A facile method for the stereoselective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones.

Article abstract of DOI:10.1248/cpb.50.706

Excellent Z or E selectivity was observed in the Horner-Wadsworth-Emmons (HWE) reactions of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate or ethyl 2-fluoro-2-diethylphosphonoacetate with aryl alkyl ketones bearing substituents on an aromatic moiety employing Sn(OSO2CF3)2 in the presence of N-ethylpiperidine.

Full text of DOI:10.1248/cpb.50.706

706
Notes
Chem. Pharm. Bull. 50(5) 706—709 (2002)
Vol. 50, No. 5
A Facile Method for the Stereoselective Horner–Wadsworth–Emmons
Reaction of Aryl Alkyl Ketones
a
Shigeki SANO, ,a Kenji YOKOYAMA,a Motoo SHIRO,b and Yoshimitsu NAGAO
*
a Faculty of Pharmaceutical Sciences, The University of Tokushima; Sho-machi, Tokushima 770–8505, Japan: and b Rigaku
Corporation; 3–9–12 Matsubara-cho, Akishima, Tokyo 196–8666, Japan.
Received January 24, 2002; accepted February 19, 2002
Excellent Z or E selectivity was observed in the Horner–Wadsworth–Emmons (HWE) reactions of methyl
bis(2,2,2-trifluoroethyl)phosphonoacetate or ethyl 2-fluoro-2-diethylphosphonoacetate with aryl alkyl ketones
bearing substituents on an aromatic moiety employing Sn(OSO2CF3)2 in the presence of N-ethylpiperidine.
Key words Horner–Wadsworth–Emmons reaction; a,b-unsaturated ester; aryl alkyl ketone; methyl bis(2,2,2-trifluoroethyl)-
phosphonoacetate; ethyl 2-fluoro-2-diethylphosphonoacetate; Wittig reaction
The Horner–Wadsworth–Emmons (HWE) reaction is an compound related to ozagrel. Ozagrel is an inhibitor of
important method for syntheses of a,b-unsaturated esters, thromboxane A2 synthetase and has already been launched
a,b-unsaturated ketones, and other conjugated systems.1) We on the market as an antithrombic and antiasthmatic drug.7—9)
have previously reported a new reaction mode for the stere- The stereoselective outcome with excellent Z-selectivity in
oselective HWE reaction that can be used to prepare a- the Sn(OSO2CF3)2-mediated HWE reactions can be rational-
hydro- and a-fluoro-a,b-unsaturated esters, as shown in ized in terms of a six-membered transition state proposed by
Chart 1.2—5) As an extension of the stereoselective HWE re- us.2) The HWE reaction employing NaH afforded a mixture
action, we describe herein highly stereoselective E- or Z- of geometric isomers in a lower stereoselective manner, as
alkene formation in the HWE reaction of aryl alkyl ketones shown in Table 2. It is worth noting that the HWE reaction of
bearing substituents on the aromatic moiety.
ketone 3b with the o-tolyl group has not been observed to
An excellent Z-selectivity was observed in the HWE reac- occur under NaH conditions, whereas the reaction readily
tions of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1)6) proceeds under Sn(OSO2CF3)2 conditions (each entry 2 in
with phenyl or naphthyl alkyl ketones using Sn(OSO2CF3)2 Tables 1 and 2). The geometry of 4a, b, d—g was confirmed
and N-ethylpiperidine. The mode of the reactions, however, by 1H–1H nuclear Overhauser effect (NOE) (400 MHz,
was remarkably different from that of HWE reactions using CDCl3) experiments. The E : Z ratios of 4a, b, d—g were de-
NaH.2) To our knowledge, detailed information regarding the termined by utilizing 1H-NMR analysis (400 MHz, CDCl3).
substituent effects of the aromatic moiety on HWE reactions
Ethyl 2-fluoro-2-diethylphosphonoacetate (2),10) an effi-
of aryl alkyl ketones under specific conditions with cient fluorinating building-block,11,12) also provided the ex-
Sn(OSO2CF3)2 has not been reported. We therefore carried cellent stereoselectivity in the HWE reaction under the
out HWE reactions of phosphonate 1 with aryl alkyl ketones Sn(OSO2CF3)2 conditions, as shown in Chart 3 and Table 3.
