Application of organolithium and related reagents in synthesis. XXVII.[1] Effect of the nucleophilic character of silyl enol ethers upon the conversion of 3-arylphthalides into 2-(1-Aryl-2-methoxycarbonyl) benzoic acids

Article abstract of DOI:10.1081/SCC-120015823

A convenient two step protocol preparation of the ortho-alkylated (by secondary substituent with the carbomethoxy group at the end of alkyl chain) aromatic carboxylic acids 6 from benzoic acids anilides 1 was developed, which exploited the reductive alkylation of phthalides 4 with silyl vinyl ethers 5a-b or silyl ketene acetals 5c-g as a key step, is described.

Full text of DOI:10.1081/SCC-120015823

This article was downloaded by: [University of Illinois Chicago]
On: 03 December 2014, At: 00:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Application of Organolithium and Related Reagents in
Synthesis. XXVII. Effect of the Nucleophilic Character
of Silyl Enol Ethers Upon the Conversion of 3-
Arylphthalides into 2-(1-Aryl-2-methoxycarbonyl)
Benzoic Acids
Adam Bieniek a , Jan Epsztajn a & Krystyna K. Kulikiewicz a
a Department of Organic Chemistry , Institute of Chemistry , University of Łódź , Łódź,
Narutowicza, Poland
Published online: 16 Aug 2006.
To cite this article: Adam Bieniek , Jan Epsztajn & Krystyna K. Kulikiewicz (2003) Application of Organolithium and
Related Reagents in Synthesis. XXVII. Effect of the Nucleophilic Character of Silyl Enol Ethers Upon the Conversion of 3-
Arylphthalides into 2-(1-Aryl-2-methoxycarbonyl) Benzoic Acids, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:4, 667-677, DOI: 10.1081/SCC-120015823
To link to this article: http://dx.doi.org/10.1081/SCC-120015823
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 667–677, 2003
Application of Organolithium and Related
Reagents in Synthesis. XXVII.[1] Effect of the
Nucleophilic Character of Silyl Enol Ethers
Upon the Conversion of 3-Arylphthalides into
2-(1-Aryl-2-methoxycarbonyl) Benzoic Acids
*
Adam Bieniek, Jan Epsztajn, and Krystyna K. Kulikiewicz
*
Department of Organic Chemistry,
Institute of Chemistry, University of Lodz,
Lodz, Narutowicza, Poland
ABSTRACT
A convenient two step protocol preparation of the ortho-alkylated
(by secondary substituent with the carbomethoxy group at the end of
alkyl chain) aromatic carboxylic acids 6 frombenzoic acids anilides 1
was developed, which exploited the reductive alkylation of phthalides 4
*Correspondence: AdamBieniek and Jan Epsztajn, Department of Organic
Chemistry, Institute of Chemistry, University of Lodz, 90-136 Lodz,
Narutowicza 68, Poland; Fax: þ(4842) 6786583; E-mail: epsztajn@krysia.uni.
lodz.pl.
667
DOI: 10.1081/SCC-120015823
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
668
Bieniek, Epsztajn, and Kulikiewicz
with silyl vinyl ethers 5a–b or silyl ketene acetals 5c–g as a key step, is
described.
Key Words: ortho-Metallation; Mukaiyama reaction; 3-Aryl-
phthalides; Silyl enol ethers; Benzoic acids.
In the course of our synthetic project we required an effective
preparative methodology for ortho-alkylated carboxylic acids of type B.
These species are key starting materials for preparation of numerous
poly-aromatic compounds including an important antagonist of
thromboxane.[2,3] Recently, we have successfully developed an effective
and regiospecific sequence of reactions for the transformation of
aromatic carboxylic acids A via their conversion into phthalides, which
upon treatment with methyl–trimethylsilyl ketene acetal in the presence
of titaniumtetrachloride (modification of the Mukaiyama [4–8] procedure)
furnished desired acids B.[9] This method opens a general strategy for
transformation of carboxylic acids A into ortho-alkylated benzoyl
acids type B in a two-step protocol starting frombenzoic acids anilides 1
(Sch. 1).
