Application of organolithium and related reagents in synthesis, Part 24.1 Synthetic strategies based on aromatic metallation. A concise regiospecific conversion of benzoic acids into 2-(1-aryl-2-methoxycarbonylethyl)benzoic acids

Article abstract of DOI:10.1055/s-2000-7610

The synthesis of the 3-arylphthalides 3 via metallation (BuLi) of the benzanilides 1 and subsequent reaction of the generated bis-lithiated anilides 2 with aromatic aldehydes is described. Conversion of 3 into the corresponding 2-(1-aryl-2-methoxycarbonylethyl)benzoic acids 4 by treatment with 1-methoxy-1-trimethylosiloxyethene in the presence of titanium tetrachloride, as a way of regiospecific transformation of benzoic acids, is also described.

Full text of DOI:10.1055/s-2000-7610

PAPER
1603
Application of Organolithium and Related Reagents in Synthesis, Part 24.1
Synthetic Strategies Based on Aromatic Metallation. A Concise Regiospecific
Conversion of Benzoic Acids into 2-(1-Aryl-2-methoxycarbonylethyl)benzoic
Acids
Jan Epsztajn,* Adam Bieniek,* Justyna A. Kowalska, Krystyna K. Kulikiewicz
Department of Organic Chemistry, University of £ódü, 90-136 £ódü, Narutowicza 68, Poland
Fax +48(42)6786583; E-mail: epsztajn@krysia.uni.lodz.pl
Received 3 April 2000; revised 2 June 2000
Our aim was to extend the scope of this idea, as a general
Abstract: The synthesis of the 3-arylphthalides 3 via metallation
procedure, for the synthesis of new ortho-substituted ben-
zoic acids B and we report here the results obtained start-
ing with a series of 3-arylphthalides. This method
(BuLi) of the benzanilides 1 and subsequent reaction of the gener-
ated bis-lithiated anilides 2 with aromatic aldehydes is described.
Conversion of 3 into the corresponding 2-(1-aryl-2-methoxycarbo-
nylethyl)benzoic acids 4 by treatment with 1-methoxy-1-trime- provides access to an efficient synthetic sequence as a
thylosiloxyethene in the presence of titanium tetrachloride, as a way
of regiospecific transformation of benzoic acids, is also described.
general strategy for transformation of aromatic carboxylic
acids A into ortho-alkylated benzoic acids B in a two-step
Key words: lithiation, anilides, phthalides, silyl enol ethers, benzo-
ic acids
protocol starting from benzoic acids anilides 1.
In a series of recent studies, we have reported8 that the
secondary carboxamide moiety provides an excellent pos-
sibility for the regiospecific synthesis of 3-arylphthalides,
which are key starting materials here. Therefore, 3-
arylphthalides 3 were obtained by the lithiation of benzoic
acids anilides 1, using BuLi in THF,8 followed by the re-
action of the generated bis(N- and C-ortho) lithiated anil-
ides 2 with aromatic aldehydes. Thus, the formed ortho
hydroxy-arylmethyl products, without isolation upon
acid-driven cyclization, yielded the corresponding
phthalides 3.
In the next step, the Mukaiyama procedure9 was used for
the synthesis of desired ortho substituted benzoic acids 4
by treatment of phthalides 3 with the corresponding meth-
ylotrimethylosilyl ketene acetal. The Mukaiyama proce-
dure,9 which was initially known in the literature as
reaction of O-silyl enol ethers in the specific aldol con-
densation, alkylation, or Michael addition, has recently
been used for alkylation of acetylated benzyl- and allyl
alcohols2b,7 in the presence of Lewis acid such as ZnCl2. It
was expected that the reaction of phthalides 3 with 1-
methoxy-1-trimethylsilyloxyethene would provide effec-
tively the desired ortho substituted benzoic acids 4 as
products of reductive alkylation. In reality, phthalide 3a
when reacted with 1-methoxy-1-trimethylsilyloxyethene
in the presence of titanium tetrachloride in methylene
chloride furnished the corresponding 2-[2-methoxycarbo-
nyl-1-(4-methoxyphenyl)ethyl]benzoic acid 4a.
