E/Z-selective synthesis of alkylidene-3-oxo-3 H-isobenzofurans by reaction of silyl enol ethers with phthaloyl dichloride

Article abstract of DOI:10.1055/s-0030-1260071

The reaction of silyl enol ethers with phthaloyl dichloride afforded alkylidene-3-oxo-3H-isobenzofurans with very good E/Z-selectivity. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260071

PAPER
2281
E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans by Reaction of
Silyl Enol Ethers with Phthaloyl Dichloride
E
/
Z
-Selective
S
a
ynthesis of
t
A
lkyl
e
idene-3-oxo
n
-
3
H
-isobenz
i
ofuran
k
s
Mkrtchyan,a Zorik Chilingaryan,a,b Gagik Ghazaryan,a,b Rüdiger Dede,a Nasir Rasool,a,c
Muhammad A. Rashid,a Alexander Villinger,a Helmar Görls,d Gnuni Karapetyan,a Tariel V. Ghochikyan,b
Ashot Saghiyan,b,e Peter Langer*a,f
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
Government College University, Faisalabad, Punjab, Pakistan
Institut für Anorganische und Analytische Chemie, Universität Jena, August-Bebel-Str. 2, 07740 Jena, Germany
CJSC Scientific Research Institute of Biotechnology, Gyurjyan Str. 14, 0056, Yerevan, Armenia
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
c
d
e
f
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Received 22 March 2011; revised 6 May 2011
knowledge, the first reactions of 3-silyloxy-2-en-1-ones
Abstract: The reaction of silyl enol ethers with phthaloyl dichlo-
with phthaloyl dichloride. These reactions provide a con-
venient approach to alkylidene-3-oxo-3H-isobenzo-
furans.
ride afforded alkylidene-3-oxo-3H-isobenzofurans with very good
E/Z-selectivity.
Key Words: cyclizations, O-heterocycles, phthalic acid deriva-
tives, silyl enol ethers
OH
OH
g-Alkylidenebutenolides are present in a number of natu-
ral products.1 They are synthetically available by lacton-
ization of 2-en-4-ynoic acids2 or by stereospecific b-
eliminations3 and other methods. Highly unsaturated de-
rivatives, such as the natural products lissoclinolide or di-
hydroxerulin, have been prepared by Wittig reaction of g-
(3-phosphaprop-2-enylidene)butenolides with aldehydes
or by the reaction of g-(3-oxaprop-2-enylidene)buteno-
lides with phosphoranes.4 Simple g-alkylidenebutenolides
can be synthesized by Wittig reaction of maleic anhy-
drides with stabilized phosphorus ylides.5 Recently, we
have reported the preparation of g-(2,4-dioxobut-1-
ylidene)butenolides by Wittig reaction of (2,4-dioxobu-
tylidene)triphenylphosphanes.6 Some years ago, we have
developed an alternative approach to g-alkylidenebuteno-
lides based on the cyclization of 1,3-bis(silyl enol ethers)7
with oxalyl chloride.8
OH
O
O
O
OH
O
senkynolide E
thunberginol F
O
O
O
O
Me
H
O
N
OMe
OMe
N
Me
O
H
O
MeO
MeO
O
dactylicapnosine
Figure 1 Structure of naturally occurring 3-alkylidene-3H-isoben-
zofuran-1-ones
3-Alkylidene-3H-isobenzofuran-1-ones can be regarded
as benzoannulated g-alkylidenebutenolides. Naturally oc-
curring derivatives include (racemic) senkyunolide E,9
thunberginol F,10 and dactylicapnosine (Figure 1).11 3-
Alkylidene-3H-isobenzofuran-1-ones have been prepared
mainly by condensation of 1,3-dicarbonyl compounds
with phthaloyl dichloride,12 Wittig reactions of phthalic
anhydride,13 and palladium-catalyzed cyclizations.14 Re-
The reaction of phthaloyl dichloride (1) with 1,3-bis(silyl-
oxy)buta-1,3-diene 2, derived from ethyl acetoacetate, has
been reported6 to result in the formation of ethyl (Z)-3-
oxo-4-[1-oxoisobenzofuran-3(1H)-ylidene]butanoate (3)
(Scheme 1). The best yields were obtained when the reac-
tion was carried out in the absence of any Lewis acid.
cently, we have reported the synthesis of 3-(2,4-dioxobut- The reaction of 1 with 3-silyloxy-2-en-1-one 4a, available
1-ylidene)-3H-isobenzofuran-1-ones based on the reac- from methyl acetoacetate in one step, resulted under iden-
tion of 1,3-bis(silyloxy)buta-1,3-dienes with phthaloyl tical conditions in the formation of a complex mixture.
dichloride.6 Herein, we report what are, to the best of our The use of Me3SiOTf (0.3 equiv) also gave unsatisfactory
results. After some experimentation, the desired product,
3-alkylidene-3H-isobenzofuran-1-one 5a, was formed in
up to 48% yield when 1.0 equivalent of TiCl4 was em-
ployed and when the reaction was carried out in the pres-
SYNTHESIS 2011, No. 14, pp 2281–2290
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260071; Art ID: N32011SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2282
S. Mkrtchyan et al.
PAPER
Me3SiO
OSiMe3
alkylidene-3H-isobenzofuran-1-one 5a can be explained
by TiCl4-mediated formation of pseudophthaloyl chloride
A,15 TiCl4-mediated formation of cation B, attack of 4a
onto the latter (intermediate C), and subsequent extrusion
of HCl.
OEt
O
2
i
+
O
ref. 6
O
OEt
The reaction of 3-silyloxy-2-en-1-ones 4a–i afforded 3-
alkylidene-3H-isobenzofuran-1-ones 5a–i in moderate
yields (Scheme 3, Table 1). In all reactions, the double
bond was formed with good to excellent E-selectivity (in
the case of 5k, there is no issue of E/Z-selectivity as sub-
stituents R1 and R2 are the same). Intermediate A could be
successfully used instead of 1 in the reaction with 4a (sim-
Cl
Cl
O
O
3 36%
O
1
Scheme 1 Synthesis of 3. Reagents and conditions: (i) CH2Cl2, –78
→ 20 °C, 6 h, 20 °C, 8 h.
Table 1 3-Alkylidene-3H-isobenzofuran-1-ones 5a–w
Me3SiO
O
4,5
a
b
c
R1
R2
E/Za
98:2
98:2
91:9
91:9
91:9
83:17
98:2
91:1
98:2
–
Yield (%)b
48
O
OMe
4a
i
OMe
OEt
Me
+
O
O
Me
68
Cl
Cl
MeO
O-i-Pr
O-i-Bu
OAllyl
O(CH2)2OMe
OMe
OEt
Me
45
O
O
5a
d
e
Me
48
O
1
Me
59
TiCl4
O
O
f
Me
37
g
h
i
n-Pr
46
O
Cl
n-Pr
41
O
MeO
25c
0d
O
OMe
O-t-Bu
Me
t-Bu
Cl Cl
O
A
C
j
Me
e
56f
56
+ 4a
– Me3SiCl
k
l
Me
–
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Et
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
O
m
n
o
p
q
r
i-Pr
49
+
–
Cl
TiCl5
n-Bu
63
B
n-C5H11
n-C7H15
n-C9H19
CH2Allyl
(CH2)4Cl
(CH2)5Cl
(CH2)2Ph
(CH2)3Ph
(CH2)4Ph
49
Scheme 2 Possible mechanism of the formation of 5a. Reagents
and conditions: (i) CH2Cl2, MS 4 Å, TiCl4, –78 → 20 °C, 16–33 h.
67
45
O
OSiMe3
R2
55
R1
O
4a–w
s
56
i
+
O
t
51
O
R2
R1
u
v
w
48
Cl
Cl
O
O
55
5a–w
O
49
1
a Isomeric ratio (by 1H NMR).
b Yields of isolated products.
Scheme 3 Synthesis of 3-alkylidene-3H-isobenzofuran-1-ones 5a–
w. Reagents and conditions: (i) CH2Cl2, MS 4 Å, TiCl4, –78 → 20 °C,
16–33 h.
c Besides, 6a was isolated in 17% yield (E/Z = 1:10, structure, see be-
low).
d Product 6b was isolated in 8% yield.
e No issue of E/Z selectivity in this example.
f From 1,3-bis(silyloxy)penta-2,4-diene in the absence of Lewis acid
(see ref. 6).
ence of molecular sieves (4 Å) (Scheme 2). The need for
a Lewis acid can be explained by the significantly lower
nucleophilicity of 4a compared to 2. The formation of 3-
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

PAPER
E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans
2283
ilar yield and selectivity). Experiments directed towards structure of 5f was independently confirmed by an X-ray
equilibration of isomerically pure product 5a under the re- crystal structure analysis (Figure 4).16
action conditions failed (no change). This result suggests
O
that the E/Z-selectivity might be explained by kinetic rea-
sons (driven by the stability of the transition state of the
elimination). A possible explanation is based on the fact
O
O
O
O
O
that the ester is able to alleviate allylic strain, whereas the
ketone is not. The E/Z-selectivity decreases with increas-
ing size of the ester group, presumably due to steric rea-
sons.