It has been shown that the rate of reaction of diaryl carbenium
ions with silyl enol ethers or silyl ketene acetals is effected by their
nucleophilicity.[10]
Therefore, appeared the question to what extent the conver-
sion of phthalides 4 into ortho-alkylated benzoic acids 6 is effected
by the nucleophilicity of used silyl enol ethers or trimethylsilyl ketene
acetals.
To this end, phthalides 4a and 4b were selected for testing the
reductive alkylation process. The 3-aryl-phthalides 4 were obtained by the
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Organolithium and Related Reagents. XXVII
669
Scheme 2. (i) n-BuLi in THF/hexane, À78ꢀC/1 h ! 0ꢀC, (ii) Ar-CHO,
À78ꢀC ! 20ꢀC/1 h, (iii) HCl (1:1), (iv) 5a–g/CH2Cl2/TiCl4/0ꢀC, (v) 5 % NaOH.
For compounds 1, 2: a: R1 ¼ H; b: R1 ¼ OMe. For compounds, 3, 4: a: R1 ¼ H,
R2 ¼ OMe, R3 ¼ H; b: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe. For compound 6:
a: R1 ¼ H, R2 ¼ OMe, R3 ¼ H, R4 ¼ Me; b: R1 ¼ H, R2 ¼ OMe, R3 ¼ H, R4 ¼ Ph;
c: R1 ¼ H, R2 ¼ OMe, R3 ¼ H, R4 ¼ OMe; d: R1 ¼ H, R2 ¼ OMe, R3 ¼ H,
R4 ¼ OC6H4F( p); e: R1 ¼ H, R2 ¼ OMe, R3 ¼ H, R4 ¼ OC6H5; f: R1 ¼ H, R2 ¼
OMe, R3 ¼ H, R4 ¼ OC6H4Me( p); g: R1 ¼ H, R2 ¼ OMe, R3 ¼ H,
R4 ¼ OC6H4OMe( p); h: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe, R4 ¼ Me; i: R1 ¼ OMe,
R2 ¼ H, R3 ¼ OMe, R4 ¼ Ph; j: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe, R4 ¼ OMe;
k: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe, R4 ¼ OC6H4F( p); l: R1 ¼ OMe, R2 ¼ H,
R3 ¼ OMe, R4 ¼ OC6H5; m: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe, R4 ¼ OC6H4Me( p);
n: R1 ¼ OMe, R2 ¼ H, R3 ¼ OMe, R4 ¼ OC6H4OMe( p).

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
670
Bieniek, Epsztajn, and Kulikiewicz
Scheme 3. a: R4 ¼ Me; b: R4 ¼ Ph; c: R4 ¼ OMe; d: R4 ¼ OC6H4F( p);
e: R4 ¼ OC6H5; f: R4 ¼ OC6H4Me( p); g: R4 ¼ OC6H4OMe( p).
lithiation of benzoic acids anilides 1, using BuLi in THF,[11–13] followed
by the reaction of the generated bis(N- and C-ortho)-lithiated anilides 2
with aromatic aldehydes. Thus, the formed ortho-hydroxy-arylmethyl
products 3, without isolation upon acid-driven cyclization, yielded the
corresponding phthalides 4 (Sch. 2).
Recently,[9] it has been shown that the reductive alkylation is
significantly affected by the substituents surrounding the reactive
centre of phthalides used and that 4a is twice as much reactive than
4b towards the reaction with 1-methoxy-1-trimethylsilyloxyethene
5c. This nucleophile was used here as a standard and all others
were referred to it. The following nucleophilic reagents 5 were tested
(Sch. 3).
Silyl enol ethers 5a and 5b as well as trimethylsilyl ketene acetals
5c–5g were prepared by treating of the corresponding ketones or acetic
acid esters sequently with lithiumdiisopropyl amide (LDA) and
trimethylsilyl chloride (TMS-Cl)[14,15] (see Experimental).