The current interest in ortho-alkylated (by secondary sub-
stituent with the carbomethoxy group at the end of alkyl
chain) aromatic carboxylic acids B as key starting materi-
als for preparation of numerous poly-aromatic com-
pounds including important physiologically active
products2 has led us to examine methods for the synthesis
of these systems.
Available methods for the preparation of ortho-alkylated
aromatic carboxylic acids generally require one of the fol-
lowing techniques. The most common approach involves
the lateral lithiation of ortho-toluic acids derivatives3,4
followed by the reaction with appropriate alkyl halides. It
appears that, this method, in the case of carboxylic acids
substituted by tertiary carbon atom, is laborious and first
requires preparation of ortho-benzylated derivatives.5,6,8c
The most attractive route so far reported for the prepara-
tion of the ortho-substituted carboxylic acids type B is the
transformation of readily available 3-arylphthalides via
reaction with the trimethylsilyl ketene acetal of ethyl pro-
pionate in the presence of ZnCl2.2b,7 However, it is still
mostly related only to specific instances.
R"
R'
COOR"'
Therefore, a question appeared to what extent fixation of
substituents in the close neighbourhood to the centre of
the reaction would affect the process. The results of the re-
action of 1-methoxy-1-trimethylsilyloxyethylene with
phthalides 3 are reported in the Table. Examination of the
data reveals that the only products obtained from the reac-
tion were the corresponding monoester of the dicarboxyl-
ic acid 4 together with recovered phthalides. In the cases
COOH
R'
COOH
A
B
Scheme 1
Synthesis 2000, No. 11, 1603–1607 ISSN 0039-7881 © Thieme Stuttgart · New York

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J. Epsztajn et al.
PAPER
Table Reaction of Phthalides 3 with 1-Methoxy-1-trimethyl-
siloxyethene
Phtalide
Product
Yield [%]
3a
3b
3c
3d
3e
3f
4a
4b
4ca
4d
4e
4f
69
67
66
66
64
34
32
22
3g
3h
4g
4h
a Part of product 4c was isolated as diacid 5c. The given yield is the
sum of products 4c and 5c.
by the methoxy group at the C-4 for the SN2-type nucleo-
philic attack by 1-methoxy-1-trimethylsilyloxyethene,
which would be in good agreement with the behaviour of
lactones in the reaction with hard acids and soft nucleo-
philic systems.10 This is especially distinct in the case of
phthalide 3h, since the steric repulsion of the 2-methoxy
and 3-methoxy groups of the phenyl ring attached at po-
sition 3 of the phthalide nuclei causes deformation of va-
lency angles of benzene nucleus (Streitweiser’s bond
rehybridization model11), which brings about an addition-
al increase of the steric hindrance around of the reaction
centre.
In summary, we have shown a versatile synthetic method
for the preparation of ortho-substituted benzoic acids type
B with an economy of steps. The synthesis involves: (i)
successive conversion of benzoic acids anilides 1 via the
direct lithiation-electrophilic substitution (aromatic alde-
hydes) sequence, into phthalides 3, and (ii) their transfor-
mation via reductive alkylation into the desired ortho-
substituted benzoic acids 4.
Mps were determined using a Boetius hot-stage apparatus and are
uncorrected. IR spectra were recorded on a Zeiss-Jena Specord 71-
1
IR (KBr pellets). H NMR spectra were determined on a Varian-
Scheme 2
Gemini-200 (200 MHz) using TMS as an internal standard. Com-
pounds were purified until observed as single spots on TLC (Kiesel-
gel GF-254, type 60). Anilides 1 and phthalide (3b) were obtained
by known methods.8b 2-Methoxybenzaldehyde, 4-methoxybenzal-
dehyde, 2,3-dimethoxybenzaldehyde and 2,5-dimethoxybenzalde-
hyde (Aldrich) were used without purification. n-BuLi (Aldrich)
was titrated before use. 1-Methoxy-1-trimethylsiloxyethene was
obtained according to a known procedure12 from methyl acetate an-
ion and chlorotrimethylsilane and it was used as a mixture with me-
thyl(trimethylsilyl) acetate as impurity. The composition of the
isomeric ratios were determined by 1H NMR (CDCl3; internal ref-
erence TMS) spectroscopy utilising the ratio of the peak areas of the
-OCH3 protons of an O-silylated (d = 3.54 ppm) to C-silylated spe-
cies (d = 3.62 ppm).
of the phthalides 3c and 3d, the formed monoesters of di-
carboxylic acids 4c and 4d were isolated after basic hy-
drolysis to the dicarboxylic acids 5c and 5d, respectively.
