Synthesis of phenylacetic acids with 2-oxoalkyl substituents in the ortho-position from o-phenylenediacetic acid

Article abstract of DOI:10.1055/s-2008-1067201

A one-step procedure for the synthesis of 2-(2-oxoalkyl)-substituted phenylacetic acids is described. Very slow addition of organolithium compounds to o-phenylenediacetic acid is the crucial feature to obtain the desired ε-oxo acids in good yields. The selective formation of the ε-oxo acids from the diacid is explained on the basis of hemiketal anion formation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067201

PAPER
2729
Synthesis of Phenylacetic Acids with 2-Oxoalkyl Substituents in the
ortho-Position from o-Phenylenediacetic Acid
Synthesisof
2
y
-[2-(2-Oxoal
e
kyl)phenyl
d
]acetic
A
cids Masood Husain, Bernhard Wünsch*
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62,
48149 Münster, Germany
Fax +49(251)8332144; E-mail: wuensch@uni-muenster.de
Received 27 March 2008; revised 8 May 2008
R
2 R = Me, 55%
3 R = Et, 36%
4 R = n-Bu, 35%
5 R = Ph, 35%
RLi, THF
CO2H
CO2H
Abstract: A one-step procedure for the synthesis of 2-(2-oxoalkyl)-
substituted phenylacetic acids is described. Very slow addition of
organolithium compounds to o-phenylenediacetic acid is the crucial
feature to obtain the desired e-oxo acids in good yields. The selec-
tive formation of the e-oxo acids from the diacid is explained on the
basis of hemiketal anion formation.
O
1
CO2H
Scheme 1
Key words: organometallic reagents, polyanions, carboxylic acids,
ketones, nucleophilic addition, heterocycles, e-oxo acids, hemiketal
anions
Then we focused our attention on the direct reaction of o-
phenylenediacetic acid with methyllithium (Scheme 1).
Indeed the reaction of diacid 1 with eight equivalents of
methyllithium provided the desired oxo acid 2, albeit in
low isolated yield (10%) along with large amounts of un-
reacted diacid 1.
The g-, d-, and e-oxo acids constitute valuable building
blocks for the asymmetric synthesis of several carbo- and
heterocycles including substituted naphthalenones,1 pyr-
rolidines,2 piperidones,3 azepines, and 3-benzazepines.4
These carbo- and heterocycles are of particular interest in
medicinal chemistry. However, the methods described for
the synthesis of oxo acids involve several steps and are,
thus, rather circumstantial and time-consuming.1,5,6
Next, the yield of 2 was improved by varying the reaction
conditions (Table 1). In order to obtain a rapid result, the
1H NMR spectrum (CD3OD) of the crude reaction mixture
was recorded. Usually the signals for only two com-
pounds (diacid 1 and oxo acid 2) were observed in the 1H
NMR spectrum indicating a clean transformation. The ra-
tio of oxo acid 2 to diacid 1 was calculated by integration
of characteristic signals (CH2CO2H singlets of 1 and
CH2COR singlets of 2–5, see Figure 1).
Although the synthesis of ketones by the reaction of car-
boxylic acids with organolithium reagents is well known,
the formation of undesired tertiary alcohols is a problem
associated with this transformation.7–9 Only a few reports
in the literature describe the reaction of diacids with orga-
nolithium reagents.10
At first the solvent diethyl ether was employed instead of
tetrahydrofuran. However, due to the low solubility of the
anionic intermediates only a very low conversion was ob-
served.
In this paper we wish to report on a general method for the
synthesis of phenylacetic acid derivatives with various 2-
oxoalkyl residues in position 2 of the phenyl ring starting
from the diacid o-phenylenediacetic acid (1). We postu-
late that the selective formation of e-oxo acids as the main
product is based on the intermediate formation of a
hemiketal anion.
At first we concentrated on the production of the phenyl-
acetic acid 2 with a 2-oxopropyl residue in position 2.
However, all attempts to transform the dimethyl ester of 1
with methyllithium8 or Tebbe reagent11,12 into the corre-
sponding methyl ester of 2 failed. In a further approach we
tried to prepare the e-oxo acid 2 by reaction of o-bro-
mophenylacetic acid and active methylene compounds
using several palladium/copper catalysts and different
bases;13 this reaction did not result in the formation of the
desired phenylacetic acid derivatives.