The detailed results of the reaction of nucleophiles 5 with the
phthalides 4 are reported in the Table 1. An examination of the data
reveals that the only products obtained fromthe reaction were the
corresponding alkylated products 6 together with recovered phthalides.
The high overall yields obtained apparently show that all other possible
reactions were minimized.
The observed yields indicated that the tested reductive alkylation of
phthalides 4 is influenced by two different effects, which are opposite to
each other. The first of themdepends upon the substituents surrounding
the reaction centre. Thus, it may be attributed to the steric hindrance
caused by the methoxy group at C-4 of the phthalide nucleus (‘‘peri’’ to
the reaction centre) for the SN2-type nucleophilic attack by nucleophiles
5. This is in good agreement with the behavior of lactones in the
reaction with hard acids and soft nucleophilic systems.[16] On the other
hand, increasing nucleophilicity of reactants 5 in both series of the
phthalides 4 effectively enhances the output of the process.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Organolithium and Related Reagents. XXVII
671
Table 1.
Product yielda (%)
Recovered Overall
Reductive alkylation
(%)
phthalide 4
(%)
yield
(%)
No. Phthalide Nucleophile
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
27
(33)
(31)
(69)
(75)
(82)
(85)
(91)
(Traces)
(Traces)
–
(65)
(65)
(29)
(21)
(13)
(10)
(6)
(95)
(95)
63
(98)
(96)
(98)
(96)
(95)
(95)
(97)
25
65
70
75
79
86
5g
5a
5b
5c
5d
5e
5f
6g
6h
6i
6j
6k
6l
6m
6n
34b
47b
50b
52b
59b
97
98
96
98
97
–
–
–
–
51
46
46
38
5g
aAll yields represent isolated pure materials. Data in parenthesis represent yields
1
identified in the case of phthalides 4a by H NMR spectroscopy.
bIsolated as dicarboxylic acid 7.
Furthermore, it was demonstrated that the highly nucleophilic
1-(4-methoxy-phenyl)-1-trimethylsilyloxyethene 5g, (very readily prepared
compound) is the most convenient reagent for the construction of ortho-
alkylated benzoic acids 6. This is especially valuable when such reagent
as 5c is yielding not satisfying results.
In the case of reaction with the least nucleophilic reagent such
as 5a and 5b, the lowest yields of alkylation products 6a and 6b
were obtained. This is, particularly, distinct in the ease of sterically
hindered phthalide 4b. Only traces of compounds 6h and 6i were
formed.
In summary, we have shown that the conversion of benzoic acid
anilides 1 into ortho-alkylated carboxylic acids 6 is governed by a steric
hindrance around the reaction centre of phthalides 4 (formed in the
first stage of the process) and nucleophilicity of silyl vinyl ethers or
silyl ketene acetals 5. Increasing nucleophilicity of 5 effectively enhances
the process.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
672
Bieniek, Epsztajn, and Kulikiewicz
EXPERIMENTAL
Melting points were determined using a Boetius hot-stage apparatus
and they are uncorrected. IR spectra were recorded on a Zeiss-Jena
1
Specord 71-IR (KBr pellets). H NMR spectra were determined on a
Varian-Gemini-200 (200 MHz) using TMS as an internal standard.
Compounds were purified until observed as single spots on TLC
(Kieselgel GF-254 type 60). n-Butyllithium( n-BuLi) (Aldrich) was
titrated before use. Anilides 1,[9] silyl enol ethers 5a[14] and 5b,[14] silyl
ketene acetal 5c,[17] and p-methoxyphenyl acetate,[18] were obtained by
known methods.