The observed yields indicated that the tested reductive
alkylation is significantly affected by the substituents sur-
rounding the reaction centre. In the cases of phthalides
3a-d, in which the substituent at position 4 of the phtha-
lide nucleus (“peri” to the reaction centre) is no higher
than a hydrogen atom, the reductive alkylation gave good
and comparable results. The presence of the ortho meth-
oxy group at the 3-phenyl ring of phthalide 3e did not pro-
duce a change in the reaction yield. On the other hand,
when the hydrogen atom at position 4 of the phthalide nu-
cleus was replaced by the methoxy group (compounds
3f,g), the output of the process decreased by more than a
half. This may be attributed to the steric hindrance caused
Phthalides 3; General Procedure
To the anilide (0.01 mol) in anhyd THF (25 mL) at -78 °C was add-
ed BuLi (0.021 mol) dropwise, and the solution was maintained at
-78 °C for 0.5 h. The mixture was warmed up to r.t., kept at this
temperature for 1 h, and then cooled to -78 °C. To the solution of
the lithiated species at -78 °C was added an aldehyde (0.011 mol).
After 1 h at -78°C, the mixture was allowed to reach r.t., stirred for
Synthesis 2000, No. 11, 1603–1607 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Application of Organolithium and Related Reagents in Synthesis
1605
1 h, then HCl (50 mL, 1:1) was added, and the mixture stirred over-
night. After partial evaporation of THF, the mixture was extracted
with CHCl3 (3 ¥ 50 mL), the layers were separated, and the organic
one was dried (MgSO4). The solvent was removed and solid residue
was crystallised to give phthalides 3.
13C NMR (CDCl3): d = 170.8, 158.1, 154.5, 136.9, 131.0, 130.5,
128.7, 128.4, 123.5, 120.4, 117.0, 115.3, 111.2, 55.8, 55.7.
Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.26; H,
5.23.
3-(2,5-Dimethoxyphenyl)-4-methoxy-3H-isobenzofuran-1-one
3-(4-Methoxyphenyl)-3H-isobenzofuran-1-one (3a)
Yield: 61%, mp: 114-116 °C (needles from EtOH), (Lit.13 mp:
113-114 °C).
IR (KBr): n = 1760 cm-1 (C=O).
1H NMR (CDCl3): d = 7.96 (d, 1H, J = 7.3 Hz, Ar-H), 7.72-7.30
(m, 2H, Ar-H), 7.36-7.25 (m, 1H, Ar-H), 7.18 (d, 2H, J = 8.6 Hz,
Ar-H), 6.89 (d, 2H, J = 8.6 Hz, Ar-H), 6.37 (s, 1H, CH), 3.89 (s, 3H,
OMe).
(3g)
Yield: 55%, mp: 142-144 °C (plates from EtOH), (Lit.14 mp: 133-
135 °C).
IR (KBr): n = 1760 cm-1 (C=O).
1H NMR (CDCl3): d = 7.56-7.44 (m, 2H, Ar-H), 7.14-7.02 (m, 1H,
Ar-H), 6.92-6.74 (m, 3H, Ar-H), 6.39 (s, 1H, CH), 3.80 (s, 3H,
OMe), 3.73 (s, 3H, OMe), 3.65 (s, 3H, OMe).
13C NMR (CDCl3): d = 170.8, 158.1, 154.5, 153.4, 152.4, 131.1,
130.5, 128.4, 120.4, 117.0, 115.3, 114.7, 112.6, 111.2, 56.5, 55.7.
13C NMR (CDCl3): d = 170.3, 160.1, 149.5, 134.1, 129.0, 128.5,
128.0, 125.5, 125.1, 122.8, 114.0, 82.5, 55.0.
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 68.11; H,
5.28.