O
O
O
O
O
O
O
O
O
5a
5b
5c
The best yield (68%) was obtained for product 5b derived
from ethyl acetoacetate. The low yield of 5i, derived from
methyl 4,4-dimethyl-3-oxopentanoate, can be explained
by fragmentation of the product by cleavage of the tert-
butyl group to give by-product 6a (17%) (Figure 2). It is
worth noting that the configuration of the double bond of
6a is opposite to the one present in 5i. The reaction of 1
with silyl enol ether 4j, derived from tert-butyl acetoace-
tate, resulted in the formation of a complex mixture from
which product 6b (Figure 2) could be isolated, albeit, in
only 8% yield. The expected product 5j was not formed.
The formation of 6b can be explained by TiCl4-mediated
cleavage of the tert-butyl ester and subsequent decarbox-
ylation. Product 5k was formed in good yield, as noted
earlier,6 by the reaction of 1 with 1,3-bis(trimethylsilyl-
oxy)penta-2,4-diene in the absence of Lewis acid. The
yield decreased when 4-(trimethylsilyloxy)pent-3-en-2-
one (4k) was employed (in the presence or absence of
TiCl4).
O
O
O
O
O
O
O
O
O
O
O
O
O
O
MeO
O
5d
5e
5f
O
O
O
O
O
O
MeO
O
O
O
O
O
O
O
O
5g
5h
5i
Figure 3 NOE correlations of 5a–i
O
O
O
O
OMe
NOE
O
O
6a
6b
Figure 2 Structures of by-products 6a,b
The configuration of the double bond of the products was
established based on NOESY experiments (Figure 3). In
5a, the aromatic hydrogen atom at d = 8.14–8.19 ppm cor-
relates with the methoxy group at 3.94 ppm. In 5b the aro-
matic hydrogen atom at d = 8.15 ppm correlates with a
triplet at 1.36 ppm and a quartet at 4.40 ppm both assigned
to the ethoxy group. In 5c, the aromatic hydrogen atom at
d = 8.15 ppm correlates with a doublet at 1.34 ppm and a
septet at 5.27 ppm both assigned to the isopropyloxy
group. In 5d the aromatic hydrogen atom at d = 8.16 ppm
correlates with a doublet at 4.08 ppm assigned to the
methylene group in the isobutyloxy moiety. In 5e, the ar-
omatic hydrogen atom at d = 8.14–8.18 ppm correlates
with a doublet of triplets at 4.83 ppm assigned to the oxy-
gen-connected methylene group in the allyloxy moiety. In
5f the aromatic hydrogen atom at d = 8.14–8.19 ppm cor-
relates with a multiplet at 4.51 ppm assigned to the meth-
ylene group directly connected to the CO2 moiety. The
Figure 4 ORTEP plot of 5f. The thermal ellipsoids represent 50%
probability.
In 5g, the aromatic hydrogen atom at d = 8.27 ppm corre-
lates with the methoxy group at 3.87 ppm. In 5h, the aro-
matic hydrogen atom at d = 8.30 ppm correlates with a
quartet at 4.35 ppm belonging to the methylene group in
the ethoxy moiety. For 5i no clear NOESY correlations
were found. However, the configuration could be deter-
mined by a crystal structure analysis (Figure 5).16 The
structure of 6a was also unambigiously confirmed by X-
ray crystal structure analysis (Figure 6).16
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

2284
S. Mkrtchyan et al.
PAPER
Figure 7 ORTEP plot of 7a
Figure 5 ORTEP plot of 5i. The thermal ellipsoids represent 50%
probability.
The reaction of 1 with silyl enol ether 8 (derived from eth-
yl acetate) in the absence of Lewis-acid afforded products
(Z)-9 and (E)-9, albeit, in low yield (Scheme 5). The use
of TiCl4 or Me3SiOTf led to the formation of a complex
mixture. The configuration of (E)-9a was elucidated by
NOESY experiments. The reaction of 1 with 2-(trimethyl-
silyloxy)prop-2-ene (prepared from acetone) afforded
product 6b (vide supra) again in low yield.
O
O
OEt
OSiMe3
NOE
OEt
O
8
(Z)-9 12%
i
Figure 6 ORTEP plot of 6a. The thermal ellipsoids represent 50%
+
probability.
O
O
Cl
Cl
O
The TiCl4-mediated reaction of 1 with 1-arylsulfonyl-2-
silyloxyprop-1-enes, available from the corresponding b-
ketosulfones in one step, afforded the 3-alkylidene-3H-
isobenzofuran-1-ones 7a and 7b, respectively
(Scheme 4). The structure of 7a was independently con-
firmed by crystal structure analysis (Figure 7).16 The rela-
tively low yields can be explained by the low
nucleophilicity of the sulfonyl-substituted silyl enol
ethers (due to the strong electron-withdrawing effect of
the sulfonyl groups). The products are formed with very
good E-selectivity.
EtO
O
1
O
(E)-9 4%
Scheme 5 Synthesis of 9. Reagents and conditions: (i) CH2Cl2, –78
→ 20 °C.
In conclusion, we have reported the synthesis of alky-
lidene-3-oxo-3H-isobenzofurans by reaction of silyl enol
ethers with phthaloyl dichloride. Acceptable yields are
obtained for products derived from 1,3-dicarbonyl com-
pounds. In contrast, poor yields were obtained for prod-
ucts derived from simple silyl enol ethers, such as 1-
ethoxy-1-(trimethylsilyloxy)ethane.
OSiMe3
O
ArO2S
i
O
+
O
Cl
Cl
ArO2S
All solvents were dried by standard methods and all reactions were
carried out under an inert atmosphere. For 1H and 13C NMR spectra,
the deuterated solvents indicated were used. Mass spectrometric
data were obtained by electron ionization (EI, 70 eV), chemical ion-
ization (CI, isobutane), or electrospray ionization (ESI). For prepar-
ative-scale chromatography silica gel 60 (0.063–0.200 mm, 70–
230 mesh) was used.
O
7a Ar = Ph 28%
7b Ar = 4-Tol 25%
O
1
Scheme 4 Synthesis of 7a,b. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 → 20 °C.
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

PAPER
E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans
2285
Alkylideneisobenzofuranes 5; General Procedure
Isopropyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)bu-
tyrate (5c)
To a CH2Cl2 solution of phthaloyl dichloride (1) was added TiCl4 at
–78 °C in the presence of molecular sieves (4Å). The appropriate si-
lyl enol ether 4, 6a,b, 8 was subsequently added and the reaction
mixture was allowed to warm to 20 °C during 16–23 h. To the solu-
tion was added CH2Cl2 (50 mL), the molecular sieves were removed
by filtration, and to the filtrate was added sat. aq NaHCO3 (50 mL).
The aqueous layer was repeatedly extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were washed with H2O (50 mL),
dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo
and the residue was purified by column chromatography (silica gel).
Starting from 1 (399 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4c (435 mg,
2.0 mmol), 5c was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 4:1) as a colorless solid (244 mg, 45%, E/Z =
10:1); mp 79–80 °C; Rf = 0.26 (n-heptane–EtOAc, 3:1). Reaction
time: 20 h.
IR (KBr): 2991 (m), 2974 (m), 1816 (s), 1726 (s), 1665 (s), 1635 (s),
1475 (m), 1372 (s), 1309 (s), 1287 (s), 1248 (s), 1052 (s), 998 cm–1
(s).
1H NMR (250 MHz, CDCl3): d = 1.34 [d, 3J = 6.3 Hz, 6 H,
Methyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)bu-
tyrate (5a)
Starting from 1 (385 mg, 1.9 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.21 mL, 1.9 mmol), and 4a (392 mg,
2.1 mmol), 5a was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 3:1) as a colorless solid (223 mg, 48%); mp
119–121 °C; Rf = 0.20 (n-heptane–EtOAc, 3:1); reaction time: 20 h.
3
CH(CH3)2], 2.61 (s, 3 H, COCH3), 5.27 (sept, J = 6.3 Hz, 1 H,
OCH), 7.71 (td, 3J = 7.4 Hz, 4J = 1.2 Hz, 1 H, Ar), 7.78 (td, 3J = 7.4
4
3
4
Hz, J = 1.5 Hz, 1 H, Ar), 7.99 (ddd, J = 7.4 Hz, J = 1.5 Hz,
5J = 0.7 Hz, 1 H, Ar), 8.15 (ddd, J = 7.4 Hz, 4J = 1.2 Hz, 5J = 0.7
3
Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 21.6 [CH(CH3)2], 31.8 (COCH3),
70.2 (OCH), 116.7, 125.3 (C), 125.9, 126.1, 132.8, 135.3 (CHAr),
136.4, 152.4, 163.8, 164.2 (C), 195.4 (COCH3).
IR (KBr): 2952 (w), 1790 (s), 1726 (s), 1706 (s), 1641 (s), 1356 (m),
1286 (m), 1235 (s), 1063 (s), 1014 (s), 973 (m), 763 (s), 695 cm–1
(s).
MS (GC-EI, 70 eV): m/z (%) = 274 (M+, 7), 259 (20), 190 (44), 174
1H NMR (250 MHz, CDCl3): d = 2.65 (s, 3 H, CCH3), 3.94 (s, 3 H,
OCH3), 7.74 (td, 3J = 7.3 Hz, 4J = 1.2 Hz, 1 H, Ar), 7.81 (td, 3J = 7.6
Hz, 4J = 1.5 Hz, 1 H, Ar), 8.00–8.05 (m, 1 H, Ar), 8.14–8.19 (m, 1
H, Ar).
(21), 173 (100), 172 (52), 43 (59).