Phthalides 4: General Procedure
n-BuLi (0.021 mol) was added dropwise to the anilide (0.01 mol)
in THF (25 mL) at ꢀ78ꢁC, and the solution was maintained at ꢀ78ꢁC
for 0.5 h. The mixture was warmed up to room temperature, kept at this
temperature for 1 h, and then cooled to ꢀ78ꢁC. An aldehyde (0.011 mol)
was added to the solution of the lithiated species at ꢀ78ꢁC. After 1 h at
ꢀ78ꢁC, the mixture was allowed to reach room temperature, stirred for
1 h, then HCl (50 mL, 1:1) was added, and the mixture stirred overnight.
After partial evaporation of THF, the mixture was extracted with CHCl3
(3 ꢂ 50 mL), the layers were separated, and the organic one was dried
(MgSO4). The solvent was removed and the solid residue was crystallised
to give phthalides 4.
3-(4-Methoxyphenyl)-3H-isobenzofuran-1-one (4a): Yield: 61%, m.p.:
[19]
114–116ꢁC (needles fromethanol), (lit.
m.p.: 113–114ꢁC); IR (KBr):
1760 cmꢀ1 (C¼O); H-NMR (CDCl3): 7.96 (d, 1H, J ¼ 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 ¼ 8.6 Hz, Ar–H), 6.89 (d, 2H, J ¼ 8.6 Hz, Ar–H), 6.37 (s, 1H, CH),
3.89 (s, 3H, OMe); 13C-NMR (CDCl3): 170.3, 160.1, 149.5, 134.1,
129.0, 128.5, 128.0, 125.5, 122.8, 114.0, 82.5, 55.0.
1
3-(2-Methoxyphenyl)-4-methoxy-3H-isobenzofuran-1-one (4b): Yield:
[9]
60%, m.p.: 188–190ꢁC (plates fromethanol); (lit.
m.p.: 188–190ꢁC);
IR (KBr): 1750 cmꢀ1 (C¼O); 1H-NMR (CDCl3): 7.58–7.46 (m, 2H,
Ar–H), 7.38–7.25 (m, 1H, Ar–H), 7.09 (dd, 1H, J1 ¼ 7.0, J2 ¼ 2.5 Hz,
Ar–H), 6.93 (d, 1H, J ¼ 8.2 Hz), 6.87–6.79 (m, 3H, Ar–H and CH),
3.84 (s, 3H, OMe), 3.73 (s, 3H, OMe); 13C-NMR (CDCl3): 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.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Organolithium and Related Reagents. XXVII
673
1-Aryloxy-1-trimethylosilyloxyethenes (5d–g): A mixture of the
appropriate aryl acetate (0.05 mol) and 15 mL of trimethylsilyl chloride
(0.12 mol) was added in 30 min at ꢀ78ꢁC to lithiumdiisopropylamide
(0.075 mol) (prepared from n-BuLi in hexane and diisopropylamine) in
40 mL THF. After additional 30 min at ꢀ78ꢁC the whole lot was allowed
to reach ambient temperature. Then the mixture was concentrated under
reduced pressure to give oily residue, which was washed with dry hexane,
and some solid impurities were filtered off, and the filtrate evaporated.
The obtained 1-aryloxy-1-trimethylsilyloxyethenes 5d–g were used
without isolation. All the rest in each case was an unreacted starting
aryl acetate. This does not have any effect upon the tested reaction.
All yields of the 1-aryloxy-1-trimethylosilyloxyethenes 5d–g were
1
determined by H-NMR (CDCl3, internal reference SiMe4) spectroscopy
utilising the peak areas of their methylene protons in relation to the methyl
protons of starting aryl acetals. The chemical shifts of the methylene and
methyl protons are, respectively as follows: ꢀ 5d: 3.48 (d, 1H, J ¼ 2.7 Hz,
CH2), 3.22 (d, 1H, J ¼ 2.7 Hz, CH2), 5e: 3.38 (d, 1H, J ¼ 2.1 Hz, CH2), 3.06
(d, 1H, J ¼ 2.1 Hz, CH2), 5f: 3.72 (d, 1H, J ¼ 3.5 Hz, CH2), 3.24 (d, 1H,
J ¼ 3.5 Hz, CH2), 5g: 3.41(d, 1H, J ¼ 2.5 Hz, CH2), 3.12 (d, 1H, J ¼ 2.5 Hz,
CH2), corresponding phenyl acetates: (ꢀ) 2.25, 2.25, 2.21, 2.27 (singlets).