3a—g bearing various substituents on the aromatic moiety, (E)-a-Fluoro-a,b-unsaturated esters 5a, b, d—f were ob-
as shown in Chart 2. Results of the HWE reactions of these tained as major products in each corresponding reaction (en-
ketones employing Sn(OSO2CF3)2 and N-ethylpiperidine are tries 1, 2, 4, 5, and 6 in Table 3). In other words, the aromatic
summarized in Table 1. In the cases of aromatic compounds and ester moieties are on the same side of the double bond of
3a, b, d, all having electron-donating methyl or methoxy (E)-5 as well as in the cases of (Z)-4. The HWE reaction of
group(s), the E : Z stereoselectivity was excellent, with ratios aryl alkyl ketone 3g with a-fluorophosphonate 2 using
of 2 : 98, 4 : 96, and 2 : 98, respectively (entries 1, 2, and 4 in Sn(OSO2CF3)2 in the presence of N-ethylpiperidine produced
Table 1). No reaction occurred in the case of ketone 3c with 5g with high E selectivity (entry 7 in Table 3). In contrast,
a bulky mesityl group (entry 3). In contrast, the similar reac- similar HWE reactions of 2 with 3a—g by the conventional
tions of ketones 3e, f, both having an electron-withdrawing methods using NaH gave E-selective products 5a, b, d—g in
nitro or trifluoromethyl group, resulted in a slightly lower a range of E : Z ratios, 80 : 20—88 : 12, as listed in Table 4.
stereoselectivity (E : Zϭ17 : 83 or 9 : 91) (entries 5 and 6). The geometries of 5a, b, d, f, g were confirmed on the basis
1
The reaction of 3g (entry 7) was carried out as an application of H–1H NOE experiments (400 MHz, CDCl3) of the corre-
of this HWE reaction to the Z-selective synthesis of 4g, a sponding primary alcohols derived by reduction of
Chart 1
To whom correspondence should be addressed. e-mail: ssano@ph2.tokushima-u.ac.jp
© 2002 Pharmaceutical Society of Japan

May 2002
707
Table 3. Sn(OSO2CF3)2-Mediated Horner–Wadsworth–Emmons Reac-
tions of 2 with Ketones 3a—ga)
Entry
Ketone
Time (h)
Yield (%)b) Alkene (E/Z)c)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
18
18
60d)
18
17
18
22
84
100
—
69
96
5a (Ͼ99 : Ͻ1)
5b (98 : 2)
—
5d (98 : 2)
5e (97 : 3)
5f (97 : 3)
5g (96 : 4)
e)
Chart 2
100
70
3g
Table 1. Sn(OSO2CF3)2-Mediated Horner–Wadsworth–Emmons Reac-
tions of 1 with Ketones 3a—ga)
a) Conditions: CH2Cl2, 0 °C, 2/Sn(OSO2CF3)2/N-ethylpiperidine/3 (1.4 : 1.68 : 1.54 :
1). b) Isolated yields. c) 1H-NMR (400 MHz, CDCl3) analysis. d) 0 °C, 20 h→rt,
40 h. e) No reaction.
Entry
Ketone
Time (h)
Yield (%)b) Alkene (E/Z)c)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
19
21
60d)
21
14
19
20
55
84
—
95
100
97
4a (2 : 98)
4b (4 : 96)
—
4d (2 : 98)
4e (17 : 83)
4f (9 : 91)
4g (8 : 92)
Table 4. NaH-Mediated Horner–Wadsworth–Emmons Reactions of 2 with
Ketones 3a—ga)
e)
Entry
Ketone
Time (h)
Yield (%)b) Alkene (E/Z)c)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
20
19
30d)
14
6
100
100
—
100
97
5a (87 : 13)
5b (88 : 12)
—
5d (87 : 13)
5e (81 : 19)
5f (83 : 17)
5g (80 : 20)
3g
65
e)
a) Conditions: CH2Cl2, 0 °C, 1/Sn(OSO2CF3)2/N-ethylpiperidine/3 (1.4 : 1.68 : 1.54 :
1). b) Isolated yields. c) 1H-NMR (400 MHz, CDCl3) analysis. d) 0 °C, 20 h→
room temperature (rt), 40 h. e) No reaction.