Figure 1 Comparison of characteristic signals of diacid 1 and oxo
acids 2–5 in the 1H NMR spectra (CD3OD); (a) CH2COR of 2–5; (b)
CH2COOH of diacid 1; and (c) CH2COOH of oxo acids 2–5.
SYNTHESIS 2008, No. 17, pp 2729–2732
x
x.
x
x
.
2
0
0
8
Advanced online publication: 24.07.2008
DOI: 10.1055/s-2008-1067201; Art ID: T05408SS
© Georg Thieme Verlag Stuttgart · New York

2730
S. M. Husain, B. Wünsch
PAPER
Table 1 Optimization of the Reaction of o-Phenylenediacetic Acid
1 with Methyllithium
Table 2 Optimization of the Reaction of Ethyllithium, Butyllithi-
um, and Phenyllithium with o-Phenylenediacetic Acid (1)
Entry Temp
Equiv of Rate of addition Time Ratiob
Entry
R
Equiv of Rate of addition of RLi Ratiob
MeLia
of MeLi
(h)
2/1
RLia
3–5/ 1
38:62
45:55
40:60
58:42
69:31
48:52
51:49
59:41
45:55
53:47
61:39
1
2
–10 °C
8
8
>10 mL/min 24
>10 mL/min 24
>10 mL/min 24
>10 mL/min 24
>10 mL/min 24
–
1
2
Et
8
>10 mL/min
>10 mL/min
>10 mL/min
2 mL/h
0 °C
17:83
60:40
35:65c
45:55d
38:62
47:53c
52:48
73:27
75:25
Et
10
15
10
10c
8
3
0 °C to r.t.
reflux (66 °C)
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
8
3
Et
4
8
4
Et
5
8
5
Et
2 mL/h
6
8
>10 mL/min
6
6
Bu
Bu
Bu
Ph
Ph
Ph
>10 mL/min
2 mL/h
7
8
>10 mL/min 96
>10 mL/min 24
7
8
8
10
8
8
10c
8
2 mL/h
9
2 mL/h
2 mL/h
24
24
9
>10 mL/min
2 mL/h
10
10
10
11
8
a All reactions used diacid 1 (2.6 mmol) and THF (35 mL), unless
otherwise noted.
10c
2 mL/h
a All reactions used diacid 1 (2.6 mmol) and THF (35 mL) unless
otherwise noted.
b Determined by integration of characteristic CH2 singlets in the 1H
NMR spectra.
b Determined by integration of characteristic CH2 singlets in the 1H
NMR spectra.
c Side products are observed in the 1H NMR spectrum in addition to
the main components 2 and 1.
c Diacid 1 (5.2 mmol), THF (70 mL).
d THF (12 mL).
In summary, performing the transformation in tetrahydro-
furan at 0 °C to room temperature and adding 8 equiva-
lents of methyllithium very slowly (2 mL/h) led to the
highest conversion of the diacid 1 into the oxo acid 2,
which was isolated in 55% yield after flash chromatogra-
phy.
Performing the reaction at –10 °C or lower temperatures
(THF) did not lead to any conversion (Table 1, entry 1).
At 0 °C only very little formation of the oxo acid 2 was ob-
served (Table 1, entry 2). However, addition of methyl-
lithium at 0 °C and subsequent stirring of the reaction
mixture at room temperature for 24 hours provided 2/1 in
a ratio of 60:40 (Table 1, entry 3). A further increase in the
reaction temperature to 66 °C (THF, reflux) reduced the
yield of oxo acid 2 (Table 1, entry 4) due to side reactions
induced by the large excess of methyllithium, as observed
in the 1H NMR spectrum.
After optimization of the reaction of diacid 1 with meth-
yllithium, the organolithium reagents ethyllithium, n-bu-
tyllithium, and phenyllithium were also investigated. The
results are summarized in Table 2. In general, the obser-
vations with these organolithium reagents confirm the
rules that were found during the optimization cycles with
methyllithium: increasing the number of equivalents of
organolithium reagent did not lead to complete transfor-
mation, but instead resulted in reduced yields of oxo acids
(Table 2, cf. entries 1–3). Very slow addition of RLi to the
solution of diacid 1 of tetrahydrofuran resulted in consid-
erable improvement of the yields (Table 2, cf. entries 2
and 4, 6 and 7, and 9 and 10). In the case of slow addition,
an increase of RLi from eight to ten equivalents together
with an increase in scale from 2.6 to 5.2 mmol led to in-
creased yields of oxo acids (Table 2, cf. entries 4 and 5, 7
and 8, and 10 and 11).
