Synthesis of (Z)-2-[(Z)-3-alkylideneisobenzofuran-1(3H)-ylidene]acetic acid derivatives by sequential coupling-cyclization between 3-(2-iodophenyl)-3- oxopropanoic acid derivatives and terminal alkynes

Article abstract of DOI:10.1055/s-2008-1032120

3-(2-Iodophenyl)-3-oxopropanoic acid derivatives reacted efficiently with various terminal alkynes in the presence of catalytic amounts of dichlorobis(triphenylphosphine)palladium and copper(I) iodide and two molar amounts of triethylamine in N,N-dimethyl

Full text of DOI:10.1055/s-2008-1032120

1094
PAPER
Synthesis of (Z)-2-[(Z)-3-Alkylideneisobenzofuran-1(3H)-ylidene]acetic Acid
Derivatives by Sequential Coupling–Cyclization between 3-(2-Iodophenyl)-3-
oxopropanoic Acid Derivatives and Terminal Alkynes
Synthesis of
(
Z
)
-2-
a
[(
Z
)-3-Alky
z
lideneisob
u
enzofuran-1(
h
3
H
)-ylidene]
i
acetic
A
cidDe
o
r
ivatives Kobayashi,* Kenichi Hashimoto, Shuhei Fukamachi, Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 14 November 2007; revised 4 January 2008
For the preparation of (Z)-2-[(Z)-3-alkylideneisobenzofu-
Abstract: 3-(2-Iodophenyl)-3-oxopropanoic acid derivatives react-
ran-1(3H)-ylidene]acetic acid derivatives 2, commercial-
ed efficiently with various terminal alkynes in the presence of cata-
ly available ethyl 3-(2-iodophenyl)-3-oxopropanoate (1a)
and 3-(2-iodophenyl)-3-oxopropanenitrile (1b), which
lytic amounts of dichlorobis(triphenylphosphine)palladium and
copper(I) iodide and two molar amounts of triethylamine in N,N-
dimethylformamide at room temperature to afford the correspond- was easily prepared from commercially available ethyl 2-
ing (Z)-2-[(Z)-3-alkylideneisobenzofuran-1(3H)-ylidene]acetic
acid derivatives in reasonable yields.
iodobenzoate and acetonitrile, were allowed to react with
terminal alkynes as illustrated in Scheme 1; the results are
summarized in Table 1. We first examined the reaction of
1a with propargyl alcohol under the conditions previously
reported by Kundu et al. for the preparation of benzo-
furans from 2-iodophenol and various terminal alkynes.4
Thus, a solution of 1a and propargyl alcohol in N,N-di-
methylformamide containing catalytic amounts of dichlo-
robis(triphenylphosphine)palladium and copper(I) iodide,
and two molar amounts of triethylamine was stirred for
2.5 hours at room temperature. The product, ethyl
(Z)-2-[(Z)-3-(2-hydroxyethylene)isobenzofuran-1(3H)-ylid-
ene]acetate (2a), was obtained in fair yield after the usual
aqueous workup followed by purification of the crude
product using preparative TLC on silica gel (Table 1, en-
try 1). The isobenzofuran structure of this product was
confirmed on the basis of its 1H NMR spectrum, which ex-
hibits the signal assignable to the vinyl proton adjacent to
the hydroxymethyl group as a triplet (J = 6.4 Hz). This ex-
cludes the possibility of the benzopyran structure; the cou-
pling constant between H4 and the methylene of the
hydroxymethyl group should be much smaller. The ste-
reochemistry of this compound was determined on the basis
of NOE experiments. Thus, an enhancement (9.5%) of the
signal at d = 7.59 assignable to H7 of the isobenzofuran
ring was observed on irradiation of the signal at d = 5.60
assignable to the vinyl proton adjacent to the ethoxycarbo-
nyl group. Irradiation of the signal at d = 5.68 assignable
to the vinyl proton adjacent to the hydroxymethyl group
resulted in an enhancement (6.7%) of the signal at d = 7.61
assignable to H4 of the isobenzofuran ring.