6
20
97
73
3g
a) Conditions: THF, 0 °C to rt, 2/NaH/3 (1.7 : 1.5 : 1). b) Isolated yields. c) 1H-
NMR (400 MHz, CDCl3) analysis. d) 0 °C, 20 h→reflux, 10 h. e) No reaction.
Table 2. NaH-Mediated Horner–Wadsworth–Emmons Reactions of 1 with
Ketones 3a—ga)
Entry
Ketone
Time (h)
Yield (%)b) Alkene (E/Z)c)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
45d)
24
54
—
—
33
99
92
58
4a (43 : 57)
—
—
4d (51 : 49)
4e (35 : 65)
4f (39 : 61)
4g (43 : 57)
f )
f )
23e)
19
19
18
16
3g
Fig. 1. Computer-Generated Drawing Derived from the X-Ray Coordi-
nates of (E)-5e
a) Conditions: THF, 0 °C to rt, 1/NaH/3 (1.7 : 1.5 : 1). b) Isolated yields. c) 1H-
NMR (400 MHz, CDCl3) analysis. d) rt. e) 0 °C, 16 h→reflux, 7 h. f ) No reac-
tion.
Sn(OSO2CF3)2-mediated HWE reactions of several aryl alkyl
ketones bearing various substituents on the aromatic moiety
proceed in a highly stereoselective manner and involve gen-
erality.
Experimental
All melting points were determined on a Yanaco micro melting point ap-
paratus and are uncorrected. IR spectra were obtained on a Perkin-Elmer
1720 IR Fourier transform spectrometer. 1H-NMR (200 and 400 MHz) spec-
tra were recorded on a JEOL JNM-FX 200, JEOL JNM-GSX400, or Bruker
ARX-400 spectrometer. Chemical shifts are given in d values (ppm) using
tetramethylsilane (TMS) as an internal standard. Electron impact (EI)-MS
were recorded on a JEOL JMS SX-102A spectrometer. Elementary combus-
tion analyses were performed by a Yanaco CHN CORDER MT-5. All reac-
tions were monitored by TLC employing 0.25-mm silica gel plates (Merck
5715; 60 F254). Preparative TLC (PTLC) was performed on 0.5-mm silica
gel plates (Merck 5744; 60 F254). Column chromatography was carried out
on silica gel (Katayama Chemical K070; 70—300 mesh, Merck 9385;
230—400 mesh). Tetrahydrofuran (THF) was distilled from sodium ben-
Chart 3
5a, b, d, f, g. In the case of 5e, the geometry of the major
product was established to be E by X-ray crystallographic
analysis.13) The diastereomer ratios of 5a, b, d—g were deter-
mined by 1H-NMR (400 MHz, CDCl3) analysis.
In conclusion, we have demonstrated that the zophenone ketyl under N2. N-Ethylpiperidine and CH2Cl2 were distilled

708
Vol. 50, No. 5
from CaH2. All other solvents were distilled prior to use. All reagents were
used as purchased.
s), 6.15 (1H, q, Jϭ0.7 Hz), 7.58—7.62 (4H, m); IR (neat) 2953, 1723, 1635,
1437, 1327, 1275, 1083, 723 cmϪ1; EI-MS Calcd for C12H11O2F3 MW
244.0711, Found m/z 244.0733 (Mϩ).
Typical Procedure for the HWE Reaction with Sn(OSO2CF3)2 To a
suspension of Sn(OSO2CF3)2 (350 mg, 0.84 mmol) and methyl bis(2,2,2-tri-
fluoroethyl)phosphonoacetate (1) (150 ml, 0.70 mmol) in anhydrous CH2Cl2
(5 ml) was added N-ethylpiperidine (106 ml, 0.77 mmol) at 0 °C. The mixture
was stirred at 0 °C for 1 h under argon, and p-methoxyphenyl ethyl ketone
(3d) (75 mg, 0.50 mmol) was added. After being stirred at 0 °C for 21 h
under argon, the reaction mixture was poured into H2O (15 ml) and then ex-
tracted with CHCl3 (50 mlϫ3). To the CHCl3 extract was added n-hexane
(180 ml), and the mixture was submitted to filtration through a silica gel
short column. The filtrate was evaporated in vacuo to afford a crude product
4d (E : Zϭ2 : 98), which was purified by PTLC [n-hexane/AcOEt (6 : 1)] to
obtain E-4d (2 mg, 2%) and Z-4d (96 mg, 93%) as a colorless oil, respec-
tively.
