Application of organolithium and related reagents in synthesis, part 31: Effective conversion of 3-arylphthalides into 2-(1-aryl-3-oxo-4- alkoxycarbonylbutyl) benzoic acids

Article abstract of DOI:10.1080/00397910600910617

A convenient three-step protocol preparation of the ortho-alkylated (longchain substituent with terminal methylcarbonyl or acetoacetate moiety) aromatic carboxylic acids 15 or 16 from benzoic acids anilides 10 was developed, which exploited the reductive

Full text of DOI:10.1080/00397910600910617

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Application of Organolithium and Related
Reagents in Synthesis, Part 31: Effective
Conversion of 3‐Arylphthalides into
2‐(1‐Aryl‐3‐oxo‐4‐alkoxycarbonyl‐butyl)benzoic
Acids
Adam Bieniek a , Krystyna K. Kulikiewicz a & Monika M. Bartczak a
a Department of Organic Chemistry , Institute of Chemistry, University of
Łódź , Łódź, Poland
Published online: 24 Nov 2006.
To cite this article: Adam Bieniek , Krystyna K. Kulikiewicz & Monika M. Bartczak (2006) Application of
Organolithium and Related Reagents in Synthesis, Part 31: Effective Conversion of 3‐Arylphthalides into
2‐(1‐Aryl‐3‐oxo‐4‐alkoxycarbonyl‐butyl)benzoic Acids, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:21, 3249-3259, DOI: 10.1080/00397910600910617
To link to this article: http://dx.doi.org/10.1080/00397910600910617
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Synthetic Communicationsw, 36: 3249–3259, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600910617
Application of Organolithium and Related
Reagents in Synthesis, Part 31: Effective
Conversion of 3-Arylphthalides into
2-(1-Aryl-3-oxo-4-alkoxycarbonyl-
butyl)benzoic Acids
Adam Bieniek, Krystyna K. Kulikiewicz, and
Monika M. Bartczak
Department of Organic Chemistry, Institute of Chemistry, University of
´ ´ ´ ´
Łodz, Łodz, Poland
Abstract: A convenient three-step protocol preparation of the ortho-alkylated (long-
chain substituent with terminal methylcarbonyl or acetoacetate moiety) aromatic
carboxylic acids 15 or 16 from benzoic acids anilides 10 was developed, which
exploited the reductive alkylation of phthalides 13 with dimethyl-6-methylene-4-(tri-
methoxysiloxy)-1,3-diox-4-ene (9) as a key step.
Keywords: Acetoacetic esters, benzoic acids, 6-methyl-1,3-dioxin-4-one, Mukaiyama
reaction
The phthalide system constitutes the central core in the synthesis of a series of
compounds that has important pharmacological properties. Several synthetic
approaches have been reported.[1] During our work,[2] we have successfully
developed an effective and regiospecific sequence of reactions for the trans-
formation of phthalides, which upon treatment with methyl-trimethylsilyl
ketene acetal in the presence of titanium tetrachloride (a modification of the
Mukaiyama[3,4] procedure) furnished the desired acids 5.[5] Most of these
approaches were reported in the recent review.[6]
Received in Poland April 4, 2006
Address correspondence to Adam Bieniek, Department of Organic Chemistry,
´ ´ ´ ´ ´ ´
Institute of Chemistry, University of Łodz, Narutowicza 68, 90-136 Łodz, Łodz,
Poland. E-mail: bieniek@uni.lodz.pl
3249

3250
A. Bieniek, K. K. Kulikiewicz, and M. M. Bartczak
Recently, a convenient route to synthesize functionalized benzoic acids,
which contain a five-carbon-atom chain in the ortho position, by utilizing a
reaction of phthalide with conjugated silyl dienolates was developed.[7]
Using this protocol, functionalized ortho-alkylated benzoic acids 6 were syn-
thesized from the corresponding diene, previously prepared from the commer-
cially available crotonic ester (Scheme 1).
