Synthesis of 1,3-Dihydro-3-oxo-2-benzofuran-1-carboxylates via Intramolecular Cyclization of 2-[2-(Dimethoxymethyl)phenyl]- 2-hydroxyalkanoates Followed by Oxidation

Article abstract of DOI:10.1002/hlca.201500175

A novel and efficient method for the preparation of 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates 4 under mild conditions has been developed. Thus, the reaction of [2-(dimethoxymethyl)phenyl]lithiums, generated easily from 1-bromo-2-(dimethoxymethyl)benze

Full text of DOI:10.1002/hlca.201500175

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Synthesis of 1,3-Dihydro-3-oxo-2-benzofuran-1-carboxylates via
Intramolecular Cyclization of 2-[2-(Dimethoxymethyl)phenyl]-
2-hydroxyalkanoates Followed by Oxidation
by Kazuhiro Kobayashi*, Minami Kuroda, and Yuuho Shigemura
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 novel and efficient method for the preparation of 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates
4 under mild conditions has been developed. Thus, the reaction of [2-(dimethoxymethyl)phenyl]lithiums,
generated easily from 1-bromo-2-(dimethoxymethyl)benzenes 1, with a-keto esters gives the corre-
sponding 2-[2-(dimethoxymethyl)phenyl]-2-hydroxyalkanoates 2. The TsOH-catalyzed cyclization of
these hydroxy acetals is followed by the oxidation of the resulting cyclic acetals 3 with PCC to give the
desired products in satisfactory yields. The reaction of [2-(dimethoxymethyl)-4,5-dimethoxyphenyl]-
lithium with (MeOC¼O)2, followed by treatment with NaBH4 or organolithiums, affords 2-[2-
(dimethoxymethyl)-4,5-dimethoxyphenyl]-2-hydroxyalkanoates 6, which can similarly be transformed
into the corresponding 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates 7 in reasonable yields.
Introduction. – The 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylic acid structure has
been recently reported to be found in some biologically active compounds [1]. This
type of heterocycles has been prepared by the method based on base-mediated
alkoxycarbonylation of 2-benzofuran-1(3H)-ones followed by alkylation [2] so far,
though recently novel methods involving a RhIII-catalyzed direct functionalization of
ortho CÀH bonds of benzoic acid derivatives [3] or an N-heterocyclic carbene-
catalyzed oxidation/oxa-Michael addition of 2-alkenylbenzaldehydes [4] have been
reported. On the other hand, we have recently developed new approaches to benzene-
fused heterocycles, such as N-substituted 3-alkoxybenzo[c]thiophen-1(3H)-imines [5],
3-(w-hydroxyalkoxy)-2-benzofuran-1(3H)-ones [6], and 3-alkoxy-1H-isoindoles [7],
through the employment of reactions of [2-(dialkoxymethyl)phenyl]lithium com-
pounds with the respective electrophiles. We therefore decided to investigate the
possibility of utilizing these Li compounds for the preparation of 1,3-dihydro-3-oxo-2-
benzofuran-1-carboxylates, and envisaged that the reaction of these Li compounds with
a-keto esters would furnish 2-[2-(dialkoxymethyl)phenyl]-2-hydroxyalkanoates 2, of
which treatment with an acid followed by oxidation would provide 1,3-dihydro-3-oxo-2-
benzofuran-1-carboxylates 4. In this article, we describe the results of our study, which
provide a facile general method for the preparation of this type of 2-benzofuran-
1(3H)-ones (phthalides).
Results and Discussion. – The synthesis of 4 from 1-bromo-2-(dimethoxymethyl)-
benzenes 1 was conducted according to the process depicted in Scheme 1. We first
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Helvetica Chimica Acta – Vol. 98 (2015)
1365
Scheme 1
examined the reaction of [2-(dimethoxymethyl)phenyl]lithiums, readily generated in
situ from the Br/Li exchange between 1 and BuLi, with a-keto esters in THF at À 788.
The reaction proved to proceed relatively cleanly to give, after usual aqueous work-up
and the subsequent purification by column chromatography (silica gel), the corre-
sponding hydroxy esters 2 in fair to good yields as compiled in Table 1.
The hydroxy esters 2, thus obtained, underwent ring closure cleanly and smoothly
by treatment with a catalytic amount of TsOH · H2O in CH2Cl2 at 08 to afford 1,3-
dihydro-3-methoxy-2-benzofuran-1-carboxylates 3 as mixtures of diastereoisomers,
contaminated by their hemiacetal forms in some cases judging from 1H-NMR
spectroscopy. We were pleased to find that the desired oxidation of unpurified 3 had
taken place with excess pyridinium chlorochromate (PCC) in CH2Cl2, and that the
corresponding products 4 were produced in generally good yields as shown in Table 1 as
well. Similar oxidation of 1-methoxy-1H-2-benzopyrans to the corresponding 1H-2-
benzopyran-1-ones with PCC has been reported previously [8]. Although most of
Table 1. Preparation of 1,3-Dihydro-3-oxoisobenzofuran-1-carboxylates 4
Entry
1
R3
R4
2
Yield
[%]a)
Temp. Time
4
Yield
[%]a)b)
1
2
3
4
5
6
7
8
9
1a (R1 ¼ R2 ¼ H)
1a
Me
Ph
Me
Me 2a
80
r.t.
