One-pot preparation of phenylpropanoid esters co-catalyzed by boric acid and piperidine

Article abstract of DOI:10.1007/s11164-011-0338-3

Phenylpropanoid esters, especially those with hydroxyl and/or methoxy groups on the benzene ring, are important medicinal chemicals or intermediates. They are usually prepared by esterification of their corresponding substituted cinnamic acids with various alcohols. However, the esterification procedures often suffer from environmentally hazardous problems when sulfuric acid is used as a catalyst or suffer from unsatisfactory yields and expensive raw material when enzyme is applied as a catalyst. In this paper, a convenient one-pot process for preparing various phenylpropanoid esters from substituted benzaldehydes bearing hydroxyl and/or methoxyl groups has been developed. The alcohols react first with malonic acid catalyzed by boric acid to form monomalonate, then without separation, let the resultant mixture immediately react with the injected various substituted benzaldehydes in the presence of piperidine to afford the desired esters with moderate to good yields. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0338-3

Res Chem Intermed (2012) 38:207–213
DOI 10.1007/s11164-011-0338-3
One-pot preparation of phenylpropanoid esters
co-catalyzed by boric acid and piperidine
•
•
•
Huan Wang Qing-Yi Wei Hong Jiang
Zhen-Hua Jiang
Received: 30 March 2011 / Accepted: 7 June 2011 / Published online: 23 June 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Phenylpropanoid esters, especially those with hydroxyl and/or methoxy
groups on the benzene ring, are important medicinal chemicals or intermediates. They
are usually prepared by esterification of their corresponding substituted cinnamic
acids with various alcohols. However, the esterification procedures often suffer from
environmentally hazardous problems when sulfuric acid is used as a catalyst or suffer
from unsatisfactory yields and expensive raw material when enzyme is applied as a
catalyst. In this paper, a convenient one-pot process for preparing various phenyl-
propanoid esters from substituted benzaldehydes bearing hydroxyl and/or methoxyl
groups has been developed. The alcohols react first with malonic acid catalyzed by
boric acid to form monomalonate, then without separation, let the resultant mixture
immediately react with the injected various substituted benzaldehydes in the presence
of piperidine to afford the desired esters with moderate to good yields.
Keywords One-pot Á Boric acid Á Phenylpropanoid esters Á Cinnamic acid
Introduction
Phenylpropanoids esters, including cinnamate, and especially those substituted
cinnamates bearing hydroxyl and/or methoxyl groups such as coumarate (hydroxy-
cinnamate), sinapate (3,5-dimethoxy-4-hydroxycinnamate), ferulate (3-(3-methoxyl-
4-hydroxyphenyl) propenoic acid ester), caffeate (3-(3,4-dihydroxyphenyl)
propenoic acid ester), are widely distributed in fruits, vegetables, and cereals, and
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-011-0338-3) contains supplementary material, which is available to authorized users.
H. Wang Á Q.-Y. Wei Á H. Jiang (&) Á Z.-H. Jiang
Department of Chemistry, Huazhong Agricultural University, Wuhan 430070, China
e-mail: jianghong0066@126.com
123

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H. Wang et al.
are common constituents of plant tissues. Apart from their antioxidant capacity, these
cinnamates, bearing hydroxyl and/or methoxyl groups, present several biological and
pharmacological properties such as antimicrobial, anti-carcinogenic, antifungal, anti-
aging, and anti-atherosclerosis effects [1–8]. Furthermore, hydrocinnamate is a key
precursor of 1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, which is used as
an analgesic, inflammation inhibitor, and antipyretic [9]. Hydrocinnamate has also
been used for the synthesis of HIV-1 protease inhibitors [10]. P-methoxycinnamates
are commercially popular UV-B screening compounds in sunscreen products [11].
Particularly, cinnamates have a wide range of industrial applications such as
plasticizers, graphics, lubricants, flavors, perfumes, and cosmetics [12]. Due to their
distinguished properties and applications of phenylpropanoid esters, there has been
great interest in devising simple and efficient methods to prepare them.
The typical methods for synthesis of phenylpropanoid esters are the direct
esterification methods of substituted cinnamic acid catalyzed by chemicals.
However, most of the procedures require strong acids such as sulfuric acid,
hydrochloride acid, and toxic chemicals such as dimethyl sulfate, methyl iodide, or
diazomethane, which are environmentally hazardous and hence unacceptable.
