One-pot synthesis of 4-substituted 3,4-dihydro-3-methoxyisocoumarins via carboxylation of α-substituted 2-lithio-β-methoxystyrenes with carbon dioxide

Article abstract of DOI:10.1002/hlca.201100297

A new type of isocoumarins (=1H-isochromen-1-ones=1H-2-benzopyran-1-ones), 4-substituted 3,4-dihydro-3-methoxyisocoumarins 2, can be obtained by a one-pot process from α-substituted 2-bromo-β-methoxystyrenes 1. Thus, lithium 2-(1-aryl(or methyl)-2-methoxyethenyl)benzoates are conveniently generated via the Br/Li exchange between 1 and BuLi, followed by the action of CO₂ on the resulting α-substituted 2-lithio-β-methoxystyrenes. Upon treating with concentrated HCl at room temperature, these lithium benzoates undergo lactonization to provide the desired 3,4-dihydroisocoumarins 2 in relatively good yields. Copyright

Full text of DOI:10.1002/hlca.201100297

Helvetica Chimica Acta – Vol. 95 (2012)
191
One-Pot Synthesis of 4-Substituted 3,4-Dihydro-3-methoxyisocoumarins via
Carboxylation of a-Substituted 2-Lithio-b-methoxystyrenes with Carbon
Dioxide
by Kazuhiro Kobayashi*, Toshiyuki Nagaoka, Yuu Shirai, Wataru Miyatani, Yuki Yokoi, and
Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4 – 101 Koyama-minami, Tottori 680 – 8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
A new type of isocoumarins (¼1H-isochromen-1-ones ¼ 1H-2-benzopyran-1-ones), 4-substituted
3,4-dihydro-3-methoxyisocoumarins 2, can be obtained by a one-pot process from a-substituted 2-
bromo-b-methoxystyrenes 1. Thus, lithium 2-(1-aryl(or methyl)-2-methoxyethenyl)benzoates are con-
veniently generated via the Br/Li exchange between 1 and BuLi, followed by the action of CO2 on the
resulting a-substituted 2-lithio-b-methoxystyrenes. Upon treating with concentrated HCl at room
temperature, these lithium benzoates undergo lactonization to provide the desired 3,4-dihydroisocou-
marins 2 in relatively good yields.
Introduction. – The well-established biological activity [1] and occurrence in the
nature [2] of compounds with the 3,4-dihydroisocoumarin skeleton have generated
considerable interest in the development of new routes to this class of important
heterocycles [3]. On the other hand, recent research in our laboratory has focused on
the utilization of a-substituted 2-lithio-b-methoxystyrenes as intermediates for the
construction of carbocyclic [4] and heterocyclic compounds [5][6]. In connection with
our work in this area, we have undertaken a search for new approaches to 4-substituted
isocoumarin (¼1H-isochromen-1-one ¼ 1H-2-benzopyran-1-one) derivatives. We have
found that 4-substituted 3,4-dihydro-3-methoxyisocoumarins 2 can be formed in
satisfactory yields by the reaction of a-substituted 2-bromo-b-methoxystyrenes 1 with
CO2 or (Boc)2O, followed by acid-mediated cyclization. Here, we describe the results of
our investigation, which provide facile methods for the preparation of this new type of
3,4-dihydroisocoumarins. To the best of our knowledge, no procedure exists for their
synthesis.
Results and Discussion. – The synthesis of 4-substituted 3,4-dihydro-3-methoxy-
isocoumarins 2 was accomplished as illustrated in Scheme 1. The starting materials, a-
substituted 2-bromo-b-methoxystyrenes 1, were synthesized by Wittig reaction of the
respective 2-bromophenyl ketones according to our recently reported procedure
[4][5]. Typically, treatment of 2-bromo-b-methoxy-a-phenylstyrene (1a) with BuLi at
08 for 1 h generated the corresponding 2-lithio intermediate, which was then allowed to
react with CO2 to give lithium 2-(2-methoxy-1-phenylethenyl)benzoates. Then,
concentrated HCl was added to the resulting mixture. Under these acidic conditions,
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Helvetica Chimica Acta – Vol. 95 (2012)
the intermediate 2-(2-methoxy-1-phenylethenyl)benzoic acid formed by protonation of
the lithium benzoate, underwent lactonization at a satisfactory rate at room temper-
ature (1 h) to give the desired 3,4-dihydro-3-methoxy-4-phenylisocoumarin (2a) as a
mixture of diastereoisomers in 70% yields as indicated in Scheme 1. The nine other a-
substituted 2-bromo-b-methoxystyrenes 1b – 1j were subjected to the reactions under
the above-mentioned conditions. The results are compiled in Scheme 1. Most of the
dihydroisocoumarins could be obtained in fair yields. These methoxy lactones proved
to be surprisingly stable and could be purified by preparative TLC on silica gel without
difficulty. However, 3,4-dihydro-3-methoxy-4-(4-methoxyphenyl)isocoumarin (2g)
could not be prepared; the action of concentrated HCl on the respective crude
carboxylic acid resulted in decarboxylation, affording a-(4-methoxyphenyl)-b-methox-
ystyrene. 4-[1,1’-Biphenyl-4-yl]-3,4-dihydro-3-methoxyisocoumarin (2h) could not be
obtained as well; the HCl conditions were found to be ineffective for the lactonization
of the respective carboxylic acid, 2-[1-[1,1’-biphenyl-4-yl]-2-methoxyethenyl]benzoic
acid. Unfortunately, reasons for these results are not clear.