The amount of solvent (concentration of the reactants)
seems to play an important role for this transformation. In-
creasing the concentration by reducing the amount of sol-
vent afforded a reduced yield of oxo acid 2 (Table 1, cf.
entries 3 and 5). Further concentration of the reaction mix-
ture led to a further decrease in the yield due to solubility
problems.
Shortening as well as prolongation of the reaction time
from 24 hours to 6 hours or to 96 hours (Table 1, cf. en-
tries 3, 6, and 7) resulted in decreased yields of 2.
Finally, the addition rate of methyllithium to the reaction
mixture turned out to be the crucial feature for high yields
of 2. Very slow addition of methyllithium increased the
yield of the oxo acid 2 considerably. Thus, an addition rate
of 2 mL/h (syringe pump) provided 73% of oxo acid 2
along with only 27% of unreacted diacid 1 (Table 1, cf.
entries 3 and 9). A slight increase in the yield was attained
using 10 equivalents of methyllithium with an addition
rate of 2 mL/h (Table 1, entry 10).
After reaction of diacid 1 with various RLi reagents, ter-
tiary alcohols, or diketones were neither isolated nor de-
tected. Therefore, we assume the reaction path depicted in
Scheme 2: initially excess RLi deprotonates the diacid 1
to give the dicarboxylate 6, which is able to form the cy-
clic ortho acid dianion 7. The lactone-like structure of 7
reacts with a further molecule of RLi to provide the tri-
anion 8, which is resistant to further RLi attack. Addition
Synthesis 2008, No. 17, 2729–2732 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-[2-(2-Oxoalkyl)phenyl]acetic Acids
2731
rity: Merck Hitachi equipment; UV detector: L-7400; autosampler:
L-7200; pump: L-7100; degasser: L-7614; column: LiChrospher 60
RP-select B (5 mm); LiCroCART 250–4 mm cartridge; flow rate:
1.000 mL/min; injection volume: 5.0 mL; detection at l = 210 nm;
solvents: A: H2O with 0.05% TFA; B: MeCN with 0.05% TFA: gra-
dient elution: 0.0 min: 90.0% of A, 10.0% of B; 4.0 min: 90.0% of
A, 10.0% of B; 29.0 min: 0.0% of A, 100.0% of B; 31.0 min: 0.0%
of A, 100.0% of B; 31.5 min: 90.0% of A, 10.0% of B; 40.0 min:
90.0% of A, 10.0% of B.
O
O
RLi
RLi
OLi
O
O
1
OLi
OLi
OLi
7
6
R
R
OH
OLi
H3O+
2–5
O
O
Reaction of o-Phenylenediacetic Acid (1) with Organolithium
Reagents; General Procedure
OH
OLi
OH
OLi
Under N2, a soln of o-phenylenediacetic acid (1, 500 mg, 2.57
mmol) in anhyd THF (35 mL) was cooled to 0 °C. Then a commer-
cially available organolithium reagent (20.6–25.7 mmol, 8–10
equiv) was added at a rate of 2 mL/h through a syringe pump. The
mixture was vigorously stirred for 24 h at r.t., cooled to 0 °C, and
quenched with 1 M HCl (30 mL). The aqueous layer was extracted
with Et2O (3 × 15 mL), the Et2O layer was dried (Na2SO4), and the
solvent was evaporated in vacuo. A 1H NMR spectrum of the crude
reaction product was recorded in CD3OD to determine the ratio of
the starting compound 1 and the formed product 2–5. Then the res-
8
9
Scheme 2
of water during workup leads to protonation of 8 to give
the hydrate 9, which results in the oxo acids 2–5 upon ring
opening.
We assume that the isolation of large amounts of starting
diacid 1 is due to a-deprotonation of 6 or 7. The resulting idue was purified by flash chromatography.
enolate or enediolate is not able to react with RLi and
2-[2-(2-Oxopropyl)phenyl]acetic Acid (2)
According to the general procedure o-phenylenediacetic acid (1,
gives the starting diacid 1 upon workup. The ratio of 1/2–
5 in the 1H NMR spectra of the crude products (Figure 1)
reflects the ratio of a-deprotonation to nucleophilic attack
of 7.