We develop this methodology for the introduction of the five-carbon-
atom chain with terminally situated b-carbonyl acid system.
1,3-bis-(Trimethylsiloxy)-1-methoxybuta-1,3-diene (7)[8,9] as synthon of
methyl acetoacetate compounds 8 was used in the reaction with phthalides
(Scheme 2). Unfortunately all runs failed.
Following that, the 2,2-dimethyl-6-methylene-4-(trimethoxysiloxy)-1,3-
diox-4-ene (9), precursor of methyl acatyloacetate terminal function, was
applied. This compound is easily available from 2,2,6-trimethyl-4H-1,3-
dioxin-4-one, by reaction with lithium diisopropyl amide (LDA) and tri-
methylsilyl chloride (TMS-Cl)[10] (see Scheme 3 and Experimental section).
It is known that the species 9 constitutes an interesting alternative to the
classic enantioselective Mukaiyama aldol reaction with silyl enol ethers. The
interest in the employment of this silyl dienolate 9 is due to the easy manipu-
lation of the dioxinone ring in the aldol adducts to a variety of five-carbon
units.[11,12] In fact, the masked acetoacetate aldol adducts serve as versatile
precursors to b-keto esters and derived compounds, which are key structural
subunits in biologically active natural products.[13,14]
The required 3-aryl-phthalides 13, which are key starting materials, were
obtained by the lithiation of benzoic acids anilides 10, using BuLi in
THF,[5,7,15] followed by the reaction of the generated bis-(N- and C-ortho)-
lithiated anilides 11 with aromatic aldehydes. Thus, the formed
ortho-hydroxy-arylmethyl products 12, without isolation by acid-driven cycli-
zation, yielded the corresponding phthalides 13 (Scheme 4).
Scheme 1.

Organolithium and Related Reagents
3251
Scheme 2.
The phthalides 13 reacted with diene 9 in the presence of TiCl4 (Mukaiyama
procedure[3,4]) to give compound 14. An examination of the data reveals that the
only products obtained from the reaction were the corresponding alkylated
products 14 together with a small amount of recovered phthalides 13. The high
overall yields apparently show that all other possible reactions were minimized.
Keeping in mind that a dioxinone ring is easily manipulatable via variety
of ways,[11,16] the next step was the transformation of this moiety to the acetyl-
acetic acid ester 15 using toluene as solvent and methanol, ethanol, or propan-
1-ol. The best results were obtained using propan-1-ol as reagent, probably
because of its high boiling temperature.
b-Ketoesters are easily decarboxylated themselves upon hydrolysis without
isolation of the acids. In the end, we tried to decarboxylate a few examples of
compounds 14 with the dioxenone moiety to methyl ketones 16 using neutral
conditions (reflux in a mixture of toluene and water). In this experiment, we
obtained the carbonyl derivatives 16 in good yields. We previously obtained
compound 16a in the reductive alkylation reaction of phthalide 13a with silyl
enol ethers.[15] When we used phthalide with steric hindrance near the
reaction center as in 13e, only traces of product 16b were obtained (Scheme 5).
The exact structure of compounds 16 were solved by X-ray analysis.[17]
In summary, we have shown that the conversion of benzoic acid anilides
10 into ortho-alkylated carboxylic acids with acetylacetic acid moiety 15 is
easy and effective. The reaction of phthalide 13 with 2,2-dimethyl-6-
methylene-4-trimethylsiloxy-1,3-diox-4-ene (9) gave the compounds with
dioxenone moiety 14. These compounds apeared to be ready for conversion
into another derivative containing long chain substituent with carbonyl (16)
or carbonyl and alkoxycarbonyl (15) groups.
Scheme 3.

3252
A. Bieniek, K. K. Kulikiewicz, and M. M. Bartczak
Scheme 4. (i) n-BuLi in THF/hexane, 2788C/1 h ! 08C; (ii) Ar-CHO,
2788C; ! 208C/1 h; (iii) HCl (1 : 1); (iv) 1) 9/CH2Cl2/TiCl4/278deg;C; 2)
KHSO4 5% aq.
