo-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pentane-
nitrile (6d)
Pale-yellow oil.
To a mixture of alkene or alkyne (1–1.5 mmol), MeCN (3 mL), H2O
(1 mL), and 4 (330 mg, 1 mmol) was added a mixture of Na2S2O4
(280 mg, 1.6 mmol) and NaHCO3 (135 mg, 1.6 mmol) at r.t. in por-
tions. The mixture was stirred for 1–6 h at this temperature and then
treated with H2O (ca. 8 mL) and extracted with Et2O (3 × 10 mL).
The combined organic extracts were washed with sat. brine and
dried (anhyd Na2SO4). After removal of ether, the crude product
was purified by column chromatography (PE–EtOAc) to give the
corresponding adduct.
IR (film): 3067, 2227, 1192, 1120, 1079, 755, 703 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.11–7.51 (m, 5 H), 4.55–4.50 (m,
1 H), 3.39–3.24 (stack, 4 H).
13C NMR (125.8 MHz, CDCl3): d = 170.8 (t, J = 33.8 Hz), 169.6,
132.8, 129.8, 128.4, 125.9, 117.3, 115.5 (t, J = 246.8 Hz), 46.2 (t,
J = 23.0 Hz), 31.0, 7.3.
19F NMR (470.5 MHz, CDCl3): d = –96.62 (ddd, JF-F = 282.3 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –100.42 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
5-(1,1-Difluoro-3-iodoheptyl)-3-phenyl-1,2,4-oxadiazole (6a)
Pale-yellow oil.
HRMS: m/z [M]+ calcd for C13H10F2IN3O: 388.9837; found:
388.9862.
IR (film): 3067, 1602, 1165, 1125, 1072, 735, 703 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.02–7.38 (m, 5 H), 4.26–4.20 (m,
1 H), 3.20–3.13 (m, 1 H), 3.02–2.92 (m, 1 H), 1.79–1.70 (m, 1 H),
1.70–1.65 (m, 1 H), 1.48–1.10 (m, 4 H), 0.83 (t, J = 7.2 Hz, 3 H).
5-(3-Acetoxy-1,1-difluoro-3-iodopropyl)-3-phenyl-1,2,4-oxadi-
azole (6e)
Pale-yellow oil.
13C NMR (125.8 MHz, CDCl3): d = 171.7 (t, J = 34.1 Hz), 169.4,
132.5, 129.6, 128.3, 126.3, 116.0 (t, J = 246.8 Hz), 47.6 (t, J = 23.1
Hz), 41.1, 33.0, 30.1, 23.7, 14.6.
19F NMR (470.5 MHz, CDCl3): d = –95.72 (ddd, JF-F = 277.6 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –102.09 (dt, JF-F = 277.6 Hz,
JH-F = 16.5 Hz, 1 F).
IR (film): 3069, 1769, 1202, 1125, 1088, 760, 693 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.11–7.51 (m, 5 H), 7.09–7.06 (m,
1 H), 3.72–3.56 (m, 1 H), 3.43–3.34 (m, 1 H), 1.92 (s, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 171.5 (t, J = 33.7 Hz), 169.9,
168.3, 132.7, 129.8, 128.3, 126.0, 114.5 (t, J = 248.1 Hz), 49.4 (t,
J = 24.1 Hz), 41.4, 21.4.
19F NMR (470.5 MHz, CDCl3): d = –96.10 (dt, JF-F = 282.3 Hz,
JH-F = 14.1 Hz, 1 F), –99.85 (ddd, JF-F = 282.3 Hz, J1H-F = 18.8
Hz, J2H-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C15H17F2IN2O: 406.0354; found:
406.0354.
5-(1,1-Difluoro-3-iodononyl)-3-phenyl-1,2,4-oxadiazole (6b)
Pale-yellow oil.
HRMS: m/z [M]+ calcd for C13H11F2IN2O3: 408.9861; found:
407.9851.
IR (film): 3068, 1196, 1123, 1062, 1073, 756, 703 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–7.50 (m, 5 H), 4.35–4.32 (m,
1 H), 3.31–3.22 (m, 1 H), 3.20–3.03 (m, 1 H), 1.87–1.84 (m, 1 H),
1.79–1.77 (m, 1 H), 1.60–1.51 (m, 1 H), 1.40–1.48 (m, 1 H), 1.48–
1.23 (m, 6 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 172.7 (t, J = 33.8 Hz), 170.5,
133.6, 130.7, 129.4, 127.3, 117.1 (t, J = 246.5 Hz), 48.6 (t, J = 23.0
Hz), 42.1, 33.3, 31.1, 29.9, 24.2, 23.7, 15.7.
4,4-Difluoro-2-iodo-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butan-1-
ol (6f)
Pale-yellow oil.
IR (film): 3439 (br), 1197, 1119, 1055, 756, 703 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–7.50 (m, 5 H), 4.48–4.42 (m,
1 H), 3.85 (d, J = 5.2 Hz, 2 H), 3.28–3.25 (m, 1 H), 3.21–3.09 (m,
1 H), 2.26 (br, 1 H, OH).
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

1774
X. Yang et al.
PAPER
13C NMR (125.8 MHz, CDCl3): d = 171.6 (t, J = 34.3 Hz), 169.5,
132.6, 129.7, 128.4, 126.1, 115.8 (t, J = 246.3 Hz), 68.7, 43.5 (t,
J = 23.4 Hz), 23.6.
HRMS: m/z [M]+ calcd for C15H17F2IN2O2: 422.0303; found:
422.0307.
6,6-Difluoro-4-iodo-2-phenyl-6-(3-phenyl-1,2,4-oxadiazol-5-
yl)hexan-1-ol (6j)
Pale-yellow oil.
IR (film): 3440 (br), 1207, 1120, 1072, 757, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.04–7.09 (m, 10 H), 4.25–4.20
(m, 0.42 H), 4.07–4.01 (m, 0.58 H), 3.78–3.68 (m, 2 H), 3.25–2.98
(stack, 3 H), 2.34–1.90 (m, 2 H), 1.18 (t, J = 6.1 Hz, OH, 1 H).
19F NMR (470.5 MHz, CDCl3): d = –96.58 (ddd, JF-F = 277.6 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.85 (dt, JF-F = 277.6 Hz,
JH-F = 16.5 Hz, 1 F).
HRMS: m/z [M]+ calcd for C12H11F2IN2O2: 379.9833; found:
379.9853.