r.t.
reflux
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
5 d
5 d
6 d
3 d
2 h
2 h
2 h
2 h
5 h
5 h
4a
88c)
Me 2b 77
Me 2c 71
Me 2d 83
4b 68c)
1b (R1 ¼ Cl, R2 ¼ H)
4c
50c)
1c (R1 ¼ MeO, R2 ¼ H) Ph
4d 59d)
1d (R1 ¼ R2 ¼ MeO)
Me
Me
Ph
Me 2e
72
68
68
4e
4f
4g
86d)
86d)
84d)
1d
1d
1d
Et
Et
2f
2g
4-ClÀC6H4 Me 2h 65
4h 84d)
1e (R1ÀR2 ¼ OCH2O)
Me
Ph
Me 2i
Me 2j
68
70
4i
4j
68d)
78d)
10
1e
r.t.
a) Yields of isolated products. b) Yields based on 2. c) Three equiv. of PCC were used. d) Two equiv. of
PCC were used.

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Helvetica Chimica Acta – Vol. 98 (2015)
compounds 3 can be oxidized at room temperature, 3c required reflux temperature, and
the yield of the corresponding product 4c was only moderate (Entry 3). Presumably, an
electron-withdrawing Cl substituent decreases the reactivity to the oxidation. Table 1
also indicates that the O-bearing substituent(s) (especially the 6-MeO group; Entries
5 – 8) on the benzene ring of the dihydroisobenzofuran structure accelerate the
oxidation.
With a new reliable method for the preparation of 1,3-dihydro-3-oxo-2-benzofuran-
1-carboxylates in hand, we turned our attention to the development of the procedure,
which enables to introduce various substituents at the 1-position of the 1,3-
dihydroisobenzofuranone ring. As outlined in Scheme 2, 1-bromo-2-(dimethoxy-
methyl)-4,5-dimethoxybenzene (1d) was treated with BuLi as described above, and
the resulting Li compound was allowed to react with (MeOC¼O)2. After aqueous
work-up, followed by purification by column chromatography (silica gel), methyl
[2-(dimethoxymethyl)-4,5-dimethoxyphenyl](oxo)acetate (5) was obtained in satis-
factory yield. Treatment of 5 with NaBH4 or organolithiums, such as BuLi, thien-2-
yllithium, and (2-chloropyridin-3-yl)lithium, resulted in smooth conversion to [2-
(dimethoxymethyl)-4,5-dimethoxyphenyl](hydroxy)alkanoates 6 in fair yields. Trans-
formation of 6 into the corresponding 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates
7 could be achieved by following the same reaction conditions as described for the
transformation of 2e – 2h into 4e – 4h in reasonable overall yields from 6 as shown in
Table 2.
Scheme 2
Table 2. Preparation of 1,3-Dihydro-3-oxoisobenzofuran-1-carboxylates 7
Entry
6
R
Yield [%]a)
7
Yield [%]a)
1
2
3
4
6a
6b
6c
6d
H
Bu
73
57
66
72
7a
7b
7c
7d
45
56
79
78
thiophen-2-yl
2-chloropyridin-3-yl
a) Yields of isolated products.

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In conclusion, we have demonstrated that 2-[2-(dimethoxymethyl)phenyl]-2-
hydroxyalkanoates, easily accessible via the reactions of 1-bromo-2-(dimethoxyme-
thyl)benzenes with a-keto esters or (MeOC¼O)2, undergo cyclization by treatment
with a catalytic amount of TsOH under mild conditions to give the corresponding cyclic
acetals, oxidation of which with PCC provides 1,3-dihydro-3-oxoisobenzofuran-1-
carboxylates. The present sequences, which allow novel and convenient synthetic
approaches to this type of heterocycles from readily available starting materials without
using any precious reagents, are also operationally simple making them of considerably
synthetic utility.
The authors would like to thank Mrs. Miyuki Tanmatsu of our university for assistance in obtaining
MS and elemental analyses data.
Experimental Part
General. All org. solvents used in this study were dried over appropriate drying agents and distilled
prior to use. M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. Thin layer
chromatography (TLC): Merck silica gel 60 PF254 (SiO2). Column chromatography (CC): Wako Gel C-
.
200E (SiO2). IR Spectra: PerkinElmer Spectrum65 FT-IR spectrophotometer; n˜ in cmÀ1 1H- and
13C-NMR spectra: JEOL ECP500 FT NMR spectrometer (500 and 125 MHz, resp.); in CDCl3; d in ppm
rel. to Me4Si as internal standard, J in Hz. HR-DART-MS (pos.) and HR-ESI-MS (pos.): Thermo
Scientific Exactive spectrometer; in m/z. Elemental analyses: Elementar Vario EL II instrument; in %.