EXPERIMENTAL
Melting points were determined using a Boetius hot-stage apparatus and are
uncorrected. IR spectra were recorded on a Zeiss-Jena Specord 71-IR (KBr
pellets). NMR analyses were performed on
a Varian-Gemini-200
(200 MHz) using TMS as an internal standard in CDCl3; chemical shifts are
quoted in parts per million (ppm). Compounds were purified until observed
as single spots with thin-layer chromatography (TLC) (Kieselgel GF-254
type 60). Tetrahydrofuran was distilled before use from sodium-benzo-
phenone ketyl, and dichloromethane was dried from molecular sieves, 3A.
Other solvents and reagents were purified according to standard procedures
where appropriate. n-Butyllithium (n-BuLi) (Aldrich) was titrated before
use. Reaction temperatures were recorded as bath temperatures. Elemental
analysis was carried out by the Centre of Molecular and Macromolecular
Studies, Polish Academy of Sciences, Lodz. Phthalides 13 were obtained by
known methods.[5,7,15]

Organolithium and Related Reagents
3253
Scheme 5.
2,2-Dimethyl-6-methylene-4-trimethylsilanyloxy-4H-
[1,3]dioxine (9)[10]
A mixture of 9.2 cm3 of the 2,2,6-trimethyl-[1,3]dioxin-4-one (0.07 mol) in
THF (20 cm3) was added in 20 min at –788C to lithium diisopropylamide
(0.075 mol, prepared from n-BuLi in hexane (0.076 mol) and diisopropyl-
amine (0.075 mol) in 125 cm3 of THF. A light solid precipitated in the
flask. Next, after 45 min, 15 cm3 of trimethylsilyl chloride (0.12 mol) in
THF (20 cm3) was added during 20 min. After additional 40 min, at –788C,
the whole lot was allowed to reach ambient temperature. Then the mixture
was concentrated under reduced pressure and the residue filtered off. The
obtained 2,2-dimethyl-6-methylene-4-trimethylsilanyloxy-4H-[1,3]dioxine
was used without isolation and purification.
All yields of the 2,2-dimethyl-6-methylene-4-trimethylsilanyloxy-4H-
[1,3]dioxine were determined by 1H NMR (CDCl3, internal reference
SiMe4) spectroscopy utilizing the peak areas of their methylene protons in

3254
A. Bieniek, K. K. Kulikiewicz, and M. M. Bartczak
1
relation to the methyl protons of starting material. Yield 95%. H NMR
(CDCl3) 4.58 (s, 1H, -CH55C-OSiMe3), 4.01 (d, 1H, J 0.8 Hz, 55CH2), 3.82
(d, 1H, J 0.8 Hz, 55CH2), 1.49 (s, 6H, 2 ꢀ Me), 0.21 (s, 9H, SiMe3).
Reaction of 2,2-Dimethyl-6-methylene-4-trimethylsilanyloxy-4H-
[1,3] Dioxine (9) with 3-Arylphtalides (13)
To the stirred solution of phtalides 13 (0.011 mol) and 2,2-dimethyl-6-
methylene-4-trimethylsilanyloxy-4H-[1,3]dioxine (9) (0.13 mol) in 75 cm3
of CH2Cl2, a solution of TiCl4 (2.0 cm3) in CH2Cl2 (10 cm3) was added
dropwise at 2788C. The mixture was stirred for an additional 6 h at this temp-
erature. Next, the whole lot was allowed to reach ambient temperature, 50 cm3
of 5% water solution of KHSO4 was added, and after 1 h the mixture was
extracted with chloroform (3 ꢀ 35 cm3). Then the combined extracts were
evaporated to dryness. The solid residue was purified by column chromato-
graphy (silica gel–chloroform/hexane 1:1 and chloroform/methanol 8:2).