Scheme 1
The transformation outlined in Scheme 2 demonstrates the two-step synthesis of 2g
from 2-bromo-b-methoxy-a-(4-methoxyphenyl)styrene (1g). Thus, treatment of 2-
lithio-b-methoxy-a-(4-methoxyphenyl)styrene, generated from 1g as mentioned above,
with (Boc)2O furnished tert-butyl 2-[2-methoxy-1-(4-methylphenyl)ethenyl]benzoate
(3) in relatively good yield. Upon treating with an equimolar amount of concentrated
HI at room temperature, lactonization of this ester proceeded smoothly in the expected
fashion, and the desired product 2g was obtained in good yield.
In Scheme 3, a procedure for the synthesis of 2h is outlined. The mixture of a-[1,1’-
biphenyl-4-yl]-2-lithio-b-methoxystyrene, generated from a-[1,1’-biphenyl-4-yl]-2-bro-
mo-b-methoxystyrene (1h), with CO2 was worked up as usual to afford crude 2-{1-[1,1’-
biphenyl-4-yl]-2-methoxyvinyl}benzoic acid (4), which was then treated with a catalytic
amount of concentrated HI in MeCN at room temperature to give the desired product
2h in a reasonable overall yield from 1h. All of the 3,4-dihydroisocoumarins 2 were
obtained as diastereoisomeric mixtures.

Helvetica Chimica Acta – Vol. 95 (2012)
193
Scheme 2
Scheme 3
The results of the study described here establish the utility of the carboxylation of a-
substituted 2-lithio-b-methoxystyrenes, followed by acid-mediated lactonization, as a
convenient method for the preparation of a new type of isocoumarins, i.e., 4-substituted
3,4-dihydro-3-methoxyisocoumarins 2. The ready availability of the starting materials
and the simplicity of operations render this method attractive.
Experimental Part
General. All of the org. solvents used were dried on the appropriate drying agents and distilled under
Ar prior to use. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-200E. M.p.:
Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR Spectra: Shimadzu FTIR-
8300 spectrometer. NMR Spectra (1H: 500 and 13C: 125 MHz): JEOL ECP 500 FT NMR spectrometer;
in CDCl3 with TMS as an internal reference. LR-MS (CI): JEOL JMS AX 505 HA spectrometer.
1-Bromo-2-(2-methoxyethenyl)benzenes 1a [5], 1b – 1d [4], 1e [5], 1f – 1h [4], and 1j [5] were
prepared by a previously reported procedure. BuLi was supplied by Asia Lithium Corporation. All other
chemicals used in this study were commercially available.
1-Bromo-4-methoxy-2-(2-methoxy-1-methylethenyl)benzene (1i). This compound was prepared by
the reaction of 1-(2-bromo-5-methoxyphenyl)ethanone with (methoxymethylene)(triphenyl)phosphor-
ane under the conditions described in [5].
1
(E)-Isomer. Yield: 39%. Colorless oil. Rf (Et2O/hexane 1:20) 0.51. IR (neat): 1667. H-NMR: 1.94
(d, J ¼ 1.4, 3 H); 3.69 (s, 3 H); 3.78 (s, 3 H); 6.03 (q, J ¼ 1.4, 1 H); 6.66 (dd, J ¼ 8.7, 3.2, 1 H); 6.74 (d, J ¼
3.2, 1 H); 7.42 (d, J ¼ 8.7, 1 H). Anal. calc. for C11H13BrO2 (257.12): C 51.38, H 5.10; found: C 51.58, H
5.08.
