A Rapid and Efficient Microwave-Assisted Synthesis of Substituted 3-Phenylpropionic Acids from Benzaldehydes in Minutes

Article abstract of DOI:10.1246/cl.2003.1186

A convenient, inexpensive, and efficient synthesis of 3-phenylpropionic acids (1a-1f) by reacting benzaldehyde (2a-2f) and malonic acid in acetic acid and piperidine into cinnamic acid (3a-3f) in 77 to 89% followed by its reduction with PdCl₂ in the biphase of formic acid and aqueous sodium hydroxide is reported under microwave irradiation which utilizes short reaction time ranging 5 to 7 min to provide 1a-1f in moderate to high yield (69-86%) depending upon methoxy, methylenedioxy, and hydroxy groups present at the phenyl ring.

Full text of DOI:10.1246/cl.2003.1186

1186
Chemistry Letters Vol.32, No.12 (2003)
A Rapid and Efficient Microwave-Assisted Synthesis of Substituted
3-Phenylpropionic Acids from Benzaldehydes in Minutes1
Anuj Sharma, Bhupendra P. Joshi, and Arun K. SinhaÃ
Natural Plant Products Division, Institute of Himalayan Bioresource Technology, Palampur (H.P.)-176061, India
(Received September 10, 2003; CL-030846)
A convenient, inexpensive, and efficient synthesis of 3-phe-
Unfortunately, results revealed the presence of 3a without ex-
pected hydrogenated product 1a. The reason for the failure of
hydrogenation step in one pot was assumed to be the presence
of acetate ions which suppressed the dissociation of formic acid
owing to common ion effect to ultimately effect generation of
hydrogen gas. We, therefore, decided to replace acetic acid with
formic acid in the condensation step which successfully provid-
ed 3a as well as allowed hydrogenation to give 1a in 37% yield
with some unreacted 3a. No further improvement in the yield of
1a occurred even with a large excess of formic acid and sodium
hydroxide. It is worthwhile to mention that progress of the reac-
tion during hydrogenation was best monitored under UV spec-
troscopy wherein cinnamic acid 3a provided four peaks at 217,
234, 294, and 318 nm while dihydrocinnamic acid 1a provided
only three peaks at 205, 228, and 279 nm. Recurrent low yield
of 1a prompted us to seek modifications in the above methodol-
ogy and it was decided to retain with acetic acid-piperidine com-
bination for condensation under microwave, though, removing
them before hydrogenation step.17 After condensation, mere ad-
dition of water to the acidic reaction mixture brought about the
precipitation of product 3a in 87% yield. However, a large ex-
cess of mineral acid is required to nullify the basicity of pyridine
and piperidine in the Knoevenagel–Doebner reaction to bring
about precipitation of cinnamic acid6 or resin bound substrate
are used to obtain cinnamic acid in solid state.18 The filtered
white solid (3a) was found pure enough for the next step on
the basis of NMR and was charged in the same pot and hydro-
genated with formic acid and aqueous sodium hydroxide in cat-
alytic amount of PdCl2 under microwave for 5–6 min to provide
the 1a in 77% yield. In attempts to increase the yield of the re-
action further, a little amount of 2-propanol or n-butanol was
added into reaction mixture which led to a significant increase
in rate of reaction and the yield of 1a upto 83% in 3 min17
(Scheme 1). The hydrogenated product 1a thus formed, was fil-
tered hot which got solidified at room temperature. As a control
experiment, the same reaction comprising condensation and hy-
drogenation was performed under conventional heating for 8 h
and 14 h respectively which provided 3a in 79% yield and 1a
in 76% yield. This observation demonstrated the advantage of
microwave irradiation over conventional method for 3a and
1a. After success of 1a, the method was successfully extended
nylpropionic acids (1a–1f) by reacting benzaldehyde (2a–2f)
and malonic acid in acetic acid and piperidine into cinnamic acid
(3a–3f) in 77 to 89% followed by its reduction with PdCl2 in the
biphase of formic acid and aqueous sodium hydroxide is report-
ed under microwave irradiation which utilizes short reaction
time ranging 5 to 7 min to provide 1a–1f in moderate to high
yield (69–86%) depending upon methoxy, methylenedioxy,
and hydroxy groups present at the phenyl ring.