HRMS (EI, 70 eV): m/z calcd for C15H14O5 (M+): 274.08358; found:
274.08319.
13C NMR (75 MHz, CDCl3): d = 31.8 (CH3CO), 53.0 (OCH3),
116.0, 125.3 (C), 126.0, 126.1, 133.0, 135.5 (CHAr), 136.2, 153.0,
164.1, 164.6 (C), 195.5 (CH3CO).
MS (GC-EI, 70 eV): m/z (%) = 246 (M+, 25), 231 (100), 204 (74),
187 (53), 174 (70), 173 (75), 172 (65), 163 (85), 104 (74), 76 (57),
43 (65).
Isobutyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)bu-
tyrate (5d)
Starting from 1 (384 mg, 1.9 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.21 mL, 1.9 mmol), and 4d (452 mg,
2.0 mmol), 5d was isolated by column chromatography (n-heptane–
EtOAc, 5:1) as a colorless solid (262 mg, 48%, mixture of isomers:
E/Z = 10:1); mp 63–65 °C; Rf = 0.36 (n-heptane–EtOAc, 3:1); reac-
tion time: 21 h.
Anal. Calcd for C13H10O5 (246.22): C, 63.42; H, 4.09. Found: C,
63.18; H, 4.05.
IR (KBr): 2969 (m), 1790 (s), 1706 (s), 1640 (s), 1473 (m), 1280
(m), 1242 (s), 1063 (s), 1011 (s), 969 cm–1 (m).
Ethyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)bu-
tyrate (5b)
1H NMR (250 MHz, CDCl3): d = 0.92 [d, 3J = 6.7 Hz, 6 H,
3
CH(CH3)2], 1.99 [m, J = 6.7 Hz, 1 H, CH(CH3)2], 2.59 (s, 3 H,
Starting from 1 (417 mg, 2.1 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.23 mL, 2.1 mmol), and 4b (419 mg,
2.1 mmol), 5b was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 3:1) as a slightly yellow solid (361 mg, 68%);
mp 117–119 °C; Rf = 0.22 (n-heptane–EtOAc, 3:1); reaction time:
23 h.
3
3
CH3CO), 4.08 (d, J = 6.4 Hz, 2 H, OCH2), 7.69 (td, J = 7.3 Hz,
4J = 1.1 Hz, 1 H, Ar), 7.76 (td, 3J = 7.6, 4J = 1.5 Hz, 1 H, Ar), 7.95
(m, 1 H, Ar), 8.16 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 18.9 [CH(CH3)2], 27.5
[CH(CH3)2], 31.6 (COCH3), 72.1 (OCH2), 116.3, 125.2 (C), 125.9,
126.0, 132.8, 135.3 (CHAr), 136.2, 152.7, 164.03, 164.05 (C), 195.4
(COCH3).
MS (EI, 70 eV): m/z (%) = 288 (M+, 2), 273 (15), 190 (21), 174 (25),
173 (100), 172 (34), 57 (16), 43 (28).
IR (KBr): 2997 (w), 1804 (s), 1742 (s), 1635 (s), 1473 (m), 1370 (s),
1313 (s), 1290 (s), 1235 (s), 1053 (s), 1004 (s), 900 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 1.36 (t, 3J = 7.1 Hz, 3 H,
CH2CH3), 2.62 (s, 3 H, COCH3), 4.40 (q, 3J = 7.1 Hz, 2 H, OCH2),
3
4
3
7.72 (td, J = 7.3 Hz, J = 1.2 Hz, 1 H, Ar), 7.79 (td, J = 7.6 Hz,
Anal. Calcd for C16H16O5 (288.30): C, 66.66; H, 5.59. Found: C,
66.28; H, 5.61.
4J = 1.5 Hz, 1 H, Ar), 7.99 (ddd, J = 7.3 Hz, 4J = 1.5 Hz, J = 0.7
Hz, 1 H, Ar), 8.15 (ddd, 3J = 7.6 Hz, 4J = 1.2 Hz, 5J = 0.7 Hz, 1 H,
Ar).
3
5
Allyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)butyrate
(5e)
13C NMR (75 MHz, CDCl3): d = 13.9 (CH2CH3), 31.8 (COCH3),
62.2 (OCH2), 116.3, 125.3 (C), 125.9, 126.1, 132.9, 135.4 (CHAr),
136.3, 152.7, 164.1, 164.2 (C), 195.5 (COCH3).
MS (GC-EI, 70 eV): m/z (%) = 260 (M+, 9), 245 (34), 218 (14), 174
(66), 173 (100), 172 (24), 104 (22), 89 (18), 76 (19), 43 (30).
Starting from 1 (397 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4e (445 mg,
2.1 mmol), 5e was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 3:1) as a colorless solid (314 mg, 59%, E/Z =
10:1); mp 94–95 °C; Rf = 0.23 (n-heptane–EtOAc, 3:1); reaction
time: 23 h.
Anal. Calcd for C14H12O5 (260.24): C, 64.61; H, 4.65. Found: C,
64.34; H, 4.63.
IR (KBr): 1804 (s), 1735 (s), 1665 (m), 1635 (s), 1373 (m), 1310
(m), 1288 (s), 1234 (s), 1052 (s), 993 (s), 894 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.63 (s, 3 H, CH3), 4.83 (dt,
3J = 5.8 Hz, 4J1 ≈ 4J2 ≈ 1.3 Hz, 2 H, OCH2), 5.30 (dq, 3J = 10.4 Hz,
4J ≈ 2J ≈ 1.3 Hz, 1 H, CHAHB=CH), 5.40 (dq, 3J = 17.3 Hz, 4J ≈ 2J ≈
1.3 Hz, 1 H, CHAHB=CH), 5.97 (ddt, 3J1 = 17.3 Hz, 3J2 = 10.4 Hz,
The preparation of this compound was reported previously, but no
spectroscopic data were given.17
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

2286
S. Mkrtchyan et al.
PAPER
3J3 = 5.8 Hz, 1 H, CH2=CH), 7.72 (td, 3J = 7.3 Hz, 4J = 1.3 Hz, 1 H,
Ar), 7.79 (td, 3J = 7.3 Hz, 4J = 1.5 Hz, 1 H, Ar), 7.97–8.02 (m, 1 H,
Ar), 8.14–8.18 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 31.8 (CH3), 66.6 (OCH2), 116.0
(C), 119.5 (CH2=CH), 125.2 (C), 126.1 (2 CH), 130.9, 133.0, 135.4
(CH), 136.2, 153.0, 163.8, 164.0 (C), 195.4 (COCH3).
MS (GC-EI, 70 eV): m/z (%) = 272 (M+, 1), 212 (23), 174 (30), 173
(100), 168 (40), 146 (30), 104 (25), 89 (21), 76 (31), 43 (53), 41
(63).
10:1); mp 62–63 °C; Rf = 0.31 (n-heptane–EtOAc, 3:1); reaction
time: 20 h.
IR (KBr): 2966 (m), 2934 (w), 2875 (w), 1791 (s), 1710 (s), 1638
(s), 1472 (m), 1278 (m), 1231 (s), 1045 (s), 981 (s), 692 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 0.96 (t, 3J = 7.3 Hz, 3 H,
3
CH2CH2CH3), 1.32 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.71 (sext,
3J = 7.3 Hz, 2 H, CH2CH2CH3), 2.86 (t, 3J = 7.3 Hz, 2 H,
3
CH2CH2CH3), 4.35 (q, J = 7.2 Hz, 2 H, OCH2), 7.69 (td, 3J = 7.3
4
3
4
Hz, J = 1.2 Hz, 1 H, Ar), 7.77 (td, J = 7.6 Hz, J = 1.4 Hz, 1 H,
Ar), 7.95 (ddd, 3J = 7.3 Hz, 4J = 1.4 Hz, 5J = 0.8 Hz, 1 H, Ar), 8.30
(m, 1 H, Ar).
Anal. Calcd for C15H12O5 (272.25): C, 66.17; H, 4.44. Found: C,
65.88; H, 4.43.
13C NMR (62 MHz, CDCl3): d = 13.5, 13.9 (CH3), 16.9
(CH2CH2CH3), 45.6 (CH2CO), 62.0 (OCH2), 116.4, 125.3 (C),
125.8, 126.4, 132.7, 135.3 (CHAr), 136.1, 152.5, 163.9, 164.2 (C),
198.3 (CH2CO).
MS (GC-EI, 70 eV): m/z (%) = 288 (M+, 0.7), 246 (13), 245 (88),
174 (15), 173 (100), 104 (11), 89 (14), 76 (11).
2-Methoxyethyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-
ylidene)butyrate (5f)
Starting from 1 (365 mg, 1.8 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.4 g), TiCl4 (0.20 mL, 1.8 mmol), and 4f (448 mg, 1.9
mmol), 5f was isolated by column chromatography (silica gel; n-
heptane–EtOAc, 2:1) as a yellow solid (194 mg, 37%, E/Z = 5:1);
mp 81–82 °C; Rf = 0.08 (n-heptane–EtOAc, 3:1); reaction time: 16
h.
Anal. Calcd for C16H16O5 (288.30): C, 66.66; H, 5.59. Found: C,
66.60; H, 5.68.