1-Bromo-2-(dimethoxymethyl)benzene (1a) [9], 1-bromo-4-chloro-2-(dimethoxymethyl)benzene
(1b) [10], 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (1c) [11], 1-bromo-2-(dimethoxymethyl)-
4,5-dimethoxybenzene (1d) [10], and 5-bromo-6-(dimethoxymethyl)-1,3-benzodioxole (1e) [10] were
prepared according to appropriate reported procedures. Methyl (4-chlorophenyl)(oxo)acetate [12] was
prepared by the reaction of 4-ClÀC6H4ÀMgBr with (MeOC¼O)2 under the conditions reported in [13].
BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were
commercially available.
Methyl 2-[2-(Dimethoxymethyl)phenyl]-2-hydroxypropanoate (2a). Representative Procedure. To a
stirred soln. of 1-bromo-2-(dimethoxymethyl)benzene (1a; 0.46 g, 2.0 mmol) in THF (6 ml) at À 788 was
added dropwise BuLi (1.6m in hexane, 2.0 mmol). After 15 min, MeC(O)COOMe (0.20 g, 2.0 mmol) was
added dropwise, and stirring was continued for 5 min at the same temp. before addition of a sat. aq.
NH4Cl soln. (20 ml). The mixture was warmed to r.t. and extracted with AcOEt (3 Â 15 ml). The
combined extracts were washed with brine (15 ml), dried (Na2SO4), and concentrated by evaporation.
The residue was purified by CC (SiO2; AcOEt/hexane 1:6) to give 2a (0.28 g, 56%). Colorless solid. M.p.
43 – 448 (hexane/CH2Cl2). IR (KBr): 3466, 1738. 1H-NMR: 1.86 (s, 3 H); 3.27 (s, 3 H); 3.37 (s, 3 H); 3.71
(s, 3 H); 4.48 (s, 1 H); 5.76 (s, 1 H); 7.34 – 7.38 (m, 2 H); 7.48 – 7.52 (m, 1 H); 7.66 – 7.70 (m, 1 H). Anal.
calc. for C13H18O5 (254.28): C 61.41, H 7.14; found: C 61.48, H 6.97.
Methyl [2-(Dimethoxymethyl)phenyl](hydroxy)phenylacetate (2b). Colorless oil. Rf (AcOEt/hexane
1:6) 0.31. IR (neat): 3480, 1733, 1600. 1H-NMR: 3.09 (s, 3 H); 3.30 (s, 3 H); 3.84 (s, 3 H); 4.73 (s, 1 H);
5.50 (s, 1 H); 6.92 (d, J ¼ 7.6, 1 H); 7.23 (t, J ¼ 7.6, 1 H); 7.34 – 7.39 (m, 4 H); 7.51 (dd, J ¼ 7.6, 1.5, 2 H); 7.71
(dd, J ¼ 7.6, 1.5, 1 H). Anal. calc. for C18H20O5 (316.35): C 68.34, H 6.37; found: C 68.18, H 6.50.
Methyl 2-[4-Chloro-2-(dimethoxymethyl)phenyl]-2-hydroxypropanoate (2c). Pale-yellow oil. Rf
1
(AcOEt/hexane 1:3) 0.32. IR (neat): 3462, 1739. H-NMR: 1.84 (s, 3 H); 3.24 (s, 3 H); 3.39 (s, 3 H);
3.71 (s, 3 H); 4.31 (s, 1 H); 5.78 (s, 1 H); 7.32 (dd, J ¼ 8.4, 2.3, 1 H); 7.42 (d, J ¼ 8.4, 1 H); 7.69 (d, J ¼ 2.3,
1 H). Anal. calc. for C13H17ClO5 (288.72): C 54.08, H 5.94; found: C 54.06, H 6.08.
Methyl [2-(Dimethoxymethyl)-4-methoxyphenyl](hydroxy)phenylacetate (2d). Pale-yellow oil. Rf
(AcOEt/hexane 1:3) 0.30. IR (neat): 3474, 1733. 1H-NMR: 2.98 (s, 3 H); 3.30 (s, 3 H); 3.81 (s, 3 H); 3.83
(s, 3 H); 4.58 (s, 1 H); 5.48 (s, 1 H); 6.73 (dd, J ¼ 8.4, 3.1, 1 H); 6.83 (d, J ¼ 8.4, 1 H); 7.26 (d, J ¼ 3.1, 1 H);
7.33 – 7.38 (m, 3 H); 7.51 (dd, J ¼ 8.4, 1.6, 2 H). Anal. calc. for C19H22O6 (346.38): C 65.88, H 6.40; found:
C 65.82, H 6.57.