Typical Procedure for the HWE Reaction with NaH To a suspen-
sion of NaH (abs. 60% in oil, 52 mg, 1.35 mmol) in anhydrous THF (5 ml)
was added methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (320 ml,
1.53 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min under argon,
and p-methoxyphenyl ethyl ketone (3d) (136 mg, 0.90 mmol) was added.
After being stirred at 0 °C for 19 h under argon, 5% HCl (15 ml) was added
and then extracted with ether (40 mlϫ3). The extract was washed with brine,
dried over anhydrous MgSO4. Evaporation in vacuo afforded a crude product
4d (E : Zϭ51 : 49), which was purified by PTLC [n-hexane/AcOEt (6 : 1)] to
obtain E-4d (34 mg, 18%) and Z-4d (28 mg, 15%) as a colorless oil, respec-
tively.
Methyl (Z)-3-[ p-(Trifluoromethyl)phenyl]-2-butenoate [(Z)-4f]: Color-
1
less oil; H-NMR (200 MHz, CDCl3) d: 2.18 (3H, d, Jϭ1.2 Hz), 3.57 (3H,
s), 5.98 (1H, q, Jϭ1.2 Hz), 7.29—7.33 (2H, m), 7.60—7.64 (2H, m); IR
(neat) 2953, 1729, 1651, 1445, 1327, 1239, 1086, 729 cmϪ1; EI-MS Calcd
for C12H11O2F3 MW 244.0711, Found m/z 244.0735 (Mϩ); Anal. Calcd for
C12H11O2F3: C, 59.02; H, 4.54. Found: C, 58.59; H, 4.62.
An Inseparable Mixture of Methyl (E)- and (Z)-3-[ p-(1H-Imidazol-1-yl-
methyl)phenyl]-2-butenoate [(E)- and (Z)-4g]: Pale yellow oil; 1H-NMR
(400 MHz, CDCl3) d: 2.16 (3H, d, Jϭ1.2 Hz, Z-isomer), 2.56 (3H, d,
Jϭ1.0 Hz, E-isomer), 3.56 (3H, s, Z-isomer), 3.76 (3H, s, E-isomer), 5.14
(2H, s, E- and Z-isomer), 5.93 (1H, d, Jϭ1.2 Hz, Z-isomer), 6.12 (1H, d,
Jϭ1.0 Hz, E-isomer), 6.91—7.65 (7H, m, E- and Z-isomer); EI-MS Calcd
for C15H16N2O2 MW 256.1212, Found m/z 256.1194 (Mϩ).
1
Ethyl (E)-2-Fluoro-3-(3,5-xylyl)-2-butenoate [(E)-5a]: Colorless oil; H-
NMR (400 MHz, CDCl3) d: 1.03 (3H, t, Jϭ7.3 Hz), 2.10 (3H, d,
4JH,Fϭ4.6 Hz), 2.29 (6H, s), 4.04 (2H, q, Jϭ7.3 Hz), 6.77 (2H, s), 6.92 (1H,
s); IR (neat) 2983, 1730, 1658, 1445, 1376, 1333, 851, 722 cmϪ1; EI-MS
Calcd for C14H17O2F MW 236.1213, Found m/z 236.1209 (Mϩ); Anal. Calcd
for C14H17O2F: C, 71.17; H, 7.25. Found: C, 70.68; H, 7.28.
