A novel approach to the synthesis of 2-aryl propionates

Article abstract of DOI:10.1081/SCC-120006466

A two step conversion of phenyl glyoxylates to 2-aryl-propionates has been accomplished. Esters of phenylglyoxylic acid have been converted to corresponding β,β-dichlorostyrenes. These on further reduction gave esters of 2-arylpropionic acids.

Full text of DOI:10.1081/SCC-120006466

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A NOVEL APPROACH TO THE SYNTHESIS OF 2-ARYL
PROPIONATES
D. V. Patil & M. S. Wadia
To cite this article: D. V. Patil & M. S. Wadia (2002) A NOVEL APPROACH TO THE SYNTHESIS
OF 2-ARYL PROPIONATES, Synthetic Communications, 32:18, 2821-2827, DOI: 10.1081/
SCC-120006466
To link to this article: http://dx.doi.org/10.1081/SCC-120006466
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 18, pp. 2821–2827, 2002
A NOVEL APPROACH TO THE
SYNTHESIS OF 2-ARYL PROPIONATES
D. V. Patil and M. S. Wadiay
*
Department of Chemistry, University of Pune,
Pune 411 007, India
ABSTRACT
A two step conversion of phenyl glyoxylates to 2-aryl-propio-
nates has been accomplished. Esters of phenylglyoxylic acid
have been converted to corresponding b,b-dichlorostyrenes.
These on further reduction gave esters of 2-arylpropionic
acids.
The chemistry of 2-arylpropionic acids is of great importance due to
their biological activity.[1,2] The compound 1 widely recognized as
Ibuprofen, is extensively used as an antiinflammatory, antipyretic and
analgesic. Because of this, the synthesis of these compounds has attracted
great interest and has been extensively reviewed.[1–3] The developments in
the synthesis of chiral 2-arylpropanoic acid have also been reviewed.[4]
*Current address: Chemistry Department, Cusrow Wadia Institute of Technology,
Pune 411 001, India. E-mail: dineshvpatil@hotmail.com
yCorrespondingauthor. E-mail: mswadia@chem.unipune.ernet.in
2821
DOI: 10.1081/SCC-120006466
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2822
PATIL AND WADIA
The hydrolysis of b,b-diflurostyrene 2 to provide 1 has been reported[5]
in 70% yield. Interestingly the hydrolysis of the corresponding dichlorostyr-
ene 2a has been reported[6] to be unsuccessful. This led us to re-examine this
reaction.
Hydrolysis of the unsubstituted dichlorostyrene 4 readily prepared
from acetophenone,[7] was attempted under a variety of conditions viz.
CF3COOH/dil H2SO4/dil. HCl, at room temperature or reflux. However
under these conditions the desired acid could not be obtained. Hydrolysis
of the substituted dichlorostyrenes 6 and 2a (prepared from the correspond-
ingketones 5 and 3) under the above conditions were also unsuccessful.
In an alternative approach it was planned to reduce the dichlorovinyl
group to a methyl group. Though several reports of the reduction of a
chlorovinyl group to the hydrocarbon are known,[9–11] there is only one
report[18] of the reduction of dichlorovinyl group to a methyl. Based on
this planningthe reaction shown below was attempted and accomplished.
The esters 7a–e of phenylglyoxylic acid, prepared in 48–66% yield,[8,17]
were characterised by their spectral data. These ketoesters on reaction with