IR (KBr): 2931 (m), 2894 (m), 1801 (s), 1740 (s), 1636 (s), 1368 (s),
1290 (s), 1240 (s), 1128 (s), 1055 (s), 991 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 2.64 (s, 3 H, CCH3), 3.38 (s, 3 H,
OCH3), 3.68 (m, 2 H, CH3OCH2), 4.51 (m, 2 H, COOCH2), 7.69–
7.82 (m, 2 H, Ar), 7.98–8.02 (m, 1 H, Ar), 8.14–8.19 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 31.8 (CH3CO), 58.9 (OCH3), 65.0,
70.0 (CH2), 116.0, 125.2 (C), 126.07, 126.09, 133.0, 135.4 (CHAr),
136.4, 152.9, 164.1, 164.3 (C), 195.3 (CH3CO).
MS (GC-EI, 70 eV): m/z (%) = 290 (M+, 0.5), 275 (10), 247 (20),
216 (17), 173 (100), 104 (14), 76 (16), 59 (32), 58 (33), 43 (49).
HRMS (EI, 70 eV): m/z calcd for C15H14O6 (M+): 290.07849; found:
290.07787.
Methyl (E)-4,4-Dimethyl-3-oxo-2-(3-oxo-3H-isobenzofuran-1-
ylidene)valerate (5i) and Methyl (Z)-(3-Oxo-3H-isobenzofuran-
1-ylidene)acetate (6a)
Starting from 1 (403 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4i (536 mg,
2.3 mmol), 5i was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 5:1) as a colorless solid (141 mg, 25%); mp
143–145 °C; Rf = 0.33 (n-heptane–EtOAc, 3:1). Compound 6a was
isolated from a second fraction as a colorless solid (69 mg, 17%,
E/Z = 1:10); mp 166–167 °C; Rf = 0.16 (n-heptane–EtOAc, 3:1); re-
action time: 16 h.
5i
IR (KBr): 2974 (m), 2962 (m), 1792 (s), 1719 (s), 1704 (s), 1631 (s),
1474 (m), 1244 (s), 1049 (s), 969 cm–1 (s).
Methyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)ca-
proate (5g)
Starting from 1 (397 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4g (443 mg,
2.0 mmol), 5g was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 4:1) as a colorless solid (245 mg, 46%); mp 79–
80 °C; Rf = 0.24 (n-heptane–EtOAc, 3:1); reaction time: 20 h.
1H NMR (250 MHz, CDCl3): d = 1.28 [s, 9 H, C(CH3)3], 3.87 (s, 3
3
4
H, OCH3), 7.71 (td, J = 7.5 Hz, J = 0.9 Hz, 1 H, Ar), 7.82 (td,
3J = 7.7 Hz, 4J = 1.3 Hz, 1 H, Ar), 7.97 (m, 1 H, Ar), 8.84 (m, 1 H,
Ar).
13C NMR (75 MHz, CDCl3): d = 27.2 [C(CH3)3], 45.2 [C(CH3)3],
52.4 (OCH3), 116.3 (C), 125.7 (CHAr), 126.0 (C), 128.0, 132.7,
135.4 (CHAr), 135.7, 153.0, 163.6, 164.4 (C), 206.5 [COC(CH3)3].
MS (CI, isobutane): m/z (%) = 289 ([M + 1]+, 100), 257 (57), 232
(32).
IR (KBr): 2968 (w), 1819 (s), 1732 (s), 1659 (s), 1638 (s), 1376 (m),
1313 (m), 1279 (s), 1250 (s), 1088 (m), 1023 (s), 978 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 0.95 (t, 3J = 7.3 Hz, 3 H,
3
3
CH2CH3), 1.69 (sext, J = 7.3 Hz, 2 H, CH2CH3), 2.85 (t, J = 7.3
Anal. Calcd for C16H16O5 (288.30): C, 66.66; H, 5.59. Found: C,
66.55; H, 5.59.
3
Hz, 2 H, COCH2), 3.87 (s, 3 H, OCH3), 7.68 (td, J = 7.5 Hz,
4J = 1.1 Hz, 1 H, Ar), 7.76 (td, J = 7.7 Hz, 4J = 1.4 Hz, 1 H, Ar),
3
7.94 (m, 1 H, Ar), 8.27 (m, 1 H, Ar).
6a
13C NMR (62 MHz, CDCl3): d = 13.4 (CH2CH3), 16.9 (CH2CH3),
45.6 (COCH2), 52.7 (OCH3), 116.0, 125.2 (C), 125.8, 126.4, 132.8,
135.4 (CHAr), 136.0, 152.8, 164.1, 164.4 (C), 198.3 (COCH2).
MS (GC-EI, 70 eV): m/z (%) = 274 (M+, 0.4), 231 (100), 187 (32),
173 (10), 163 (47), 104 (18), 76 (15), 59 (12).
IR (KBr): 2951 (m), 1794 (s), 1719 (s), 1682 (s), 1328 (s), 1270 (s),
1198 (s), 1157 (s), 1025 (s), 978 (s), 782 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 3.84 (s, 3 H, OCH3), 5.89 (s, 1 H,
CHCO), 7.66–7.83 (m, 3 H, Ar), 7.97 (dt, 3J = 7.5 Hz, 4J = 1.1 Hz,
1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 52.0 (OCH3), 95.6 (CHCO), 121.2
(CHAr), 124.7 (C), 126.0, 132.4, 135.1 (CHAr), 138.9, 154.2, 164.1,
165.5 (C).
MS (GC-EI, 70 eV): m/z (%) = 204 (M+, 22), 174 (11), 173 (100),
146 (10), 89 (29).
Anal. Calcd for C15H14O5 (274.27): C, 65.69; H, 5.15. Found: C,
65.49; H, 5.14.
Ethyl (E)-3-Oxo-2-(3-oxo-3H-isobenzofuran-1-ylidene)ca-
proate (5h)
Starting with 1 (400 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4h (480 mg,
2.1 mmol), 5h was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 5:1) as a colorless solid (232 mg, 41%, E/Z =
Anal. Calcd for C11H8O4 (204.18): C, 64.71; H, 3.95. Found: C,
64.68; H, 3.86.
The spectroscopic data (1H NMR, IR) were in accordance with
those reported in the literature.18
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

PAPER
E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans
2287
(Z)-3-(2-Oxopropylidene)-3H-isobenzofuran-1-one (6b)
3J = 7.4 Hz, 4J = 1.3 Hz, 1 H, CHAr), 7.96–8.00 (m, 1 H, CHAr), 8.31
(d, 3J = 7.5 Hz, 1 , CHAr).
13C NMR (62.9 MHz, CDCl3): d = 22.5 [CH2CH(CH3)2], 24.3
[CH2CH(CH3)2], 52.7 [CH2CH(CH3)2], 52.8 (OCH3), 116.4, 125.5
(CAr), 126.0, 126.5, 132.9, 135.4 (CHAr), 136.2, 152.9 (CAr), 164.2,
164.5, 198.1 (C=O).
Starting from 1 (406 mg, 2.0 mmol), CH2Cl2 (6 mL), molecular
sieves (4 Å, 0.400 g), TiCl4 (0.22 mL, 2.0 mmol), and 4j (474 mg,
2.1 mmol), 6b was isolated by column chromatography (silica gel;
n-heptane–EtOAc, 3:1) as a yellow-brown solid (29 mg, 8%); mp
135–137 °C; Rf = 0.26 (n-heptane–EtOAc, 2:1); reaction time: 20 h.
IR (KBr): 3045 (m), 2917 (m), 1793 (s), 1782 (s), 1669 (s), 1637
(m), 1368 (m), 1261 (s), 984 (s), 976 (s), 695 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.64 (s, 3 H, CH3), 6.02 (s, 1 H,
CHCO), 7.68–7.84 (m, 3 H, Ar), 8.00 (dt, 3J = 7.5 Hz, 4J ≈ 5J ≈ 1.1
Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 31.4 (CH3), 105.4, 121.6 (CH),
124.4 (C), 126.1, 132.5, 135.2 (CH), 139.2, 153.0, 165.1 (C), 196.6
(CHCO).
MS (GC, 70 eV): m/z (%) = 274 (M+, 1), 257 (2), 231 (100), 205
(24), 187 (38), 173 (25), 163 (57), 104 (21), 76 (15), 59 (12).
HRMS (EI): m/z calcd for C15H14O5 (M+): 274.08923; found:
274.088688.
Anal. Calcd for C16H16O5 (274.27): C, 65.69; H, 5.15. Found: C,
65.57; H, 5.53.
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]hep-
tanoate (5n)
MS (EI, 70 eV): m/z (%) = 188 (M+, 11), 174 (11), 173 (100), 89
(29), 49 (28).
Starting from 1 (0.609 g, 3.0 mmol), 4n (0.760 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5n was obtained as a color-
less solid (0.541 g, 63%); mp 114–117 °C; reaction time: 20 h.
HRMS (EI, 70 eV): m/z calcd for C11H8O3 (M+): 188.04680; found:
188.04625.
IR (ATR): 2960 (w), 2933 (w), 2872 (w), 1798 (s), 1728 (s), 1708
(m), 1662 (w), 1632 (s), 1590 (w), 1470 (m), 1428 (m), 1397 (w),
1376 (w), 1374 (w), 1279 (m), 1232 (s), 1199 (m), 1163 (m), 1088
(m), 1036 (s), 1005 (m), 967 (s), 891 (m), 813 (m), 765 (m), 713
(m), 688 (s), 577 cm–1 (m).
Anal. Calcd for C11H8O3 (188.18): C, 70.21; H, 4.29. Found: C,
70.18; H, 4.06.