6,6-Difluoro-4-iodo-6-(3-phenyl-1,2,4-oxadiazol-5-yl)hexan-1-
ol (6g)
Pale-yellow oil.
13C NMR (125.8 MHz, CDCl3): d (major) = 171.4 (t, J = 34.1 Hz),
169.4, 139.9, 132.6, 129.7, 129.6, 128.8, 128.3, 127.5, 126.1, 116.0
(t, J = 247.0 Hz), 67.9, 49.9, 48.4 (t, J = 23.1 Hz), 42.6, 21.5;
d (minor) = 171.4 (t, J = 34.1 Hz), 169.4, 141.5, 132.6, 129.7,
129.4, 128.6, 128.3, 128.1, 126.1, 116.0 (t, J = 247.0 Hz), 66.9,
48.6, 47.3 (t, J = 23.6 Hz), 44.5, 21.7.
IR (film): 3382 (br), 1197, 1132, 1095, 1054, 1019, 749, 692 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–7.50 (m, 5 H), 4.41–4.36 (m,
1 H), 3.72 (t, J = 6.2 Hz, 2 H), 3.33–3.22 (m, 1 H), 3.17–3.05 (m, 1
H), 1.99–1.95 (m, 2 H), 1.88–1.83 (m, 1 H), 1.75–1.68 (m, 1 H),
1.50 (br, 1 H, OH).
13C NMR (125.8 MHz, CDCl3): d = 172.6 (t, J = 34.3 Hz), 170.5,
133.6, 130.7, 129.4, 127.1, 117.0 (t, J = 246.8 Hz), 63.3, 48.6 (t,
J = 23.2 Hz), 38.6, 34.1, 23.1.
19F NMR (470.5 MHz, CDCl3): d = –95.45 (ddd, JF-F = 277.6 Hz,
J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –100.79 (dt, JF-F = 277.6 Hz,
JH-F = 18.8 Hz, 1 F).
19F NMR (470.5 MHz, CDCl3): d (major) = –93.98 (ddd, JF-F
277.7 Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –99.42 (dt, JF-F
=
=
277.7 Hz, JH-F = 18.8 Hz, 1 F); d (minor) = –95.37 (dt, JF-F = 277.7
Hz, JH-F = 14.1 Hz, 1 F), –100.18 (dt, JF-F = 277.7 Hz, JH-F = 18.8
Hz, 1 F).
HRMS: m/z [M]+ calcd for C20H19F2IN2O2: 484.0459; found:
484.0471.
HRMS: m/z [M]+ calcd for C14H15F2IN2O2: 408.0146; found:
408.0132.
5-[Difluoro(2-iodocyclohexyl)methyl]-3-phenyl-1,2,4-oxadi-
azole (8)
Pale-yellow oil.
IR (film): 3067, 1601, 1195, 1169, 1076, 747, 694 cm–1.
6,6-Difluoro-4-iodo-3,3-dimethyl-6-(3-phenyl-1,2,4-oxadiazol-
5-yl)hexan-1-ol (6h)
Pale-yellow oil.
IR (film): 3438 (br), 1179, 1121, 1078, 755, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13–7.50 (m, 5 H), 4.27–4.25 (m,
1 H), 3.80–3.74 (m, 2 H), 3.27–3.05 (m, 2 H), 1.87–1.67 (m, 2 H),
1.25 (br, 1 H, OH), 1.16 (s, 3 H), 1.13 (s, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 171.8 (t, J = 34.7 Hz), 169.5,
132.5, 129.7, 128.4, 126.3, 116.3 (t, J = 244.7 Hz), 60.0, 44.0 (t,
J = 23.7 Hz), 43.6, 38.3, 37.2, 26.8, 25.7.
1H NMR (500 MHz, CDCl3): d (major) = 8.04–7.40 (m, 5 H), 4.37–
4.33 (m, 1 H), 2.95–2.83 (m, 1 H), 2.14–1.31 (m, 8 H); d (minor) =
8.04–7.40 (m, 5 H), 4.65–4.68 (m, 1 H), 2.32–2.25 (m, 1 H), 2.14–
1.31 (m, 8 H).
13C NMR (125.8 MHz, CDCl3): d (major) = 172.0 (t, J = 34.5 Hz),
169.5, 132.4, 129.6, 128.3, 126.4, 117.4 (t, J = 249.7 Hz), 50.7 (t,
J = 21.4 Hz), 37.8, 27.0, 25.7, 24.0, 22.7; d (minor) = 171.7 (t,
J = 34.7 Hz), 169.4, 132.9, 129.8, 128.4, 126.3, 115.4 (t, J = 248.9
Hz), 49.3 (t, J = 22.6 Hz), 39.8, 28.5, 25.2, 24.7, 23.0.
19F NMR (470.5 MHz, CDCl3): d = –95.21 (dt, JF-F = 277.6 Hz,
JH-F = 14.1 Hz, 1 F), –102.56 (dt, JF-F = 277.6 Hz, JH-F = 16.5 Hz,
1 F).
HRMS: m/z [M]+ calcd for C16H19F2IN2O2: 436.0459; found:
436.0468.
19F NMR (470.5 MHz, CDCl3): d (major) = –97.30 (d, JF-F = 277.6
Hz, 1 F), –106.90 (d, JF-F = 277.6 Hz, 1 F); d (minor) = –102.97 (dd,
JF-F = 277.6 Hz, JH-F = 14.1 Hz, 1 F), –105.72 (dd, JF-F = 277.6 Hz,
JH-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C15H15F2IN2O: 404.0197; found:
404.0237.
6,6-Difluoro-4-iodo-2-methyl-6-(3-phenyl-1,2,4-oxadiazol-5-
yl)hexan-1-ol (6i)
Pale-yellow oil.
IR (film): 3341 (br), 1194, 1120, 1070, 755, 703 cm–1.
5-[Difluoro(2-iodocyclopentyl)methyl]-3-phenyl-1,2,4-oxadi-
azole (10)
Pale yellow oil.
IR (film): 3068, 1602, 1211, 1128, 1071, 747, 701 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13–7.49 (m, 5 H), 4.43 (q,
J = 6.0 Hz, 1 H), 3.46–3.41 (m, 1 H), 2.26–2.14 (stack, 2 H), 2.09–
2.01 (m, 1 H), 1.93–1.82 (m, 2 H), 1.79–1.72 (m, 1 H).
13C NMR (125.8 MHz, CDCl3): d = 171.8 (t, J = 34.8 Hz), 169.4,
132.5, 129.7, 128.4, 126.3, 117.3 (t, J = 247.3 Hz), 57.6 (t, J = 22.2
Hz), 41.9, 26.6, 26.0, 19.3.