3-phenylpropionic acids are important biologically active
compounds and are generally found in nature2 in traces. More-
over, 3-phenylpropionic acids are useful intermediates in the
synthesis of a variety of organic compounds3 including drugs
such as anti-AIDS,4 nonsteroidal, anti-inflammatory,5 and anti-
psychotic6 drugs. Various protocols are reported for the synthe-
sis of 3-phenylpropionic acids e.g. reaction of cinnamaldehyde
with RuCl3/tri-cyclohexylphosphine4 or trimethylsilylcyanide/
Lewis base,7 reaction of hydrocinnamaldehyde with sodium
nitrite,8 reaction of cinnamic acid with Iridium (I) catalyst9 or
biocatalyst,10 hydrocarboxylation of styrene,5,11 etc. However,
the most common method to prepare 3-phenylpropionic acid
remains two steps synthesis comprising the Knoevenagel–
Doebner12 condensation between aryl aldehyde and malonic acid
in the presence of pyridine and piperidine to provide correspond-
ing cinnamic acid in 6–18 h which is further hydrogenated into
desired 3-phenylpropionic acid in 4–50 h.6,13 But all of them
are limited by drawbacks such as expensive reagents, longer re-
action time, tedious work up involving column purification, low
yields and lastly environmental pollution. Hence, there remains a
scope for development of an efficient general method for the
synthesis of phenylpropionic acids.
In recent past, microwave-assisted14 synthesis of organic
compounds has attracted a considerable amount of attention ow-
ing to several benefits such as shorter reaction time, reduction of
the usual thermal degradation, better yield and most importantly,
ecofriendly behaviour as compared to conventional heating.12
As per our ongoing interest in microwave-assisted synthesis of
organic molecules,15 we decided to prepare 3-(3,4-dimethoxy-
phenyl)propionic acid (1a), a versatile antipsychotic drug6 inter-
mediate, by condensing 3,4-dimethoxybenzaldehyde (2a) with
malonic acid in the presence of acetic acid and piperidine fol-
lowed by reduction16 of double bond of 3a with formic acid,
aqueous sodium hydroxide and PdCl2 into 1a in one pot, two
steps under microwave irradiation intermittent for 5–7 min.17
In selecting acetic acid and piperidine as a condensing agent un-
der microwave irradiation, we thought that acetic acid would not
allow evaporation of piperidine in open atmosphere during mi-
crowave irradiation besides inexpensive nature of acetic acid.
R1
R1
R1
R2
COOH
R2
CHO
COOH
R2
acetic acid
piperidine
PdCl2
NaOH/HCOOH
+ CH2(COOH)2
R5
microwave
3 to 4 min
microwave
2 to3 min.
R5
R5
R3
R3
R3
R4
R4
R4
phenylpropionic acid
cinnamic acid
benzaldehyde malonic acid
(b) R2= R3= R4= OMe; R1= R5= H
(d) R4= OMe; R1= R2 =R3= R5= H
(f) R2=OH; R1=R3=R4= R5= H
(a) R2= R3= OMe; R1= R2= R5= H
(c) R2+ R3= -OCH2CH2O-; R1= R2= R5= H
(e) R1= R2=R3=R4= R5= H
Scheme 1.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.12 (2003)
1187
Table 1. Conversion of benzaldehyde derivatives into phenyl-
propionic acid via corresponding cinnamic acid
39, 8329 (1998).
5
6
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J. Solodar, J. Org. Chem., 37, 1840 (1972).
Cinnamic acid (3)
Run Benzaldehyde (2)
Phenylpropionic acid (1)
CHO
COOH
COOH
a
83%, 3 min
MeO
87%, 2 min
MeO
MeO
MeO
OMe
OMe
OMe
OMe
MeO
CHO
COOH
MeO
MeO
COOH
7
8
9
b
89%, 2 min
86%, 3 min
MeO
MeO
OMe
OMe
COOH
CHO
COOH
c
81%, 2min
78%, 3 min
O
O
O
O
O
O
10 K. Ohmiya, M. Takeuchi, and W. Chen, Appl. Microbiol.
Biotechnol., 23, 274 (1986).
COOH
CHO
COOH
d
78%, 3 min
MeO
81%, 3 min
MeO
11 M. Masahiro, S. Nobuhiro, and N. Masakatsu, J. Chem. Soc.,
Perkin Trans. 1, 1998, 1993; A. Seayad, S. Jayasree, and R.
V. Chaudhari, J. Mol. Catal. A: Chem., 172, 151 (2001).
12 G. Jones, ‘‘Organic Reactions,’’ John Wiley and Sons, New
York (1967), Vol. 15, p 204; B. S. Furniss, A. J. Hannaford,
V. Rogers, P. W. G. Smith, and A. R Tatchell, ‘‘Vogel’s
Textbook of Practical Organic Chemistry,’’ 4th ed., ELBS,
UK (1978), p 802.