Key words: alkynes, coupling, furans, palladium, ring closure
The transition-metal-catalyzed coupling–cyclization se-
quence between aryl halides carrying an appropriate func-
tional group at the o-position and terminal alkynes has
been successfully employed for the synthesis of a variety
of benzene-fused heterocyclic compounds.1 We found
that ethyl 3-(2-iodophenyl)-3-oxopropanoate (1a) and 3-
(2-iodophenyl)-3-oxopropanenitrile (1b) underwent cou-
pling with terminal alkynes, followed by ring closure, in
the presence of catalytic amounts of palladium and copper
catalysts to afford the corresponding 3-substituted ethyl
(Z)-2-[(Z)-3-alkylideneisobenzofuran-1(3H)-ylidene]ace-
tates and (Z)-2-[(Z)-3-alkylideneisobenzofuran-1(3H)-
ylidene]acetonitriles 2, respectively. 3-Alkylideneisoben-
zofuran-1(3H)-one derivatives have held considerable in-
terest not only for organic chemists, but also for medicinal
chemists, because of their biological activity.2 According-
ly, a number of efficient methods for the preparation of
this class of molecules have recently been reported.3 We
now show the results of our investigation, which provide
access to vinylogous analogues of 3-alkylideneisobenzo-
furan-1(3H)-one derivatives; these compounds may be bi-
ologically interesting, but are not easily available by other
routes.
R
I
(2 equiv)
H
R
O
In order to explore the scope of the present palladium-cat-
alyzed sequence, we next examined the reactions of 1a
with a variety of terminal alkynes. When propargyl alco-
hol derivatives were used as the coupling partner of 1a,
the reactions proceeded more cleanly to afford the corre-
sponding products 2b and 2c in good yields (entries 2 and
3). The corresponding products 2d, 2f, and 2g were ob-
tained in moderate to fair yields by using a propargyl ether
or propargyl amines (entries 4, 6, and 7, respectively). We
may ascribe the lower yield of 2e by using propargyl ben-
PdCl2(PPh3)2 (3.5 mol%)
CuI (13 mol%)
Et3N (2 equiv), DMF, r.t.
COCH2Y
1a Y = CO2Et
1b Y = CN
1c Y = CONMe2
Y
2
Scheme 1
SYNTHESIS 2008, No. 7, pp 1094–1098
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032120; Art ID: F21207SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (Z)-2-[(Z)-3-Alkylideneisobenzofuran-1(3H)-ylidene]acetic Acid Derivatives
1095
Table 1 (Z)-2-[(Z)-3-Alkylideneisobenzofuran-1(3H)-ylidene]acetic Acid Derivatives 2
Entry
Substrates
Time
Product
Yielda (%)
1
R
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
CH2OH
2.5 h
1 d
2a
2b
2c
2d
2e
2f
73
82
75
63
34
59
64
44
48
60
68
47
47
44
52
0b
C(Me)2OH
3
1-hydroxycyclohexyl
40 h
1 h
4
CH2OMe
5
CH2OBz
4.5 h
2 h
6
CH2NMe2
7
CH2NMePh
19 h
3 h
2g
2h
2i
8
CH2SPh
9
[(4,6-dimethylpyrimidin-2-yl)sulfanyl]methyl
19 h
2 d
10
11
12
13
14
15
16
Bu
2j
Ph
2 h
2k
2l
CH2OH
1 d
1-hydroxycyclohexyl
2 d
2m
2n
2o
2p
CH2OMe
18 h
10 h
20 h
Ph
Ph
a Isolated yields.
b An intractable mixture of products was obtained.