1
Ethyl (Z)-2-Fluoro-3-(3,5-xylyl)-2-butenoate [(Z)-5a]: Colorless oil; H-
NMR (400 MHz, CDCl3) d: 1.36 (3H, t, Jϭ7.3 Hz), 2.32 (6H, s), 2.39 (3H,
d, 4JH,Fϭ3.7 Hz), 4.32 (2H, q, Jϭ7.3 Hz), 6.95—6.97 (3H, m); IR (neat)
2984, 1724, 1644, 1446, 1369, 1289, 1062 cmϪ1
; EI-MS Calcd for
Methyl (E)-3-(3,5-Xylyl)-2-butenoate [(E)-4a]: Colorless oil; 1H-NMR
(200 MHz, CDCl3) d: 2.33 (6H, s), 2.55 (3H, s), 3.75 (3H, s), 6.11 (1H, s),
7.01—7.08 (3H, m); IR (neat) 2950, 1718, 1628, 1377, 1316, 1218, 1165,
1107 cmϪ1; EI-MS Calcd for C13H16O2 MW 204.1150, Found m/z 204.1150
(Mϩ).
C14H17O2F MW 236.1213, Found m/z 236.1203 (Mϩ); Anal. Calcd for
C14H17O2F: C, 71.17; H, 7.25. Found: C, 70.93; H, 7.37.
Ethyl (E)-2-Fluoro-3-(o-tolyl)-2-butenoate [(E)-5b]: Colorless oil; 1H-
NMR (400 MHz, CDCl3) d: 0.97 (3H, t, Jϭ6.8 Hz), 2.09 (3H, d, 4JH,Fϭ
4.1 Hz), 2.21 (3H, s), 4.00 (2H, q, Jϭ6.8 Hz), 6.98—6.99 (1H, m), 7.14—
7.21 (3H, m); IR (neat) 2985, 1732, 1664, 1445, 1376, 1284, 1053,
864 cmϪ1; EI-MS Calcd for C13H15O2F MW 222.1056, Found m/z 222.1029
(Mϩ).
Methyl (Z)-3-(3,5-Xylyl)-2-butenoate [(Z)-4a]: Colorless oil; 1H-NMR
(400 MHz, CDCl3) d: 2.15 (3H, d, Jϭ1.4 Hz), 2.31 (6H, s), 3.56 (3H, s),
5.88 (1H, q, Jϭ1.4 Hz), 6.81 (2H, s), 6.94 (1H, s); IR (neat) 2949, 1732,
1642, 1601, 1435, 1284, 1160, 1106 cmϪ1; EI-MS Calcd for C13H16O2 MW
204.1150, Found m/z 204.1175 (Mϩ).
Ethyl (Z)-2-Fluoro-3-(o-tolyl)-2-butenoate [(Z)-5b]: Colorless oil; 1H-
NMR (400 MHz, CDCl3) d: 1.38 (3H, t, Jϭ7.3 Hz), 2.25 (3H, s), 2.35 (3H,
d, 4JH,Fϭ3.2 Hz), 4.34 (2H, q, Jϭ7.3 Hz), 7.06—7.07 (1H, m), 7.19—7.23
(3H, m); IR (neat) 2984, 1724, 1657, 1489, 1370, 1263, 1058, 861 cmϪ1; EI-
MS Calcd for C13H15O2F MW 222.1056, Found m/z 222.1052 (Mϩ); Anal.
Calcd for C13H15O2F: C, 70.25; H, 6.80. Found: C, 70.06; H, 6.87.
Ethyl (E)-2-Fluoro-3-( p-methoxyphenyl)-2-butenoate [(E)-5d]: Colorless
oil; 1H-NMR (200 MHz, CDCl3) d: 1.10 (3H, t, Jϭ7.1 Hz), 2.13 (3H, d,
4JH,Fϭ4.4 Hz), 3.82 (3H, s), 4.08 (2H, q, Jϭ7.1 Hz), 6.86—6.90 (2H, m),
7.10—7.15 (2H, m); IR (neat) 2984, 1729, 1654, 1577, 1466, 1377, 1151,
833 cmϪ1; EI-MS Calcd for C13H15O3F MW 238.1005, Found m/z 238.1012
(Mϩ); Anal. Calcd for C13H15O3F: C, 65.54; H, 6.35. Found: C, 65.16; H,
6.35.