(Z)-Isomer. Yield: 32%. Colorless oil. Rf (Et2O/hexane 1:20) 0.40. IR (neat). 1674. 1H-NMR: 1.85
(d, J ¼ 1.4, 3 H), 3.57 (s, 3 H); 3.78 (s, 3 H); 6.00 (q, J ¼ 1.4, 1 H); 6.67 (dd, J ¼ 8.7, 2.7, 1 H); 6.73 (d,
J ¼ 2.7, 3 H); 7.45 (d, J ¼ 8.7, 1 H). Anal. calc. for C11H13BrO2 (257.12): C 51.38, H 5.10; found: C 51.30, H
5.14.

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3,4-Dihydro-3-methoxy-4-phenylisocoumarin (¼ 3,4-Dihydro-3-methoxy-4-phenyl-1H-2-benzopyr-
an-1-one; 2a). General Procedure. To a stirred soln. of 1a (0.31 g, 1.1 mmol) in Et2O (6 ml) at 08 was
added dropwise BuLi (1.6m in hexane; 1.1 mmol), and the mixture was stirred for 1.5 h at the same temp.
A fine stream of CO2 were passed through the resulting soln. for 30 min, and then 2 ml of conc. HCl were
added. The resulting mixture was vigorously stirred for an additional hour. Five ml each of Et2O and H2O
were added, and the layers were separated. The aq. layer was extracted with Et2O (2 ꢀ 5 ml), and the
combined extracts were washed with brine (10 ml), dried (Na2SO4), and evaporated. The residue was
purified by prep. TLC (SiO2) to afford 2a (0.14 g, 50%) as a mixture of stereoisomers (ca. 6 :4). Pale-
yellow oil. Rf (AcOEt/hexane 1:5) 0.16. IR (neat): 1732. 1H-NMR: 3.52 (s, 1.8 H); 3.56 (s, 1.2 H); 4.36 (d,
J ¼ 2.7, 0.4 H); 4.56 (d, J ¼ 3.2, 0.6 H); 5.42 (d, J ¼ 3.2, 0.6 H); 5.44 (d, J ¼ 2.7, 0.4 H); 6.95 (d, J ¼ 7.8,
0.6 H); 7.10 (d, J ¼ 7.8, 1.2 H); 7.16 (d, J ¼ 7.8, 0.4 H); 7.28 – 7.46 (m, 4.8 H); 7.49 (ddd, J ¼ 7.8, 7.3, 1.4,
0.6 H); 7.55 (ddd, J ¼ 7.8, 7.3, 1.4, 0.4 H); 8.17 (dd, J ¼ 7.8, 1.4, 0.6 H); 8.20 (d, J ¼ 7.8, 0.4 H). 13C-NMR:
48.64; 48.77; 56.84; 57.20; 104.28; 106.07; 124.59; 125.06; 127.60; 127.65; 127.68; 127.91; 127.96; 128.32;
128.51; 128.77; 128.93; 129.83; 129.87; 130.56; 133.96; 134.37; 135.41; 138.13; 139.40; 139.98; 163.52;
164.03. MS: 255 (100, [M þ 1]þ). Anal. calc. for C16H14O3 (254.28): C 75.57, H 5.55; found: C 75.40, H
5.59.
3,4-Dihydro-3-methoxy-4-(3-methylphenyl)isocoumarin (¼ 3,4-Dihydro-3-methoxy-4-(3-methyl-
phenyl)-1H-2-benzopyran-1-one; 2b). A mixture of stereoisomers (ca. 1:1). Yellow oil. Rf (AcOEt/
hexane 1:5) 0.32. IR (neat): 1732, 1605. 1H-NMR: 2.31 (s, 1.5 H); 2.36 (s, 1.5 H); 3.52 (s, 1.5 H); 3.56 (s,
1.5 H); 4.32 (d, J ¼ 2.3, 0.5 H); 4.52 (d, J ¼ 3.2, 0.5 H); 5.42 (d, J ¼ 3.2, 0.5 H); 5.44 (d, J ¼ 2.7, 0.5 H);
6.88 – 6.97 (m, 1.5 H); 7.08 – 7.22 (m, 3 H); 7.26 (dd, J ¼ 7.8, 7.3, 0.5 H); 7.39 – 7.46 (m, 1 H), 7.49 (ddd, J ¼
7.8, 7.3, 1.4, 0.5 H); 7.55 (ddd, J ¼ 7.8, 7.3, 1.4, 0.5 H); 8.17 (dd, J ¼ 7.8, 1.4, 0.5 H); 8.20 (dd, J ¼ 7.8, 1.4,
0.5 H). 13C-NMR: 21.39; 21.43; 48.62; 48.80; 56.85; 57.24; 104.38; 106.13; 124.57; 125.07; 125.38; 127.58;
127.60; 127.71; 127.87; 128.42; 128.48; 128.74; 128.81; 128.83; 128.99; 129.83; 129.87; 131.23; 133.95;
134.37; 135.34; 138.12; 138.18; 138.70; 139.55; 140.11; 163.59; 164.09. MS: 269 (100, [M þ 1]þ). Anal. calc.
for C17H16O3 (268.31): C 76.10, H 6.01; found: C 75.83, H 6.25.