The spectroscopic data (1H NMR) were in accordance with those
presented in the literature.19
1H NMR (300 MHz, CDCl3): d = 0.90 (t, 3J = 7.3 Hz, 3 H,
CH2CH3), 1.31–1.43 (m, 2 H, CH2CH2CH2CH3), 1.61–1.71 (m, 2 H,
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]pen-
tanoate (5l)
Starting from 1 (0.609 g, 3.0 mmol), 4l (0.720 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5l was obtained as a color-
less solid (0.436 g, 56%); mp 94–95 °C; reaction time: 20 h.
3
CH2CH2CH2CH3), 2.87 (t, J = 7.3 Hz, CH2CH2CH2CH3), 3.88 (s,
3 H, OCH3), 7.70 (td, 3J = 7.5 Hz, 4J = 1.0 Hz, 1 H, CHAr), 7.77 (td,
3J = 7.5 Hz, 4J = 1.30 Hz, 1 H, CHAr), 7.96 (dq, 3J = 7.5 Hz, 4J = 0.8
Hz, 1 H, CHAr), 8.31 (dt, 3J = 7.9 Hz, 4J = 0.9 Hz, 1 H, CHAr).
IR (ATR): 2990 (w), 2951 (w), 1789 (m), 1739 (m), 1662 (w), 1633
(m), 1593 (m), 1473 (w), 1423 (m), 1360 (m), 1309 (w), 1284 (m),
1245 (m), 1186 (m), 1108 (w), 1078 (m), 1023 (m), 1001 (m), 969
(m), 898 (m), 772 (s), 695 (s), 647 (m), 577 cm–1 (m).
13C NMR (62.9 MHz, CDCl3): d = 13.8 (CH2CH3), 22.0, 25.5, 43.6
(CH2), 52.8 (OCH3), 116.2, 125.4 (CAr), 125.9, 126.5, 132.8, 135.4
(CHAr), 136.0, 152.8 (CAr), 164.2, 164.4, 199.0 (C=O).
MS (GC, 70 eV): m/z (%) = 288 (M+, 2), 246 (22), 231 (100), 214
(28), 187 (45), 173 (19), 163 (62), 104 (25), 76 (18), 59 (13).
HRMS (ESI): m/z calcd for C16H17O5 (M+ + H): 289.10705; found:
289.10697.
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3J = 7.2 Hz, 3 H,
CH2CH3), 2.93 (q, 3J = 7.2 Hz, 2 H, CH2CH3), 3.90 (s, 3 H, OCH3),
7.72 (td, 3J = 7.5 Hz, 4J = 1.1 Hz, 1 H, CHAr), 7.80 (td, 3J = 7.5 Hz,
3
4
4J = 1.2 Hz, 1 H, CHAr), 7.98 (dq, J = 7.5 Hz, J = 1.0 Hz, 1 H,
CHAr), 8.31 (dt, 3J = 7.5 Hz, 4J = 0.8 Hz, 1 H, CHAr).
Anal. Calcd for C16H16O5 (288.30): C, 66.66; H, 5.59. Found: C,
66.46; H, 5.11.
13C NMR (75.5 MHz, CDCl3): d = 7.7 (CH2CH3), 37.4 (CH2CH3),
52.9 (OCH3), 116.1, 125.4 (CAr), 126.0, 126.5, 132.9, 135.5 (CHAr),
136.2, 153.0 (CAr), 164.3, 164.5, 199.0 (C=O).
MS (GC, 70 eV): m/z (%) = 260 (M+, 2), 231 (100), 187 (34), 163
(46), 104 (18), 76 (17), 57 (10).
HRMS (EI): m/z calcd for C14H12O5 (M+): 260.06792; found:
260.068072.
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]octanoate
(5o)
Starting from 1 (0.609 g, 3.0 mmol), 4o (0.800 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5o was obtained as a color-
less solid (0.443 g, 49%); mp 79–80 °C; reaction time: 20 h.
IR (ATR): 2952 (w), 2871 (s), 1796 (s), 1707 (s), 1641 (s), 1588
(w), 1468 (m), 1437 (m), 1402 (w), 1284 (m), 1235 (s), 1176 (m),
1102 (m), 1051 (s), 1037 (s), 1006 (m), 978 (s), 895 (w), 797 (w),
761 (s), 731 (m), 690 (s), 586 (w), 537 cm–1 (m).
Anal. Calcd for C14H12O5 (260.24): C, 64.61; H, 4.65. Found: C,
64.61; H, 4.67.
Methyl 5-Methyl-3-oxo-2-[3-oxo-3H-isobenzofuran-1-
ylidene]hexanoate (5m)
Starting from 1 (0.609 g, 3.0 mmol), 4m (0.760 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5m was obtained as a color-
less solid (0.864 g, 49%); mp 99–100 °C; reaction time: 20 h.
1H NMR (300 MHz, CDCl3): d = 0.86 [t, 3J = 7.0 Hz, 3 H,
CH2CH2(CH2)2CH3], 1.29–1.35 [m, 4 H, CH2CH2(CH2)2CH3],
3
1.62–1.72 [m, 2H, CH2CH2(CH2)2CH3], 2.86 [t, J = 7.3 Hz, 2 H,
3
CH2CH2(CH2)2CH3], 3.87 (s, 3 H, OCH3), 7.69 (td, J = 7.4 Hz,
3
4
4J = 1.0 Hz, 1 H, CHAr), 7.77 (td, J = 7.4 Hz, J = 1.3 Hz, 1 H,
CHAr), 7.93–7.96 (m, 1 H, CHAr), 8.29 (dt, 3J = 7.5 Hz, 4J = 1.0 Hz,
1 H, CHAr).
IR (ATR): 2955 (w), 2872 (w), 1794 (s), 1728 (m), 1708 (s), 1668
(w), 1633 (s), 1470 (m), 1434 (m), 1401 (w), 1365 (m), 1351 (m),
1308 (m), 1278 (s), 1231 (s), 1200 (m), 1182 (m), 1125 (w), 1101
(w), 1084 (m), 1042 (s), 1026 (s), 982 (s), 959 (s), 901 (m), 812 (m),
764 (s), 688 (s), 642 (m), 588 (w), 533 cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 0.97 [s, 1 H, CH2CH(CH3)2], 1.00
[s, 1 H, CH2CH(CH3)2], 2.22–2.33 [sept, 1 H, 3J = 6.8 Hz,
CH2CH(CH3)2], 2.78 [d, 3J = 6.8 Hz, 2 H, CH2CH(CH3)2], 3.90 (s,
3 H, OCH3), 7.71 (td, 3J = 7.4 Hz, 4J = 1.0 Hz, 1 H, CHAr), 7.79 (td,
13C NMR (62.9 MHz, CDCl3): d = 13.9 (CH2CH3), 22.5, 23.2, 31.1,
43.9 (CH2), 52.9 (OCH3), 116.3, 125.5 (CAr), 126.0, 126.5, 132.9,
135.4 (CHAr), 136.3, 152.9 (CAr), 164.2, 164.6, 198.6 (C=O).
MS (GC, 70 eV): m/z (%) = 302 (M+, 2), 246 (22), 231 (100), 214
(41), 187 (40), 173 (23), 163 (58), 104 (22).
HRMS (ESI): m/z calcd for C17H19O5 (M+ + H): 303.1227; found:
303.12239.
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

2288
S. Mkrtchyan et al.
PAPER
Anal. Calcd for C17H18O5 (302.32): C, 67.54; H, 6.00. Found: C,
66.37; H, 5.82.
IR (ATR): 3071 (w), 2952 (w), 1849 (w), 1790 (m), 1731 (s), 1707
(m), 1635 (m), 1470 (m), 1435 (m), 1286 (m), 1234 (s), 1162 (m),
1106 (m), 1050 (m), 1006 (m), 970 (m), 900 (s), 837 (m), 798 (m),
767 (m), 710 (s), 691 (s), 641 cm–1 (m).
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]decanoate
(5p)
Starting from 1 (0.609 g, 3.0 mmol), 4p (0.898 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5p was obtained as a yellow
solid (0.657 g, 67%); mp 113–116 °C; reaction time: 20 h.
1H NMR (300 MHz, CDCl3): d = 2.43–2.50 (m,
2
H,
CH2CH2CHCH2), 3.02 (t, 3J = 7.3 Hz, 2 H, CH2CH2CHCH2), 3.91
(s, 3 H, OCH3), 4.98–5.12 (m, 2 H, CH2CH2CHCH2), 5.80–5.94 (m,
3
2 H, CH2CH2CHCH2), 7.72 (td, J = 7.4 Hz, 4J = 1.0 Hz, 1 H,
IR (ATR): 2927 (w), 2855 (w), 1849 (w), 1790 (m), 1731 (s), 1635
(m), 1598 (m), 1470 (m), 1434 (w), 1356 (m), 1284 (w), 1233 (s),
1105 (m), 1047 (m), 1027 (m), 973 (m), 898 (s), 837 (m), 798 (m),
765 (m), 690 (s), 641 (m), 532 cm–1 (s).
CHAr), 7.80 (td, 3J = 7.5 Hz, 4J = 1.2 Hz, 1 H, CHAr), 7.98–8.01 (m,
1 H, CHAr), 8.30–8.33 (m, 1 H, CHAr).
13C NMR (75.5 MHz, CDCl3): d = 27.5, 43.1 (CH2CH2CH), 52.9
(OCH3), 115.5 (CH2CHCH2), 116.3, 125.5 (CAr), 126.0, 126.5,
133.0, 135.5 (CHAr), 136.1 (CH2CHCH2), 136.8, 153.1 (CAr), 164.1,
164.4, 197.5 (C=O).