Ethyl (Z)-2-Fluoro-3-( p-methoxyphenyl)-2-butenoate [(Z)-5d]: Colorless
oil; 1H-NMR (200 MHz, CDCl3) d: 1.37 (3H, t, Jϭ7.1 Hz), 2.43 (3H, d,
4JH,Fϭ3.7 Hz), 3.83 (3H, s), 4.33 (2H, q, Jϭ7.1 Hz), 6.89—6.94 (2H, m),
7.36—7.40 (2H, m); IR (neat) 2984, 1719, 1607, 1460, 1369, 1304, 1182,
834 cmϪ1; EI-MS Calcd for C13H15O3F MW 238.1005, Found m/z 238.1006
(Mϩ); Anal. Calcd for C13H15O3F: C, 65.54; H, 6.35. Found: C, 65.65; H,
6.38.
Methyl (E)-3-(o-Tolyl)-2-butenoate [(E)-4b]: Colorless oil; 1H-NMR
(400 MHz, CDCl3) d: 2.29 (3H, s), 2.45 (3H, d, Jϭ0.9 Hz), 3.75 (3H, s),
5.77 (1H, q, Jϭ0.9 Hz), 7.06—7.08 (1H, m), 7.15—7.21 (3H, m); IR (neat)
2950, 1719, 1642, 1375, 1265, 1170, 765 cmϪ1; EI-MS Calcd for C12H14O2
MW 190.0994, Found m/z 190.0991 (Mϩ).
Methyl (Z)-3-(o-Tolyl)-2-butenoate [(Z)-4b]: Colorless oil; 1H-NMR
(400 MHz, CDCl3) d: 2.12 (3H, d, Jϭ0.9 Hz), 2.20 (3H, s), 3.53 (3H, s),
5.99 (1H, q, Jϭ0.9 Hz), 6.94—6.96 (1H, m), 7.17—7.19 (3H, m); IR (neat)
2950, 1732, 1647, 1373, 1202, 1122, 768 cmϪ1; EI-MS Calcd for C12H14O2
MW 190.0994, Found m/z 190.0996 (Mϩ).
Methyl (E)-3-( p-Methoxyphenyl)-2-butenoate [(E)-4d]: Colorless oil;
1H-NMR (200 MHz, CDCl3) d: 2.57 (3H, d, Jϭ1.0 Hz), 3.74 (3H, s), 3.83
(3H, s), 6.11 (1H, q, Jϭ1.0 Hz), 6.87—6.92 (2H, m), 7.43—7.47 (2H, m);
IR (neat) 3015, 1709, 1605, 1514, 1438, 1253, 1213, 833 cmϪ1; EI-MS
Calcd for C12H14O3 MW 206.0943, Found m/z 206.0939 (Mϩ); Anal. Calcd
for C12H14O3: C, 69.89; H, 6.84. Found: C, 70.00; H, 6.96.
Methyl (Z)-3-( p-Methoxyphenyl)-2-butenoate [(Z)-4d]: Colorless oil; 1H-
NMR (200 MHz, CDCl3) d: 2.17 (3H, d, Jϭ1.2 Hz), 3.58 (3H, s), 3.81 (3H,
s), 5.88 (1H, q, Jϭ1.2 Hz), 6.86—6.90 (2H, m), 7.17—7.22 (2H, m); IR
(neat) 2950, 1725, 1608, 1511, 1377, 1251, 833 cmϪ1; EI-MS Calcd for
C12H14O3 MW 206.0943, Found m/z 206.0934 (Mϩ); Anal. Calcd for
C12H14O3: C, 69.89; H, 6.84. Found: C, 69.55; H, 6.91.
Methyl (E)-3-( p-Nitrophenyl)-2-butenoate [(E)-4e]: Colorless needles
(EtOH): mp 206—208.5 °C; 1H-NMR (200 MHz, CDCl3) d: 2.60 (3H, d,
Jϭ1.0 Hz), 3.79 (3H, s), 6.19 (1H, q, Jϭ1.0 Hz), 7.60—7.64 (2H, m),
8.22—8.26 (2H, m); IR (KBr) 3079, 2958, 1743, 1729, 1515, 1345, 1292,
1147, 1010, 853 cmϪ1; EI-MS Calcd for C11H11NO4 MW 221.0688, Found
m/z 221.0701 (Mϩ); Anal. Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33.