3-(4-Methoxyphenyl)-5-methoxy-3H-isobenzofuran-1-one (3c)
Yield: 54%, mp: 114-116 °C (plates from EtOH).
IR (KBr): n = 1750 cm-1 (C=O).
1H NMR (CDCl3): d = 7.85 (d, 1H, J = 8.6 Hz, Ar-H), 7.21-7.14
(m, 2H, Ar-H), 7.05 (dd, 1H, J = 8.1, 2.1 Hz, Ar-H), 6.94-6.85 (m,
2H, Ar-H), 6.70 (d, 1H, J = 1.8 Hz, Ar-H), 6.27 (s, 1H, CH), 3.83
(s, 3H, OMe), 3.81 (s, 3H, OMe).
3-(2,3-Dimethoxyphenyl)-4-methoxy-3H-isobenzofuran-1-one
(3h)
Yield: 40%, mp: 193-195 °C (needles from EtOH).
IR (KBr): n = 1770 cm-1 (C=O).
1H NMR (CDCl3): d = 7.60-7.44 (m, 2H, Ar-H), 7.08 (dd, 1H,
J = 8.0, 3.6 Hz, Ar-H), 7.02-6.88 (m, 2H, Ar-H), 6.78 (s, 1H, CH),
6.45 (dd, 1H, J2 = 8.0, 2.2 Hz, Ar-H), 3.88 (s, 6H, 2 ¥ OMe), 3.72
(s, 3H, OMe).
13C NMR (CDCl3): d = 170.3, 164.9, 160.4, 152.6, 128.8, 128.4,
127.0, 118.2, 116.9, 114.3, 106.6, 82.1, 55.8, 55.3.
Anal. Calcd for C16H14O4:.C, 71.10; H, 5.22. Found: C, 70.97; H,
5.18.
13C NMR (CDCl3): d = 170.8, 154.4, 152.8, 148.2, 137.1, 131.1,
129.2, 128.3, 124.0, 119.9, 117.0, 115.4, 113.2, 61.3, 55.8, 55.6.
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.85; H,
5.34.
3-(4-Methoxyphenyl)- 7-methoxy-3H-isobenzofuran-1-one (3d)
Yield: 68%, mp: 127-129 °C (needles from EtOH).
IR (KBr): n = 1750 cm-1 (C=O).
1H NMR (CDCl3): d = 7.60-7.50 (m, 1H, Ar-H), 7.20-7.11 (m, 2H,
Ar-H), 6.96-6.76 (m, 4H, Ar-H), 6.25 (s, 1H, CH), 4.00 (s, 3H,
OMe), 3.78 (s, 3H, OMe).
13C NMR (CDCl3): d = 168.5, 160.2, 158.4, 152.6, 136.4, 128.6,
128.5, 114.6, 114.2, 113.3, 110.7, 81.6, 56.1, 55.3.
Reaction of 1-Methoxy-1-trimethylsilyloxyetene with 3-
Arylphthalides
To stirred solution of phthalide (0.01 mol) and 1-methoxy-1-trime-
thylsilyloxyethene (0.03 mol) in 10 mL of CH2Cl2, a solution of
TiCl4 (2.0 mL) in CH2Cl2 (10 mL) was added dropwise at 0 °C. The
mixture was stirred overnight at r.t.. Next, 5% KHSO4 (50 mL) was
added, and after 1 h the mixture was extracted with CHCl3
(3 ¥ 25 mL). To the combined extracts, after removal of the solvent
till dryness, 5% Na2CO3 (100 mL) was added. After filtering same
solids, the aqueous layer was acidified with 5% HCl. The precipi-
tated product 4a-h were filtered and purified by crystallisation. In
the case of phthalide 3c, the residue after extraction with Na2CO3
was extracted with 5% NaOH (100 mL). In this case, the product
was isolated as dicarboxylic acid 5c after acidification of the alka-
line solution with 5% HCl. The corresponding product was filtered
and purified by crystallisation. The monoacid 4d was formed as an
oil, therefore basic hydrolysis at r.t. with 5% NaOH furnished dicar-
boxylic acid 5d.
Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.22; H,
5.30.
3-(2,5-Dimethoxyphenyl)-3H-isobenzofuran-1-one (3e)
Yield: 77%, mp: 93-95 °C (needles from EtOH/H2O, 8:2), (Lit.14
mp: 80 °C).