19F NMR (470.5 MHz, CDCl3): d = –105.51 (d, JH-F = 18.8 Hz, 2 F).
HRMS: m/z [M]+ calcd for C14H13F2IN2O: 390.0041; found:
1H NMR (500 MHz, CDCl3): d = 8.12–7.47 (m, 5 H), 4.45–4.42 (m,
0.46 H), 4.38–4.32 (m, 0.54 H), 3.59–3.50 (m, 2 H), 3.36–3.23 (m,
1 H), 3.15–3.08 (m, 1 H), 2.19–2.15 (m, 0.46 H), 1.96–1.88 (stack,
1.54 H), 1.48–1.44 (m, 1 H), 1.27 (br, 1 H, OH), 1.01 (d, J = 6.4 Hz,
1.46 H), 0.91 (d, J = 6.7 Hz, 1.54 H).
13C NMR (CDCl3): d (major) = 171.7 (t, J = 33.6 Hz), 169.5, 132.6,
129.7, 128.3, 126.2, 116.0 (t, J = 246.8 Hz), 68.5, 48.5 (t, J = 23.1
Hz), 44.7, 37.4, 21.1, 15.6; d (minor) = 171.7 (t, J = 33.6 Hz), 169.5,
132.6, 129.7, 128.3, 126.2, 116.0 (t, J = 246.8 Hz), 67.1, 48.0 (t,
J = 23.6 Hz), 45.7, 36.4, 20.1, 17.8.
390.0088.
19F NMR (470.5 MHz, CDCl3): d (major) = –100.03 (ddd, JF-F
122.4 Hz, JH-F = 18.8 Hz, 1 F), –100.48 (dt, JF-F = 122.4 Hz, JH-F
=
=
5-{1,1-Difluoro-2-[4-(iodomethyl)tetrahydrofuran-3-yl]ethyl}-
3-phenyl-1,2,4-oxadiazole (12)
Pale-yellow oil.
18.8 Hz, 1 F);d (minor) = –94.61 (ddd, JF-F = 277.6 Hz, J1H-F = 11.8
Hz, J2H-F = 4.7 Hz, 1 F), –95.20 (ddd, JF-F = 277.6 Hz, J1H-F = 11.8
Hz, J2H-F = 4.7 Hz, 1 F).
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

PAPER
Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
1775
IR (film): 3067, 1602, 1190, 1119, 1072, 757, 704 cm–1.
5-[1,1-Difluoro-2-(tetrahydrofuran-2-yl)ethyl]-3-phenyl-1,2,4-
oxadiazoles 17g–j; General Procedure
1H NMR (500 MHz, CDCl3): d (major) = 8.12–7.50 (m, 5 H), 4.22–
4.00 (m, 2 H), 3.77 (dd, J1 = 8.5 Hz, J2 = 4.5 Hz, 1 H), 3.70 (t,
J = 8.5 Hz, 1 H), 3.29 (dd, J1 = 10.0 Hz, J2 = 5.0 Hz, 1 H), 3.2 (t,
J = 10.0 Hz, 1 H), 2.85–2.81(m, 1 H), 2.73–2.38 (stack, 2 H), 2.29–
2.48 (m, 1 H); d (minor) = 8.12–7.50 (m, 5 H), 4.20 (t, J = 8.0 Hz,
2 H), 4.38 (dd, J1 = 8.0 Hz, J2 = 6.6 Hz, 1 H), 3.61–3.49 (2 H, m),
3.34 (dd, J1 = 10.0 Hz, J2 = 5.0 Hz, 1 H), 3.19 (dd, J1 = 10.0 Hz,
J2 = 8.0 Hz, 1 H), 2.29–2.48 (stack, 2 H), 2.36–2.25 (m, 1 H).
A soln of 6g–j (0.5 mmol) in DMF (2 mL) was stirred at 100 °C for
3 h. After cooling to r.t., the mixture was treated with H2O (ca. 10
mL) and then extracted with Et2O (3 × 10 mL). The combined or-
ganic layers were washed consecutively with 10% Na2SO3, brine,
and H2O and then dried (anhyd Na2SO4). The solvent was removed
to give an oil. Pure 17g–j were obtained after column chromato-
graph (PE–EtOAc, 80:1).
13C NMR (125.8 MHz, CDCl3): d (major) = 172.3 (t, J = 34.6 Hz),
169.5, 132.6, 129.8, 128.4, 126.1, 116.3 (t, J = 245.1 Hz), 74.2,
72.3, 45.8, 37.4, 34.4 (t, J = 23.2 Hz), 3.7; d (minor) = 172.3 (t,
J = 34.6 Hz), 169.5, 132.6, 129.8, 128.4, 126.1, 116.1 (t, J = 245.1
Hz), 74.7, 74.5, 48.5, 40.8, 39.7 (t, J = 23.0 Hz), 7.4.
5-[1,1-Difluoro-2-(tetrahydrofuran-2-yl)ethyl]-3-phenyl-1,2,4-
oxadiazole (17g)
Pale-yellow oil.
IR (film): 3068, 1260, 1196, 1175, 1094, 761, 705 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.14–7.48 (m, 5 H), 4.20–4.15 (m,
1 H), 3.78–3.71 (m, 1 H), 3.68–3.63 (m, 1 H), 2.82–2.69 (m, 1 H),
2.61–2.52 (m, 1 H), 2.14–2.08 (m, 1 H), 1.94–1.82 (m, 2 H), 1.64–
1.56 (m, 1 H).
13C NMR (125.8 MHz, CDCl3): d = 172.7 (t, J = 34.1 Hz), 169.3,
132.4, 129.6, 128.3, 126.5, 117.2 (t, J = 245.1 Hz), 73.3 (t, J = 5.3
Hz), 68.6, 42.7 (t, J = 22.5 Hz), 32.5, 26.1.
19F NMR (470.5 MHz, CDCl3): d = –102.09 (ddd, JF-F = 278.3 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –94.45 (dt, JF-F = 278.3 Hz,
JH-F = 13.9 Hz, 1 F).