3,4-Dihydro-3-methoxy-4-(4-methylphenyl)isocoumarin (¼ 3,4-Dihydro-3-methoxy-4-(4-methyl-
phenyl)-1H-2-benzopyran-1-one; 2c). A mixture of stereoisomers (ca. 1 :1). Pale-yellow oil. Rf
(AcOEt/hexane 1:20) 0.34. IR (neat): 1732, 1602. 1H-NMR: 2.32 (s, 1.5 H); 2.37 (s, 1.5 H); 3.51 (s,
1.5 H); 3.56 (s, 1.5 H); 4.32 (d, J ¼ 2.7, 0.5 H); 4.52 (d, J ¼ 3.2, 0.5 H); 5.40 (d, J ¼ 3.2, 0.5 H); 5.42 (d, J ¼
2.7, 0.5 H); 6.96 – 7.00 (m, 1.5 H); 7.12 – 7.22 (m, 3.5 H); 7.39 – 7.45 (m, 1 H); 7.49 (ddd, J ¼ 7.8, 7.3, 1.4,
0.5 H); 7.54 (ddd, J ¼ 7.8, 7.3, 1.4, 0.5 H); 8.16 (d, J ¼ 7.8, 0.5 H); 8.19 (d, J ¼ 7.8, 0.5 H). 13C-NMR: 20.99;
21.11; 48.33; 48.45; 56.88; 57.25; 104.45; 106.21; 124.60; 125.11; 127.57; 127.69; 127.86; 128.21; 128.76;
129.29; 129.66; 129.84; 129.89; 130.45; 132.37; 133.95; 134.37; 135.19; 137.49; 137.75; 139.72; 140.24;
163.59; 164.10. MS: 269 (100, [M þ 1]þ). Anal. calc. for C17H16O3 (268.31): C 76.10, H 6.01; found: C
76.01, H 6.03.
4-[4-(1,1-Dimethylethyl)phenyl]-3,4-dihydro-3-methoxyisocoumarin (¼4-[4-(tert-Butyl)phenyl]-3,4-
dihydro-3-methoxy-1H-2-benzopyran-1-one; 2d). A mixture of stereoisomers (ca. 3 :2). Colorless oil. Rf
(AcOEt/hexane 1:10) 0.35. IR (neat): 1732, 1605. 1H-NMR: 1.28 (s, 3.6 H); 1.34 (s, 5.4 H); 3.52 (s,
1.8 H); 3.56 (s, 1.2 H); 4.33 (d, J ¼ 2.3, 0.4 H); 4.53 (d, J ¼ 3.2, 0.6 H); 5.41 (d, J ¼ 3.2, 0.6 H); 5.44 (d, J ¼
2.3, 0.4 H); 6.97 (d, J ¼ 7.8, 0.6 H); 7.01 (d, J ¼ 8.2, 0.8 H); 7.18 (d, J ¼ 7.8, 0.4 H); 7.24 (d, J ¼ 8.7, 1.2 H);
7.32 (d, J ¼ 8.2, 0.8 H); 7.37 – 7.40 (m, 1.8 H); 7.43 (ddd, J ¼ 7.8, 7.3, 1.4, 0.4 H); 7.48 (ddd, J ¼ 7.8, 7.3, 1.4,
0.6 H); 7.55 (ddd, J ¼ 7.8, 7.3, 1.4, 0.4 H); 8.16 (dd, J ¼ 7.8, 1.4, 0.6 H); 8.19 (dd, J ¼ 7.8, 1.4, 0.4 H).
13C-NMR: 31.22; 31.29; 34.44; 34.51; 48.16; 48.37; 56.82; 57.20; 104.46; 106.17; 124.63; 125.10; 125.46;
125.86; 127.52; 127.71; 127.84; 127.90; 128.84; 129.79; 129.84; 130.18; 132.25; 133.90; 134.33; 135.12;
139.58; 140.27; 150.59; 150.81; 163.56; 164.10. MS: 311 (100, [M þ 1]þ). Anal. calc. for C20H22O3 (310.39):
C 77.39, H 7.14; found: C 77.10, H 7.18.