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2-ARYL PROPIONATES
2823
triphenylphosphine and tetrachloromethane in dichloromethane furnished
the dichlorostyrene 8a–e in 62–69% yield. The dihalostyrenes were charac-
terised by their spectral properties and elemental analysis. Though this
reagent in THF has been reported[12] to give dichloromethylenation of lac-
tones and acetates, no such reaction was observed in the present conditions
and the ester group was recovered unchanged. The dichlorostyrenes were
then reduced using5% Pd–C in methanol to provide the desired esters 9a–e
in 77–87% yield. The methyl ester 9d was hydrolysed in aq. NaOH to
provide (ꢀ) Ibuprofen 1 in 92% yield.
Thus a new, simple, two step process for the conversion of phenyl
glyoxylate to 2-arylpropionates was accomplished. The interesting feature
is the selective dichloromethylenation of keto function of ketoesters.
Though a two step process for the conversion of lactone carbonyl to
CH–CH3 is known,[18] the present example is an extension for the conversion
of a keto group to a CH–CH3 grouping.
EXPERIMENTAL
All meltingpoints and boilingpoints are uncorrected. The yields of all
the compounds reported are of crystallised or distilled pure compounds. All
solvents were distilled and dried. Elemental analysis were obtained using
Hosli’s rapid carbon hydrogen analyser. IR spectra were recorded on
Perkin-Elmer FT-IR Model (1615). PMR spectra were recorded on Jeol
FX 90Q (90 MHz) instrument in CDCl3, values are given in ꢀ.
General Procedure for the Preparation of Ketones and
Arylglyoxylic Esters
These were prepared by the known methods.[8,16,17]
3: Yield 80%, b.p. 265–268ꢁ (lit.[16] 94–100ꢁ/1.5 mm),1H NMR: 0.91
(6H, d, J ¼ 6.5 Hz, CH(CH3)2), 1.88 (1H, m, CHMe2), 2.57 (2H, d, J ¼ 7.5 Hz,
Ar–CH2–CH–Me2), 2.59 (3H, s, COCH3), 7.37 (2H, d, J ¼ 7.5 Hz, ArH),
8.0 (2H, d, J ¼ 7.5 Hz ArH).
5: Gift from Dr. H.R. Sonawane of NCL Pune.
7a: Yield 48%, b.p. 258–260ꢁ (lit.[8,17a] b.p. 100–102ꢁ/2.3 mm). IR
1
(neat): 1750, 1700 cmÀ1. H NMR: 4.10 (3H, s, COOCH3), 7.75 (3H, m,
ArH), 8.25 (2H, dd, J ¼ 2.0 and 8.0 Hz, ArH).
7b: Yield 65%, b.p. 268–270ꢁ (Lit.[12,17b] b.p. 122ꢁ/5 mm). IR (neat):
1740, 1680 cmÀ1. 1H NMR: 2.34 (3H, s, Ar–CH3), 4.05 (3H, s, OCH3), 7.48
(2H, d, J ¼ 7.5 Hz, ArH), 8.10 (2H, d, J ¼ 7.5 Hz, ArH).

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2824
PATIL AND WADIA
7c: Yield 58%, m.p. 46–47ꢁ (Lit.[8,17c] m.p. 46–48ꢁ). IR (nujol): 1740,
1
1680 cmÀ1. H NMR: 4.00 and 4.10 each (3H, s, ArOCH3, COOCH3), 7.20
(2H, d, J ¼ 9.0 Hz, ArH), 8.30 (2H, d, J ¼ 9.0 Hz, ArH).
7d: Yield 66%, b.p. 239ꢁ. IR (neat): 1760, 1700 cmÀ1. H NMR: 0.91
1
(6H, d, J ¼ 9.0 Hz, ÀCH(CH3)2), 2.0 (1H, m, CH2–CH(CH3)2), 2.62 (2H, d,
J ¼ 10.0 Hz, CH2–CH(CH3)2), 4.10 (3H, s, OCH3), 7.54 (2H, d, J ¼ 9.0 Hz,
ArH), 8.20 (2H, d, J ¼ 9.0 Hz, ArH). Analysis: C13H16O3, required: C, 70.91;
H, 7.27%. Found: C, 70.72; H, 7.22%.
7e: Yield 56%, b.p. 304ꢁ (Lit.[13,17d] b.p. 112ꢁ/0.6 mm). IR (neat): 1740,
1680 cmÀ1
.
1H NMR: 1.43 (3H, t, J ¼ 7.5 Hz, OCH2CH3), 2.48 (3H, s,
ArCH3), 4.60 (2H, q, J ¼ 7.5 Hz, ÀOCH2CH3), 7.60 (2H, d, J ¼ 9.0 Hz,
ArH), 8.23 (2H, d, J ¼ 9.0 Hz, ArH).
General Procedure for the Dichloromethylenation of
Ketones or Ketoesters[7]
Triphenyl phosphine (30 mmole) was dissolved in dry dichloro-
methane (20 mL) and tetrachloromethane (22 mmole) was added to the sol-
ution of ketones (10 mmole) or ketoester (10 mmole) at room temperature.
The resultingmixture was refluxed for 48 h. After solvent removal, SiO 2 (3 g)
was added to the residue and this was loaded on a SiO2 (30 g) column. The
ester was obtained in the hexane-EtOAc (98 : 2) fraction.
4: Yield 70%, b.p. 212–214ꢁ (Lit.[6] 92–95ꢁ/13 mm). H NMR: 2.10
1
(3H, s, H3C–C¼CCl2), 7.25 (5H, s, ArH).
2a: Yield 90%, thick liq. (Lit.[6] oil). IR (neat): 1620, 1470, 930 cmÀ1
.
1H NMR: 0.91 (6H, d, J ¼ 6.5 Hz, CH(CH3)2), 1.88 (1H, m, CH2CH(CH3)2),
2.20 (3H, s, CH3C¼CCl2), 2.48 (2H, d, J ¼ 6.5 Hz, ArCH2), 7.19 (2H, d,
J ¼ 9.0 Hz, ArH), 7.27 (2H, d , J ¼ 9.0 Hz, ArH).
6: Yield 65%, m.p. 72–74ꢁ. IR (nujol): 1640, 1610, 1510, 1490,
1
870 cmÀ1. H NMR: 2.25 (3H, s, CH3C¼CCl2), 3.80 (3H, s, ÀOCH3), 7.18
(3H, m, ArH), 7.80 (3H, m, ArH). Mass m/z: 270 (11%), 268 (57%), 266
(95%), 225 (17%), 223 (29%), 220 (28%), 218 (96%), 183 (100%). Analysis:
C14H12Cl2O, required: C, 62.92; H, 4.49%. Found: C , 62.77; H, 4.43%.
8a: Yield 62%, b.p. 262ꢁ. IR: (neat): 1740, 1610, 1600, 1500, 720,
1
700 cmÀ1. H NMR: 3.91 (3H, s, ÀOCH3), 7.65 (5H, bs, ArH). Analysis:
C10H8Cl2O2, required: C, 51.95; H, 3.46%. Found: C, 52.05; H, 3.57%.
8b: Yield 65%, yellowish oil. IR (neat): 1740, 1605, 1430, 790 cmÀ1
.
1H NMR: 2.33 (3H, s, ArCH3), 3.70 (3H, s, COOCH3), 7.13 (4H, bs, ArH).
Analysis: C11H10Cl2O2, required: C, 53.87; H, 4.08%. Found: C, 53.98;
H, 4.18%.