zoate to the leaving-group ability of the benzoyloxy group propargyl alcohol, 1-ethynylcyclohexanol, methyl propar-
(entry 5). The reactions using propargyl sulfides were gyl ether, and ethynylbenzene under the above-mentioned
conducted under the same conditions to give the corre- conditions, the corresponding (Z)-2-[(Z)-3-alkylidene-
sponding products 2h and 2i, but in somewhat lower isobenzofuran-1(3H)-ylidene]acetonitriles 2l–o were
yields (entries 8 and 9). Although an aliphatic alkyne, formed in moderate yields (entries 12–15). Unfortunately,
such as hex-1-yne, was sluggish in this coupling–cycliza- however, the reaction of 3-(2-iodophenyl)-N,N-dimethyl-
tion sequence under the same conditions, the reaction af- 3-oxopropanamide (1c) with ethynylbenzene under the
forded a fair yield of the desired product 2j (entry 10). same reaction conditions resulted in the formation of an
Phenylacetylene also worked well in this reaction to give intractable mixture of products, from which no more than
the corresponding products 2k in fair yield (entry 11). The a trace of the desired products 2p was isolated (entry 16);
structure determination of most of these products was we do not have any explanation for this result.
achieved in a manner similar to that described for 2a. Al-
The exclusive formation of the 5-exo cyclization products
though the structure of the products 2b, 2c, and 2k could
3 may be ascribed to the basic conditions in the present re-
not be determined in a similar manner, reasonable chemi-
actions, because Uchiyama et al. have reported that 2-(2-
cal shifts of the signals assigned to the vinyl protons of the
phenylethynyl)benzoic acid underwent 5-exo cyclization
under basic conditions to provide 3-benzylideneisobenzo-
furan-1(3H)-one while it underwent 6-endo cyclization
under acidic conditions to provide 3-phenyl-2-benzopyr-
3-alkylidene groups supported the isobenzofuran struc-
ture.3h,5 The signals for H4 of the corresponding (2-ben-
zopyran-1-ylidene)acetic acid derivatives would appear at
a much lower magnetic field.3h,5 A limitation of the
an-1-one.5
present method was indicated by the reactions of 1a with
In conclusion, we have shown that a palladium-catalyzed
propargyl bromide and methyl acetylenecarboxylate,
coupling–cyclization sequence between 3-(2-iodophe-
which gave only intractable mixtures of products.
nyl)-3-oxopropanoic acid derivatives and terminal
alkynes provides an efficient method for the preparation
In order to evaluate the generality of the present isobenzo-
furan formation, we then examined the palladium-cata-
lyzed reaction of 3-(2-iodophenyl)-3-oxopropanenitrile
(1b). We found that when compound 1b was treated with
of
(Z)-2-[(Z)-3-alkylideneisobenzofuran-1(3H)-ylid-
ene]acetic acid derivatives. Since the method employs
readily available starting materials and is experimentally
Synthesis 2008, No. 7, 1094–1098 © Thieme Stuttgart · New York

1096
K. Kobayashi et al.
PAPER
g, 1.4 mmol) in DMF (2 mL) containing PdCl2(PPh3)2 (18 mg,
0.025 mmol) and CuI (18 mg, 0.092 mmol) was stirred at r.t. for 2.5
h. CH2Cl2 and H2O (10 mL each) were added and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL)
and the combined organic layers were washed with 5% aq NaOH
(3 × 10 mL) and dried (anhyd MgSO4). After evaporation of the sol-
vent, the residue was separated by column chromatography (silica
gel, THF–hexane, 1:10) to give 2a as a white solid; yield: 0.13 g
(73%); mp 99–101 °C (hexane–CH2Cl2).
simple, it may prove useful in organic synthesis. We are
now exploring the applicability of the present procedure
to the synthesis of related heterocycles.
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were de-
termined with a Shimadzu FTIR-8300 spectrophotometer. 1H NMR
spectra were determined in CDCl3 using TMS as an internal refer-
ence with a JEOL ECP500 FT NMR spectrometer operating at 500
MHz. 13C NMR spectra were determined in CDCl3 using TMS as an
internal reference with a JEOL ECP500 FT NMR spectrometer op-
erating at 125 MHz. LR-MS spectra (EI, 70 eV) were measured by
a JEOL JMS-AX505 HA spectrometer. TLC was carried out on a
Merck Kieselgel 60 PF254. Column chromatography was performed
using Merck Kieselgel 60 (0.063–0.200 mm). All of the organic sol-
vents used in this study were dried over appropriate drying agents
and distilled prior to use.
IR (KBr): 3466, 1697, 1684, 1643, 1612 cm–1.