Found: C, 59.65; H, 5.10; N, 6.23.
Methyl (Z)-3-( p-Nitrophenyl)-2-butenoate [(Z)-4e]: Colorless needles
(EtOH): mp 117.5—120 °C; 1H-NMR (200 MHz, CDCl3) d: 2.20 (3H, d,
Jϭ1.2 Hz), 3.57 (3H, s), 6.01 (1H, q, Jϭ1.2 Hz), 7.33—7.37 (2H, m),
8.21—8.25 (2H, m); IR (KBr) 2953, 1743, 1728, 1632, 1515, 1345, 1010,
852 cmϪ1; EI-MS Calcd for C11H11NO4 MW 221.0688, Found m/z 221.0707
(Mϩ); Anal. Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C,
59.77; H, 5.09; N, 6.26.
Ethyl (E)-2-Fluoro-3-( p-nitrophenyl)-2-butenoate [(E)-5e]: Colorless
1
plates (EtOH): mp 97—98 °C; H-NMR (400 MHz, CDCl3) d: 1.09 (3H, t,
4
Jϭ7.3 Hz), 2.17 (3H, d, JH,Fϭ4.6 Hz), 4.09 (2H, q, Jϭ7.3 Hz), 7.35—7.37
(2H, m), 8.22—8.24 (2H, m); IR (KBr) 3011, 2966, 1725, 1662, 1515, 1349,
1271, 1156, 1046, 852 cmϪ1; EI-MS Calcd for C12H12NO4F MW 253.0750,
Found m/z 253.0748 (Mϩ); Anal. Calcd for C12H12NO4F: C, 56.92; H, 4.78;
N, 5.53. Found: C, 56.98; H, 4.86; N, 5.52.
Ethyl (Z)-2-Fluoro-3-( p-nitrophenyl)-2-butenoate [(Z)-5e]: Colorless
needles (EtOH): mp 70.5—72 °C; 1H-NMR (400 MHz, CDCl3) d: 1.39 (3H,
t, Jϭ7.3 Hz), 2.46 (3H, d, 4JH,Fϭ3.7 Hz), 4.36 (2H, q, Jϭ7.3 Hz), 7.54—7.56
(2H, m), 8.24—8.26 (2H, m); IR (KBr) 3001, 1719, 1646, 1519, 1352, 1278,
1152, 1052, 855 cmϪ1; EI-MS Calcd for C12H12NO4F MW 253.0750, Found
m/z 253.0737 (Mϩ); Anal. Calcd for C12H12NO4F: C, 56.92; H, 4.78; N,
5.53. Found: C, 56.73; H, 4.77; N, 5.41.
Ethyl (E)-2-Fluoro-3-[ p-(trifluoromethyl)phenyl]-2-butenoate [(E)-5f]:
1
Colorless oil; H-NMR (400 MHz, CDCl3) d: 1.04 (3H, t, Jϭ7.3 Hz), 2.15
4
(3H, d, JH,Fϭ4.1 Hz), 4.06 (2H, q, Jϭ7.3 Hz), 7.29—7.31 (2H, m), 7.60—
7.63 (2H, m); IR (neat) 1730, 1665, 1618, 1446, 1327, 1269, 1166, 1048,
775 cmϪ1; EI-MS Calcd for C13H12O2F4 MW 276.0773, Found m/z 276.0775
(Mϩ); Anal. Calcd for C13H12O2F4: C, 56.53; H, 4.38. Found: C, 56.36; H,
Methyl (E)-3-[ p-(Trifluoromethyl)phenyl]-2-butenoate [(E)-4f]: Color-
1
less oil; H-NMR (200 MHz, CDCl3) d: 2.58 (3H, d, Jϭ0.7 Hz), 3.77 (3H,

May 2002
709
4.44.
2) Sano S., Yokoyama K., Fukushima M., Yagi T., Nagao Y., Chem. Com-
mun., 1997, 559—560 (1997).