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2-ARYL PROPIONATES
2825
8c: Yield 69%, b.p. 299ꢁ. IR (neat): 1720, 1590, 1485, 850 cmÀ1
.
1H NMR: 3.90, 3.92 (each 3H, s, ÀOCH3), 7.17 (2H, d, J ¼ 9.0 Hz, ArH),
7.60 (2H, d, J ¼ 9.0 Hz, ArH). Analysis: C11H10Cl2O3, required: C, 50.57;
H, 3.83%. Found: C, 50.79; H, 3.93%.
8d: Yield 65%, b.p. 315ꢁ. IR (neat): 1735, 1640, 1610, 1590, 1510,
1
870 cmÀ1. H NMR: 0.94 (6H, d, J ¼ 9.0 Hz, H2C–CH(CH3)2), 1.84 (1H,
m, H2C–CH(CH3)2), 2.54 (2H, d, J ¼ 9.0 Hz, ÀCH2–CH(CH3)2), 3.94
(3H, s, ÀOCH3), 7.37 (2H, d, J ¼ 8.0 Hz, ArH), 7.51 (2H, d, J ¼ 8.0 Hz,
ArH). Analysis: C14H16Cl2O2, required: C, 58.53; H, 5.57%. Found:
C, 58.79; H, 5.71%.
8e: Yield 66%, b.p. 207ꢁ. IR (neat): 1735, 1610, 1590, 1510, 850 cmÀ1
.
1H NMR: 1.23 (3H, t, J ¼ 6.0 Hz, ÀCH2CH3), 2.40 (3H, s, ArCH3), 4.40
(2H, q, J ¼ 6.0 Hz COOCH2CH3), 7.48 (4H, m, ArH). Analysis:
C12H12Cl2O2, required: C, 55.59; H, 4.63%. Found: C, 55.7; H, 4.72%.
Attempted Hydrolysis of b,b-Dichlorostyrene 2a, 4, and 6
b,b-Dichlorostyrene (20 mmole) and HCl or H2SO4 (dil. or conc.) or
TFA (22 mmole) in benzene (25 mL) were stirred at room temperature for
72 h. As the reaction did not take place (TLC) the mixture in each case was
then refluxed for 72 h. Even then there was no product formation (TLC).
Usual work up (by ether extraction) gave an oil identified by TLC, IR as the
startingdichlorostyrenes.
General Procedure for the Preparation of a-Arylpropanoic
Esters 9a–e from 8a–e
To a solution of arylpropanoic ester (8, 1 mmole) in methanol (40 mL)
in thick glass hydrogenation bottle, 5% palladium over charcoal (ꢂ 40 mg)
was added. This mixture is shaken with hydrogen (ꢂ90 lb/in2) in hydroge-
nation apparatus at room temperature until uptake of hydrogen ceases
(16 h). The catalyst was removed by filtration and washed with methanol.
After complete removal of solvent, product was purified by passage through
silica gel column using hexane–EtOAc (98 : 2).
9a: Yield 77%, b.p. 220–221ꢁ (Lit.[14] 104–106ꢁ/18 mm). IR (neat):
1736, 1600 cmÀ1
.
1H NMR: 1.46 (3H, d, J ¼ 7.5 Hz, Ar–CHCH3), 3.71
(3H, s, COOCH3), 3.80 (1H, q, J ¼ 7.5 Hz, ArCH–CH3), 7.48 (5H, s, ArH).
9b: Yield 78%, b.p. 243–244ꢁ (Lit.[14] 111–112ꢁ/13 mm). IR (neat):
1720, 1500 cmÀ1
.
1H NMR: 1.51 (3H, d, J ¼ 7.5 Hz, Ar–CHCH3), 2.37