19F NMR (470.5 MHz, CDCl3): d (major) = –97.41 (ddd, JF-F
277.6 Hz, J1H-F = 21.2 Hz, J2H-F = 9.4 Hz, 1 F), –100.3 (ddd, JF-F
=
=
277.6 Hz, J1H-F = 21.2 Hz, J2H-F = 9.4 Hz, 1 F); d (minor) = –97.37
(ddd, JF-F = 277.6 Hz, J1H-F = 21.2 Hz, J2H-F = 9.4 Hz, 1 F), –100.0
(ddd, JF-F = 277.6 Hz, J1H-F = 21.2 Hz, J2H-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C15H15F2IN2O2: 420.0146; found:
420.0193.
(E)-5-(1,1-Difluoro-3-iodo-3-phenylallyl)-3-phenyl-1,2,4-oxadi-
azole (14)
Pale-yellow oil.
IR (film): 3059, 1629, 1186, 1159, 1071, 756, 697 cm–1.
HRMS: m/z [M]+ calcd for C14H14F2N2O2: 280.1023; found:
280.1021.
1H NMR (500 MHz, CDCl3): d = 7.95–7.45 (m, 5 H), 7.21–7.11 (m,
5 H), 7.01 (t, JH-F = 10.0 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): d = 172.3 (t, J = 35.2 Hz), 170.2,
142.0, 134.7 (t, J = 29.1 Hz), 133.4, 131.1, 130.6, 129.8, 129.3,
129.0, 127.2, 112.8 (t, J = 244.4 Hz), 112.4 (t, J = 10.1 Hz).
19F NMR (470.5 MHz, CDCl3): d = –87.42 (d, JH-F = 10.0 Hz, 2 F).
HRMS: m/z [M]+ calcd for C17H11F2IN2O: 423.9884; found:
5-[2-(3,3-Dimethyltetrahydrofuran-2-yl)-1,1-difluoroethyl]-3-
phenyl-1,2,4-oxadiazole (17h)
Colorless liquid.
IR (film): 3069, 1179, 1124, 1099, 757, 706 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13–7.48 (m, 5 H), 3.75–3.67
(stack, 3 H), 2.53–2.43 (m, 2 H), 1.75–1.71 (m, 2 H), 1.08 (s, 3 H),
0.96 (s, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 172.8 (t, J = 34.8 Hz), 169.2,
132.3, 129.6, 128.3, 126.6, 116.8 (t, J = 246.0 Hz), 80.7, 66.6, 41.7,
41.0, 38.3 (t, J = 22.9 Hz), 25.7, 22.3.
19F NMR (470.5 MHz, CDCl3): d = 102.69 (ddd, JF-F = 272.9 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), 93.54 (dt, JF-F = 272.9 Hz,
JH-F = 14.1 Hz, 1 F).
423.9876.
4,4-Difluoro-2-iodo-4-(3-phenyl-1,2,4-oxadiazol-5-yl)but-2-en-
1-ol (16)
(E)-16 and (Z)-16 were obtained as pale-yellow oils.
(Z)-16
IR (film): 3433 (br), 1631, 1191, 1124, 1073, 754, 693 cm–1.
HRMS: m/z [M]+ calcd for C16H18F2N2O2: 308.1336; found:
308.1324.
1H NMR (500 MHz, CDCl3): d = 8.01–7.42 (m, 5 H), 6.76 (t, JH-F
=
13.1 Hz, 1 H), 4.39 (d, J = 6.3 Hz, 2 H), 2.49 (t, J = 6.3 Hz, 1 H,
OH).
5-[1,1-Difluoro-2-(4-methyltetrahydrofuran-2-yl)ethyl]-3-phe-
nyl-1,2,4-oxadiazole (17i)
Colorless liquid.
IR (film): 2962, 1200, 1177, 1146, 1069, 760, 704 cm–1.
13C NMR (125.8 MHz, CDCl3): d = 170.0 (t, J = 36.2 Hz), 167.8,
131.0, 130.8 (t, J = 28.7 Hz), 128.1, 126.6, 124.3, 118.6 (t, J = 7.42
Hz), 110.4 (t, J = 245.6 Hz), 65.2.
19F NMR (470.5 MHz, CDCl3): d = –88.63 (d, JH-F = 13.1 Hz, 2 F).
HRMS: m/z [M]+ calcd for C12H9F2IN2O2: 377.9677; found:
1H NMR (500 MHz, CDCl3): d (trans) = 8.05–7.40 (m, 5 H), 4.26–
4.18 (m, 1 H), 3.78 (dd, J1 = 8.4 Hz, J2 = 6.9 Hz, 1 H), 3.14 (dd,
J1 = 8.4 Hz, J2 = 6.8 Hz, 1 H), 2.71–2.63 (m, 1 H), 2.61–2.40 (m, 1
H), 2.30–2.18 (m, 1 H), 1.80–1.70 (stack, 2 H), 0.93 (d, J = 6.6 Hz,
3 H); d (cis) = 8.05–7.40 (m, 5 H), 4.12–4.06 (m, 1 H), 3.72 (t,
J = 7.9 Hz, 1 H), 3.19 (t, J = 7.9 Hz, 1 H), 2.71–2.63 (m, 1 H), 2.61–
2.40 (m, 1 H), 2.30–2.18 (stack, 2 H), 1.23–1.15 (m, 1 H), 0.96 (d,
J = 6.3 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d (trans) = 172.7 (t, J = 34.3 Hz),
169.3, 132.4, 129.6, 128.3, 126.6, 116.1 (t, J = 245.8 Hz), 75.7,
72.9–72.8 (m), 43.0 (t, J = 22.3 Hz), 40.6, 33.6, 18.5; d (cis) = 172.6
(t, J = 34.1 Hz), 169.3, 132.4, 129.6, 128.3, 126.5, 116.0 (t,
J = 244.7 Hz), 75.2, 74.0–73.9 (m), 43.1 (t, J = 22.5 Hz), 41.9, 34.9,
18.0.
377.9676.
(E)-16
IR (film): 3439 (br), 1650, 1206, 1124, 1066, 755, 691 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.03–7.41 (m, 5 H), 7.10 (t, JH-F
11.0 Hz, 1 H), 4.30 (s, 2 H), 2.74 (s, 1 H, OH).
=
13C NMR (125.8 MHz, CDCl3): d = 169.9 (t, J = 36.0 Hz), 167.9,
130.9, 128.1, 126.6, 124.7 (t, J = 29.6 Hz), 124.5, 114.2 (t, J = 8.8
Hz), 111.3 (t, J = 242.6 Hz), 70.7.
19F NMR (470.5 MHz, CDCl3): d = –91.14 (d, JH-F = 11.0 Hz, 2 F).
HRMS: m/z [M]+ calcd for C12H9F2IN2O2: 377.9677; found:
377.9676.