1H NMR: d = 1.35 (t, J = 7.3 Hz, 3 H), 2.24 (t, J = 6.0 Hz, 1 H), 4.26
(q, J = 7.3 Hz, 2 H,), 4.65 (dd, J = 6.4, 6.0 Hz, 2 H), 5.60 (s, 1 H),
5.68 (t, J = 6.4 Hz, 1 H), 7.45 (dd, J = 7.8, 7.3 Hz, 1 H), 7.52 (dd,
J = 7.8, 7.3 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz,
1 H).
13C NMR: d = 14.36, 57.27, 60.03, 88.31, 103.03, 120.23, 121.12,
129.71, 131.55, 132.71, 133.93, 152.46, 161.61, 165.56.
MS: m/z (%) = 246 (33) [M+], 217 (100).
N-Methyl-N-(prop-2-ynyl)aniline was prepared by the reported pro-
cedure.6 All other chemicals used in this study were commercially
available.
Anal. Calcd for C14H14O4: C, 68.28; H, 5.73. Found: C, 67.96; H,
5.69.
3-(2-Iodophenyl)-3-oxopropanenitrile (1b)
Ethyl (Z)-2-[(Z)-3-(2-Hydroxy-2-methylpropylidene)isobenzo-
furan-1(3H)-ylidene]acetate (2b)
White solid; mp 61–64 °C (hexane–Et2O).
IR (KBr): 3408, 1693, 1681, 1643 cm–1.
This compound was obtained by treating ethyl 2-iodobenzoate with
an equimolar molar amount of 2-lithioacetonitrile (generated by the
action of BuLi upon MeCN in THF at –78 °C) for 15 min as a white
solid; yield: 57%; mp 86–88 °C (hexane–CH2Cl2).
1H NMR: d = 1.36 (t, J = 7.3 Hz, 3 H), 1.60 (s, 6 H,), 3.55 (s, 1 H),
4.28 (q, J = 7.3 Hz, 2 H), 5.60 (s, 1 H), 5.66 (s, 1 H), 7.45 (ddd,
J = 7.8, 7.3, 1.4 Hz, 1 H), 7.52 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.55
(d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H).
IR (KBr): 2260, 1690 cm–1.
1H NMR: d = 4.06 (s, 2 H), 7.23 (ddd, J = 8.2, 7.3, 2.3 Hz, 1 H),
7.44–7.55 (m, 2 H), 8.00 (dd, J = 8.2, 0.9 Hz, 1 H).
Anal. Calcd for C9H6INO: C, 39.88; H, 2.23; N, 5.17. Found: C,
39.76; H, 2.34; N, 5.15.
MS: m/z (%) = 274 (15) [M+], 259 (46), 213 (100).
Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 69.70; H,
6.82.
3-(2-Iodophenyl)-N,N-dimethyl-3-oxopropanamide (1c)
This compound was obtained by treating ethyl 2-iodobenzoate with
N,N-dimethylacetamide in the presence of NaH in THF at reflux
temperature for 2.5 h as a yellow oil as a tautomeric mixture with
the corresponding enol amide (ca. 3:7); yield: 47%; Rf = 0.30 (THF–
hexane, 1:3).
Ethyl (Z)-2-{(Z)-3-[(1-Hydroxycyclohexyl)methylene]isobenzo-
furan-1(3H)-ylidene}acetate (2c)
White solid; mp 100–101 °C (hexane–Et2O).
IR (KBr): 3396, 3350, 1715, 1692, 1670, 1643 cm–1.
1H NMR: d = 1.21–1.98 (m, 13 H), 3.61 (s, 1 H), 4.28 (q, J = 7.3 Hz,
2 H), 5.59 (s, 1 H), 5.65 (s, 1 H), 7.45 (ddd, J = 7.8, 7.3, 0.9 Hz, 1
H), 7.52 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H),
7.61 (d, J = 7.8 Hz, 1 H).
IR (neat): 3200–2600, 1705, 1628, 1605 cm–1.