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2826PATIL AND WADIA
(3H, s, ArCH3), 3.77 (3H, s, COOCH3), 4.23 (1H, q, J ¼ 7.5 Hz, Ar–CH–
CH3), 7.45 (4H, m, ArH).
9c: Yield 85%, b.p. 280ꢁ. IR (neat): 1736, 1605 cmÀ1. H NMR: 1.48
1
(3H, d, J ¼ 9.0 Hz, ArCHCH3), 3.74 and 3.88 (each 3H, s, COOCH3,
ArOCH3), 4.22 (1H, q, J ¼ 9.0 Hz, ArCH), 7.08 (2H, d, J ¼ 9.0 Hz, ArH),
7.46 (2H, d, J ¼ 9.0 Hz, ArH). Analysis: C11H14O3, required: C, 68.04;
H, 7.21%. Found: C, 68.21; H, 7.38%.
9d: Yield 87%, b.p. 283ꢁ (Lit.[14] 104–106ꢁ/1.0 mm). IR (neat): 1739,
1495 cmÀ1. 1H NMR: 0.91 (6H, d, J ¼ 9.0 Hz, ArCH2–CH(CH3)2), 1.51 (3H,
d, J ¼ 9.0 Hz, ArCHCH3), 1.88 (1H, m, Ar–CH2–CH(CH3)2), 2.48 (2H, d,
J ¼ 10.0 Hz, ArCH2CH(CH3)2), 3.77 (3H, s, ÀCOOCH3), 3.80 (1H, q,
J ¼ 9.0 Hz, Ar–CHCH3), 7.20–7.60 (4H, m, ArH).
9e: Yield 76%, b.p. 241ꢁ (Lit.[15] yellow oil). IR (neat): 1734,
1
1500 cmÀ1. H NMR: 1.22 (3H, t, J ¼ 7.5 Hz, ÀOCH2CH3), 1.51 (3H, d,
J ¼ 7.5 Hz, CHCH3), 2.37 (3H, s, ArCH3), 3.77 (1H, q, J ¼ 7.5 Hz,
ÀCHCH3), 4.23 (2H, q, J ¼ 7.5 Hz, ÀCOOCH2CH3), 7.45 (4H, s, ArH).
Hydrolysis of Ester 9d to 2-(40-Isobutylphenyl) Propanoic Acid 2
The methyl ester 9d (0.190 g, 0.86 mmole) and sodium hydroxide (2N,
5 mL) was stirred at 80ꢁ for 2 h. Usual workup gave a white solid which was
recrystallised from 80% methanol. Yield (0.168 g) 92%, m.p. 75ꢁ (lit.[14]
75–76ꢁ). IR (nujol): 3300–2500 (broad OH), 1718, 1507, 866. 1H NMR:
0.88 (6H, d, J ¼ 6.5 Hz, –CH(CH3)2), 1.47 (3H, d, J ¼ 7.5 Hz, Ar–CH–CH3),
1.87 (1H, m, ÀCH2CH(CH3)2), 2.47 (2H, d, J ¼ 6.5 Hz, CH2–CH(CH3)2),
3.73 (1H, q, J ¼ 7.5 Hz, Ar–CH–CH3), 7.07 (2H, d, J ¼ 8.0 Hz, ArH), 7.35
(2H, d, J ¼ 8.0 Hz, ArH).
ACKNOWLEDGMENT
We thank Dr. H.R. Sonawane, NCL, Pune for helpful discussions.
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2-ARYL PROPIONATES
2827
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Received in the UK June 14, 2001