MS (GC, 70 eV): m/z (%) = 286 (M+, 1), 254 (14), 231 (61), 217
(35), 198 (33), 187 (66), 173 (51), 163 (100), 146 (17), 104 (44), 91
(13), 76 (37), 55 (32).
1H NMR (250 MHz, CDCl3): d = 0.82–0.87 [m,
3
H,
CH2CH2(CH2)4CH3], 1.22–1.37 [m, 8 H, CH2CH2(CH2)4CH3],
1.62–1.73 [m, 2 H, CH2CH2(CH2)4CH3], 2.87 [t, 3J = 7.3 Hz, 2 H,
3
CH2CH2(CH2)4CH3], 3.88 (s, 3 H, OCH3), 7.67 (td, J = 7.5 Hz,
3
4
4J = 0.9 Hz, 1 H, CHAr), 7.78 (td, J = 7.5 Hz, J = 1.0 Hz, 1 H,
CHAr), 7.96 (d, J = 7.5 Hz, 1 H, CHAr), 8.31 (d, 3J = 7.5 Hz, 1 H,
3
HRMS (EI): m/z calcd for C16H14O5 (M+): 286.08358; found:
286.083628.
CHAr).
13C NMR (62.9 MHz, CDCl3): d = 14.0 [(CH2)6CH3], 22.5, 23.5,
28.9, 29.0, 31.6, 43.9 [(CH2)6CH3], 52.8 (OCH3), 116.3, 125.4
(CAr), 125.9, 126.5 132.8, 135.4 (CHAr), 136.1, 152.8 (CAr), 164.2,
164.5, 198.6 (C=O).
MS (GC, 70 eV): m/z (%) = 330 (M+, 2), 298 (9), 271 (10), 246 (24),
231 (100), 214 (53), 204 (11), 187 (40), 173 (31), 104 (20), 76 (12),
59 (11).
Anal. Calcd for C16H14O5 (286.28): C, 67.13; H, 4.93. Found: C,
65.79; H, 4.66.
Methyl 7-Chloro-3-oxo-2-[3-oxo-3H-isobenzofuran-1-
ylidene]heptanoate (5s)
Starting from 1 (0.609 g, 3.0 mmol), 4s (0.872 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5s was obtained as a color-
less solid (0.547 g, 56%); mp 111–112 °C; reaction time: 20 h.
HRMS (EI): m/z calcd for C19H22O5 (M+): 330.14618; found:
330.146053.
IR (ATR): 2953 (w), 2873 (w), 1793 (s), 1725 (s), 1708 (s), 1634
(s), 1470 (w), 1434 (m), 1403 (w), 1352 (w), 1280 (m), 1230 (s),
1093 (w), 1016 (s), 968 (s), 901 (m), 813 (w), 761 (m), 731 (m), 690
(s), 646 (m), 583 (w), 534 cm–1 (w).
Anal. Calcd for C19H22O5 (330.37): C, 69.07; H, 6.71. Found: C,
68.77; H, 6.75.
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]decanoate
(5q)
Starting from 1 (0.609 g, 3.0 mmol), 4q (1.080 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5q was obtained as a color-
less solid (0.518 g, 45%); mp 130–133 °C; reaction time: 20 h.
1H NMR (300 MHz, CDCl3): d = 1.81–1.83 [m,
4
H,
CH2(CH2)2CH2Cl], 2.89–2.94 [m, 2 H, CH2(CH2)2CH2Cl], 3.51–
3.55 [m, 2 H, CH2(CH2)2CH2Cl], 3.87 (s, 3 H, OCH3), 7.69 (td,
3J = 7.4 Hz, 4J = 1.0 Hz, 1 H, CHAr), 7.76 (td, 3J = 7.6 Hz, 4J = 1.3
Hz, 1 H, CHAr), 7.90–7.98 (m, 1 H, CHAr), 8.25–8.28 (m, 1 H,
CHAr).
IR (ATR): 2923 (m), 2853 (m), 1798 (s), 1729 (m), 1709 (m), 1634
(s), 1470 (m), 1434 (m), 1402 (w), 1351 (m), 1280 (m), 1230 (s),
1180 (m), 1090 (w), 1206 (s), 970 (s), 898 (m), 813 (m), 764 (m),
714 (m), 689 cm–1 (s).
13C NMR (69.2 MHz, CDCl3): d = 20.7, 31.5, 42.7, 44.6 (CH2),
52.8 (OCH3), 115.8, 125.2 (CAr), 125.9, 126.4, 132.9, 135.4 (CHAr),
135.9, 153.0 (CAr), 164.0, 164.2, 197.7 (C=O).
MS (GC, 70 eV): m/z (%) = 322 (M+, 1), 231 (100), 187 (24), 173
(11), 163 (42), 69 (16).
1H NMR (300 MHz, CDCl3): d = 0.82–0.86 [m,
5
H,
CH2CH2(CH2)6CH3], 1.25–1.40 [m, 10 H, CH2CH2(CH2)8CH3],
1.63–1.70 [m, 2 H, CH2CH2(CH2)8CH3], 2.87 [t, 3J = 7.3 Hz, 2 H,
CH2CH2(CH2)8CH3], 3.88 (s, 3 H, OCH3), 7.67–7.72 (m, 1 H,
CHAr), 7.77 (td, 3J = 7.6 Hz, 4J = 1.1 Hz, 1 H, CHAr), 7.95–7.97 (m,
1 H, CHAr), 8.31 (d, 3J = 7.8 Hz, 1 H, CHAr).
HRMS (EI): m/z calcd for C16H16ClO5 (M + H): 323.06808; found:
323.06797.
Anal. Calcd for C16H15ClO5 (322.75): C, 59.54; H, 4.68. Found: C,
58.32; H, 4.58.
13C NMR (62.9 MHz, CDCl3): d = 14.0 (CH2CH3), 22.6, 23.5, 28.9,
29.2, 29.4, 31.8, 43.9 (CH2), 52.8 (OCH3), 116.2, 125.4 (CAr),
125.9, 126.5, 132.8, 135.4 (CHAr), 152.8, 164.2, 164.5, 198.6 (CAr).
MS (GC, 70 eV): m/z (%) = 358 (M+, 2), 299 (10), 246 (25), 214
(59), 231 (100), 187 (34), 163 (49).
Methyl 8-Chloro-3-oxo-2-[3-oxo-3H-isobenzofuran-1-
ylidene]octanoate (5t)
Starting from 1 (0.609 g, 3.0 mmol), 4t (0.802 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5t was obtained as a color-
less solid (0.524 g, 51%); mp 120–121 °C; reaction time: 20 h.
HRMS (EI): m/z calcd for C21H26O5 (M+): 358.17748; found:
358.177166.
IR (ATR): 3114 (w), 2937 (w), 2853 (w), 1792 (s), 1707 (s), 1641
(s), 1588 (w), 1469 (m), 1436 (m), 1402 (w), 1349 (w), 1294 (m),
1236 (s), 1171 (m), 1122 (w), 1067 (w), 1036 (s), 968 (s), 908 (m),
864 (m), 814 (m), 760 (s), 729 (m), 690 (s), 647 (s), 588 (w), 536
cm–1 (m).
Anal. Calcd for C21H26O5 (358.43): C, 70.37; H, 7.31. Found: C,
70.51; H, 6.85.
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]hept-6-
enoate (5r)
Starting from 1 (0.609 g, 3.0 mmol), 4r (0.920 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5r was obtained as a yellow
solid (0.293 g, 55%); mp 116–117 °C; reaction time: 20 h.
1H NMR (300 MHz, CDCl3): d = 1.45–1.57 (m,
2
H,
H,
H,
H,
CH2CH2CH2CH2CH2Cl),
CH2CH2CH2CH2CH2Cl),
CH2CH2CH2CH2CH2Cl),
1.69–1.86
(m,
4
2.92
3.54
(t,
(t,
3J = 7.2 Hz,
3J = 6.7 Hz,
2
2
CH2CH2CH2CH2CH2Cl), 3.90 (s, 3 H, OCH3), 7.72 (td, 3J = 7.5 Hz,
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

PAPER
E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans
2289
3
4
4J = 1.0 Hz, 1 H, CHAr), 7.80 (td, J = 7.6 Hz, J = 1.3 Hz, 1 H,
Anal. Calcd for C21H18O5 (350.36): C, 71.99; H, 5.18. Found: C,
CHAr), 7.97–8.03 (m, 1 H, CHAr), 8.31–8.34 (m, 1 H, CHAr).
70.32; H, 5.11.
13C NMR (69.2 MHz, CDCl3): d = 22.8, 26.2, 32.4, 43.6, 44.8
(CH2), 52.9 (OCH3), 116.1, 125.4 (CAr), 126.0, 126.6, 132.9, 135.5
(CHAr), 136.2, 153.1 (CAr), 164.2, 164.4, 198.1 (C=O).
MS (GC, 70 eV): m/z (%) = 336 (M+, 1), 246 (17), 231 (100), 214
(25), 187 (27), 173 (16), 163 (52), 69 (28).