Enzyme-catalyzed esterification ways have the reputation of green, but these
methods often suffer from unsatisfactory yields and expensive raw material [13–19].
Knoevenagel condensation between substituted benzaldehyde and monomalonate is
a useful alternative to the esterification method. Monomalonate can usually be
prepared by the reaction of alcohols and Meldrum’s acid [20]. Monomalonate can
also be synthesized by the monoesterification of malonic acid catalyzed by boric
acid [21]. Inspired by this method for monomalonate, we successfully developed a
general, efficient, and convenient process for the synthesis of phenylpropanoid
esters from malonic acid, alcohols, and corresponding benzaldehydes in one-pot in
the presence of boric acid and piperidine. Briefly, the alcohols reacted with malonic
acid to form monomalonates, which without separation, immediately reacted with
aldehydes in the presence of piperidine to afford the title compounds (Scheme 1).
R3
O
R2
CHO
CO2H
CO2H
OR1
H3BO3
+
R1OH
piperidine
CO2H
without separation
R3
O
OR1
R2
R1=CH3, CH2CH3, CH (CH3)2; R2=H, OH, OCH3; R3=H, OH, OCH3
Scheme 1 The synthesis route for phenylpropanoid esters
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One-pot preparation of phenylpropanoid esters
209
Results and discussion
The reactions involved the one-pot condensation of malonic acid, alcohols, and
aldehydes in the presence of a catalytic amount of boric acid and pyridine to afford
phenylpropanoid esters in moderate to excellent yield (70–86%). The ratio of
malonic acid, alcohol, aldehyde, boric acid, and piperidine was in a molar ratio of
1:1:0.7:0.1:0.3. First, the influence of the adding order of reagents on the yields was
investigated. Procedure 2 (entry 2 in Table 1): first let the reaction between
benzaldehyde, cinnamic acid, ethanol, and boric acid take place in toluene for 18 h.
Piperidine was then injected and the reaction was continued for another 12 h. The
conversion of aldehyde was evaluated by GC and the yields of product refer to the
isolated ones. The yield by procedure 2 is about 72.1%. Procedure 3 (entry 3 in
Table 1) is by treatment of benzaldehyde, cinnamic acid, ethanol, boric acid, and
piperidine all together in toluene for 30 h, then the conversation of aldehyde and the
isolated yield was evaluated. The yield by procedure 3 was about 50.3%. This
indicates that the adding order of raw material had great effects on the yields when
the conversation of aldehyde was almost the same (above 99%). Procedure 1 is the
best working one among the three procedures (entry 1 in Table 1), in which
monomalonate was first produced by the reaction of malonic acid and alcohol
catalyzed by boric acid. Then Knoevenagel condensation of monomalonate was
carried out by injection of aldehyde and piperidine leading to the formation of ethyl
cinnamate in 84.7% yield. Therefore, in the following synthesis of the target
products, procedure 1 was adopted as the typical method. The possible reaction
mechanism is as follows: First monomalonates were produced by the reaction of
cinnamic acid and alcohols catalyzed by boric acid [21], then monomalonates
reacted with aldehydes, leading to Knoevenagel condensation products catalyzed by
piperidine. Finally, the condensed products were decarboxylated under the heating
condition and the presence of catalysts gave the title compounds.
In order to explore the scope and limitations of this synthetic methodology, we
have extended this procedure for different alcohols and benzaldehydes bearing
hydroxyl and/or methoxyl groups, which the corresponding esters often possess
various medicinal functions. The desired esters were obtained and are listed in
Table 2. Table 2 shows that lower isolated yields were obtained for aromatic
aldehydes bearing electron-donating groups on the benzene ring, which may be
ascribed to the lower electropositivity of the carbonyl. The electron-donating effects
intrinsically deactivate the electrophilic carbon center of the aldehyde group for
nucleophilic attack of the enolate anion of monomalonate. The yields of the esters
Table 1 Synthesis of ethyl
Entry
Time
(h)
Conversion of
benzaldehyde (%)
Yield of ethyl
cinnamate (%)
cinnamate catalyzed by boric
acid by three different
procedures
1
2
3
30
30
30
99.6
99.8
99.1
84.7
72.1
50.3
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H. Wang et al.