MeO
CHO
COOH
COOH
e
78%, 3 min
74%, 4 min
CHO
COOH
COOH
f
77%, 3 min
69%, 4 min
OH
OH
CHO
COOH
OH
No Reaction
g
81%, 3 min
Cl
Cl
CHO
13 S. Takayuki, H. Takayuki, and I. Kunisuke, U. S. Patent
6339170 (2002).
h
No Reaction
HO
OMe
14 A. K. Bose, B. K. Banik, N. Lavlinskaia, M. Jayaraman, and
M. S. Manhas, CHEMTECH, 1997, 18; B. K. Banik, K. J.
Barakat, D. R. Wagle, M. S. Manhar, A. K. Bose, J. Org.
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Hallberg, Drug Discovery Today, 6, 406 (2001); G. Kaupp,
M. R. Naimi-Jamal, and J. Schmeyers, Tetrahedron, 59,
3753 (2003).
for a variety of substituted phenylpropionic acids bearing meth-
oxy, dimethoxy, trimethoxy, and hydroxy groups except for
3-chlorobenzaldehyde (2g) which did not provide the corre-
sponding 3-(4-chlorophenyl)propionic acid though 3-(4-chloro-
phenyl)propenoic acid (3g) was obtained in good yield (81%).
Similarly, 4-hydroxy-3-methoxybenzaldehyde (2h) did not pro-
vide either 4-hydroxy-3-methoxycinnamic acid or 4-hydroxy-3-
methoxyphenylpropionic acid (Table 1). It is worthwhile to
mention that precipitation of the solid during condensation as
well as hydrogenation is an added advantage in our method, as
reported methods for obtaining both cinnamic acid and phenyl-
propionic acid as solids are through resin bound solid phase syn-
thesis.18,19
15 A. K. Sinha, B. P. Joshi, and R. Acharya, Chem. Lett., 32, 780
(2003); A. K. Sinha, B. P. Joshi, and R. Dogra, U. S. Patent
6544390 (2003); A. K. Sinha, B. P. Joshi, A. Sharma, J. K.
Kumar, and V. K. Kaul, Nat. Prod. Res., 17, 419 (2003).
16 B. Elamin, J. Park, and G. E. Means, Tetrahedron Lett., 29,
5599 (1988); J. B. Arterburn, M. Pannala, A. M. Gonzalez,
and R. M. Chamberlin, Tetrahedron Lett., 41, 7847 (2000).
17 General procedure for the preparation of substituted 3-phenyl-
propionic acids (1a–1f) from phenylaldehydes (2a–2f): A mix-
ture of benzaldehyde (2a–2h) (0.005 mol), malonic acid
(0.01 mol), piperidine (0.012 mol) and acetic acid (15 mL)
were taken in a 100-mL Erlenmeyer flask and placed inside
a Kenstar microwave oven (2450 MHz, 900 W) and irradiated
for 2–3 min in parts. The mixture was poured in ice cold water
and precipitated solid was filtered to afford cinnamic acid (3a–
3g) in 77–89% yield which were found pure enough to be used
in the next step without additional purification. For the next
step, 3a–3g (0.025 mol) was dissolved 2.5 M NaOH (45 mL
or more till pH attained around 9–10), PdCl2 (10–15 mg) and
a few drops of 2-propanol (1–2 mL) followed by dropwise
addition of HCOOH (10–15 mL or more) until the mixture
becomes acidic (pH attained around 2–3) and then irradiation
under microwave for 2–3 minutes. The reaction mixture was
filterd while hot and filtrate upon standing at room temperature
provided as a solid which after recrystallisation with mixture of
ethyl acetate and hexane gave substituted phenylpropionic acid
(1a–1f) in 69–86% yield whose mp and NMR spectra data was
found similar to reported values.2,6
In conclusion, we have devised an efficient and rapid meth-
odology for the preparation of substituted 3-phenylpropionic
acids from benzaldehydes under microwave irradiation within
5–7 min which is a better yielding, economical and an environ-
ment friendly process.
Two of us (BPJ and AS) are indebted to CSIR, Delhi for the
award of SRF and JRF respectively. The authors gratefully ac-
knowledge the Director of I.H.B.T., Palampur for his kind coop-
eration and encouragement.
References and Notes
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3
4
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Published on the web (Advance View) November 27, 2003; DOI 10.1246/cl.2003.1186