1H NMR: d = 3.00 (s, 1.8 H), 3.06 (s, 4.2 H), 4.10 (s, 0.6 H), 5.51
(s, 0.7 H), 7.07 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.7 H), 7.15 (ddd, J = 7.8,
7.3, 1.4 Hz, 0.3 H), 7.38 (ddd, J = 7.8, 7.3, 1.4 Hz, 0.7 H), 7.43–7.51
(m, 1 H), 7.64 (dd, J = 7.8, 1.4 Hz, 0.3 H), 7.91 (dd, J = 7.8, 1.4 Hz,
0.7 H), 7.94 (dd, J = 7.8, 1.4 Hz, 0.3 H), 8.2–8.9 (br, 0.7 H).
MS: m/z (%) = 314 (42) [M+], 267 (81), 225 (100).
Anal. Calcd for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.40; H,
7.10.
Anal. Calcd for C11H12INO2: C, 41.66; H, 3.81; N, 4.42. Found: C,
41.54; H, 3.82; N, 4.39.
Ethyl (Z)-2-[(Z)-3-(2-Methoxyethylidene)isobenzofuran-1(3H)-
ylidene]acetate (2d)
White solid; mp 42–45 °C (hexane–Et2O).
IR (KBr): 1705, 1688, 1639 cm–1.
1H NMR: d = 1.37 (t, J = 7.3 Hz, 3 H), 3.44 (s, 3 H), 4.27 (q, J = 7.3
Hz, 2 H), 4.47 (d, J = 7.3 Hz, 2 H), 5.59 (t, J = 7.3 Hz, 1 H), 5.61 (s,
1 H), 7.46 (dd, J = 7.8, 7.3 Hz, 1 H), 7.53 (ddd, J = 7.8, 7.3, 1.4 Hz,
1 H), 7.61 (d, J = 7.8 Hz, 2 H).
4,6-Dimethyl-2-(prop-2-ynylsulfanyl)pyrimidine
Treatment of 4,6-dimethylpyrimidine-2-thiol with an equimolar
amount of propargyl bromide in the presence of an equimolar
amount of Et3N in THF at r.t. for 2 h gave the title compound as a
white solid; yield: 71%; mp 29–31 °C (hexane–Et2O).
IR (KBr): 3211, 2114 cm–1.
1H NMR: d = 2.17 (t, J = 2.7 Hz, 1 H), 2.41 (s, 6 H), 3.96 (d, J = 2.7
Hz, 2 H), 6.72 (s, 1 H).
MS: m/z (%) = 260 (7.2) [M+], 229 (16), 173 (100).
Anal. Calcd for C9H10N2S: C, 60.64; H, 5.65; N, 15.72. Found: C,
60.53; H, 5.40; N, 15.63.
Anal. Calcd for C15H16O4: C, 69.22; H, 6.20. Found: C, 69.14; H,
6.16.
Ethyl (Z)-2-[(Z)-3-(2-Hydroxyethylidene)isobenzofuran-1(3H)-
ylidene]acetate (2a); Typical Procedure
A mixture of ethyl 3-(2-iodophenyl)-3-oxopropanoate (1a, 0.23 g,
Ethyl (Z)-2-[(Z)-3-(2-Benzoyloxyethylidene)isobenzofuran-
1(3H)-ylidene]acetate (2e)
Pale-yellow solid; mp 95–98 °C (hexane–Et2O).
0.71 mmol), propargyl alcohol (78 mg, 1.4 mmol), and Et3N (0.14
Synthesis 2008, No. 7, 1094–1098 © Thieme Stuttgart · New York

PAPER
Synthesis of (Z)-2-[(Z)-3-Alkylideneisobenzofuran-1(3H)-ylidene]acetic Acid Derivatives
1097
IR (KBr): 1701, 1687, 1636 cm–1.
13C NMR: d = 14.43, 23.85, 26.69, 59.93, 88.13, 100.88, 115.66,
120.15, 121.13, 129.43, 131.36, 133.00, 134.11, 152.63, 161.73,
165.58, 167.06, 170.74.