500 mg, 2.57 mmol) was treated with 1.6 M MeLi in Et2O (12.8 mL,
20.6 mmol). In the crude product the ratio of 1/2 was 24:76. Purifi-
cation by flash chromatography [2 cm, EtOAc–cyclohexane–
HCO2H, 20:79.5:0.5, 25 cm, 15 mL, Rf = 0.21 (EtOAc–cyclohex-
ane–HCO2H, 50:49.5:0.5)] led to a pale yellow oil that solidified
upon standing at –30 °C, colorless solid; yield: 272 mg (55%); mp
42–44 °C. In ref.5,6 compound 2 is mentioned. However a prepara-
tive procedure and spectroscopic and analytical data are not avail-
able.
In the case of ortho-substitution the lactone-like interme-
diate 7 is activated for nucleophilic attack of RLi resulting
in considerable amounts of oxo acids 2–5. In order to
prove this hypothesis of the formation of a hemiketal an-
ion, the meta-substituted diacid, m-phenylenediacetic ac-
id, and the para-substituted diacid, p-phenylenediacetic
acid, were treated with a large excess of methyllithium us-
ing the optimized reaction conditions found for the ortho
derivative 1. Neither in the case of meta- nor para-substi-
tuted phenylenediacetic acids were any oxo acids isolated
or detected, indicating that a-deprotonation is the predom-
inant process.
Purity by HPLC method (see general part): tR = 13.6 min (99.8%).
FT-IR (ATR, film): 3201 (w, COOH), 3058, 3022 (w, C–Harom),
2970, 2919 (w, C–Haliph), 1701 [s, C=O, C(=O)OH], 1157, 747
cm–1 (m, 1,2-disubstituted benzene).
1H NMR (CDCl3): d = 2.17 (s, 3 H, COCH3), 3.62 (s, 2 H,
CH2COOH), 3.80 (s, 2 H, CH2COCH3), 7.16–7.27 (m, 4 Harom),
9.35 (s, 1 H, CO2H).
13C NMR (CDCl3): d = 29.7 (1 C, COCH3), 38.9 (1 C, CH2COCH3),
In conclusion, a one-step synthesis of phenylacetic acids
with various 2-oxoalkyl side chains in the ortho position 48.8 (1 C, CH2CO2H), 127.9, 128.2, 131.3, 131.4 (4 C, Ph-CH),
has been elaborated. Although the yields are only in the
range of 35–55% the desired 2-[2-(2-oxoalkyl)phe-
132.8, 133.6 (2 C, Ph-C), 177.2 (1 C, CH2COCH3), 206.6 (1 C,
CH2CO2H).
MS (EI): m/z (%) = 192 [M+, 9], 132 [C9H8O+ (M+ – CH2COOH –
nyl]acetic acids are accessible in only one step starting
+
+
H), 82], 104 [C8H8 , 100], 91 [C7H7 ].
with inexpensive, commercially available starting materi-
al. Also the reaction of diacids with organolithium re-
agents was studied carefully, and the mechanism for the
product formation was given on the basis of an intermedi-
ate hemiketal anion.
Anal. Calcd for C11H12O3 (192.2): C, 68.74; H, 6.29. Found: C,
68.56; H, 6.25.
2-[2-(2-Oxobutyl)phenyl]acetic Acid (3)
According to the general procedure o-phenylenediacetic acid (1,
500 mg, 2.57 mmol) was treated with 1.7 M EtLi in Bu2O (12.1 mL,
20.6 mmol). In the crude product the ratio of 1/3 was 31:69. Purifi-
cation by flash chromatography [2 cm, EtOAc–cyclohexane–
HCO2H, 20:79.5:0.5, 25 cm, 15 mL, Rf = 0.30 (EtOAc–cyclohex-
ane–HCO2H, 50:49.5:0.5)] led to a colorless viscous oil that solidi-
fied upon standing at –30 °C, colorless solid; yield: 191 mg (36%);
mp 44–46 °C.
