A facile synthesis of phenylacetic acids via Willgerodt-Kindler reaction under PTC condition

Article abstract of DOI:10.1081/SCC-120015559

Phenylacetic acids are efficiently synthesized from acetophenones via thiomorpholides under Phase Transfer Catalytic (PTC) condition. The reaction proceeds efficiently by using triethyl benzyl ammonium chloride (TEBA) as PTC and the reaction time decreased dramatically upto 1/5th (24-5) to afford pure products in good to excellent yield.

Full text of DOI:10.1081/SCC-120015559

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A Facile Synthesis of Phenylacetic Acids via Willgerodt-
Kindler Reaction Under PTC Condition
M. Mujahid Alam a & Srinivas R. Adapa a b
a Inorganic Division, Indian Institute of Chemical Technology, Hyderabad, A.P., India
b Inorganic Division, Indian Institute of Chemical Technology, Hyderabad, 500 007, A.P., India
Version of record first published: 20 Aug 2006.
To cite this article: M. Mujahid Alam & Srinivas R. Adapa (2003): A Facile Synthesis of Phenylacetic Acids via Willgerodt-
Kindler Reaction Under PTC Condition, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:1, 59-63
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 1, pp. 59–63, 2003
A Facile Synthesis of Phenylacetic Acids
via Willgerodt-Kindler Reaction
Under PTC Condition
M. Mujahid Alamand Srinivas R. Adapa *
Inorganic Division, Indian Institute of Chemical Technology,
Hyderabad, A.P., India
ABSTRACT
Phenylacetic acids are efficiently synthesized from acetophenones
via thiomorpholides under Phase Transfer Catalytic (PTC) condi-
tion. The reaction proceeds efficiently by using triethyl benzyl ammo-
nium chloride (TEBA) as PTC and the reaction time decreased
dramatically upto 1/5th (24–5) to afford pure products in good to
excellent yield.
*Correspondence: Srinivas R. Adapa, Inorganic Division, Indian Institute of
Chemical Technology, Hyderabad 500 007, A.P., India. E-mail: asrinivas_
rao@iict.ap.nic.in.
59
DOI: 10.1081/SCC-120015559
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60
Alamand Adapa
Phenylacetic acids are very important compounds as they are show-
ing broad range of biological activity, i.e., antibacterial,[2] analgesic,[3]
virucidal,[4] prostaglandin synthetase response,[5] plant growth regula-
ter,[6] etc. They are used as important intermediates in the syntheses
of benzamido and phenylacetamido phenyl benzoxazole derivatives,[7]
N-(aryl/hetero aryl acetyl) amino acid esters,[8] caprolactams,[9] benzo-
dioxinones,[10] imidazoles,[11] N-(propynyl)aryl acetamides,[12] phenylfur-
anone,[13] halobenzyl isoquinolines,[14] estradiene and estratriene,[15] and
[16]
anticancer calcui m channel blockers.
Phenylacetic acids have been synthesized by (i) rhodium-catalyzed
carbonylation,[17] (ii) hydrogenation of mandelic acid derivatives to the
corresponding phenylacetic acid derivatives catalyzed by Pd/C,[18]
(iii) carbonylation of benzyl chloride in the presence of water-soluble com-
plex, [PdCl2{PPh2(m-C6H4SO3Na)}2], and surfactants under two-phase
conditions,[19] (iv) microwave induced Willgerodt-Kindler reactions
of styrenes,[20] (v) microwave-assisted rapid hydrolysis and preparation
of thioamides by Willgerodt-Kindler reaction,[21] (vi) production of
phenylacetic acid by liquid phase oxidation of acetophenone with
sulphur in the presence of aqueous ammonia.[22]
Although, all these methods have some limitations such as long reac-
tion times, hazardous reaction conditions and use of microwave ovens
which are not commonly available in all the research laboratories.
Therefore in view of the above said limitations and their pharmaceutical
and biological importance, there is an intense demand to develop a new
and efficient method for the synthesis of biologically active phenylacetic
acids under mild and ecofriendly reaction conditions. In this paper, we wish
to report an efficient synthesis of phenylacetic acid and its derivatives in
good to excellent yield under Phase Transfer Catalytic (PTC) conditions.
The reaction has been carried out at 100ꢀC taking triethyl benzyl
ammonium chloride (TEBA) as phase transfer catalyst. When thiomor-
pholides have been hydrolyzed with TEBA (114 mg, 0.05 mmol) under
basic conditions the hydrolysis takes place within 8 h as indicated by TLC
to afford phenylacetic acids in 80% yield. These results encouraged
us to investigate the effect of TEBA (PTC) in hydrolysis, accordingly a
series of thiomorpholides have been hydrolyzed into the corresponding
phenylacetic acids in excellent yield (Sch. 1).
It is note worthy that the reaction time decreased dramatically almost
up to 1/5th (i.e., from 24 to 5 h). Furthermore the products are isolated in
almost pure form and do not require any further purification.
It is observed that the reaction follows the effect of substituent on
benzene ring. The activated thiomorpholides are hydrolyzed faster than