IR (KBr): n = 1750 cm-1 (C=O).
1H NMR (CDCl3): d = 7.89 (d, 1H, J = 7.4 Hz, Ar-H), 7.65-7.40
(m, 3H, Ar-H), 6.97-6.60 (m, 4H, Ar-H), 3.86 (s, 3H, OMe), 3.65
(s, 3H, OMe).
13C NMR (CDCl3): d = 170.9, 153.6, 150.9, 150.3, 134.3, 129.0,
126.0, 125.3, 123.0, 114.4, 112.5, 112.1, 77.86, 56.1, 55.6.
2-[2-Methoxycarbonyl-1-(4-methoxyphenyl)ethyl]benzoic Acid
(4a)
Yield: 69%, mp: 148-150 °C (plates from MeOH/H2O, 1:1).
IR (KBr): n = 1710, 1690 cm-1 (C=O).
Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.32; H,
5.41.
1H NMR (CDCl3): d = 7.94 (d, 1H, J = 8.1 Hz, Ar-H), 7.55-7.40
(m, 1H, Ar-H), 7.38-7.20 (m, 4H, Ar-H), 6.88-6.78 (m, 2H, Ar-H),
5.53 (m, 1H, CH), 3.76 (s, 3H, OMe), 3.53 (s, 3H, OMe), 3.08 (d,
2H, J = 7.8 Hz, CH2).
13C NMR (CDCl3): d = 172.6, 172.4, 158.1, 145.4, 135.1, 132.7,
131.2, 129.2, 128.9, 128.4, 126.4, 113.8, 55,2, 51.8, 40.8, 40.7.
3-(2-Methoxyphenyl)-4-methoxy-3H-isobenzofuran-1-one (3f),
Yield: 60%, mp: 188-190 °C (plates from EtOH).
IR (KBr): n = 1750 cm-1 (C=O).
1H NMR (CDCl3): d = 7.58-7.46 (m, 2H, Ar-H), 7.38-7.25 (m, 1H,
Ar-H), 7.09 (dd, 1H, J = 7.0, 2.5 Hz, Ar-H), 6.93 (d, 1H, J = 8.2
Hz), 6.87-6.79 (m, 3H, Ar-H and CH) 3.84 (s, 3H, OMe), 3.73 (s,
3H, OMe).
Anal. Calcd for C18H18O5: C, 68.78; H, 5.77. Found: C, 68.85; H,
5.70.
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J. Epsztajn et al.
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4-Chloro-2-[2-methoxycarbonyl-1-(4-methoxyphenyl)eth-
yl]benzoic Acid (4b)
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.80; H,
5.47.
Yield: 67%, mp: 160-162 °C (needles from benzene/hexane,
10:15).
2-[1-(2,5-Dimethoxyphenyl)-2-methoxycarbonylethyl]benzoic
Acid (4e)
Yield: 64%, mp 193-195 °C (plates from PrOH).
IR (KBr): n = 1720, 1700 cm-1 (C=O).
1H NMR (CDCl3): d = 7.78-7.70 (m, 1H, Ar-H), 7.44-7.16 (m, 3H,
Ar-H), 6.80-6.65 (m, 3H, Ar-H), 5.67 (m, 1H, CH), 3.71 (s, 3H,
OMe), 3.60 (s, 3H, OMe), 3.55 (s, 3H, OMe) 3.10-2.90 (m, 2H,
CH2).
13C NMR (CDCl3): d = 176.9, 170.4, 153.4, 132.2, 131.6, 130.2,
127.8, 126.5, 113.8, 113.7, 111.2, 110.8, 55.7, 55.5, 52.4, 39.0,
35.6.
IR (KBr): n = 1730, 1690 cm-1 (C=O).
1H NMR (CDCl3): d = 7.91 (d, 1H, J = 9.0 Hz, Ar-H), 7.37-7.15
(m, 4H, Ar-H), 6.90-6.78 (m, 2H, Ar-H), 5.66 (m, 1H, CH), 3.77
(s, 3H, OMe), 3.60 (s, 3H, OMe), 3.02 (d, 2H, J = 8.1 Hz, CH2).