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

1776
X. Yang et al.
PAPER
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-4,4-
dimethyl-4,5-dihydrofuran-2(3H)-one (19b)
Colorless liquid.
19F NMR (470.5 MHz, CDCl3): d (trans) = –94.30 (dt, JF-F = 277.7
Hz, JH-F = 14.1 Hz, 1 F), –102.42 (ddd, JF-F = 277.7 Hz, J1H-F = 18.8
Hz, J2H-F = 14.1 Hz, 1 F); d (cis) = –94.94 (dt, JF-F = 277.7 Hz,
JH-F = 14.1 Hz, 1 F), –101.63 (ddd, JF-F = 277.7 Hz, J1H-F = 18.8 Hz,
J2H-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C15H16F2N2O2: 294.1180; found:
294.1167.
IR (film): 1789, 1197, 1157, 1085, 758, 706 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–7.49 (m, 5 H), 4.49–4.45 (m,
1 H), 2.81–2.62 (m, 2 H), 2.46 (d, J = 16.9 Hz, 1 H), 2.38 (d,
J = 16.9 Hz, 1 H), 1.25 (s, 3 H), 1.11 (s, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 176.3, 172.7 (t, J = 34.0 Hz),
170.4, 133.6, 130.7, 129.3, 127.2, 116.4 (t, J = 245.5 Hz), 82.5,
45.5, 41.3, 38.0 (t, J = 24.0 Hz), 26.0, 23.0.
5-[1,1-Difluoro-2-(4-phenyltetrahydrofuran-2-yl)ethyl]-3-phe-
nyl-1,2,4-oxadiazole (17j)
Colorless liquid.
19F NMR (470.5 MHz, CDCl3): d = –95.90 (dt, JF-F = 282.3 Hz,
JH-F = 14.1 Hz, 1 F), –100.33 (dt, JF-F = 282.3 Hz, JH-F = 14.1 Hz,
1 F).
HRMS: m/z [M]+ calcd for C16H16F2N2O3: 322.1129; found:
322.1136.
IR (film): 2939, 1602, 1323, 1198, 1125, 1097, 1073, 758, 700 cm–1.
1H NMR (500 MHz, CDCl3): d (trans) = 8.14–7.19 (m, 10 H), 4.56–
4.50 (m, 1 H), 4.12 (dd, J1 = 8.6 Hz, J2 = 7.4 Hz, 1 H), 3.66 (dd,
J1 = 8.6 Hz, J2 = 7.7 Hz, 1 H), 3.51–3.44 (m, 1 H), 2.98–2.72 (m, 1
H), 2.68–2.54 (m, 1 H), 2.29–2.22 (m, 1 H), 2.18–2.12 (m, 1 H);
d (cis) = 8.14–7.19 (m, 10 H), 4.40–4.33 (m, 1 H), 4.07 (t, J = 8.3
Hz, 1 H), 3.76 (t, J = 8.3 Hz, 1 H), 3.51–3.44 (m, 1 H), 2.98–2.72
(m, 1 H), 2.68–2.54 (stack, 2 H), 1.85–1.78 (m, 1 H).
13C NMR (125.8 MHz, CDCl3): d (trans) = 172.6 (t, J = 34.2 Hz),
169.4, 142.4, 132.4, 129.7, 129.4, 128.4, 127.9, 127.4, 126.5, 116.1
(t, J = 245.9 Hz), 75.3, 73.6, 44.9, 43.1 (t, J = 22.3 Hz), 40.8;
d (cis) = 172.5 (t, J = 32.9 Hz), 169.4, 142.1, 132.4, 129.7, 129.4,
128.4, 127.9, 127.4, 126.5, 116.0 (t, J = 245.9 Hz), 74.9, 74.3, 45.9,
42.8 (t, J = 22.7 Hz), 41.9.
19F NMR (470.5 MHz, CDCl3): d (trans) = –94.26 (dt, JF-F = 282.4
Hz, JH-F = 14.1 Hz, 1 F), –102.29 (ddd, JF-F = 282.4 Hz, J1H-F = 23.5
Hz, J2H-F = 18.8 Hz, 1 F); d (cis) = –94.89 (dt, JF-F = 282.4 Hz,
JH-F = 14.1 Hz, 1 F), –101.4 (dt, JF-F = 282.4 Hz, JH-F = 18.8 Hz,
1 F).
HRMS: m/z [M]+ calcd for C20H18F2N2O2: 356.1336; found:
356.1337.
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-3-meth-
yl-4,5-dihydrofuran-2(3H)-one (19c)
Obtained as a mixture of cis- and trans-isomers.
cis-19c
Colorless liquid.
IR (film): 1779, 1169, 1119, 1075, 758, 705 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.11–7.50 (m, 5 H), 4.77–4.74 (m,
1 H), 3.05–2.93 (m, 1 H). 2.75–2.68 (stack, 3 H), 1.77–1.67 (m, 1
H), 1.31 (d, J = 6.6 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 178.7, 171.6 (t, J = 34.0 Hz),
169.4, 132.6, 129.7, 128.3, 126.1, 115.0 (t, J = 245.5 Hz), 72.1, 42.3
(t, J = 23.0 Hz), 38.3, 36.0, 15.4.
19F NMR (470.5 MHz, CDCl3): d = –96.25 (ddd, JF-F = 282.3 Hz,
J1H-F = 19.3 Hz, J2H-F = 11.8 Hz, 1 F), –99.64 (ddd, JF-F = 282.3 Hz,
J1H-F = 19.3 Hz, J2H-F = 15.5 Hz, 1 F).
Reaction of 4 with Pent-4-enoic Acids 18; General Procedure
A mixture of pent-4-enoic acid 18 (2 mmol), NaOH (80 mg, 2
mmol), H2O (2 mL), and MeCN (6 mL) was stirred at r.t. for 5 min
and then 4 (650 mg, 2 mmol) was added. To the mixture was then
added Na2S2O4 (560 mg, 3.2 mmol) and NaHCO3 (270 mg, 3.2
mmol) in portions and the mixture was stirred for 6–8 h. H2O (ca.
15 mL) was the added and the soln extracted with Et2O (3 × 20 mL).
The combined organic layers were washed with sat. brine and dried
(anhyd Na2SO4). After evaporation of ether, the crude product was
purified by column chromatography (PE–EtOAc) to give the corre-
sponding lactones.
HRMS: m/z [M]+ calcd for C15H14F2N2O3: 308.0971; found:
308.0971
trans-19c
Colorless liquid.