1H NMR: d = 1.38 (t, J = 7.3 Hz, 3 H), 4.28 (q, J = 7.3 Hz, 2 H),
5.34 (d, J = 7.3 Hz, 2 H), 5.64 (s, 1 H), 5.75 (t, J = 7.3 Hz, 1 H), 7.44
(t, J = 7.8 Hz, 2 H), 7.48 (t, J = 7.8 Hz, 1 H), 7.53–7.58 (m, 2 H),
7.63 (d, J = 7.8 Hz, 2 H), 8.09 (d, J = 7.3 Hz, 2 H).
13C NMR: d = 14.42, 59.37, 60.10, 89.14, 97.69, 120.55, 121.19,
128.34, 129.70, 130.14, 130.17, 131.57, 132.96, 133.33, 133.63,
154.20, 161.26, 165.36, 166.57.
MS: m/z (%) = 368 (48) [M+], 229 (100).
Anal. Calcd for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60. Found: C,
64.87; H, 5.72; N, 7.47.
Ethyl (Z)-2-[(Z)-3-Pentylideneisobenzofuran-1(3H)-ylidene]ac-
etate (2j)
Pale-yellow viscous oil; Rf = 0.23 (THF–hexane, 1:20).
IR (neat): 1713, 1686, 1645 cm–1.
MS: m/z (%) = 350 (28) [M+], 245 (76), 199 (100).
Anal. Calcd for C21H18O5: C, 71.99; H, 5.18. Found: C, 72.00; H,
5.06.
1H NMR: d = 0.95 (t, J = 7.3 Hz, 3 H), 1.36 (t, J = 7.3 Hz, 3 H), 1.43
(sextet, J = 7.3 Hz, 2 H), 1.53 (quint, J = 7.3 Hz, 2 H), 2.55 (dt,
J = 7.8, 7.3 Hz, 2 H), 4.25 (q, J = 7.3 Hz, 2 H), 5.47 (t, J = 7.8 Hz,
1 H), 5.55 (s, 1 H), 7.39 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.49 (ddd,
J = 7.8, 7.3, 0.9 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.8
Hz, 1 H).
Ethyl (Z)-2-{(Z)-3-[2-(Dimethylamino)ethylidene]isobenzofu-
ran-1(3H)-ylidene}acetate (2f)
Yellow oil; Rf = 0.10 (THF–acetone, 1:1).
IR (neat): 1705, 1690, 1647 cm–1.
1H NMR: d = 1.37 (t, J = 7.3 Hz, 3 H), 2.35 (s, 6 H), 3.46 (d, J = 6.9
Hz, 2 H), 4.27 (q, J = 7.3 Hz, 2 H), 5.56 (t, J = 6.9 Hz, 1 H), 5.58 (s,
1 H), 7.44 (dd, J = 8.2, 7.3 Hz, 1 H), 7.52 (ddd, J = 8.2, 7.3, 0.9 Hz,
1 H), 7.60 (d, J = 8.2 Hz, 2 H).
MS: m/z (%) = 272 (100) [M+].
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 74.72; H,
7.52.
MS: m/z (%) = 273 (12) [M+], 230 (100).
Ethyl (Z)-2-[(Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene]ac-
etate (2k)
Pale-yellow solid; mp 94–95 °C (hexane–Et2O).
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.16; H, 6.96; N, 5.04.
IR (KBr): 1678, 1639 cm–1.
Ethyl (Z)-2-[(Z)-3-{2-[Methyl(phenyl)amino]ethylidene}isoben-
zofuran-1(3H)-ylidene]acetate (2g)
Pale-yellow solid; mp 95–98 °C (hexane–Et2O).
IR (KBr): 1711, 1688, 1645 cm–1.
1H NMR: d = 1.38 (t, J = 7.3 Hz, 3 H), 3.03 (s, 3 H), 4.29 (q, J = 7.3
Hz, 2 H), 4.47 (d, J = 6.9 Hz, 2 H), 5.54 (t, J = 6.9 Hz, 1 H), 5.61 (s,
1 H), 6.74 (t, J = 7.3 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 2 H), 7.25 (dd,
J = 8.2, 7.3 Hz, 2 H), 7.43 (ddd, J = 7.8, 6.9, 0.9 Hz, 1 H), 7.49 (dd,
J = 7.8, 6.9 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz,
1 H).
1H NMR: d = 1.45 (t, J = 7.3 Hz, 3 H), 4.36 (q, J = 7.3 Hz, 2 H), 5.69
(s, 1 H), 6.33 (s, 1 H), 7.29 (t, J = 7.3 Hz, 1 H), 7.43–7.47 (m, 3 H),
7.56 (dd, J = 7.8, 7.3 Hz, 1 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.71 (d,
J = 7.8 Hz, 1 H), 8.02 (d, J = 7.3 Hz, 2 H).