13C NMR (CDCl3): d = 172.1, 171.9, 158.3, 148.0, 139.2, 134.2,
132.8, 128.8, 127.3, 126.7, 114.0, 55.3, 55.2, 51.9, 40.5.
Anal. Calcd for C18H17ClO5: C, 61.99; H, 4.91; Cl, 10.16. Found: C,
62.05; H, 4.96; Cl, 10.08.
4-Methoxy-2-[2-methoxycarbonyl-1-(4-methoxyphenyl)-eth-
yl]benzoic Acid (4c)
Yield: 23%, mp: 125-127 °C (needles from benzene/hexane,
85:15).
Anal. Calcd for C19H20O6: C, 66.27; H, 5.85. Found: C,65.30; H,
65.92.
IR (KBr): n = 1740, 1690 cm-1 (C=O).
3-Methoxy-2-[2-methoxycarbonyl-1-(2-methoxyphenyl)eth-
yl]benzoic Acid (4f)
Yield: 34%, mp: 204-206 °C (plates from EtOH).
IR (KBr): n = 1740, 1690 cm-1 (C=O).
1H NMR (CDCl3): d = 7.39 (d, 1H, J = 7.8 Hz, Ar-H), 7.31-7.11
(m, 3H, Ar-H), 6.98-6.82 (m, 2H, Ar-H), 6.74 (d, 1H, J = 7.8 Hz,
Ar-H), 5.22 (dd, 1H, J = 12.0, 3.8 Hz, CH), 4.11 (dd, 1H, J = 17.9,
12.0 Hz, CH2), 3.08 (dd, 1H, J = 17.5, 5.1 Hz, CH2), 3.69 (s, 3H,
OMe), 3.67 (s, 3H, OMe), 3.66 (s, 3H, OMe).
13C NMR (CDCl3): d = 176.8, 170.5, 158.2, 156.9, 136.6, 128.6,
128.0, 127.6, 126.9, 122.2, 119.3, 114.4, 110.0, 55.4, 54.6, 52.7,
35.3, 34.2.
1H NMR (CDCl3): d = 11.59 (s, 1H, COOH), 8.08-7.99 (m, 1H,
Ar-H), 7.27-7.16 (m, 2H, Ar-H), 6.87-6.69 (m, 4H, Ar-H), 5.81
(m, 1H, CH), 3.76 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.57 (s, 3H,
OMe), 3.04 (d, 2H, J = 5.5 Hz, CH2).
13C NMR (CDCl3): d = 172.2, 163.0, 158.04, 148.9, 135.0, 134.3,
129.0, 128.9, 120.6, 114.95, 113.8, 110.7, 55.3, 55.2, 51.7, 40.9,
40.8, 30.9.
Anal. Calcd for C19H20O6: C, 66.27; H, 5.85. Found: C; 66.30; H,
5.70.
3-(2-Carboxy-5-methoxyphenyl)-3-(4-methoxyphenyl)prop-
anoic Acid (5c)
Yield: 43%, mp: 183-185 °C (needles from toluene).
Anal. Calcd for C18H18O6: C, 66.27; H, 5.87. Found: C, 66.13; H,
5.90.
IR (KBr): n = 1710, 1690 cm-1 (C=O).
3-Methoxy-2-[-1-(2,5-dimethoxyphenyl)-2-methoxycarbonyl-
ethyl]benzoic Acid (4g)
Yield: 32%, mp: 186-188 °C (plates from EtOAc).
IR (KBr): n = 1740, 1710 cm-1 (C=O).
1H NMR (CDCl3): d = 12.33 (s, 2H, COOH), 7.78 (d, 1H, J = 8.5
Hz, Ar-H), 7.28-7.18 (m, 2H, Ar-H), 6.92-6.77 (m, 4H, Ar-H),
5.64 (t, 1H, J = 7.7 Hz, CH), 3.76 (s, 3H, OMe), 3.69 (s, 3H, OMe),
2.94 (d, 2H, J = 7.7 Hz, CH2).