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Methyl 2-[2-(Dimethoxymethyl)-4,5-dimethoxyphenyl]-2-hydroxypropanoate (2e). Yellow oil. Rf
1
(AcOEt/hexane 1:1) 0.29. IR (neat): 3491, 1738, 1610. H-NMR: 1.85 (s, 3 H); 3.29 (s, 3 H); 3.36 (s,
3 H); 3.72 (s, 3 H); 3.91 (s, 6 H); 4.36 (s, 1 H); 5.72 (s, 1 H); 7.00 (s, 1 H); 7.22 (s, 1 H). Anal. calc. for
C15H22O7 (314.33): C 57.32, H 7.05; found: C 57.26, H 7.18.
Ethyl 2-[2-(Dimethoxymethyl)-4,5-dimethoxyphenyl]-2-hydroxypropanoate (2f). Yellow oil. Rf
1
(AcOEt/hexane 2 :3) 0.27. IR (neat): 3483, 1732, 1610. H-NMR: 1.23 (t, J ¼ 7.6, 3 H); 1.84 (s, 3 H);
3.28 (s, 3 H); 3.36 (s, 3 H); 3.91 (s, 6 H); 4.10 – 4.30 (m, 2 H); 4.43 (s, 1 H); 5.78 (s, 1 H); 6.98 (s, 1 H); 7.23
(s, 1 H). Anal. calc. for C16H24O7 (328.36): C 58.53, H 7.37; found: C 58.29, H 7.08.
Ethyl [2-(Dimethoxymethyl)-4,5-dimethoxyphenyl](hydroxy)phenylacetate (2g). Colorless oil. Rf
1
(AcOEt/hexane 1:2) 0.29. IR (neat): 3480, 1730, 1609. H-NMR: 1.29 (t, J ¼ 7.6, 3 H); 3.05 (s, 3 H);
3.30 (s, 3 H); 3.69 (s, 3 H); 3.91 (s, 3 H); 4.28 – 4.35 (m, 2 H); 4.64 (s, 1 H); 5.42 (s, 1 H); 6.53 (s, 1 H); 7.22
(s, 1 H); 7.32 – 7.38 (m, 3 H); 7.54 (d, J ¼ 6.9, 2 H). Anal. calc. for C21H26O7 (390.43): C 64.60, H 6.71;
found: C 64.53, H 6.76.
Methyl (4-Chlorophenyl)[2-(dimethoxymethyl)-4,5-dimethoxyphenyl]hydroxyacetate (2h). Colorless
oil. Rf (AcOEt/hexane 1:2) 0.29. IR (neat): 3474, 1733, 1608. 1H-NMR: 3.13 (s, 3 H); 3.30 (s, 3 H); 3.69
(s, 3 H); 3.85 (s, 3 H); 3.91 (s, 3 H); 4.73 (s, 1 H); 5.41 (s, 1 H); 6.44 (s, 1 H); 7.22 (s, 1 H); 7.35 (d, J ¼ 8.4,
2 H); 7.49 (d, J ¼ 8.4, 2 H). Anal. calc. for C20H23ClO7 (410.85): C 58.47, H 5.64; found: C 58.21, H 5.71.
Methyl 2-[6-(Dimethoxymethyl)-1,3-benzodioxol-5-yl]-2-hydroxypropanoate (2i). Pale-yellow oil. Rf
(AcOEt/hexane 1:2) 0.28. IR (neat): 3474, 1738, 1622. 1H-NMR: 1.81 (s, 3 H); 3.26 (s, 3 H); 3.34 (s, 3 H);
3.72 (s, 3 H); 4.28 (s, 1 H); 5.70 (s, 1 H); 5.98 (s, 1 H); 5.99 (s, 1 H); 6.99 (s, 1 H); 7.19 (s, 1 H). Anal. calc.
for C14H18O7 (298.29): C 56.37, H 6.08; found: C 56.09, H 6.36.
Methyl [6-(Dimethoxymethyl)-1,3-benzodioxol-5-yl](hydroxy)phenylacetate (2j). Colorless solid.
M.p. 109 – 1108 (hexane/CH2Cl2). IR (neat): 3468, 1734, 1624. 1H-NMR: 3.08 (s, 3 H); 3.29 (s, 3 H); 3.84
(s, 3 H); 4.58 (s, 1 H); 5.45 (s, 1 H); 5.95 (s, 2 H); 6.41 (s, 1 H); 7.20 (s, 1 H); 7.34 – 7.39 (m, 3 H); 7.52 (dd,
J ¼ 8.4, 1.6, 2 H). Anal. calc. for C19H20O7 (360.36): C 63.33, H 5.59; found: C 63.10, H 5.67.