4-(4-Chlorophenyl)-3,4-dihydro-3-methoxyisocoumarin (¼4-(4-Chlorophenyl)-3,4-dihydro-3-me-
thoxy-1H-2-benzopyran-1-one; 2e). A mixture of stereoisomers (ca. 3 :2). Pale-yellow oil. Rf (Et2O/
hexane 1:1) 0.45. IR (neat): 1732. 1H-NMR: 3.52 (s, 1.8 H); 3.56 (s, 1.2 H); 4.33 (d, J ¼ 2.7, 0.4 H); 4.54 (d,
J ¼ 3.2, 0.6 H); 5.39 (d, J ¼ 3.2, 0.6 H); 5.40 (d, J ¼ 2.7, 0.4 H); 6.94 (d, J ¼ 7.8, 0.6 H); 7.05 (d, J ¼ 8.2,
1.2 H); 7.14 (d, J ¼ 7.8, 0.4 H); 7.26 (d, J ¼ 8.2, 0.8 H); 7.30 (d, J ¼ 8.2, 0.8 H); 7.35 (d, J ¼ 8.2, 1.2 H); 7.43
(dd, J ¼ 7.8, 7.3, 0.6 H); 7.46 (dd, J ¼ 7.8, 7.3, 0.4 H); 7.51 (ddd, J ¼ 7.8, 7.3, 1.4, 0.6 H); 7.57 (ddd, J ¼ 7.8, 7.3,

Helvetica Chimica Acta – Vol. 95 (2012)
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1.4, 0.4 H); 8.17 (d, J ¼ 7.8, 0.6 H), 8.21 (d, J ¼ 7.8, 0.4 H). 13C-NMR: 48.15; 48.17; 56.92; 57.24; 103.92;
105.79; 124.59; 125.08; 127.56; 127.86; 128.16; 128.65; 128.75; 129.16; 129.73; 130.01; 130.08; 131.90;
133.76; 134.02; 134.03; 134.09; 134.49; 136.65; 139.01; 139.49; 163.27; 163.76. MS: 289 (100, [M þ 1]þ).
Anal. calc. for C16H13ClO3 (288.73): C 66.56, H 4.54; found: C 66.60, H 4.57.
3,4-Dihydro-3-methoxy-4-(3-methoxyphenyl)isocoumarin (¼ 3,4-Dihydro-3-methoxy-4-(3-methoxy-
phenyl)-1H-2-benzopyran-1-one; 2f). A mixture of stereoisomers (ca. 4 :1). Yellow oil. Rf (AcOEt/
1
hexane 3 :10) 0.32. IR (neat): 1732. H-NMR: 3.52 (s, 2.4 H); 3.56 (s, 0.6 H); 3.75 (s, 0.6 H); 3.79 (s,
2.4 H); 4.32 (d, J ¼ 2.3, 0.2 H); 4.54 (d, J ¼ 2.3, 0.8 H); 5.42 (d, J ¼ 2.3, 0.8 H); 5.45 (d, J ¼ 2.3, 0.2 H);
6.64 – 6.82 (m, 1 H); 6.89 – 6.93 (m, 2 H); 6.97 (d, J ¼ 7.8, 0.8 H); 7.09 – 7.31 (m, 1.4 H); 7.39 – 7.56 (m,
1.8 H); 8.16 (d, J ¼ 7.8, 0.8 H); 8.19 (d, J ¼ 7.8, 0.2 H). 13C-NMR: 48.61; 48.77; 55.16; 55.19; 56.86; 57.22;
104.26; 106.00; 112.62; 113.28; 114.56; 116.31; 120.59; 122.94; 124.55; 125.03; 127.61; 127.67; 127.94;
128.77; 129.48; 129.83; 129.88; 129.97; 133.96; 134.37; 136.91; 139.30; 139.69; 139.86; 159.63; 159.93;
163.47; 163.97. MS: 285 (100, [M þ 1]þ). Anal. calc. for C17H16O4 (284.31): C 71.82, H 5.67; found: C 71.58,
H 5.80.