1H NMR (500 MHz, CDCl3): d = 8.11–7.50 (m, 5 H), 4.96–4.94 (m,
1 H), 3.02–2.90 (m, 1 H), 2.79–2.67 (stack, 2 H), 2.34–2.29 (m, 1
H), 2.22–2.17 (m, 1 H), 1.32 (d, J = 7.4 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d = 177.5, 169.9 (t, J = 33.9 Hz),
167.8, 132.9, 128.0, 126.6, 124.5, 113.4 (t, J = 245.5 Hz), 70.4, 40.5
(t, J = 23.0 Hz), 36.6, 32.4, 14.6.
19F NMR (470.5 MHz, CDCl3): d = –95.68 (ddd, JF-F = 268.2 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –100.44 (ddd, JF-F = 268.2
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-4,5-di-
hydrofuran-2(3H)-one (19a)
Colorless liquid.
IR (film): 1780, 1188, 1156, 1088, 758, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.11–7.50 (m, 5 H), 4.93–4.87 (m,
1 H), 3.04–2.96 (m, 1 H), 2.79–2.71 (m, 1 H), 2.61–2.51 (stack, 3
H), 2.10–2.05 (m, 1 H).
13C NMR (125.8 MHz, CDCl3): d = 176.3, 172.5 (t, J = 34.0 Hz),
169.2, 132.4, 129.5, 128.1, 125.9, 114.9 (t, J = 245.0 Hz), 74.2, 42.0
(t, J = 23.3 Hz), 28.9, 28.6.
19F NMR (470.5 MHz, CDCl3): d = –95.86 (ddd, JF-F = 282.3 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.92 (ddd, JF-F = 282.3 Hz,
J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F).
HRMS: m/z [M]+ calcd for C15H14F2N2O3: 308.0971; found:
308.0971.
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-3-ethyl-
4,5-dihydrofuran-2(3H)-one (19d)
Colorless liquid.
IR (film): 1781, 1168, 1119, 1078, 757, 704 cm–1.
1H NMR (500 MHz, CDCl3): d (cis) = 8.11–7.50 (m, 5 H), 4.81–
4.73 (m, 1 H), 3.08–2.90 (m, 1 H), 2.80–2.60 (stack, 3 H), 1.76–1.70
(m, 1 H), 1.63–1.48 (m, 2 H), 1.01 (t, J = 7.5 Hz, 3 H); d (trans) =
8.11–7.50 (m, 5 H), 4.95–4.90 (m, 1 H), 3.08–2.90 (m, 1 H), 2.80–
2.60 (stack, 2 H), 1.98–1.82 (m, 2 H), 1.63–1.48 (m, 2 H), 1.01 (t,
J = 7.4 Hz, 3 H).
HRMS: m/z [M]+ calcd for C14H12F2N2O3: 294.0816; found:
294.0790.
13C NMR (125.8 MHz, CDCl3): d (cis) = 176.3, 170.0 (t, J = 34.0
Hz), 167.7, 130.9, 128.0, 126.6, 124.5, 113.4 (t, J = 245.4 Hz), 70.6,
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

PAPER
Synthesis of Difluoromethylene-Containing 1,2,4-Oxadiazole Compounds
1777
40.7, 40.6 (t, J = 23.0 Hz), 33.9, 22.0, 10.4; d (trans) = 176.4, 170.0
(t, J = 34.0 Hz), 167.7, 130.9, 128.0, 126.6, 124.5, 113.4 (t,
J = 245.4 Hz), 70.7, 40.4 (t, J = 22.8 Hz), 39.1, 32.3, 22.7, 10.5.
19F NMR (470.5 MHz, CDCl3): d (cis) = –96.20 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –99.74 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –95.71 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –100.34
(ddd, JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
IR (film): 1778, 1164, 1121, 1087, 757, 704 cm–1.
1H NMR (500 MHz, CDCl3): d (cis) = 8.11–7.50 (m, 5 H), 4.78–
4.70 (m, 1 H), 3.08–2.89 (m, 1 H), 2.81–2.62 (stack, 2 H), 2.49–2.30
(m, 1 H), 1.93–1.78 (stack, 2 H), 1.49–1.20 (m, 2 H), 1.02 (t, J = 7.1
Hz, 3 H), 0.92 (d, J = 7.0 Hz, 3 H); d (trans) = 8.11–7.50 (m, 5 H),
4.90–4.85 (m, 1 H), 3.08–2.89 (m, 1 H), 2.81–2.62 (stack, 2 H),
2.52–2.48 (m, 1 H), 2.19–1.98 (stack, 2 H), 1.49–1.20 (m, 2 H), 1.02
(t, J = 7.1 Hz, 3 H), 0.92 (d, J = 7.0 Hz, 3 H).
HRMS: m/z [M]+ calcd for C16H16F2N2O3: 322.1129; found:
322.1116.
13C NMR (125.8 MHz, CDCl3): d (cis) = 177.3, 171.5 (t, J = 34.0
Hz), 169.5, 132.6, 129.7, 128.3, 126.1, 115.0 (t, J = 245.4 Hz), 72.1,
42.4 (t, J = 23.0 Hz), 36.3, 34.8, 28.4, 26.4, 17.6, 15.6; d (trans) =
177.8, 171.6 (t, J = 34.0 Hz), 169.5, 132.6, 129.7, 128.3, 126.1,
115.0 (t, J = 245.4 Hz), 72.4, 42.6 (t, J = 23.2 Hz), 35.6, 34.1, 28.2,
26.6, 17.4, 15.9.
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-3-pro-
pyl-4,5-dihydrofuran-2(3H)-one (19e)
Colorless liquid.
IR (film): 1778, 1260, 1166, 1087, 759, 703 cm–1.
19F NMR (470.5 MHz, CDCl3): d (cis) = –95.91 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –100.57 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –95.89 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –99.76 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 9.2 Hz, 1 F).
HRMS: m/z [M]+ calcd for C18H20F2N2O3: 350.1442; found:
350.1443.