1,3-Dihydro-3-oxo-2-benzofuran-1-carboxylates 4. General Procedure. To a stirred soln. of
2
(1.0 mmol) in CH2Cl2 (3 ml) at 08 was added TsOH · H2O (9.6 mg, 0.050 mmol). Stirring was continued
for 10 min, then, the mixture was diluted with CH2Cl2 (20 ml) and a sat. aq. NaHCO3 soln. (20 ml) was
added. The layers were separated, and the aq. layer was extracted with CH2Cl2 (2 Â 5 ml). The combined
org. layers were washed with brine (15 ml), dried (Na2SO4), and concentrated by evaporation. A mixture
of the residual crude product 3 and excess PCC (see Table 1) in CH2Cl2 (10 ml) containing Celiteꢁ (1.9 g)
was stirred at the temp. indicated in Table 1. The progress of the reaction was monitored by TLC (SiO2;
AcOEt/hexane 1:7). After consumption of the starting material, the mixture was filtered under reduced
pressure. The filtrate was concentrated by evaporation and the residue was purified by CC (SiO2; AcOEt/
hexane 1:5) to afford the desired product.
Methyl 1,3-Dihydro-1-methyl-3-oxo-2-benzofuran-1-carboxylate (4a). Colorless solid. M.p. 56 – 578
(hexane/CH2Cl2; [14]: 57 – 588). The 1H-NMR data of this product were identical to those reported in [2].
Methyl 1,3-Dihydro-3-oxo-1-phenyl-2-benzofuran-1-carboxylate (4b). Colorless solid. M.p. 94 – 968
(hexane/CH2Cl2; [15]: 968). IR (KBr): 1779, 1743. 1H-NMR: 3.82 (s, 3 H); 7.37 – 7.40 (m, 3 H); 7.49 – 7.53
(m, 2 H); 7.63 (t, J ¼ 7.6, 1 H); 7.77 (t, J ¼ 7.6, 1 H); 7.90 (d, J ¼ 7.6, 1 H); 7.94 (d, J ¼ 7.6, 1 H). 13C-NMR:
53.60; 88.03; 124.74; 125.36; 125.88; 126.04; 128.85; 129.45; 130.34; 134.52; 136.13; 147.12; 168.63; 168.70.
Methyl 5-Chloro-1,3-dihydro-1-methyl-3-oxo-2-benzofuran-1-carboxylate (4c). Colorless solid. M.p.
104 – 1058 (hexane/CH2Cl2). IR (KBr): 1781, 1746. 1H-NMR: 1.91 (s, 3 H); 3.76 (s, 3 H); 7.57 (d, J ¼ 8.4,
1 H); 7.68 (dd, J ¼ 8.4, 1.5, 1 H); 7.87 (d, J ¼ 1.5, 1 H). 13C-NMR: 23.63; 53.50; 84.75; 123.49; 125.77;
126.84; 134.90; 136.59; 147.14; 167.61; 169.28. HR-DART-MS: 241.0260 ([M þ H]þ, C11H10ClO4þ ; calc.
241.0262). Anal. calc. for C11H9ClO4 (240.64): C 54.90, H 3.77; found: C 54.84, H 3.84.
Methyl 1,3-Dihydro-5-methoxy-3-oxo-1-phenyl-2-benzofuran-1-carboxylate (4d). White solid. M.p.
88 – 908 (hexane/CH2Cl2). IR (neat): 1778, 1742, 1621. 1H-NMR: 3.81 (s, 3 H); 3.89 (s, 3 H); 7.30 (dd, J ¼
8.4, 2.3, 1 H); 7.34 (d, J ¼ 2.3, 1 H); 7.37 – 7.39 (m, 3 H); 7.48 – 7.50 (m, 2 H); 7.75 (d, J ¼ 8.4, 1 H).
13C-NMR: 53.50; 55.89; 87.87; 107.63; 123.28; 125.59; 126.13; 126.99; 128.80; 129.34; 136.35; 139.35;
161.57; 168.65; 168.90. HR-ESI-MS: 299.0914 ([M þ H]þ, C17H15O5þ ; calc. 299.0914). Anal. calc. for
C17H14O5 (298.29): C 68.45, H 4.73; found: C 68.38, H 4.74.

Helvetica Chimica Acta – Vol. 98 (2015)
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Methyl 1,3-Dihydro-5,6-dimethoxy-1-methyl-3-oxo-2-benzofuran-1-carboxylate (4e). Colorless solid.
M.p. 132 – 1338 (hexane/CH2Cl2). IR (KBr): 1768, 1752 (sh.), 1601. 1H-NMR: 1.89 (s, 3 H); 3.76 (s, 3 H);
3.95 (s, 3 H); 4.00 (s, 3 H); 6.99 (s, 1 H); 7.28 (s, 1 H). 13C-NMR: 23.78; 53.26; 56.36; 56.54; 84.12; 103.30;
106.06; 116.93; 143.56; 151.19; 155.11; 169.35; 170.22. HR-ESI-MS: 267.0862 ([M þ H]þ, C13H15O6þ ; calc.
267.0863). Anal. calc. for C13H14O6 (266.25): C 58.64, H 5.30; found: C 58.34, H 5.18.