The products 14 were purified by crystallization.
2-[2-(2,2-Dimethyl-6-oxo-6 H-[1,3]dioxin-4-yl)-1-(4-
methoxyphenyl)-ethyl]-benzoic Acid (14a)
Yield 85%; mp 84–868C (needles from diisopropyl ether/ethyl acetate/
hexane 8:2:1); IR (KBr): 1713, 1690 cm21 (C55O); 1H NMR (CDCl3)
8.04–8.00 (m, 1H, Ar-H), 7.55–7.48 (m, 1H, Ar-H), 7.36–7.20 (m, 4H,
Ar-H), 6.86–6.81 (m, 2H, Ar-H), 5.61 (t, 1H, J 8.2 Hz, Ar2CH), 5.24
(s, 1H, 55CH-C55O), 3.77 (s, 3H, OMe), 3.10–2.88 (m, 2H, CH2), 1.46
(s, 3H, Me), 1.44 (s, 3H, Me); 13C NMR (CDCl3) 172.6, 169.8, 161.5,
158.2, 145.2, 134.1, 132.9, 131.5, 129.0, 128.5, 128.3, 126.5, 113.8, 106.5,
94.6, 55.0, 41.0, 39.6, 24.5, 24.4. Anal. calcd. for C22H22O6: C, 69.10; H,
5.80. Found: C, 69.01; H, 5.63.
2-[2-(2,2-Dimethyl-6-oxo-6 H-[1,3]dioxin-4-yl)-1-(4-methoxy-
phenyl)-ethyl]-6-methoxy-benzoic Acid (14b)
Yield 84%; mp 78–808C (needles from diisopropyl ether/ethyl acetate 8:2);
IR (KBr): 1723, 1700 cm21 (C55O); 1H NMR (CDCl3) 8.11 (br s, 1H,
COOH), 7.40–7.15 (m, 3H, Ar-H), 6.95–6.70 (m, 4H, Ar-H), 5.23 (s, 1H,
55CH-C55O), 4.65 (t, 1H, J 10.4 Hz, Ar2CH), 3.87 (s, 3H, OMe), 3.76 (s, 3H,
OMe), 3.10–2.41 (m, 2H, CH2), 1.47 (s, 3H, Me), 1.42 (s, 3H, Me); 13C NMR
(CDCl3) 171.6, 169.4, 161.6, 158.2, 156.3, 141.3, 133.5, 130.7, 128.7, 123.0,
119.2, 113.8, 109.3, 106.8, 94.8, 68.6, 55.8, 55.0, 42.8, 39.4, 24.5, 24.1, 22.5.
Anal. calcd. for C23H24O7: C, 66.98; H 5.87. Found: C, 66.73; H, 5.91.

Organolithium and Related Reagents
3255
2-[2-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-1-(4-methoxy-
phenyl)-ethyl]-3-methoxy-benzoic Acid (14c)
Yield 80%; mp 121–1238C (needles from benzene/hexane – 9:1); IR (KBr):
1720, 1710 cm21 (C55O); 1H NMR (CDCl3) 7.45–7.41 (m, 1H, Ar-H);
7.34–7.19 (m, 3H, Ar-H); 7.01–6.95 (m, 1H, Ar-H); 6.80–6.72 (m, 2H, Ar-
H); 5.38 (t, 1H, J ¼ 7.4 Hz, Ar2CH); 5.15 (s, 1H, J 7.4 Hz, 55CH-C55O); 3.73
(s, 3H, OMe); 3.69 (s, 3H, OMe); 3.36–3.06 (m, 2H, CH2); 1.45 (s, 3H, Me);
1.34 (s, 3H, Me). 13C NMR (CDCl3) 173.1, 170.9, 161.6, 158.7, 157.9, 134.0,
131.8, 131.7, 128.7, 128.1, 122.8, 115.7, 113.3, 106.5, 55.6, 55.2, 39.3, 36.3,
24.9, 24.3. Anal. calcd. for C23H24O7: C, 66.98;H, 5.87. Found:C, 67.01; H, 5.94.