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Willgerodt-Kindler Reaction Under PTC Condition
61
Scheme 1.
Table 1. Conversion of acetophenones to phenylacetic acids catalyzed by TEBA
under Willgerodt-Kindler reaction condition.
Time
(h)
Yield
(%)
Entry
Substrate A
Product B
1
2
Acetophenone
2-Acetyl
naphthalene
4-Isobutyl
acetophenone
4-Cl acetophenone
4-Br acetophenone
2-Amino
acetophenone
4-Hydroxy
acetophenone
4-Methoxy
2-hydroxy
acetophenone
1-Hydroxy
acetyl naphthalene
4-Methoxy
acetophenone
Phenylacetic acid
2-Naphthaleneacetic
acid
4-Isobutyl phenylacetic
acid
4-Cl phenylacetic acid
4-Br phenylacetic acid
2-Amino phenylacetic
acid
4-Hydroxy phenylacetic
acid
4-Methoxy
2-hydroxy phenyl
acetic acid
1-Hydroxy naphthalene
acetic acid
4-Metoxy
5
5
80
80
3
6
78
4
5
6
8
8
6
78
78
70
7
8
6
6
65
63
9
6
6
63
60
10
phenylacetic acid
deactivated thiomorpholides. In the reaction the other sensitive groups
suchaschloro,bromo,methoxy,amino, hydroxy, alkyl,etc.,areunaffected.
All the products are characterized by comparing their physical data,
1H-NMR, Mass, IR of authentic samples.

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62
Alamand Adapa
Thus, the present method is an efficient and facile for the synthesis of
phenylacetic acids from acetophenones via their thiomorpholides under
phase transfer conditions. The reaction is far superior to other earlier
reported methods with regards to its simplicity, selectivity, reaction time,
and yield (Table 1).
Typical procedure for the preparation of phenylacetic acid: Aceto-
phenone (1.20 g, 10 mmol), sulfur (0.64 g, 20 mmol), morpholine (3 mL,
30 mmol), p-toluene sulphonic acid (0.06 g, 0.35 mmol) were added and
held at reflux under constant stirring in an oil bath at 120–130ꢀC for 8 h.
After completion of the reaction as indicated by TLC, the reaction mix-
ture was allowed to cool and 20% NaOH and triethyl benzyl ammonium
chloride (TEBA) (114 mg, 0.05 mmol) were added to the reaction mixture
and continued hydrolysis for further 8 h at 100ꢀC. After completion of
the reaction as indicated by TLC, the reaction mixture was cooled and
filtered, the filtrate was acidified with HCl to pH 6 and then filtered off.
The filtrate was further acidified to pH 2 and thus crude phenylacetic acid
was obtained. The acid was then taken into 10% NaHCO3 solution and
was washed with ethyl acetate (3 Â 30 mL), separated the organic layer,
and the aqueous layer was acidified with dilute HCl, to yield the pure
phenylacetic acid as solid. In case of products from hydroxy acetophe-
nones, the products were extracted into ethyl acetate. The dried organic
layer was evaporated under reduced pressure to yield pure phenylacetic
acid.
ACKNOWLEDGMENTS
The authors wish to thank Dr. K. V. Raghavan, Director of IICT
and Dr. B. M. Choudary, Head of the Division, for their encouragement.
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Received in the UK October 22, 2001

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