Ethyl 1,3-Dihydro-5,6-dimethoxy-1-methyl-3-oxo-2-benzofuran-1-carboxylate (4f). Colorless solid.
1
M.p. 132 – 1338 (hexane/CH2Cl2). IR (KBr): 1769, 1740, 1601. H-NMR: 1.25 (t, J ¼ 7.6, 3 H); 1.88 (s,
3 H); 3.95 (s, 3 H); 4.00 (s, 3 H); 4.12 – 4.20 (m, 1 H); 4.22 – 4.28 (m, 1 H); 6.99 (s, 1 H); 7.28 (s, 1 H).
13C-NMR: 13.94; 23.79; 56.34; 56.51; 62.46; 84.14; 103.31; 106.04; 116.97; 143.68; 151.12; 155.03; 169.43;
169.64. HR-ESI-MS: 281.1023 ([M þ H]þ, C14H17O6þ ; calc. 281.1020). Anal. calc. for C14H16O6 (280.28): C
60.00, H 5.75; found: C 59.90, H 5.73.
Ethyl 1,3-Dihydro-5,6-dimethoxy-3-oxo-1-phenyl-2-benzofuran-1-carboxylate (4g). White solid. M.p.
1
117 – 1198 (hexane/CH2Cl2). IR (neat): 1769, 1736, 1601. H-NMR: 1.29 (t, J ¼ 7.6, 3 H); 3.96 (s, 3 H);
4.00 (s, 3 H); 4.22 – 4.28 (m, 1 H); 4.31 – 4.37 (m, 1 H); 7.22 (s, 1 H); 7.31 (s, 1 H); 7.38 – 7.39 (m, 3 H);
7.44 – 7.46 (m, 2 H). 13C-NMR: 14.00; 56.38; 56.58; 62.79; 87.49; 105.86; 105.88; 117.65; 126.24; 128.82;
129.37; 136.59; 141.66; 151.38; 154.66; 168.53; 168.98. HR-ESI-MS: 343.1167 ([M þ H]þ, C19H19O6þ ; calc.
343.1176). Anal. calc. for C19H18O6 (342.35): C 66.66, H 5.30; found: C 66.56, H 5.18.
Methyl 1-(4-Chlorophenyl)-1,3-dihydro-5,6-dimethoxy-3-oxo-2-benzofuran-1-carboxylate (4h). Col-
1
orless amorphous powder. Rf (AcOEt/hexane 1:2) 0.33. IR (neat): 1772, 1741, 1600. H-NMR: 3.91 (s,
3 H); 3.96 (s, 3 H); 4.01 (s, 3 H); 7.17 (s, 1 H); 7.30 (s, 1 H); 7.36 (d, J ¼ 9.2, 2 H); 7.42 (d, J ¼ 9.2, 2 H).
13C-NMR: 53.63; 56.42; 56.65; 86.74; 105.54; 106.00; 117.40; 127.68; 129.06; 135.00; 135.57; 141.29; 151.58;
155.15; 168.66; 168.90. HR-ESI-MS: 363.0624 ([M þ H]þ, C18H16ClO6þ ; calc. 363.0630). Anal. calc. for
C18H15ClO6 (362.76): C 59.60, H 4.17; found: C 59.38, H 4.19.
Methyl 5,7-Dihydro-5-methyl-7-oxofuro[3,4-f][1,3]benzodioxole-5-carboxylate (4i). Colorless solid.
M.p. 113 – 1148 (hexane/CH2Cl2). IR (KBr): 1771, 1745 (sh.), 1611. 1H-NMR: 1.85 (s, 3 H); 3.76 (s, 3 H);
6.13 (s, 1 H); 6.14 (s, 1 H); 6.96 (s, 1 H); 7.18 (s, 1 H). 13C-NMR: 23.77; 53.29; 84.04; 102.06; 102.89;
104.34; 118.87; 145.65; 150.02; 153.94; 168.55; 169.60. HR-ESI-MS: 251.0546 ([M þ H]þ, C12H11O6þ ; calc.
251.0550). Anal. calc. for C12H10O6 (250.21): C 57.60, H 4.03; found: C 57.33, H 4.17.
Methyl 5,7-Dihydro-7-oxo-5-phenylfuro[3,4-f][1,3]benzodioxole-5-carboxylate (4j). Colorless solid.
M.p. 162 – 1638 (hexane/CH2Cl2). IR (KBr): 1772, 1740, 1610. 1H-NMR: 3.82 (s, 3 H); 6.15 (s, 2 H); 7.19
(s, 1 H); 7.21 (s, 1 H); 7.38 – 7.39 (m, 3 H); 7.46 – 7.48 (m, 2 H). 13C-NMR: 53.54; 87.29; 102.97; 104.17;
104.55; 119.30; 125.97; 128.87; 129.43; 136.26; 143.78; 150.18; 153.88; 168.11; 168.72. HR-ESI-MS:
313.0706 ([M þ H]þ, C17H13O6þ ; calc. 313.0707). Anal. calc. for C17H12O6 (312.28): C 65.39, H 3.87; found:
C 65.15, H 3.85.