2-[2-(2,2-Dimethyl-6-oxo-6 H-[1,3]dioxin-4-yl)-1-(2-methoxy-
phenyl)-ethyl]-4-methoxy-benzoic Acid (14d)
Yield 82%; mp 120–1228C (needles from diisopropyl ether/ethyl acetate/
hexane 8:2:1); IR (KBr): 1724, 1710 cm21 (C55O); 1H NMR (CDCl3)
7.45–7.19 (m, 4H, Ar-H); 7.01–6.97 (m, 1H, Ar-H); 6.78–6.73 (m, 2H, Ar-
H); 5.36 (t, 1H, J 8.1 Hz, Ar2CH); 5.15 (s, 1H, 55CH-C55O); 3.74 (s, 3H,
OMe); 3.70 (s, 3H, OMe); 3.37–3.05 (m, 2H, CH2); 1.45 (s, 3H, Me); 1.34
(s, 3H, Me). 13C NMR (CDCl3) 172.2, 170.8, 161.6, 158.7, 157.8, 134.0, 131.7,
128.7, 128.1, 122.8, 115.6, 113.4, 106.4, 94.0, 55.5, 55.1, 39.3, 36.3, 24.8, 24.2.
Anal. calcd. for C23H24O7: C, 66.98; H, 5.87. Found: C, 66.83; H, 6.06.
2-[2-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-1-(2-methoxy-
phenyl)-ethyl]-3-methoxy-benzoic Acid (14e)
Yield 70%; mp 143–1458C (needles from benzene); IR (KBr): 1724,
1
1693 cm21 (C55O); H NMR (CDCl3) 7.45–7.40 (m, 2H, Ar-H); 7.32–
7.14 (m, 2H, Ar-H); 7.03–6.90 (m, 2H, Ar-H); 6.81–6.77 (m, 1H, Ar-H);
5.66 (t, 1H, J 8.4 Hz, Ar2CH); 5.27 (s, 1H, ¼CH–C55O); 3.77 (s, 3H,
OMe); 3.72 (s, 3H, OMe); 3.45–3.18 (m, 2H, CH2); 1.47 (s, 3H, Me); 1.44
(s, 3H, Me). 13C NMR (CDCl3) 174.2, 171.3, 161.8, 159.1, 157.2, 133.0,
130.4, 129.0, 128.5, 128.3, 127.7, 127.5, 122.1, 119.7, 115.2, 110.3, 106.3,
55.4, 55.0, 35.0, 34.7, 24.7, 24.4. Anal. calcd. for C23H24O7: C, 66.98; H,
5.87. Found: C, 66.93; H, 6.01.
2-[1-(2,4-Dimethoxy-phenyl)-2-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-
4-yl)-ethyl]-6-methoxy-benzoic Acid (14f)
Yield 75%; mp 142–1448C (needles from benzene/hexane 9:1); IR (KBr):
1
1724, 1704 cm21 (C55O); H NMR (CDCl3) 8.69 (br s, 1H, COOH); 7.34–

3256
A. Bieniek, K. K. Kulikiewicz, and M. M. Bartczak
7.24 (m, 1H, Ar-H); 7.08–7.04 (m, 1H, Ar-H); 6.94–6.77 (m, 2H, Ar-H); 6.43–
6.36 (m, 2H, Ar-H); 5.20 (s, 1H, 55CH-C55O); 4.98 (t, 1H, J 8.0 Hz, Ar2CH);
3.83 (s, 3H, OMe); 3.74 (s, 3H, OMe); 3.72 (s, 3H, OMe); 3.05–2.83 (m, 2H,
CH2); 1.43 (s, 3H, Me); 1.40 (s, 3H, Me). 13C NMR (CDCl3) 172.1, 169.9,
161.6, 159.8, 157.8, 156.5, 142.1, 130.8, 128.3, 122.5, 122.3, 120.1, 109.3,
106.6, 104.0, 98.7, 94.7, 56.0, 55.2, 38.5, 36.7, 24.6, 24.5. Anal. calcd. for
C24H26O8: C, 65.15; H, 5.92. Found: C, 65.10; H, 5.96.