MS: m/z (%) = 292 (92) [M+], 220 (100).
Anal. Calcd for C19H16O3: C, 78.06; H, 5.52. Found: C, 77.89; H,
5.54.
(Z)-2-[(Z)-3-(2-Hydroxyethylidene)isobenzofuran-1(3H)-
ylidene]acetonitrile (2l)
Pale-yellow solid; mp 148–149 °C (hexane–CH2Cl2).
IR (KBr): 3450, 3384, 2208, 1641 cm–1.
1H NMR: d = 1.69 (s, 1 H), 4.65 (d, J = 6.9 Hz, 2 H), 5.00 (s, 1 H),
5.72 (t, J = 6.9 Hz, 1 H), 7.49 (dd, J = 7.8, 7.3 Hz, 1 H), 7.58 (dd,
J = 7.8, 7.3 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 7.8 Hz,
1 H).
MS: m/z (%) = 335 (22) [M+], 229 (100).
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
74.84; H, 6.34; N, 4.06.
Ethyl (Z)-2-{(Z)-3-[3-(Phenylsulfanyl)ethylidene]isobenzofu-
ran-1(3H)-ylidene}acetate (2h)
Yellow viscous oil; Rf = 0.33 (THF–hexane, 1:10).
IR (neat): 1709, 1688, 1651 cm–1.
MS: m/z (%) = 199 (32) [M+], 170 (100).
1H NMR: d = 1.37 (t, J = 7.3 Hz, 3 H), 4.08 (d, J = 8.2 Hz, 2 H),
4.29 (q, J = 7.3 Hz, 2 H), 5.52 (t, J = 8.2 Hz, 1 H), 5.58 (s, 1 H), 7.13
(tt, J = 7.3, 1.4 Hz, 1 H), 7.23 (dd, J = 8.2, 7.3 Hz, 2 H), 7.40–7.46
(m, 3 H), 7.48 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.53 (d, J = 7.8 Hz,
1 H), 7.57 (d, J = 7.8 Hz, 1 H).
Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.34; H, 4.51; N, 6.91.
(Z)-2-{(Z)-3-[(1-Hydroxycyclohexyl)methylene]isobenzofuran-
1(3H)-ylidene}acetonitrile (2m)
Pale-yellow solid; mp 88–92 °C (hexane–Et2O).
IR (KBr): 3420, 2210, 1641, 1614 cm–1.
1H NMR: d = 1.39–1.98 (m, 10 H), 2.48 (s, 1 H), 4.99 (s, 1 H), 5.66
(s, 1 H), 7.47 (ddd, J = 7.8, 6.9, 1.8 Hz, 1 H), 7.55–7.60 (m, 3 H).
MS: m/z (%) = 338 (4.5) [M+], 229 (100).
Anal. Calcd for C20H18O3S: C, 70.98; H, 5.36. Found: C, 70.71; H,
5.50.
Ethyl (Z)-2-[(Z)-3-{2-[(4,6-Dimethylpyrimidin-2-yl)sulfa-
nyl]ethylidene}isobenzofuran-1(3H)-ylidene]acetate (2i)
White solid; mp 86–87 °C (hexane–Et2O).
IR (KBr): 1713, 1686, 1655 cm–1.
MS: m/z (%) = 267 (61) [M+], 224 (100).
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.39; H, 6.68; N, 5.19.
1H NMR: d = 1.36 (t, J = 7.3 Hz, 3 H), 2.41 (s, 6 H), 4.27 (q, J = 7.3
Hz, 2 H), 4.30 (d, J = 7.8 Hz, 2 H), 5.60 (s, 1 H), 5.73 (t, J = 7.8 Hz,
1 H), 6.70 (s, 1 H), 7.42 (dd, J = 7.8, 7.3 Hz, 1 H), 7.49 (dd, J = 7.8,
7.3 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H).