1H NMR (500 MHz, CDCl3): d (cis) = 8.11–7.50 (m, 5 H), 4.77–
4.74 (m, 1 H), 3.07–2.98 (m, 1 H), 2.80–2.60 (stack, 3 H), 1.90–1.86
(m, 1 H), 1.75–1.71 (m, 1 H), 1.50–1.37 (m, 3 H), 0.96 (t, J = 7.1
Hz, 3 H); d (trans) = 8.11–7.50 (m, 5 H), 4.95–4.90 (m, 1 H), 3.07–
2.98 (m, 1 H), 2.80–2.60 (stack, 2 H), 2.27–2.20 (m, 2 H), 1.94–1.87
(m, 1 H), 1.50–1.37 (m, 3 H), 0.96 (t, J = 7.1 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d (cis) = 178.2, 171.6 (t, J = 34.0
Hz), 169.4, 132.6, 129.7, 128.3, 126.1, 115.0 (t, J = 245.5 Hz), 72.3,
42.4 (t, J = 23.0 Hz), 40.8, 36.3, 32.8, 21.1, 14.4; d (trans) = 178.6,
171.6 (t, J = 34.0 Hz), 169.4, 132.6, 129.7, 128.3, 126.1, 115.0 (t,
J = 245.5 Hz), 72.4, 42.2 (t, J = 22.7 Hz), 39.2, 34.5, 33.3, 21.1,
14.3.
19F NMR (470.5 MHz, CDCl3): d (cis) = –96.16 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.64 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –95.74 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.64 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
3-Benzyl-5-[2,2-difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)eth-
yl]-4,5-dihydrofuran-2(3H)-one (19h)
Colorless liquid.
IR (film): 1780, 1164, 1122, 1093, 752, 701 cm–1.
1H NMR (500 MHz, CDCl3): d (cis) = 8.09–7.49 (m, 5 H), 7.32–
7.17 (m, 5 H), 4.75–4.70 (m, 1 H), 3.27 (dd, J1 = 14.1 Hz, J2 = 4.3
Hz, 1 H), 3.01–2.89 (stack, 2 H), 2.76 (dd, J1 = 14.1 Hz, J2 = 9.3 Hz,
1 H), 2.70–2.57 (m, 1 H), 2.50–2.46 (m, 1 H), 1.80–1.73 (m, 1 H);
d (trans) = 8.09–7.49 (m, 5 H), 7.32–7.17 (m, 5 H), 4.64–4.58 (m,
1 H), 3.16 (dd, J1 = 13.8 Hz, J2 = 4.6 Hz, 1 H), 3.01–2.89 (stack, 2
H), 2.85 (dd, J1 = 13.8 Hz, J2 = 5.0 Hz, 1 H), 2.70–2.57 (m, 1 H),
2.31–2.26 (m, 1 H), 2.15–2.10 (m, 1 H).
HRMS: m/z [M]+ calcd for C17H18F2N2O3: 336.1285; found:
336.1284.
13C NMR (125.8 MHz, CDCl3): d (cis) = 177.3, 171.5 (t, J = 34.0
Hz), 169.4, 138.7, 132.6, 129.7, 129.6, 129.5, 128.3, 127.5, 126.1,
114.9 (t, J = 245.0 Hz), 72.4, 42.9, 42.3 (t, J = 23.0 Hz), 36.6, 35.7;
d (trans) = 177.9, 171.5 (t, J = 34.0 Hz), 169.4, 138.3, 132.6, 129.7,
129.6, 129.5, 128.3, 127.7, 126.1, 114.9 (t, J = 245.0 Hz), 72.4, 42.2
(t, J = 22.8 Hz), 41.2, 36.9, 33.6.
19F NMR (470.5 MHz, CDCl3): d (cis) = –96.62 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –99.67 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –95.89 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –100.46 (dt,
JF-F = 282.3 Hz, JH-F = 18.8 Hz, 1 F).
3-Butyl-5-[2,2-difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-
4,5-dihydrofuran-2(3H)-one (19f)
Colorless liquid.
IR (film): 1780, 1166, 1118, 1084, 757, 703 cm–1.
1H NMR (500 MHz, CDCl3): d (cis) = 8.11–7.50 (m, 5 H), 4.77–
4.74 (m, 1 H), 3.07–2.90 (m, 1 H), 2.80–2.60 (stack, 3 H), 1.85–1.78
(m, 1 H), 1.75–1.71 (m, 1 H), 1.58–1.37 (m, 5 H), 0.95 (t, J = 7.1
Hz, 3 H); d (trans) = 8.11–7.50 (m, 5 H), 4.95–4.90 (m, 1 H), 3.07–
2.90 (m, 1 H), 2.80–2.60 (stack, 2 H), 2.26–2.24 (m, 2 H), 1.94–1.87
(m, 1 H), 1.58–1.37 (m, 5 H), 0.95 (t, J = 7.1 Hz, 3 H).
13C NMR (125.8 MHz, CDCl3): d (cis) = 178.1, 171.5 (t, J = 34.0
Hz), 169.2, 132.4, 129.5, 128.1, 125.9, 114.9 (t, J = 245.4 Hz),
72.1, 42.1 (t, J = 22.9 Hz), 40.7, 36.0, 30.2, 29.8, 22.8, 14.4;
d (trans) = 178.4, 171.5 (t, J = 34.0 Hz,), 169.2, 132.4, 129.5, 128.1,
125.9, 114.9 (t, J = 245.4 Hz), 72.1, 42.0 (t, J = 22.6 Hz), 39.1,
34.2, 30.7, 29.8, 22.8, 14.3.
19F NMR (470.5 MHz, CDCl3): d (cis) = –96.14 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.64 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –95.71 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –100.94 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C21H18F2N2O3 calcd 384.1285; found:
384.1300.
5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-3-phe-
nyl-4,5-dihydrofuran-2(3H)-one (19i)
White solid; mp 76.3–77.3 °C.
IR (KBr): 1771, 1211, 1162, 1115, 1089, 754, 702 cm–1.
1H NMR (500 MHz, CDCl3): d (cis) = 8.12–7.52 (m, 5 H), 7.40–
7.28 (m, 5 H), 4.96–4.90 (m, 1 H), 3.92 (dd, J1 = 12.7 Hz, J2 = 8.6
Hz, 1 H), 3.16–3.01(m, 1 H), 3.00–2.95 (m, 1 H), 2.86–2.78 (m, 1
H), 2.31–2.24 (m, 1 H); d (trans) = 8.12–7.52 (m, 5 H), 7.40–7.28
(m, 5 H), 5.10–5.05 (m, 1 H), 3.98 (dd, J1 = 9.2 Hz, J2 = 6.2 Hz, 1
H), 3.16–3.01 (m, 1 H), 2.86–2.78 (m, 1 H), 2.73–2.68 (m, 1 H),
2.64–2.55 (m, 1 H).
HRMS: m/z [M]+ calcd for C18H20F2N2O3: 350.1442; found:
350.1444.