Reaction of 2-[2-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-1-
phenylethyl]-benzoic Acid (14) with Alcohols
A solution of 0.01 mol of adequate acid 14 in 20 cm3 of toluene and 10 cm3 of
alcohol was heated to boiling for 5–10 h. After the solvent was evaporated in
vacuo, crude products were purified by crystallization.
2-[4-Methoxycarbonyl-1-(4-methoxyphenyl)-3-oxobutyl]-benzoic
Acid (15a)
Reflux time: 5 h. Yield 63%; mp 113–1158C (needles from diisopropyl
ether/ethyl acetate/hexane 8:3:1); IR (KBr): 1744, 1710, 1690 cm21
1
(C55O); H NMR (CDCl3) 7.96–7.91 (m, 1H, Ar-H), 7.50–7.41 (m, 1H,
Ar-H), 7.30–7.15 (m, 4H, Ar-H), 6.84–6.80 (m, 2H, Ar-H), 5.61 (t, 1H,
J 7.8 Hz, CH), 3.76 (s, 3H, OMe), 3.68 (s, 3H, OMe), 3.44 (d, 2H, J 2.0 Hz,
CO-CH2-CO), 3.33 (d, 2H, J 7.8 Hz, CH2); 13C NMR (CDCl3) 201.2,
170.8, 158.2 157.8, 145.5, 134.5, 132.6, 131.2, 128.9, 128.5, 126.4, 113.9,
56.4, 55.2, 52.4, 49,3, 48.8, 39.9. Anal. calcd. for C20H20O6: C, 67.40; H,
5.61. Found: C, 67.44; H, 5.59.
2-[4-Ethoxycarbonyl-1-(4-methoxyphenyl)-3-oxobutyl]-benzoic
Acid (15b)
Reflux time: 6 h. Yield 45%; mp 88–908C (needles from diisopropyl ether/
1
ethyl acetate/hexane 8:3:1); IR (KBr): 1740, 1710, 1690 cm21 (C55O); H
NMR (CDCl3) 7.98–7.94 (m, 1H, Ar-H), 7.49–7.41 (m, 1H, Ar-H), 7.31–
7.16 (m, 4H, Ar-H), 6.84–6.79 (m, 2H, Ar-H), 5.65 (t, 1H, J 7.7 Hz, CH),
4.15 (q, 2H, J 7.2 Hz, CH2), 3.76 (s, 3H, OMe), 3.42 (s, 2H, CO-CH2-CO),
3.34 (d, 2H, J 7.7 Hz, CH2), 1.23 (t, 3H, J 7.2 Hz, Me); 13C NMR (CDCl3)
201.3, 171.7, 167.1, 158.2, 145.7, 134.7, 132.7, 131.4, 129.2, 129.0, 128.8,
128.5, 126.4, 113.9, 61.4, 55.2, 49.3, 49.1, 39.9, 30.9, 13.9. Anal. calcd. for
C21H22O6: C, 68.10; H, 5.94. Found: C, 68.07; H, 6.01.