1H NMR (CDCl3): d = 7.31-7.12 (m, 2H, Ar-H), 7.00 (d, 1H,
J = 2.3 Hz, Ar-H), 6.88 (dd, 1H, J = 7.7, 4.2 Hz, Ar-H), 6.73-6.60
(m, 1H, Ar-H), 5.21 (dd, 1H, J = 11.5, 4.6 Hz, CH), 3.91 (dd, 1H,
J = 17.8, 11.5 Hz, CH2), 3.78 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.67
(s, 3H, OMe), 3.65 (s, 3H, COOMe), 3.08 (dd, 1H, J = 17.6, 4.6 Hz,
CH2).
13C NMR (CDCl3): d = 172.2, 163.0, 158.0, 148.9, 135.0, 134.3,
129.1, 128.9, 120.6, 115.0, 113.8, 110.7, 55.3, 55.2, 51.8, 40.8,
30.9.
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.36; H,
5.43.
13C NMR (CDCl3): d = 176.4, 170.6, 158.2, 152.7, 151.4, 136.4,
129.9, 128.1, 126.8, 122.3, 115.6, 114.4, 111.1, 110.4, 55.8, 55.4,
55.1, 52.6, 35.4, 34.4, 29.7.
2-Methoxy-6-[2-methoxycarbonyl-1-(4-methoxyphenyl)eth-
yl]benzoic Acid (4d)
Yield: (66%), oil.
Anal. Calcd for C20H22O7: C, 64.16; H, 5.92. Found: C, 64.40; H,
5.74.
IR (KBr): n = 1720, 1690 cm-1 (C=O).
1H NMR (CDCl3): d = 7.35-7.12 (m, 3H, Ar-H), 6.88-6.72 (m, 4H,
Ar-H), 4.76 (m, 1H, CH), 3.80 (s, 3H, OMe), 3.70 (s, 3H, OMe),
3.57 (s, 3H, OMe), 3.09 (d, 2H, J = 8.1 Hz, CH2).
3-Methoxy-2-[-1-(2,3-dimethoxyphenyl)-2-methoxycarbonyl-
ethyl]benzoic Acid (4h)
Yield: 22%, mp: 77-79 °C (needles from Et2O/heptane, 1:1).
IR (KBr): n = 1720, 1710 cm-1 (C=O).
3-(2-Carboxy-3-methoxyphenyl)-3-(4-methoxyphenyl)prop-
anoic Acid (5d)
Yield: 90%, mp 165-167 °C (plates from toluene).
IR (KBr): n = 1710, 1680 cm-1 (C=O).
1H NMR (CDCl3): d = 9.00 (s, 2H, COOH), 7.30-7.16 (m, 4H, Ar-
H), 6.84-6.74 (m, 3H, Ar-H), 4.78 (t, 1H, J = 7.8 Hz, CH), 3.82 (s,
3H, OMe), 3.74 (s, 3H OMe), 3.11 (d, 2H, J = 8.0, CH2).
13C NMR (CDCl3): d = 177.9, 173.5, 158.3, 156.4, 142.7, 134.0,
131.1, 128.7, 122.6, 119.5, 114.0, 109.3, 76.4, 56.0, 55.1, 42.1,
40.5.
1H NMR (CDCl3): d = 7.40-7.18 (m, 3H, Ar-H), 7.02-6.83 (m, 3H,
Ar-H), 5.36 (t, 1H, J = 6.6 Hz, CH), 3.78 (s, 3H, OMe), 3.62 (s, 3H,
OMe), 3.61 (s,3H, OMe), 3.51 (s, 3H, OMe), 3.33 (d, 2H, J = 6.6
Hz, CH2).
13C NMR (CDCl3): d = 174.6, 171.2, 158.3, 152.3, 146.9, 134.8,
129.3, 128.0, 122.7, 122.5, 120.2, 114.9, 110.8, 59.8, 55.6, 55.5,
52.2, 36.1, 35.3.
Anal. Calcd for C20H22O7: C, 64.16; H, 5.92. Found: C, 63.84; H,
6.15.
Synthesis 2000, No. 11, 1603–1607 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Application of Organolithium and Related Reagents in Synthesis
1607
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Acknowledgement
This work was supported by Grant-in-Aid for Scientific Research
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Synthesis 2000, No. 11, 1603–1607 ISSN 0039-7881 © Thieme Stuttgart · New York