3-sec-Butyl-5-[2,2-difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-
yl)ethyl]-4,5-dihydrofuran-2(3H)-one (19g)
Colorless liquid.
13C NMR (125.8 MHz, CDCl3): d (cis) = 176.1, 171.5 (t, J = 33.9
Hz), 169.5, 136.3, 132.6, 129.7, 129.6, 128.7, 128.3, 128.1, 126.1,
115.0 (t, J = 245.6 Hz), 72.2, 47.1, 42.2 (t, J = 23.1 Hz), 38.9;
d (trans) = 176.4, 171.5 (t, J = 33.9 Hz), 169.5, 136.8, 132.6, 129.8,
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York

1778
X. Yang et al.
PAPER
(2) Thaisrivongs, A.; Pals, D. T.; Kati, W. M.; Turner, S. R.;
Thomasco, L. M. J. Med. Chem. 1985, 28, 1553.
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Y.; Sai, H.; Ikekawa, N. Tetrahedron Lett. 1984, 25, 4933.
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3288; and references cited therein.
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129.7, 128.5, 128.3, 128.1, 126.1, 115.0 (t, J = 245.6 Hz), 72.6,
45.5, 42.1 (t, J = 22.9 Hz), 37.2.
19F NMR (470.5 MHz, CDCl3): d (cis) = –95.78 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –99.64 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F); d (trans) = –96.18 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 9.4 Hz, 1 F), –100.03 (ddd,
JF-F = 282.3 Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F).
HRMS: m/z [M]+ calcd for C20H16F2N2O3: 370.1129; found:
370.1129.
N-{5-[2,2-Difluoro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-2-
oxotetrahydrofuran-3-yl}-4-methoxybenzamide (19j)
White solid; mp 150.0–150.5 °C.
IR (KBr): 3383, 1773, 1656, 1185, 1113, 1072, 768, 703 cm–1.
(7) Mylari, L. B.; Banavara, L.; Beyer, T. A.; Scott, P. J.;
Aldinger, C. E.; Dee, M. F. J. Med. Chem. 1992, 35, 457.
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1H NMR (500 MHz, CDCl3): d (cis) = 8.11–6.84 (m, 10 H, PhH,
NH), 4.95–4.90 (m, 1 H), 4.80–4.75 (m, 1 H), 3.83 (s, 3 H), 3.13–
2.95 (stack, 2 H), 2.89–2.76 (m, 1 H), 2.19–2.12 (m, 1 H);
d (trans) = 8.11–6.84 (m, 10 H, PhH, NH), 5.23–5.17 (m, 1 H),
4.75–4.69 (m, 1 H), 3.83 (s, 3 H), 3.13–2.95 (m, 1 H), 2.89–2.76 (m,
1 H), 2.73–2.66 (m, 1 H), 2.60–2.52 (m, 1 H).
13C NMR (125.8 MHz, CDCl3): d (cis) = 174.8, 171.5 (t, J = 34.0
Hz), 169.5, 167.9, 163.5, 132.6, 129.7, 129.6, 128.4, 126.0, 125.3,
115.0 (t, J = 245.0 Hz), 114.6, 72.6, 56.1, 49.4, 42.2 (t, J = 23.0 Hz),
37.3; d (trans) = 175.0, 171.5 (t, J = 34.0 Hz), 169.5, 167.8, 163.5,
132.6, 129.7, 129.6, 128.4, 126.1, 125.2, 115.0 (t, J = 245.0 Hz),
114.6, 72.2, 56.1, 51.1, 42.2 (t, J = 23.0 Hz), 35.5.
19F NMR (470.5 MHz, CDCl3): d (cis) = –95.73 (ddd, JF-F = 282.3
Hz, J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –99.60 (dt, JF-F = 282.3
Hz, JH-F = 18.8 Hz, 1 F); d (trans) = –95.73 (ddd, JF-F = 282.3 Hz,
J1H-F = 18.8 Hz, J2H-F = 14.1 Hz, 1 F), –100.78 (dt, JF-F = 282.3 Hz,
JH-F = 18.9 Hz, 1 F).
19, 721.
(10) Chang, C. S.; Lin, Y. T.; Shih, S. R.; Lee, C. C.; Lee, Y. C.
J. Med. Chem. 2005, 48, 3522.
(11) Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R.
J. Med. Chem. 1991, 34, 2060.
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Tucker, S. P.; Watson, K. G. Aust. J. Chem. 2004, 57, 553.
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Hadjipavlou-Litina, D. Eur. J. Med. Chem. 1998, 33, 715.
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A.; Stewart, A. O.; Fry, D. G. J. Med. Chem. 2001, 44, 3469.
(16) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Lanza, C. Z.;
Spinelli, D. Eur. J. Org. Chem. 2004, 5, 974.
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Chem. 2005, 126, 63.
HRMS: m/z [M]+ calcd for C22H19F2N3O5: 443.1293; found:
443.1294.
5-(1,1-Difluoro-3-phenylallyl)-3-phenyl-1,2,4-oxadiazole (20)
A mixture of 14 (420 mg, 1.0 mmol), AcOH (0.5 mL), H2O (0.5
mL) and freshly activated Zn powder (75 mg, 1.2 mmol) was stirred
at r.t. When the reaction was complete, the mixture was diluted with
H2O (5 mL) and extracted with CHCl3 (2 × 10 mL) and dried (an-
hyd Na2SO4). Column chromatography gave a colorless oil 20;
yield: 240 mg (80%).
IR (film): 3061, 3032, 1649, 1288, 1200, 1119, 1061 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.11–7.18 (m, 10 H), 7.11 (d,
J = 12.4 Hz, 1 H), 6.17 (q, J = 12.4 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): d = 172.2 (t, J = 35.6 Hz), 169.2,
141.1 (t, J = 8.2 Hz), 134.5, 132.3, 129.5, 129.4, 129.3, 128.8,
128.2, 126.3, 122.4 (t, J = 27.5 Hz), 112.9 (t, J = 239.6 Hz).
19F NMR (470.5 MHz, CDCl3): d = –87.28 (d, JH-F = 12.4 Hz, 2 F).
HRMS: m/z [M]+ calcd for C17H12N2OF2: 298.0918; found:
298.0919.
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Acknowledgment
We thank the National Natural Science Foundation of China (Grant
No. 20672034) for financial support.
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and references cited therein.
Synthesis 2007, No. 12, 1768–1778 © Thieme Stuttgart · New York