Organolithium and Related Reagents
3257
3-Methoxy-2-[1-(4-methoxyphenyl)-3-oxo-4-
propoxycarbonylbutyl]-benzoic Acid (15c)
Reflux time: 8 h. Yield 67%; light-yellow oil; IR (CHCl3): 1720, 1716,
1
1697 cm21 (C55O); H NMR (CDCl3) 7.39–7.35 (m, 1H, Ar-H), 7.28–7.24
(m, 1H, Ar-H), 7.19–7.15 (m, 2H, Ar-H), 6.96–6.91 (m, 1H, Ar-H), 6.78–6.73
(m, 2H, Ar-H), 5.35 (t, 1H, J 6.9 Hz, CH), 4.05 (t, 2H, J 6.7 Hz, CH2), 3.73
(s, 3H, OMe), 3.62 (s, 3H, OMe), 3.54 (d, 2H, J 5.8 Hz, CH2), 3.46 (d, 2H,
J 2.1 Hz, CO-CH2-CO), 1.70–1.52 (m, 2H, CH2-CH2-CH3), 0.89 (t, 3H,
J 7.3 Hz, CH3); 13C NMR (CDCl3) 203.7, 172.1, 167.0, 158.0, 157.6, 133.9,
133.4, 131.1, 128.7, 127.9, 122.2, 115.2, 113.2, 67.0, 55.6, 55.2, 49.3, 45.5,
39.3, 37.7, 21.8, 10.3. Anal. calcd. for C23H26O7: C, 66.65; H, 6.32. Found: C,
66.56; H, 6.34.
3-Methoxy-2-[1-(2-methoxyphenyl)-3-oxo-4-
propoxycarbonylbutyl]-benzoic Acid (15d)
Reflux time: 10 h. Yield 54%; mp 129–1318C (needles from benzene/hexane
8:2); IR (KBr): 1729, 1720, 1690 cm21 (C55O); 1H NMR (CDCl3) 7.37–7.33
(m, 1H, Ar-H), 7.27–7.10 (m, 4H, Ar-H), 6.91–6.83 (m, 1H, Ar-H),
6.74–6.70 (m, 1H, Ar-H), 5.28 (t, 1H, J 4.5 Hz, CH), 4.05 (t, 2H, J 6.6 Hz,
CH2), 3.68 (s, 3H, OMe), 3.64 (s, 3H, OMe), 3.50 (d, 2H, J 2.2 Hz, CH2),
3.35 (dd, 2H, J1 3.4 Hz, J2 17.9 Hz, CO-CH2-CO), 1.65–1.55 (m, 2H,
CH2-CH2-CH3), 0.87 (t, 3H, J 7.4 Hz, CH3); 13C NMR (CDCl3) 207.1,
170.5, 158.2, 157.1, 139.1, 128.6, 128.1, 128.0, 127.6, 122.4, 119.4, 114.6,
110.2, 67.2, 55.4, 54.6, 49.2, 45.0, 33.3, 21.7, 10.1. Anal. calcd. for
C23H26O7: C, 66.65; H, 6.32. Found: C, 66.87; H, 6.14.
2-[1-(2,4-Dimethoxyphenyl)-3-oxo-4-propoxycarbonylbutyl]-6-
methoxy-benzoic Acid (15e)
Reflux time: 10 h. Yield 48%; light-yellow oil; IR (KBr): 1737, 1713 cm21
1
(C55O); H NMR (CDCl3) 7.29–7.21 (m, 1H, Ar-H), 7.16–7.06 (m, 1H,
Ar-H), 6.82–6.74 (m, 2H, Ar-H), 6.44–6.35 (m, 2H, Ar-H), 5.06 (t, 1H,
J 7.7 Hz, J 6.8 Hz, CH), 4.04 (t, 2H, J ¼ 6.8 Hz, CH2), 3.83 (s, 3H, OMe),
3.74 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.45 (s, 2H, CH2), 3.32 (dd, 2H, J1
2.3 Hz, J2 7.5 Hz, CO-CH2-CO), 1.70–1.52 (m, 2H, CH2-CH2-CH3), 0.89
(t, 3H J 7.4 Hz, CH3); 13C NMR (CDCl3) 202.3, 170.7, 167.1, 159.6, 157.3,
156.3, 142.4, 130.7, 127.4, 122.6, 119.6, 113.0, 109.0, 103.7, 66.9, 55.9,
55.2, 55.0, 48.8, 48.4, 35.4, 21.7, 10.2. Anal. calcd. for C24H28O8: C, 64.85;
H, 6.35. Found: C, 64.90; H, 6.11.