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]-7-phenyl-
heptanoate (5w)
Starting from 1 (0.609 g, 3.0 mmol), 4w (1.000 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5w was obtained as a color-
less solid (0.513 g, 49%); mp 116–117 °C; reaction time: 20 h.
HRMS (EI): m/z calcd for C17H18ClO5 (M + H): 337.08373; found:
337.08363.
IR (ATR): 3025 (w), 2950 (w), 1794 (s), 1728 (s), 1708 (s), 1633
(s), 1496 (w), 1471 (m), 1454 (m), 1434 (m), 1351 (m), 1282 (m),
1230 (s), 1180 (m), 1094 (m), 1015 (s), 967 (s), 897 (m), 812 (m),
731 (s), 689 (s), 648 (m), 585 (w), 533 cm–1 (w).
Anal. Calcd for C17H17ClO5 (336.77): C, 60.63; H, 5.09. Found: C,
59.02; H, 4.97.
1H NMR (300 MHz, CDCl3): d = 1.82–1.89 (m,
4
H,
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]-5-phenyl-
pentanoate (5u)
Starting from 1 (0.609 g, 3.0 mmol), 4u (0.920 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5u was obtained as a color-
less solid (0.480 g, 48%); mp 117–118 °C; reaction time: 20 h.
CH2CH2CH2CH2Ph) 2.75–2.80 (m, 2 H, CH2CH2CH2CH2Ph), 3.05
3
(t, J = 6.1 Hz, 2 H, CH2CH2CH2CH2Ph), 4.01 (s, 3 H, OCH3),
7.27–7.31 (m, 3 H, CHAr), 7.35–7.40 (m, 2 H, CHAr), 7.83 (td,
3J = 7.4 Hz, 4J = 1.0 Hz, 1 H, CHAr), 7.91 (td, 3J = 7.5 Hz, 4J = 1.3
Hz, 1 H, CHAr), 8.10–8.13 (m, 1 H, CHAr), 8.44–8.46 (m, 1 H,
CHAr).
13C NMR (62.9 MHz, CDCl3): d = 23.1, 30.6, 35.6, 43.6 (CH2),
52.8 (OCH3), 116.0, 125.3 (CAr), 125.6, 125.9, 126.4, 128.2, 128.3,
132.8, 135.4 (CHAr), 136.1, 142.1, 152.9 (CAr), 164.1, 164.4, 198.2
(C=O).
MS (GC, 70 eV): m/z (%) = 364 (M+, 1), 304 (16), 287 (24), 231
(38), 205 (37), 187 (41), 173 (69), 131 (15), 104 (84), 91 (100), 76
(22), 59 (24).
HRMS (ESI+): m/z calcd for C22H20O5 + Na (M+ + Na): 387.12029;
found: 387.12049.
IR (ATR): 3026 (w), 2951 (w), 1794 (s), 1728 (m), 1708 (m), 1666
(m), 1634 (s), 1496 (w), 1471 (m), 1424 (m), 1401 (m), 1352 (m),
1281 (m), 1230 (s), 1178 (m), 1093 (m), 1095 (s), 1010 (s), 970 (s),
900 (m), 812 (m), 762 (m), 688 (s), 590 (w), 554 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 3.09–3.14 (m, 2 H, CH2CH2Ph),
3.29–3.34 (m, 2 H, CH2CH2Ph), 3.93 (s, 3 H, OCH3), 7.30–7.35 (m,
5 H, CHAr), 7.79 (td, 3J = 7.5 Hz, 4J = 1.1 Hz, 1 H, CHAr), 7.86 (td,
3J = 7.6 Hz, 4J = 1.3 Hz, 1 H, CHAr), 8.05–8.08 (m, 1 H, CHAr), 8.38
(dt, 3J = 7.9 Hz, 4J = 0.9 Hz, 1 H, CHAr).
13C NMR (75.5 MHz, CDCl3): d = 29.6, 45.6 (CH2), 52.9 (OCH3),
115.9, 125.5 (CAr), 126.0, 126.1, 126.5, 128.4, 128.5, 133.0, 135.5
(CHAr), 136.2, 140.7, 153.2 (CAr), 164.1, 164.4, 197.4 (C=O).
MS (GC, 70 eV): m/z (%) = 336 (M+, 1), 304 (17), 286 (11), 260
(57), 231 (33), 205 (22), 187 (32), 173 (64), 163 (48), 131 (26), 104
(100), 91 (47), 77 (30), 59 (18).
Anal. Calcd for C22H20O5 (364.39): C, 72.51; H, 5.53. Found: C,
71.27; H, 5.53.
Ethyl (Z)-(3-Oxo-3H-isobenzofuran-1-ylidene)acetate [(Z)-9]
and Ethyl (E)-(3-Oxo-3H-isobenzofuran-1-ylidene)acetate [(E)-
9]
HRMS (EI): m/z calcd for C20H16O5 (M+): 336.09923; found:
Starting from 1 (272 mg, 1.34 mmol), CH2Cl2 (4.5 mL), and 8 (440
mg, 2.8 mmol), (Z)-9 was isolated by column chromatography (sil-
ica gel; n-heptane–EtOAc, 20:1 → 3:1) as a colorless solid (36 mg,
12%); mp 128–130 °C; Rf = 0.19 (n-heptane–EtOAc, 3:1). Com-
pound (E)-9 was isolated from a preceding fraction (n-heptane–
EtOAc = 20:1) as a colorless solid (12 mg, 4%); mp 63–64 °C; Rf =
0.45 (n-heptane–EtOAc, 3:1); reaction time: 20 h.
336.099597.
Anal. Calcd for C20H16O5 (336.34): C, 71.42; H, 4.79. Found: C,
70.80; H, 4.89.
Methyl 3-Oxo-2-[3-oxo-3H-isobenzofuran-1-ylidene]-6-phenyl-
hexanoate (5v)
Starting from 1 (0.609 g, 3.0 mmol), 4v (0.960 g, 3.3 mmol), TiCl4
(0.570 g, 3.0 mmol) in CH2Cl2 (6 mL), 5v was obtained as a color-
less solid (0.603 g, 55%); mp 119–120 °C; reaction time: 20 h.
(Z)-9
IR (KBr): 2987 (w), 1791 (s), 1719 (s), 1676 (s), 1469 (m), 1323 (s),
1170 (s), 1157 (s), 989 (s), 781 cm–1 (s).
IR (ATR): 3025 (w), 2933 (w), 2858 (w), 1795 (s), 1728 (m), 1708
(m), 1633 (s), 1495 (w), 1471 (m), 1453 (m), 1434 (m), 1351 (m),
1281 (m), 1230 (s), 1180 (m), 1094 (w), 1024 (s), 968 (s), 900 (m),
813 (m), 748 (m), 688 (s), 584 (w), 533 cm–1 (w).
3
1H NMR (250 MHz, CDCl3): d = 1.34 (t, J = 7.1 Hz, 3 H, CH3),
4.29 (q, 3J = 7.1 Hz, 2 H, OCH2), 5.88 (s, 1 H, CHCO), 7.65–7.82
(m, 3 H, Ar), 7.96 (dt, 3J = 7.4 Hz, 4J = 1.1 Hz, 1 H, Ar).
1H NMR (300 MHz, CDCl3): d = 2.10–2.20 (m,
2
H,
13C NMR (62 MHz, CDCl3): d = 14.2 (CH3), 60.9 (OCH2), 96.0
(CHCO), 121.2 (CHAr), 124.7 (C), 125.9, 132.3, 135.0 (CHAr),
138.9, 154.0, 163.6, 165.6 (C).
MS (GC-EI, 70 eV): m/z (%) = 218 (M+, 10), 190 (17), 174 (15),
173 (100), 146 (49), 105 (10), 89 (34), 76 (11).
CH2CH2CH2Ph), 2.82 (m,
2 H, CH2CH2CH2Ph), 3.04 (t,
3J = 7.1 Hz, 2 H, CH2CH2CH2Ph), 4.00 (s, 3 H, OCH3), 7.27–7.38
(m, 5 H, CHAr), 7.83 (td, 3J = 7.5 Hz, 4J = 1.0 Hz, 1 H, CHAr), 7.89
(td, 3J = 7.5 Hz, 4J = 1.3 Hz, 1 H, CHAr), 8.07–8.10 (m, 1 H, CHAr),
8.38 (d, 3J = 7.9 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): d = 25.1, 34.8, 43.1 (CH2), 52.8
(OCH3), 115.9, 125.4 (CAr), 125.8, 125.9, 126.5, 128.3, 128.4,
132.9, 135.4 (CHAr), 136.1, 141.6, 153.0 (CAr), 164.1, 164.4, 198.1
(C=O).
Anal. Calcd for C12H10O4 (218.21): C, 66.05; H, 4.62. Found: C,
65.92; H, 4.73.
1
The spectroscopic data (IR, H NMR) were in accordance with
those reported in the literature.19
MS (GC, 70 eV): m/z (%) = 350 (M+, 2), 246 (37), 214 (100), 204
(18), 187 (17), 174 (40), 163 (26), 104 (37), 91 (43), 76 (13), 59
(12).
(E)-9
IR (KBr): 2981 (w), 2934 (w), 1790 (s), 1714 (s), 1652 (s), 1471
(m), 1377 (m), 1243 (s), 1146 (m), 1040 (s), 783 cm–1 (m).
HRMS (EI): m/z calcd for C21H19O5 (M + H): 351.1227; found:
351.12268.