1-(Fluorophenoxy)-1-trimethylsiloxyethene (5d): Yield 59%, oil
1H-NMR (CDCl3): 7.05–6.77 (m, 4H, Ar–H), 3.48 (d, 1H, J ¼ 2.7
H2, CH2), 3.22 (d, 1H, J ¼ 2.7 H2, CH2), 0.24 (s, 9H, SiMe3).
1
1-Phenoxy-1-trimethylsiloxyethene[15] (5e): Yield 67%, oil H-NMR
(CDCl3): 7.07–6.57 (m, 5H, Ar–H), 3.38 (d, 1H, J ¼ 2.1 Hz, CH2), 3.06
(d, 1H, J ¼ 2.1 Hz, CH2), 0.01 (s, 9H, SiMe3).
1-(4-Methylphenoxy)-1-trimethylsiloxyethene (5f ): Yield 85%, oil
1H-NMR (CDCl3): 7.43–7.26 (m, 4H, Ar–H), 3.72 (d, 1H, J ¼ 3.5 Hz,
CH2), 3.24 (d, 1H, J ¼ 3.5 Hz, CH2), 2.61 (s, 3H, Me), 0.30 (s, 9H, SiMe3).
1-(4-Methoxyphenoxy)-1-trimethylsiloxyethene (5g): Yield 57%, oil
1H-NMR (CDCl3): 7.20–6.98 (m, 2H, Ar–H), 6.80–6.62 (m, 2H, Ar–H),
3.77 (s, 3H, OMe), 3.41 (d, 1H, J ¼ 2.5 Hz, CH2), 3.12 (d, 1H, J ¼ 2.5 Hz,
CH2), 0.28 (s, 9H, SiMe3).
Reaction of vinyl silyl ether 5a–b or silyl ketene acetal 5c–g
with 3-arylphtalides 4: To stirred solution of phthalides 4 (0.01 mol)
and vinyl silyl ether 5a–b or silyl ketene acetal 5c–g (0.02 mol) in
100 mL of CH2Cl2, a solution of TiCl4 (2.0 mL) in CH2Cl2 (15 mL) was
added dropwise at 0ꢁC for 5a–b or at ꢀ60ꢁC for 5c–g. The mixture was
stirred for additional 1.5 h at the appropriate temperature and
overnight at room temperature. Next 50 mL of 5% of water solution of
KHSO4 was added, and after 1 h the mixture was extracted with chloro-
form(3 ꢂ 35 mL). Then the whole lot of the combined extracts was eva-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
674
Bieniek, Epsztajn, and Kulikiewicz
porated till dryness. To the solid residue derived fromphthalide 4a 10%
water solution of Na2CO3 (100 mL) was added and stirred for 2 h. After
filtering off unreacted phthalide 4a, the aqueous layer was acidified with
10% HCl. The precipitated products 6a–g were filtered and purified by
crystallization.
The yields and ratio of the products fromthe reactions of phthalides
4a and 4b with silyl enol ether (5a–b) as well as 1-aryloxy-1-trimethyl-
silyloxyethenes (5c), (5d), (5e), (5f ), and (5g) were determined as follows,
and collected in the Table 1.
In the case of the phthalide 4a the yields of the products were deter-
mined by 1H-NMR (CDCl3; internal reference SiMe4) spectroscopy
utilizing the peak areas of its methine proton and the methine protons
of the alkylated products 6a–6g. The chemical shifts of the methine
protons of 4a and 6a–6g, are respectively as follows: ꢀ 4a—6.37 (singlet)
and ꢀ 6a—5.58, 6b—5.79, 6c—5.53, 6d—5.74, 6e —5.77, 6f—5.78, 6g—
5.80 (triplets). For the testing, small part of the combined extracts was
evaporated till dryness and directed for NMR spectroscopy.