3258
A. Bieniek, K. K. Kulikiewicz, and M. M. Bartczak
4-Methoxy-2-[1-(2-methoxyphenyl)-3-oxo-4-
propoxycarbonylbutyl]-benzoic Acid (15f)
Reflux time: 10 h. Yield 47%; light-yellow oil; IR (KBr): 1716, 1685, cm21
1
(C55O); H NMR (CDCl3) 7.26–7.10 (m, 2H, Ar-H), 6.92–6.69 (m, 4H,
Ar-H), 5.92 (t, 1H, J 7.6 Hz, J 6.7 Hz, CH), 4.05 (t, 2H, J ¼ 6.7 Hz, CH2),
3.76 (s, 3H, OMe), 3.71 (s, 3H, OMe), 3.50 (d, 2H, J 4.1 Hz, CO-CH2-CO),
3.29 (d, 2H, J 7.7 Hz, CH2), 1.70–1.55 (m, 2H, CH2-CH2-CH3), 0.89
(t, 3H, J 7.5 Hz, CH3); 13C NMR (CDCl3) 201.8, 172.0, 167.4, 162.8,
157.1, 147.9, 133.9, 131.1, 127.9, 127.2, 120.5, 115.0, 110.8, 110.7, 66.9,
55.3, 55.2, 48.6, 48.2, 35.5, 21.7, 10.2. Anal. calcd. for C23H26O7: C, 66.65;
H, 6.32. Found: C, 66.55; H, 6.40.
2-[1-(4-Methoxyphenyl)-3-oxobutyl]-benzoic Acid (16a)
Reflux time: 10 h. Yield 50%; mp 153–1548C (white needles from benzene/
1
hexane 9:1) lit.[15] mp 92–948C; IR (CHCl3): 1728, 1707, cm21 (C55O); H
NMR (CDCl3) 7.45–7.35 (m, 2H, Ar-H), 7.25–7.15 (m, 4H, Ar-H), 6.83–
6.78 (m, 2H, Ar-H), 5.58 (t, 1H, J 8.0 Hz, CH), 3.74 (s, 3H, OMe), 3.20
(dd, 2H, J1 4.5 Hz, J2 7.6 Hz, CH2), 2.13 (s, 3H, Me); 13C NMR (CDCl3)
208.0, 172.2, 158.2, 145.8, 134.9, 132.7, 131.2, 128.9, 128.5, 126.4, 113.9,
55.2, 50.2, 40.2, 29.8. Anal. calcd. for C18H18O4: C, 72.47; H, 6.08. Found:
C, 72.33; H, 6.10.
3-Methoxy-2-[1-(2-methoxyphenyl)-3-oxobutyl]-benzoic Acid (16b)
Reflux time: 10 h. Yield 47%; mp 162–1648C (white needles from benzene/
hexane 9:1); IR (CHCl3): 1710, 1689, cm21 (C55O); 1H NMR (CDCl3) 7.30–
7.23 (m, 3H, Ar-H), 7.15–7.11 (m, 2H, Ar-H), 6.90–6.86 (m, 2H, Ar-H), 5.39
(t, 1H, J 7.1 Hz, CH), 3.74 (s, 3H, OMe), 3.61 (s, 3H, OMe), 3.28 (dd, 2H,
J1 4.7 Hz, J2 18.3 Hz, CH2), 2.21 (s, 3H, Me); 13C NMR (CDCl3) 212.3,
170.9, 157.8, 157.7, 135.1, 133.5, 128.6, 128.2, 121.9, 114.8, 113.3, 55.6,
55.1, 45.7, 38.6, 30.2. Anal. calcd. for C19H20O5: C, 69.50; H, 6.14. Found:
C, 69.20; H, 6.10.
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