TLC: Silica gel 60 F254 plates (Merck). Flash chromatography: sili-
ca gel 60, 40–64 mm (Merck); parentheses include: diameter of the
column, eluent, fraction size, Rf value. Melting point: melting point
apparatus SMP 3 (Stuart Scientific), uncorrected. MS: MAT GCQ
(Thermo-Finnigan). HRMS: MicroTof (Bruker Daltronics, Bre-
men), calibration with sodium formate clusters before measure-
1
ment. IR: IR spectrophotometer 480Plus FT-ATR-IR (Jasco). H
Purity by HPLC method (see general part): tR = 14.9 min (98.9%).
NMR (400 MHz), 13C NMR (100 MHz): Mercury plus 400 spec-
trometer (Varian); TMS as reference and coupling constants given
with 0.5 Hz resolution. Elemental analysis: CHN-Rapid Analysator
(Fons-Heraeus). HPLC method for determination of the product pu-
FT-IR (ATR, film): 3187 (w, COOH), 3065, 3023 (w, C–Harom),
2977, 2935 (w, C–Haliph.), 1703 [s, C=O, C(=O)OH], 1154, 749
cm–1 (m, 1,2-disubstituted benzene).
Synthesis 2008, No. 17, 2729–2732 © Thieme Stuttgart · New York

2732
S. M. Husain, B. Wünsch
PAPER
1H NMR (CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H, CH3), 2.49 (q, J = 7.3
Hz, 2 H, CH2CH3), 3.64 (s, 2 H, CH2COOH), 3.80 (s, 2 H,
CH2COEt), 7.16–7.28 (m, 4 Harom), 10.57 (br s, 1 H, CO2H).
13C NMR (CDCl3): d = 7.9 (1 C, COCH2CH3), 35.7 (1 C,
COCH2CH3), 39.1 (1 C, CH2COEt), 47.6 (1 C, PhCH2CO), 127.8,
128.1, 131.2, 131.3 (4 C, Ph-CH), 132.9, 133.9 (2 C, Ph-C), 177.5
(1 C, CH2COEt), 209.3 (1 C, CO2H).
HCO2H, 10:89.5:0.5, 25 cm, 15 mL, Rf = 0.34 (EtOAc–cyclohex-
ane–HCO2H, 50:49.5:0.5)] led to a pale yellow solid that gave a col-
orless solid upon recrystallization (hexane–CH2Cl2); yield: 229 mg
(35%); mp 187–187.7 °C.
Purity by HPLC method (see general part): tR = 18.9 min (99.2%).
FT-IR (ATR, film): 3202 (w, COOH), 3062, 3019 (w, C–Harom),
2954, 2920 (w, C–Haliph), 1700 (s, C=O), 1684 [s, C(=O)OH], 1206,
746 cm–1 (m, 1,2-disubstituted benzene).
1H NMR (CDCl3): d = 3.64 (s, 2 H, CH2COPh), 4.41 (s, 2 H,
CH2CO2H), 7.15–7.17 (m, 1 Harom), 7.24–7.36 (m, 3 Harom), 7.47 (t,
J = 7.7 Hz, 2 Harom), 7.58 (t, J = 7.4 Hz, 1 Harom), 8.02 (d, J = 7.3 Hz,
2 Harom).
MS (EI): m/z (%) = 206 [M+, 5], 132 [C9H8O+ (M+ – CH2CO2H,
+
+
CH3), 100], 104 [C8H8 , 89], 91 [C7H7 , 43].
Anal. Calcd for C12H14O3 (206.2): C, 69.89; H, 6.84. Found: C,
69.75; H, 6.81.
2-[2-(2-Oxohexyl)phenyl]acetic Acid (4)
13C NMR (CDCl3): d = 39.2 (1 C, CH2CO), 43.2 (1 C, CH2CO2H),
127.9, 128.1, 128.6, 128.9, 131.2, 131.3, 132.9 (9 C, Ph-CH), 133.6,
134.0, 136.8 (3 C, Ph-C), 177.2 (1 C, CO2H), 197.9 (1 C, C=O).
According to the general procedure o-phenylenediacetic acid (1,
500 mg, 2.57 mmol) was treated with 1.6 M BuLi in hexane (12.8
mL, 20.6 mmol). In the crude product the ratio of 1/4 was 41:59. Pu-
rification by flash chromatography [2 cm, EtOAc–cyclohexane–
HCO2H, 10:89.5:0.5, 25 cm, 15 mL, Rf = 0.39 (EtOAc–cyclohex-
ane–HCO2H, 50:49.5:0.5)] led to a pale yellow solid that gave a col-
orless solid upon recrystallization (hexane–CH2Cl2); yield: 211 mg
(35%); mp 59–61 °C.