3,4-Dihydro-3,6-dimethoxy-4-methylisocoumarin (¼ 3,4-Dihydro-3,6-dimethoxy-4-methyl-1H-2-ben-
zopyran-1-one; 2i). A mixture of stereoisomers (ca. 3 :2). Pale-yellow solid. M.p. 75 – 858 (after
purification by PLC on SiO2). IR (KBr): 1728, 1715. 1H-NMR: 1.357 (d, J ¼ 6.9, 1.2 H); 1.364 (d, J ¼ 6.9,
1.8 H); 3.05 – 3.10 (m, 0.6 H); 3.27 – 3.29 (m, 0.4 H); 3.55 (s, 1.8 H); 3.57 (s, 1.2 H); 3.87 (s, 1.8 H); 3.88 (s,
1.2 H); 5.16 (d, J ¼ 2.3, 0.6 H); 5.25 (d, J ¼ 3.2, 0.4 H); 6.73 (d, J ¼ 2.3, 0.6 H), 6.77 (d, J ¼ 2.3, 0.4 H); 6.88
(dd, J ¼ 8.7, 2.3, 1 H); 8.05 (d, J ¼ 8.7, 1 H). 13C-NMR: 13.25; 19.01; 36.32; 37.84; 55.48 (2 overlapped Cs);
56.76; 57.12; 104.55; 106.12; 111.51; 112.13; 112.64; 113.25; 116.21; 116.91; 132.41; 132.51; 143.95; 144.92;
153.23; 153.95; 154.22; 154.26. MS: 223 (100, [M þ 1]þ). Anal. calc. for C12H14O4 (222.24): C 64.85, H
6.35; found: C 64.81, H 6.43.
3,4-Dihydro-3,6-dimethoxy-4-phenylisocoumarin (¼ 3,4-Dihydro-3,6-dimethoxy-4-phenyl-1H-2-ben-
zopyran-1-one; 2j). A mixture of diastereoisomers (ca. 7:3). Pale-yellow oil. Rf (AcOEt/hexane 1:5)
0.50. IR (neat): 1728, 1607. 1H-NMR: 3.51 (s, 0.9 H); 3.56 (s, 2.1 H); 3.75 (s, 0.9 H); 3.80 (s, 2.1 H); 4.29
(d, J ¼ 2.8, 0.7 H); 4.51 (s, 0.3 H); 5.39 (s, 0.3 H); 5.40 (d, J ¼ 2.8, 0.7 H); 6.42 (d, J ¼ 2.7, 0.3 H); 6.62 (d,
J ¼ 2.3, 0.7 H); 6.90 (dd, J ¼ 8.7, 2.7, 0.3 H); 6.94 (dd, J ¼ 8.7, 2.3, 0.7 H); 7.12 (d, J ¼ 8.7, 1 H); 7.28 – 7.38
(m, 4 H); 8.12 (d, J ¼ 8.7, 0.3 H); 8.15 (d, J ¼ 8.7, 0.7 H). 13C-NMR: 49.07; 49.11; 55.44; 55.50; 56.85; 57.22;
104.09; 105.86; 113.01; 113.16; 113.31; 114.16; 117.22; 117.66; 127.74; 128.01; 128.32; 128.55; 128.97;
130.58; 132.30; 132.34; 135.41; 138.13; 141.73; 142.45; 163.33; 163.87; 164.14; 164.39. MS: 285 (100, [M þ
1]þ). Anal. calc. for C17H16O4 (284.31): C 71.82, H 5.67; found: C 71.70, H 5.54.
1,1-Dimethylethyl 2-[2-Methoxy-1-(4-methoxyphenyl)ethenyl]benzoate (¼tert-Butyl 2-[2-Methoxy-
1-(4-methoxyphenyl)ethenyl]benzoate; 3). To a stirred soln. of 1-lithio-2-[2-methoxy-1-(4-methoxyphen-
yl)ethenyl]benzene, generated from 1g (0.18 g, 0.55 mmol) and BuLi (1.65m in hexane; 0.55 mmol), as
described for the preparation of 2a, in Et2O (5 ml) at 08 was added (Boc)2O (0.12 g, 0.55 mmol). After
20 min, H2O (15 ml) was added, and the mixture was extracted with Et2O (3 ꢀ 10 ml). The combined
extracts were washed with H2O and then brine (15 ml each), and dried (Na2SO4). After evaporation of
the solvent, the residue was purified by CC (SiO2) to afford 3 (0.13 g, 68%) as a mixture of stereoisomers
((E)/(Z) ¼ ca. 3 :2). An anal. specimen of each isomer was obtained by fractional CC.
Data of (E)-3. Colorless oil. Rf (THF/hexane 1:20) 0.38. IR (neat): 1709, 1634, 1607. 1H-NMR: 1.28
(s, 9 H); 3.76 (s, 3 H); 3.77 (s, 3 H); 6.12 (s, 1 H); 6.80 (d, J ¼ 9.2, 2 H); 7.24 (dd, J ¼ 7.8, 1.4, 1 H); 7.33
(ddd, J ¼ 7.8, 7.3, 1.4, 1 H); 7.35 (d, J ¼ 9.2, 2 H); 7.40 (ddd, J ¼ 7.8, 7.3, 1.4, 1 H); 7.65 (dd, J ¼ 7.8, 1.4, 1 H).