Methyl [2-(Dimethoxymethyl)-4,5-dimethoxyphenyl](oxo)acetate (5) was prepared by the reaction
of [2-(dimethoxymethyl)-4,5-dimethoxyphenyl]lithium with (MeOC¼O)2 as described for the prepara-
tion of 2a. Pale-yellow solid. M.p. 91 – 928 (hexane/CH2Cl2). IR (KBr): 1756, 1734, 1699, 1601. 1H-NMR:
3.27 (s, 6 H); 3.91 (s, 3 H); 3.93 (s, 3 H); 3.96 (s, 3 H); 5.68 (s, 1 H); 7.08 (s, 1 H); 7.10 (s, 1 H). Anal. calc.
for C14H18O7 (298.29): C 56.37, H 6.08; found: C 56.30, H 6.12.
Methyl [2-(Dimethoxymethyl)-4,5-dimethoxyphenyl](hydroxy)acetate (6a). To a stirred soln. of 5
(0.20 g, 0.67 mmol) in MeOH (4 ml) at 08 was added NaBH4 (25 mg, 0.67 mmol). After 5 min, the
resulting mixture was worked up and the crude mixture was purified as described for the preparation of
2a to give 6a (0.17 g, 86%). Colorless oil. Rf (AcOEt/hexane 1:2) 0.43. IR (neat): 3475, 1744, 1609.
1H-NMR: 3.30 (s, 3 H), 3.37 (s, 3 H); 3.63 (d, J ¼ 4.6, 1 H); 3.76 (s, 3 H); 3.88 (s, 3 H); 3.91 (s, 3 H); 5.52
(d, J ¼ 4.6, 1 H); 5.62 (s, 1 H); 6.84 (s, 1 H); 7.13 (s, 1 H). Anal. calc. for C14H20O7 (300.31): C 55.99, H
6.71; found: C 55.75, H 6.72.
Methyl 2-[2-(Dimethoxymethyl)-4,5-dimethoxyphenyl]-2-hydroxyhexanoate (6b). To a stirred soln.
of 5 (0.20 g, 0.67 mmol) in THF (3 ml) was added BuLi (1.6m in hexane, 0.67 mmol) dropwise. After
5 min, the resulting mixture was worked up, and the crude mixture was purified as described for the
preparation of 2a to give 6b (0.14 g, 57%). Pale-yellow oil. Rf (AcOEt/hexane 1:1) 0.36. IR (neat): 3494,
1735, 1608. 1H-NMR: 0.93 (t, J ¼ 6.9, 3 H); 1.21 – 1.29 (m, 1 H); 1.35 – 1.47 (m, 3 H); 2.05 – 2.22 (m, 2 H);
3.26 (s, 3 H); 3.39 (s, 3 H); 3.72 (s, 3 H); 3.90 (s, 6 H); 4.42 (s, 1 H); 5.85 (s, 1 H); 6.99 (s, 1 H); 7.24 (s,
1 H). Anal. calc. for C18H28O7 (356.42): C 60.66, H 7.92; found: C 60.64, H 8.07.

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Methyl [2-(Dimethoxymethyl)-4,5-dimethoxyphenyl](hydroxy)(thiophen-2-yl)acetate (6c). Com-
pound 6c was prepared by treating 5 with thien-2-yllithium as described for the preparation of 6b.
Pale-yellow oil. Rf (AcOEt/hexane 1:2) 0.21. IR (neat): 3463, 1739, 1608. 1H-NMR: 3.32 (s, 3 H); 3.32 (s,
3 H); 3.64 (s, 3 H); 3.85 (s, 3 H); 3.90 (s, 3 H); 4.88 (s, 1 H); 5.63 (s, 1 H); 6.52 (s, 1 H); 7.05 (dd, J ¼ 4.6,
3.8, 1 H); 7.12 (dd, J ¼ 3.8, 1.5, 1 H); 7.26 (s, 1 H); 7.37 (dd, J ¼ 4.6, 1.5, 1 H). Anal. calc. for C18H22O7S
(382.43): C 56.53, H 5.80; found: C 56.30, H 5.96.
Methyl (2-Chloropyridin-3-yl)[2-(dimethoxymethyl)-4,5-dimethoxyphenyl]hydroxyacetate (6d).