In the case of products fromphthalide 4b the obtained solid residue
after evaporating CHCl3 was extracted with 5% water solution of NaOH
(100 mL). This caused hydrolysis of the formed monocarboxylic acid
6j–n, which converted theminto dicarboxylic acid 7. After filtering
some solid impurities, the aqueous solution of dicarboxylic acid 7
sodiumsalts were acidified with 10% HCl. The precipitated acid 7 was
filtered and purified by crystallization. Therefore, the yields resulted from
used ketene silyl acetals 5c–g are represented by amount of isolated
dicarboxylic acid 7.
2-[1-(4-Methoxyphenyl)-2-methylcarbonylethyl]benzoic acid (6a):
Yield 27%, m.p. 92–94ꢁC (needles frombenzene); IR (KBr): 1712,
1690 cmꢀ1 (C¼O); 1H-NMR (CDCl3): 7.96–7.92 (m, 1H, Ar–H),
7.48–7.41 (m, 1H, Ar–H), 7.31–7.16 (m, 4H, Ar–H), 6.84–6.80 (m, 1H,
Ar–H), 5.58 (t, 1H, J ¼ 7.8 Hz, CH), 3.76 (s, 3H, OMe), 3.24–3.20 (m, 2H,
CH2); 13C-NMR (CDCl3): 207.9, 171.9, 158.1, 145.6, 134.8, 132.6, 131.1,
129.2, 128.9, 128.4, 126.3, 113.9, 55.2, 50.2, 40.2, 29.8. Anal. calcd. for
C18H18O4: C 72.47; H 6.08. Found: C 72.47; H 6.01.
2-[1-(4-Methoxyphenyl)-2-phenylcarbonylethyl]benzoic acid (6b): Yield
25%, m.p. 130–132ꢁC (needles frombenzene); IR (KBr): 1713, 1680 cm ꢀ1
1
(C¼O); H-NMR (CDCl3): 7.98–7.85 (m, 2H, Ar–H), 7.79–7.15 (m, 9H,
Ar–H), 6.90–6.40 (m, 2H, Ar–H), 5.79 (t, 1H, J ¼ 4.0 Hz, CH), 3.78 (s, 3H,
OMe), 3.40–3.29 (m, 2H, CH2); 13C-NMR (CDCl3): 205.1, 171.8, 159.2,
145.2, 137.0, 134.7, 133.1, 133.0, 130.4, 129.3, 128.7, 128.4, 128.2, 126.1,
114.9, 55.6, 52.2, 34.2. Anal. calcd. for C23H20O4: C 77.65; H 5.59. Found:
C 77.68; H 5.57.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Organolithium and Related Reagents. XXVII
675
2-[2-Methoxy-1-(4-methoxyphenyl)carbonylethyl]benzoic acid (6c):
Yield 65%, m.p. 147–149ꢁC (plates fromMeOH/H O, 1:1), (lit.[9] m.p.
2
148–150ꢁC); IR (KBr): 1710, 1690 cmꢀ1 (C¼O); H-NMR (CDCl3): 7.94
1
(d, 1H, J ¼ 8.1 Hz, Ar–H), 7.55–7.40 (m, 1H, Ar–H), 5.53 (m, 1H, CH),
3.76 (s, 3H, OMe), 3.53 (s, 3H, OMe), 3.08 (d, 2H, J ¼ 7.8 Hz, CH2);
13C-NMR (CDCl3): 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. Anal. calcd. for
C18H18O5: C 68.78; H 5.77. Found: C 68.85; H 5.70.