3) Sano S., Ando T., Yokoyama K., Nagao Y., Synlett, 1998, 777—779
(1998).
4) Sano S., Yakugaku Zasshi, 120, 432—444 (2000).
5) Sano S., Yokoyama K., Teranishi R., Shiro M., Nagao Y., Tetrahedron
Lett., 43, 281—284 (2002).
Ethyl (Z)-2-Fluoro-3-[p-(trifluoromethyl)phenyl]-2-butenoate [(Z)-5f]:
1
Colorless oil; H-NMR (400 MHz, CDCl3) d: 1.38 (3H, t, Jϭ7.3 Hz), 2.44
4
(3H, d, JH,Fϭ3.7 Hz), 4.35 (2H, q, Jϭ7.3 Hz), 7.48—7.50 (2H, m), 7.64—
7.66 (2H, m); IR (neat) 1727, 1619, 1326, 1307, 1269, 1128, 733 cmϪ1; EI-
MS Calcd for C13H12O2F4 MW 276.0773, Found m/z 276.0770 (Mϩ); Anal.
Calcd for C13H12O2F4: C, 56.53; H, 4.38. Found: C, 56.70; H, 4.49.
An Inseparable Mixture of Ethyl (E)- and (Z)-2-Fluoro-3-[p-(1H-imida-
zol-1-ylmethyl)phenyl]-2-butenoate [(E)- and (Z)-5g]: Pale yellow oil; H-
6) Still W. C., Gennari C., Tetrahedron Lett., 24, 4405—4408 (1983).
7) Iizuka K., Akahane K., Momose D., Nakazawa M., J. Med. Chem., 24,
1139—1148 (1981).
8) Naito J., Komatsu H., Ujiie A., Hamano S., Kubota T., Tsuboshima
M., Eur. J. Pharmacol., 91, 41—48 (1983).
9) Hiraku S., Taniguchi K., Wakitani K., Omawari N., Kira H., Miyamoto
T., Okegawa T., Kawasaki A., Ujiie A., Jpn. J. Pharmacol., 41, 393—
401 (1986).
1
NMR (400 MHz, CDCl3) d: 1.06 (3H, t, Jϭ7.1 Hz, E-isomer), 1.38 (3H, t,
Jϭ7.3 Hz, Z-isomer), 2.12 (3H, d, 4JH,Fϭ4.4 Hz, E-isomer), 2.42 (3H, d,
4JH,Fϭ2.2 Hz, Z-isomer), 4.07 (2H, q, Jϭ7.1 Hz, E-isomer), 4.34 (2H, q,
Jϭ7.3 Hz, Z-isomer), 5.14 (2H, s, E- and Z-isomer), 6.92—7.56 (7H, m, E-
and Z-isomer); EI-MS Calcd for C16H17N2O2 MW 288.1274, Found m/z
288.1287 (Mϩ).
10) Machleidt H., Wessendorf R., Justus Liebigs Ann. Chem., 674, 1—10
(1964).
Acknowledgements This work was partially supported by Grants-in-
Aid for Scientific Research on Priority Areas (A) from the Ministry of Edu- 11) Burton D. J., Yang Z.-Y., Qiu W., Chem. Rev., 96, 1641—1715 (1996)
cation, Culture, Sports, Science, and Technology, Japan and for Scientific and references cited therein.
Research (B) from Japan Society for the Promotion of Science. The finan- 12) Shen Y., Acc. Chem. Res., 31, 584—592 (1998) and references cited
cial assistance of the Yamanouchi Award in Synthetic Organic Chemistry,
Japan and the Takeda Science Foundation are also greatly appreciated.
therein.
13) The crystallographic data of (E)-5e are as follows. (E)-5e:
C12H12NO4F, Mϭ253.23, monoclinic, P21/n, aϭ12.485(4) Å, bϭ
6.989(1) Å, cϭ13.984(4) Å, bϭ103.47(1)°, Vϭ1186.6(5) Å3, Zϭ4,
References and Notes
1) Maryanoff B. E., Reitz A. B., Chem. Rev., 89, 863—927 (1989) and
references cited therein.
D
Calcdϭ1.417 g/cm3.