Anal. calc. for C21H24O4 (340.41): C 74.09, H 7.11; found: C 73.96, H 7.15.
Data of (Z)-3. Colorless oil. Rf (THF/hexane 1:20) 0.25. IR (neat) 1711, 1641, 1606. 1H-NMR: 1.37
(s, 9 H); 3.67 (s, 3 H); 3.76 (s, 3 H); 6.49 (s, 1 H); 6.78 (d, J ¼ 9.2, 2 H); 7.07 (d, J ¼ 9.2, 2 H); 7.21 (dd, J ¼
7.8, 1.4, 1 H); 7.31 (ddd, J ¼ 7.8, 7.3, 1.4, 1 H); 7.43 (ddd, J ¼ 7.8, 7.3, 1.4, 1 H); 7.76 (dd, J ¼ 7.8, 1.4, 1 H).
Anal. calc. for C21H24O4 (340.41): C 74.09, H 7.11; found: C 73.87, H 7.15.
3,4-Dihydro-3-methoxy-4-(4-methoxyphenyl)isocoumarin (¼ 3,4-Dihydro-3-methoxy-4-(4-methoxy-
phenyl)-1H-2-benzopyran-1-one; 2g). To a stirred soln. of 3 (86 mg, 0.25 mmol) in MeCN (2 ml) at 08
was added conc. HI (32 mg, 0.25 mmol). After stirring for 3 h, sat. aq. NaHCO3 (10 ml) was added, and
MeCN was removed by evaporation. The mixture was extracted with AcOEt (3 ꢀ 5 ml), and the
combined extracts were washed with brine (5 ml) and dried (Na2SO4). After evaporation of the solvent,

196
Helvetica Chimica Acta – Vol. 95 (2012)
the residue was purified by PLC (SiO2) to give 2g (62 mg, 88%) as a mixture of diastereoisomers ((E)/
(Z) ¼ ca. 3 :2). Pale-yellow solid. M.p. 80 – 838. IR (KBr): 1732, 1611. 1H-NMR: 3.52 (s, 1.2 H); 3.56 (s,
1.8 H); 3.78 (s, 1.8 H); 3.83 (s, 1.2 H); 4.30 (d, J ¼ 2.7, 0.6 H); 4.52 (d, J ¼ 3.2, 0.4 H); 5.39 (d, J ¼ 3.2,
0.4 H); 5.40 (d, J ¼ 2.7, 0.6 H); 6.85 (d, J ¼ 9.2, 1.2 H); 6.91 (d, J ¼ 8.7, 0.8 H); 6.96 (d, J ¼ 7.8, 0.4 H); 7.01
(d, J ¼ 9.2, 1.2 H); 7.16 (d, J ¼ 7.8, 0.6 H); 7.25 (d, J ¼ 8.7, 0.8 H); 7.39 – 7.45 (m, 1 H); 7.49 (ddd, J ¼ 7.8, 7.3,
1.4, 0.4 H); 7.55 (ddd, J ¼ 7.8, 7.3, 1.4, 0.6 H); 8.16 (dd, J ¼ 7.8, 1.4, 0.4 H); 8.19 (dd, J ¼ 7.8, 1.4, 0.6 H).
13C-NMR: 47.87; 47.95; 55.20; 55.21; 56.83; 57.20; 104.46; 106.23; 113.93; 114.32; 124.54; 125.07; 127.31;
127.52; 127.62; 127.80; 128.72; 129.36; 129.77; 129.84; 130.19; 131.61; 133.92; 134.34; 139.81; 140.34;
159.01; 159.29; 163.56; 164.04. MS: 285 (100, [M þ 1]þ). Anal. calc. for C17H16O4 (284.31): C 71.82, H 5.67;
found: C 71.70, H 5.94.