2-[1-(4-Methoxyphenyl)-2-(4-fluorophenyl)carbonylethyl]benzoic acid
(6d): Yield 70%, m.p. 190–192ꢁC (needles fromtoluene); IR (KBr):
1760, 1695 cmꢀ1 (C¼O); 1H-NMR (CDCl3): 12.52 (br, 1H, COOH),
7.86–7.83 (m, 1H, Ar–H), 7.45–7.14 (m, 5H, Ar–H), 7.04–6.95 (m, 2H,
Ar–H), 6.85–6.76 (m, 4H, Ar–H), 5.74 (t, 1H, J ¼ 8.1 Hz, CH), 3.76 (s,
3H, OMe), 3.32–3.26 (m, 2H, CH2); 13C-NMR (CDCl3): 170.0, 169.3,
162.2, 157.9, 157.3, 146.3, 146.1, 144.2, 134.9, 131.5, 130.9, 130.4, 128.8,
128.1, 126.1, 123.0, 122.8, 115.9, 115.5, 113.7, 78.7, 55.0, 40.7, 39.4. Anal.
calcd. for C23H19FO5: C 70.04; H 4.86. Found: C 70.84; H 4.81.
2-[1-(4-Methoxyphenyl)-2-phenoxycarbonylethyl]benzoic acid (6e):
Yield 75%, m.p. 167–169ꢁC (needles fromtoluene); IR (KBr): 1720,
1690 cmꢀ1 (C¼O); 1H-NMR (CDCl3): 7.88–7.83 (m, 1H, Ar–H),
7.49–7.38 (m, 2H, Ar–H), 7.35–7.25 (m, 5H, Ar–H), 7.22–7.12 (m, 1H,
Ar–H), 6.87–6.79 (m, 4H, Ar-H), 5.77 (t, 1H, J ¼ 8.2 Hz, CH), 3.76 (s,
3H, OMe), 3.30–3.25 (m, 2H, CH2); 13C-NMR (CDCl3): 170.0, 169.5,
157.9, 150.5, 144.2, 135.0, 131.5, 130.9, 130.4, 129.1, 128.9, 128.1, 126.1,
125.6, 121.4, 113.7, 55.1, 40.8. Anal. calcd. for C23H20O5: C 73.39; H
5.36. Found: C 73.48; H 5.39.
2-[1-(4-Methoxyphenyl)-2-(4-methylphenyl)carbonylethyl]benzoic acid
(6f): Yield 79%, m.p. 170–172ꢁC (needles fromtoluene); IR (KBr):
1
1760, 1690 cmꢀ1 (C¼O); H-NMR (CDCl3): 8.01–7.97 (m, 1H, Ar–H),
7.55–7.34 (m, 3H, Ar–H), 7.33–7.25 (m, 2H, Ar–H), 7.08–7.04 (m, 2H,
Ar–H), 7.86–6.81 (m, 2H, Ar–H), 6.71–6.68 (m, 2H, Ar–H), 5.78 (t, 1H,
J ¼ 7.8 Hz, CH), 3.77 (s, 3H, OMe), 3.32–3.26 (m, 2H, CH2); 13C-NMR
(CDCl3): 172.4, 170.6, 158.2, 148.3, 145.4, 135.3, 134.8, 132.9, 131.5,
129.8, 129.0, 128.8, 128.5, 126.5, 121.1, 113.9, 55.2, 41.1, 20.8. Anal.
calcd. for C24H22O5: C 73.83; H 5.68. Found: C 74.05; H 5.97.
2-[1-(4-Methoxyphenyl)-2-(4-methoxyphenyl)carbonylethyl]benzoic acid
(6g): Yield 85%, m.p. 113–115ꢁC (needles fromtoluene); IR (KBr): 1760,
1685 cmꢀ1 (C¼O); 1H-NMR (CDCl3): 8.02–7.98 (m, 1H, Ar–H),
7.54–7.34 (m, 2H, Ar–H), 7.33–7.24 (m, 3H, Ar–H), 6.87–6.69 (m, 6H,
Ar–H), 5.80 (t, 1H, J ¼ 8.2 Hz, CH), 3.75 (s, 3H, OMe), 3.72 (s, 3H,
OMe), 3.31–3.25 (m, 2H, CH2); 13C-NMR (CDCl3): 172.8, 170.7,
158.2, 157.1, 145.5, 144.0, 134.8, 132.9, 131.5, 129.0, 128.8, 128.5,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
676
Bieniek, Epsztajn, and Kulikiewicz
126.5, 122.1, 114.3, 113.9, 55.5, 55.2, 41.1, 29.7. Anal. calcd. for
C24H22O6: C 71.05; H 5.50. Found: C 70.93; H 5.46.