(Z)-2-[(Z)-3-(2-Methoxyethylidene)isobenzofuran-1(3H)-
ylidene]acetonitrile (2n)
Pale-yellow solid; mp 77–79 °C (hexane–CH2Cl2).
IR (KBr): 2210, 1645 cm–1.
Synthesis 2008, No. 7, 1094–1098 © Thieme Stuttgart · New York

1098
K. Kobayashi et al.
PAPER
1H NMR: d = 3.44 (s, 3 H), 4.42 (d, J = 7.3 Hz, 2 H), 4.99 (s, 1 H),
5.64 (t, J = 7.3 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8
Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H).
References
(1) (a) Kobayashi, K.; Uneda, T.; Kawakita, M.; Morikawa, O.;
Konishi, H. Tetrahedron Lett. 1997, 38, 837. (b) Chaplin, J.
H.; Flynn, B. L. Chem. Commun. 2001, 1594. (c) Kabalka,
G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017.
(d) Bossharth, E.; Desbordes, P.; Monteiro, M.; Balme, G.
Org. Lett. 2003, 5, 2441. (e) Sakai, N.; Annaka, K.;
Konakahara, T. Org. Lett. 2004, 6, 1527.
(2) (a) Zamilpa, A.; Herrera-Ruiz, M.; del Olmo, E.; López-
Pérez, J. L.; Tortoriello, J.; San Feliciano, A. Bioorg. Med.
Chem. Lett. 2005, 15, 3483. (b) Bedoya, L. M.; del Olmo,
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(3) (a) Lee, K. Y.; Kim, J. M.; Kim, J. N. Synlett 2003, 357.
(b) Kapoor, M.; Dhawan, S. N.; Mor, S.; Bhatia, S. C.;
Gupta, S. C.; Hundal, M. S. Tetrahedron 2003, 59, 5027.
(c) Albrecht, U.; Nguyen, V. T. H.; Langer, P. Synthesis
2006, 1111. (d) Mor, S.; Dhawan, S. N.; Kapoor, M.;
Kumar, D. Tetrahedron 2007, 63, 594. (e) Coelho, F.;
Veronese, D.; Pavam, C. H.; de Paula, V. I.; Buffon, R.
Tetrahedron 2006, 62, 4563. (f) Duchene, A.; Thibonnet, J.;
Parrain, J. L.; Anselmi, E.; Abarbri, M. Synthesis 2007, 597.
(g) Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48,
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pertinent references cited in these papers.
MS: m/z (%) = 213 (58) [M+], 182 (100).
Anal. Calcd for C13H11NO2: C, 73.23; H, 5.20; N, 6.57. Found: C,
73.18; H, 5.10; N, 6.48.
(Z)-2-[(Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene]aceto-
nitrile (2o)
Pale-yellow solid; mp 97–99 °C (hexane–Et2O).
IR (KBr): 2205, 1637, 1614 cm–1.
1H NMR: d = 5.07 (s, 1 H), 6.36 (s, 1 H), 7.31 (t, J = 7.3 Hz, 1 H),
7.45 (t, J = 7.3 Hz, 2 H), 7.49 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.61
(ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.72 (d,
J = 7.8 Hz, 1 H), 7.88 (d, J = 7.3 Hz, 2 H).
13C NMR: d = 66.05, 104.77, 116.01, 120.10, 121.20, 128.02,
128.88, 129.59 (two overlapped C’s), 129.79, 132.27, 133.31,
135.89, 149.68, 167.01.
MS: m/z (%) = 245 (100) [M+].
Anal. Calcd for C17H11NO: C, 83.25; H, 4.52; N, 5.71. Found: C,
83.09; H, 4.54; N, 5.69.
Acknowledgment
We are grateful to Mrs. Miyuki Tanmatsu of this Faculty for deter-
mining mass spectra and performing combustion analyses.
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Synthesis 2008, No. 7, 1094–1098 © Thieme Stuttgart · New York