4-[1,1’-Biphenyl-4-yl]-3,4-dihydro-3-methoxyisocoumarin (¼4-[1,1’-Biphenyl-4-yl]-3,4-dihydro-3-
methoxy-1H-2-benzopyran-1-one; 2h). 1-{1-[1,1’-Biphenyl-4-yl]-2-methoxyethenyl}-2-bromobenzene
(0.20 g, 0.55 mmol) was treated successively with BuLi (1.6m in hexane, 0.55 mmol) and CO2 gas as
described for the preparation of 2a. The resulting mixture was worked up as described for the
preparation of 3. The crude product 4 (0.18 g) was dissolved in MeCN (2 ml) and treated with a drop of
conc. HI at r.t. for 20 min under stirring. Sat. aq. NaHCO3 (10 ml) was added, and MeCN was removed by
evaporation. The resulting mixture was extracted with AcOEt (3 ꢀ 5 ml), and the combined extracts
were washed with H2O (10 ml) and dried (Na2SO4). After evaporation of the solvent, the residue was
purified by CC (SiO2; AcOEt/hexane 1:5) to afford 2h (66 mg, 55%). Mixture of diastereoisomers ((E)/
1
(Z) ca. 7:3). Pale-yellow solid. M.p. 52 – 558. IR (KBr): 1732, 1603. H-NMR: 3.55 (s, 0.9 H); 3.59 (s,
2.1 H); 4.41 (d, J ¼ 2.7, 0.7 H); 4.61 (d, J ¼ 2.7, 0.3 H); 5.46 (d, J ¼ 2.7, 0.3 H), 5.48 (d, J ¼ 2.7, 0.7 H); 7.02 –
7.62 (m, 12 H); 8.19 (dd, J ¼ 7.8, 1.4, 0.3 H); 8.22 (dd, J ¼ 7.8, 1.4, 0.7 H). 13C-NMR: 48.38; 48.48; 56.91;
57.28; 104.29; 106.45; 124.63; 125.10; 127.01; 127.03; 127.22; 127.42; 127.45; 127.67; 127.70; 127.74; 128.00;
128.10; 128.75; 128.78; 129.91; 129.97; 130.97 (2 overlapped Cs); 134.03; 134.44; 137.13 (2 overlapped Cs);
139.40; 139.96; 140.33; 140.49; 140.69; 140.84; 163.52; 164.03. MS: 331 (100, [M þ 1]þ). Anal. calc. for
C22H18O3 (330.38): C 79.98, H 5.49; found: C 79.74, H 5.60.
We thank Mrs. Miyuki Tanmatsu for recording mass spectra and performing combustion analyses.
REFERENCES
[1] S. Kamisuki, C. Ishimaru, K. Onoda, I. Kuriyama, N. Ida, F. Sugawara, H. Yoshida, Y. Mizushima,
Bioorg. Med. Chem. 2007, 15, 3109; S. Shinkaruk, B. Bennetau, P. Babin, J.-M. Schmitter, V.
Lamothe, C. Bennetau-Pelissero, M. C. Urdaci, Bioorg. Med. Chem. 2008, 16, 9383.
[2] T. Kokubun, N. C. Veitch, P. D. Bridge, M. S. J. Simmonds, Phytochemistry 2003, 62, 779; G. Gao, S.
Qi, S. Zhang, H. Yin, Z. Xiao, M. Li, Q. Li, Pharmazie 2008, 63, 542; Z.-Y. Zhou, R. Liu, M.-Y. Jiang,
L. Zhang, Y. Niu, Y.-C. Zhu, Z.-J. Dong, J.-K. Liu, Chem. Pharm. Bull. 2009, 57, 975.
[3] N. Tahara, T. Fukuda, M. Iwao, Tetrahedron Lett. 2004, 45, 5117; Y. Kurosaki, T. Fukuda, M. Iwao,
Tetrahedron 2005, 61, 3289; S. K. Mandal, S. C. Roy, Tetrahedron Lett. 2007, 48, 4131; K. Uchida, T.
Fukuda, M. Iwao, Tetrahedron 2007, 63, 7178; S. K. Mandal, S. C. Roy, Tetrahedron 2008, 64, 11050;
M. Sher, A. Ali, H. Reinke, P. Langer, Tetrahedron Lett. 2008, 49, 5400; M. D. Obushak, V. S.
Matiychuk, V. V. Turytsya, Tetrahedron Lett. 2009, 50, 6112; I. Ullah, M. Sher, R. A. Khera, A. Ali,
M. F. Ibad, A. Villinger, C. Fischer, P. Langer, Tetrahedron 2010, 66, 1874; A. Rioz-Martꢂnez, G.
˜
de Gonzalo, D. E. Torres Pazmino, M. W. Fraaije, V. Gotor, J. Org. Chem. 2010, 75, 2073.
[4] K. Kobayashi, Y. Shirai, T. Nagaoka, H. Konishi, Synth. Commun. 2009, 39, 2866.
[5] K. Kobayashi, K. Hayashi, K. Miyamoto, O. Morikawa, H. Konishi, Synthesis 2006, 2934.
[6] K. Kobayashi, T. Nagaoka, S. Fukamachi, Y. Shirai, O. Morikawa, H. Konishi, Synthesis 2007, 3032;
K. Kobayashi, K. Hayashi, C. Num, S. Fukamachi, H. Konishi, Heterocycles 2008, 75, 1225; K.
Kobayashi, D. Nakai, K. Hayashi, H. Konishi, Heterocycles 2008, 75, 3025.
Received July 25, 2011