3-(2-Carboxy-6-methoxyphenyl)-3-(2-methoxyphenyl)propanoic acid
(7): M.p. 258–260ꢁC (plates fromethanol); IR (KBr): 1710, 1680 cm
ꢀ1
1
(C¼O); H-NMR (CDCl3): 7.43–7.39 (m, 1H, Ar–H), 7.22–7.06 (m, 3H,
Ar–H), 6.90–6.83 (m, 2H, Ar–H), 6.74–6.70 (m, 1H, Ar–H), 5.45 (t, 1H,
J ¼ 8.0 Hz, CH), 3.64 (s, 6H, 2 ꢂ OMe), 3.50–3.37 (m, 1H, CH2),
3.24–3.12 (m, 1H, CH2); 13C-NMR (CDCl3): 175.3, 170.7, 158.4, 157.0,
135.6, 129.8, 129.6, 128.2, 127.1, 126.8, 121.2, 119.3, 114.0, 110.0, 55.3,
54.7, 35.5, 34.5. Anal. calcd. for C18H18O6: C 65.45; H 5.49. Found: C
65.27; H 5.61.
REFERENCES
1. Epsztajn, J.; Malinowski, Z.; Brzezinski, J.Z.; Karzatka, M.
Synthesis 2001, Part 26, 2085.
2. Terao, S. Advanced in Prostaglandin, Thromboxane, and Leukotriene
Research; Samuelson, B., Wang, P.y.-K., Sun, F.F., Eds.; Raven:
New York, 1989; Vol. 19, 65.
3. Hall, S.E. Med. Res. Rev. 1991, 11, 503.
4. Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817.
5. Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043.
6. Reetz, M.T. Top. Curr. Chem. 1982, 106, 1.
7. Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417.
8. Mahrwald, R. J. Prakt. Chem/Chem.-Ztg. 1999, 341, 191.
9. Epsztajn, J.; Bieniek, A.; Kowalska, J.A.; Kulikiewicz, K.K.
Synthesis 2000, 1603.
10. Burfeindt, J.; Patz, M.; Muller, M.; Mayr, H. J. Am. Chem. Soc.
1998, 120, 3629.
11. Epsztajn, J.; Bieniek, A.; Kowalska, J.A. Tetrahedron 1991, 47, 1697.
12. Epsztajn, J.; Bieniek, A.; Kowalska, J.A.; Scianowski, J. Monatsh.
Chem. 1992, 123, 1125.
13. Epsztajn, J.; Bieniek, A.; Kowalska, J.A. Monatsh. Chem. 1996,
127, 701.
14. Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J.
Tetrahedron 1987, 43, 2075.
15. Slougui, N.; Rousseau, G. Synth. Commun. 1987, 17, 1.
16. Node, M.; Nishide, K.; Ochiai, M.; Fuji, K.; Fujita, E. J. Org.
Chem. 1981, 46, 5163.
17. Ainsworth, C.; Chen, F.; Kuo, Y.N. J. Organometal. Chem. 1972,
46, 59.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Organolithium and Related Reagents. XXVII
677
18. Jiang, X.K.; Hui, Y.Z.; Fan, W.Q. J. Am. Chem. Soc. 1984, 106,
3839.
19. Gokhale, S.M.; Joshi, R.R.; Narasimhan, N.S. Indian J. Chem.,
Sect. B 1987, 26, 1030.
Received in the Netherlands February 24, 2002

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.