MS (EI): m/z (%) = 254 [M+, 7], 132 [C9H8O+, 100], 105 [PhCO+,
+
86], 91 [C7H7 , 8].
Anal. Calcd for C16H14O3 (254.3): C, 75.58; H, 5.55. Found: C,
75.35; H, 5.42.
Purity by HPLC method (see general part): tR = 18.9 min (97.8%).
Acknowledgment
FT-IR (ATR, film): 3023 (w, COOH), 2951, 2931 (w, C–Harom),
2868.8 (w, C–Haliph), 1713 [s, C(=O)OH], 1690 (s, C=O), 1240, 742
cm–1 (m, 1,2-disubstituted benzene).
1H NMR (CDCl3): d = 0.87 (t, J = 7.3 Hz, 3 H, CH2CH2CH2CH3),
1.25–1.32 (m, 2 H, CH2CH2CH2CH3), 1.50–1.57 (m, 2 H,
CH2CH2CH2CH3), 2.48 (t, J = 7.4 Hz, 2 H, CH2CH2CH2CH3), 3.63
(s, 2 H, CH2COOH), 3.78 (s, 2 H, CH2COBu), 7.14–7.17 (m, 1
Harom), 7.24–7.27 (m, 3 Harom).
13C NMR (CDCl3): d = 14.0 (1 C, CH2CH2CH2CH3), 22.4 (1 C,
CH2CH2CH2CH3), 26.0 (1 C, CH2CH2CH2CH3), 39.0 (1 C,
CH2CO2H), 42.3 (1 C, CH2COCH2CH2CH2CH3), 47.9 (1 C,
PhCH2CO), 127.9, 128.1, 131.2 (4 C, Ph-CH), 132.9, 133.7 (2 C,
Ph-C), 176.9 (1 C, CO2H), 208.9 (1 C, C=O).
We wish to thank the NRW Graduate School of Chemistry for a sti-
pend, which is funded by the Government of the State Nordrhein-
Westfalen and the DAAD.
References
(1) Wünsch, T.; Meyers, A. I. J. Org. Chem. 1990, 55, 4233.
(2) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656.
(3) Amat, M.; Escolano, C.; Llor, N.; Huguet, M.; Pérez, M.;
Bosch, J. Tetrahedron: Asymmetry 2003, 14, 1679.
(4) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem.
2001, 66, 1413.
(5) Bobranski, B.; Konieczny, M. Rocz. Chem. 1962, 36, 639.
(6) Konieczny, M. Pol. Bull Acad. Polon. Sci., Ser. Sci. Chim.
1959, 7, 229.
MS (EI): m/z (%) = 234 [M+, 4], 132 [C9H8O+ (M+ – CH2CO2H –
+
+
CH2CH2CH2CH2), 100], 104 [C8H8 , 68], 91 (C7H7 , 40].
(7) Jorgensen, M. J. Org. React. 1970, 18, 1.
Anal. Calcd for C14H18O3 (234.3): C, 71.77; H, 7.74. Found: C,
71.61; H, 7.72.
(8) Rubottom, G. M.; Kim, C. J. Org. Chem. 1983, 48, 1550.
(9) Levine, R.; Karten, M. T. J. Org. Chem. 1976, 41, 1176.
(10) Maier, G. Chem. Ber. 1965, 98, 2438.
2-[2-(2-Oxo-2-phenylethyl)phenyl]acetic Acid (5)
(11) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am.
According to the general procedure o-phenylenediacetic acid (1,
500 mg, 2.57 mmol) was treated with 2.0 M PhLi in Bu2O (10.3 mL,
20.6 mmol). In the crude product the ratio of 1/5 was 39:61. Purifi-
cation by flash chromatography [2 cm, EtOAc–cyclohexane–
Chem. Soc. 1980, 102, 3270.
(12) Pine, S. H.; Shen, G. S.; Hoang, H. Synthesis 1991, 165.
(13) McKillop, A.; Bruggink, A. Tetrahedron 1975, 31, 2607.
Synthesis 2008, No. 17, 2729–2732 © Thieme Stuttgart · New York