1H NMR (250 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H, CH3),
4.30 (q, J = 7.1 Hz, 2 H, OCH2), 6.15 (s, 1 H, COCH), 7.70 (td,
3
3
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York

2290
S. Mkrtchyan et al.
PAPER
3J = 7.5 Hz, 4J = 1.0 Hz, 1 H, Ar), 7.82 (ddd, 3J1 = 7.9 Hz, 3J2 = 7.3
Hz, 4J = 1.2 Hz, 1 H, Ar), 7.97 (m, 1 H, Ar), 9.06 (m, 3J = 7.9 Hz, 1
H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 60.9 (OCH2), 102.5
(CHCO), 125.3 (CHAr), 126.5 (C), 128.2, 132.5, 135.3 (CHAr),
136.1, 157.8, 165.5, 165.7 (C).
MS (CI, isobutane): m/z (%) = 219 ([M + 1]+, 38).
HRMS (CI neg., isobutane): m/z calcd for C12H10O4 (M–):
Tetrahedron Lett. 1998, 39, 7799. (b) Xu, C.; Negishi, E.-i.
Tetrahedron Lett. 1999, 40, 431.
(3) (a) Siegel, K.; Brückner, R. Chem. Eur. J. 1998, 4, 1116.
(b) Görth, F. C.; Brückner, R. Synthesis 1999, 1520.
(4) (a) Goerth, F.; Umland, A.; Brückner, R. Eur. J. Org. Chem.
1998, 1055. (b) v. d. Ohe, F.; Brückner, R. Tetrahedron
Lett. 1998, 39, 1909. (c) Hanisch, I.; Brückner, R. Synlett
2000, 374.
(5) (a) Ingham, C. F.; Massy-Westropp, R. A.; Reynolds, G. D.;
Thorpe, W. D. Aust. J. Chem. 1975, 28, 2499. (b) Knight,
D. W.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979,
62.
(6) Albrecht, U.; Nguyen, V. T. H.; Langer, P. Synthesis 2006,
1111.
(7) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
(8) For a review of cyclizations of 1,3-bis(silyl enol ethers) with
oxalyl chloride, see: Langer, P. Synlett 2006, 3369.
(9) (a) Naito, T.; Katsuhara, T.; Niitsu, K.; Ikeya, Y.; Okada,
M.; Mitsuhashi, H. Phytochemistry 1992, 31, 639.
(b) Hagemaier, J.; Batz, O.; Schmidt, J.; Wray, V.;
Hahlbrock, K.; Strack, D. Phytochemistry 1999, 51, 629.
(c) Pushan, W.; Xuanliang, G.; Yixiong, W.; Fukuyama, Y.;
Miura, I.; Sugawara, M. Phytochemistry 1984, 23, 2033.
(d) Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R.
Tetrahedron 2000, 56, 2533. (e) Li, S.; Wang, Z.; Fang, X.;
Yang, Y.; Li, Y. Synth. Commun. 1997, 27, 1783.
(f) Kobayashi, M.; Mitsuhashi, H. Chem. Pharm. Bull. 1987,
35, 4789. (g) Kobayashi, M.; Fujita, M.; Mitsuhashi, H.
Chem. Pharm. Bull. 1987, 35, 1427.
218.05846; found: 218.05779.
The spectroscopic data (1H NMR) were in accordance with those re-
ported in the literature.19
3-[2-Oxo-1-(phenylsulfonyl)propylidene]-2-benzofuran-1-one
(7a)
Starting from 1 (0.62 ml, 4.3 mmol), silyl enol ether (1.17 g, 4.3
mmol), and TiCl4 (0.47 mL, 4.3 mmol), 7a was isolated as a color-
less solid (398 mg, 28%); mp 186 °C; reaction time: 20 h.
IR (KBr): 3098 (w), 2922 (w), 2854 (w), 1811 (s), 1711 (s), 1624
(s), 1473 (m), 1252 (s), 1001 (s), 721 (m), 618 (s), 595 cm–1 (m).
1H NMR (300 MHz, acetone-d6): d = 2.65 (s, 3 H, CH3), 7.65–7.83
(m, 4 H, ArH), 7.96 (m, 1 H, ArH), 8.03–8.16 (m, 3 H, ArH), 8.91
(d, 1 H, J = 8.1 Hz, ArH).
13C NMR (75 MHz, acetone-d6): d = 33.1 (CH3), 125.7 (C), 127.2
(CH), 128.7 (2 C, CH), 129.6 (C), 130.6 (CH), 130.7 (2 C, CH),
132.1 (CH), 135.4 (C), 135.6, 137.1 (CH), 142.7, 154.4, 164.6,
195.5 (C).
GC-MS (CI, 70 eV): m/z (%) = 328 ([M + H]+, 48), 287 (100), 189
(10) (a) Yoshikawa, M.; Uchida, E.; Chatani, N.; Murakami, N.;
Yamahara, J. Chem. Pharm. Bull. 1992, 40, 3121.
(b) Umehara, K.; Matsumoto, M.; Nakamura, M.; Miyase,
T.; Kuroyanagi, M.; Noguchi, H. Chem. Pharm. Bull. 2000,
48, 566.
(11) Zhang, G.-L.; Ruecker, G.; Breitmaier, E.; Nieger, M.;
Mayer, R.; Steinbeck, C. Phytochemistry 1995, 40, 299.
(12) (a) Ruggli, P.; Zickendraht, C. Helv. Chim. Acta 1945, 28,
1377. (b) Bülow, R.; Koch, S. Ber. Dtsch. Chem. Ges. 1904,
37, 579. (c) Scheiber, J. Justus Liebigs Ann. Chem. 1912,
389, 151. (d) Maruyama, K.; Osuka, A. J. Org. Chem. 1980,
45, 1898. For reactions of pseudophthaloyl chloride, see:
(e) Naik, S. N.; Pandey, B.; Ayyangar, N. R. Synth.
Commun. 1988, 18, 625.
(13) (a) Chordia, M. D.; Narasimhan, N. S. J. Chem. Soc., Perkin
Trans. 1 1991, 371. (b) Hanack, M.; Zipplies, T. J. Am.
Chem. Soc. 1985, 107, 6127. (c) Kayser, M. M.; Hatt, K. L.;
Hooper, D. L. Can. J. Chem. 1992, 70, 1985. (d) Abell, A.
D.; Hoult, D. A.; Morris, K. M.; Taylor, J. M.; Trent, J. O.
J. Org. Chem. 1993, 58, 1531.
(50), 173 (6), 143 (7), 73 (10).
Anal. Calcd for C17H12O5S (328.34): C, 62.19; H, 3.68: Found: C,
61.65; H, 3.78.
3-[2-Oxo-1-(4-methylphenylsulfonyl)propylidene]-2-benzofu-
ran-1-one (7b)
Starting from 1 (0.18 mL, 1.0 mmol), silyl enol ether (300 mg, 1.0
mmol), and TiCl4 (0.11 mL, 1.0 mmol), 7b was isolated as a highly
viscous oil (90 mg, 25%); reaction time: 20 h.
IR (KBr): 3128 (w), 2923 (m), 2853 (w), 1794 (s), 1701 (s), 1627
(s), 1594 (m), 1572 (m), 1325 (s), 1306 (m), 1153 (s), 701 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 2.35 (s, 3 H,
CH3), 7.25–7.29 (m, 2 H, ArH), 7.66–7.72 (m, 2 H, ArH), 7.81–7.94
(m, 3 H, ArH), 8.83–8.87 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 23.0, 33.2 (CH3), 126.3 (C), 126.6
(CH), 126.9 (C) 128.2 (2 C, CH), 129.0 (CH), 130.3 (2 C, CH),
133.7 (CH), 134.7, 136.1, 138.4, 146.0, 152.0, 163.8, 195.0 (C).
GC-MS (CI, 70 eV): m/z (%) = 343 ([M + H]+, 40), 301 (100), 278
(14) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem. Commun. 1993,
(20), 236 (30), 155 (6).
HRMS (EI): m/z calcd for C18H14O5S (M+): 342.05565; found:
342.05513.
86.
(15) For the AlCl3-catalyzed transformation of 1 into A, see ref.
12e.
(16) CCDC-821844 (5i), CCDC-823020 (5f), CCDC-823021
(6a), and CCDC-824363 (7a) contain all crystallographic
details of this publication and are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
References
(1) For reviews, see for example: (a) Rao, Y. S. Chem. Rev.
1976, 76, 625. (b) Pattenden, G. Prog. Chem. Nat. Prod.
1978, 35, 133. (c) Gill, M.; Steglich, W. Prog. Chem. Org.
Nat. Prod. 1987, 51, 1. (d) Knight, D. W. Contemp. Org.
Synth. 1994, 1, 287. (e) Negishi, E.-i.; Kotora, M.
Tetrahedron 1997, 53, 6707. For reviews of syntheses of
g-alkylidenebutenolides, see: (f) Brückner, R. Chem.
Commun. 2001, 141. (g) Brückner, R. Curr. Org. Chem.
2001, 5, 679.
(17) Fischer, E.; Koch, H. Ber. Dtsch. Chem. Ges. 1883, 16, 651.
(18) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin
Trans. 1 1998, 561.
(19) Renfrew, A. H.; Bostock, S. B. J. Chem. Soc., Perkin Trans.
(2) (a) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
1 1977, 84.
Synthesis 2011, No. 14, 2281–2290 © Thieme Stuttgart · New York