Compound 6d was prepared by treating 5 with (2-chloropyridin-3-yl)lithium, generated by the reported
1
method [16]. Yellow oil. Rf (AcOEt/hexane 4 :3) 0.32. IR (neat): 3469, 1743, 1608. H-NMR: 3.20 (s,
3 H); 3.28 (s, 3 H); 3.78 (s, 3 H); 3.91 (s, 3 H); 3.95 (s, 3 H); 5.00 (s, 1 H); 5.64 (s, 1 H); 6.68 (s, 1 H); 7.17
(dd, J ¼ 7.6, 4.6, 1 H); 7.34 (s, 1 H); 7.42 (dd, J ¼ 7.6, 1.5, 1 H); 8.37 (dd, J ¼ 4.6, 1.5, 1 H). Anal. calc. for
C19H22ClNO7 (411.84): C 55.41, H 5.38, N 3.40; found: C 55.38, H 5.60, N 3.18.
Compounds 7a – 7d were prepared as described for the preparation of 4e – 4h (see the General
Procedure for 4 described above and Table 1).
Methyl 1,3-Dihydro-5,6-dimethoxy-3-oxo-2-benzofuran-1-carboxylate (7a). Pale-yellow solid. M.p.
124 – 1268 (hexane/CH2Cl2). IR (KBr): 1770, 1740 (sh.), 1602. 1H-NMR: 3.83 (s, 3 H); 3.95 (s, 3 H); 4.00
(s, 3 H); 5.80 (s, 1 H); 7.07 (s, 1 H); 7.30 (s, 1 H). 13C-NMR: 53.14; 56.37; 56.56; 77.26; 103.95; 106.17;
116.91; 138.45; 151.37; 166.20; 167.70; 159.68. HR-ESI-MS (ESI): 253.0712 ([M þ H]þ, C12H13O6þ ; calc.
253.0707). Anal. calc. for C12H12O6 (252.22): C 57.14, H 4.80; found: C 56.91, H 4.93.
Methyl 1-Butyl-1,3-dihydro-5,6-dimethoxy-3-oxo-2-benzofuran-1-carboxylate (7b). Colorless solid.
M.p. 118 – 1198 (hexane/Et2O). IR (KBr): 1769, 1741, 1602. 1H-NMR: 0.87 (t, J ¼ 7.6, 3 H); 1.22 – 1.35 (m,
4 H); 1.96 – 2.02 (m, 1 H); 2.38 – 2.44 (m, 1 H); 3.77 (s, 3 H); 3.95 (s, 3 H); 4.00 (s, 3 H); 7.00 (s, 1 H); 7.28
(s, 1 H). 13C-NMR: 13.75; 22.37; 25.39; 37.01; 53.13; 56.33; 56.55; 87.08; 103.55; 106.95; 117.29; 142.45;
151.14; 155.08; 169.55; 170.11. HR-ESI-MS: 309.1334 ([M þ H]þ, C16H21O6þ ; calc. 309.1333). Anal. calc.
for C16H20O6 (308.33): C 62.33, H 6.54; found: C 62.30, H 6.34.
Methyl 1,3-Dihydro-5,6-dimethoxy-3-oxo-1-(thiophen-2-yl)-2-benzofuran-1-carboxylate (7c). Pale-
yellow oil. Rf (AcOEt/hexane 1:2) 0.21. IR (neat): 1771, 1743, 1601. 1H-NMR: 3.85 (s, 3 H); 3.96 (s, 3 H);
4.01 (s, 3 H); 7.01 (t, J ¼ 4.6, 1 H); 7.22 (br. s, 2 H); 7.29 (s, 1 H); 7.36 (d, J ¼ 4.6, 1 H). 13C-NMR: 53.75;
56.42; 56.65; 84.54; 105.34; 105.86; 117.05; 127.00; 127.19; 127.22; 138.99; 141.82; 151.63; 155.09; 168.41;
168.56. HR-ESI-MS: 335.0584 ([M þ H]þ, C16H15O6Sþ; calc. 335.0584). Anal. calc. for C16H14O6S
(334.34): C 57.48, H 4.22; found: C 57.18, H 4.26.
Methyl 1-(2-Chloropyridin-3-yl)-1,3-dihydro-5,6-dimethoxy-3-oxo-2-benzofuran-1-carboxylate (7d).
Colorless solid. M.p. 86 – 878 (hexane/CH2Cl2). IR (KBr): 1774, 1741, 1600. 1H-NMR: 3.85 (s, 3 H); 3.99
(s, 3 H); 4.00 (s, 3 H); 7.10 (s, 1 H); 7.23 (dd, J ¼ 7.6, 4.6, 1 H); 7.36 (s, 1 H); 7.49 (dd, J ¼ 7.6, 1.5, 1 H); 8.45
(dd, J ¼ 4.6, 1.5, 1 H). 13C-NMR: 53.92; 56.48; 56.74; 86.06; 105.13; 106.61; 118.32; 122.29; 131.80; 137.33;
139.24; 150.17; 151.38; 151.98; 155.21; 168.46; 168.53. HR-ESI-MS: 364.0582 ([M þ H]þ, C17H15ClNO6þ ;
calc. 364.0582). Anal. calc. for C17H14ClNO6 (363.75): C 56.13, H 3.88, N 3.85; found: C 55.88, H 3.80, N
3.61.
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Received July 6, 2015