Yield (%)a
Table 2 Synthesis of phenylpropanoid esters
Entry
R1
R2
R3
Time (h)
1
Me
H
H
30
30
30
35
35
35
35
35
35
35
35
35
86.3
84.7
78.2
78.3
76.1
70.6
83.9
79.5
75.2
76.9
74.3
70.1
2
Et
H
H
3
Isopropyl
Me
H
H
4
OH
OH
OH
OMe
OMe
OMe
OH
OH
OH
H
5
Et
H
6
Isopropyl
Me
H
7
H
8
Et
H
9
Isopropyl
Me
H
10
11
12
OMe
OMe
OMe
Et
Isopropyl
The procedure follows Scheme 1
a
Isolated yields after purification on silica gel. All the products were characterized by IR, MS, and
1HNMR
were found to decrease in going from primary to secondary alcohols, which is in
accordance with the reactivity of the alcohols. Tertiary alcohols provided very low
title esters, which may be attributed to the higher steric hindrance.
The reaction is very facile to be operated, as it is a one-pot process. All the
products were characterized by IR, MS, and 1HNMR, and the spectra and analytical
data are in agreement with their structures.
Conclusions
In summary, boric acid and piperidine was shown to be an effective and cheap
co-catalyst for the preparation of phenylpropanoid esters derivatives. The one-pot
process offers several unique advantages such as enhanced yields, economic raw
material, operational simplicity, and mild reaction conditions.
Experimental section
All the substituted aldehydes, malonic acid, and other chemicals were purchased
from Shanghai Reagent Co. The 1H NMR spectra were obtained with a DPX
600 MHz spectrometer in CDCl3 with TMS as internal standard. The IR spectra
were recorded on an Avatar 330 instrument as potassium bromide pellets. The MS
spectra were performed by using an Agilent 5975c mass spectrometer in the EI
mode. Yields refer to isolated products.
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One-pot preparation of phenylpropanoid esters
211
Typical procedure for the synthesis of phenylpropanoid ester
Malonic acid (1.001 g, 9.62 mmol), and boric acid (0.059 g, 0.96 mmol) were
added to the ethanol (0.56 mL, 9.62 mmol) in a two-necked round-bottomed flask
with a drying tube. After refluxing for about 18 h, benzaldehyde (0.72 g,
6.73 mmol), piperidine (0.3 mL, 2.89 mmol) and toluene (5 mL) were added into
the mixture with stirring. When the reaction was finished by TLC monitoring,
solvents were removed by distillation under vacuum. The residue was dissolved in
ethyl acetate (about 30 mL), then washed with saturated solutions of sodium
bicarbonate(20 mL 9 2), sodium bisulfite (20 mL 9 2), distilled water (20 mL),
respectively. The organic phase was dried by anhydrous MgSO4 overnight. After
removal of the solvent, the crude product was given. Pure product was produced by
silica gel column chromatography.
Methyl cinnamate (1), Pale yellow solid, mp 31–32 °C, IR (KBr, cm-1), 1,717
1
(C=O), 1,638 (C=C), 1,272, 1,173 (C–O–C), H NMR (600 MHz, CDCl3, d ppm),
7.670–7.644 (1H, d, J = 15.6 Hz, =CH), 7.479–7.454 (2H, m, ArH), 7.378–7.318
(3H, m, ArH), 6.390–6.363 (1H, d, J = 16.2 Hz, =CH), 3.740 (3H, s, OCH3). MS
(m/z, %), 162 (M?, 60%), 131 (100%), 103 (70%), 77 (45%).
Ethyl cinnamate (2), colorless oil, IR (KBr, cm-1), 1713 (C=O), 1,637 (C=C),
1,268, 1,173 (C–O–C), 1H NMR (600 MHz, CDCl3, d ppm), d 7.635–7.609 (1H, d,
J = 15.6 Hz, =CH), 7.491–7.412 (2H, m, ArH), 7.363–7.315 (3H, m, ArH),
6.387–6.361 (1H, d, J=15.6 Hz, =CH), 4.237–4.196 (2H, q, J = 7.8 Hz, CH2),
1.285–1.263 (3H, t, J = 6.6 Hz, CH3), MS (m/z, %), 176 (M?, 40%), 131 (100%),
103 (50%), 77 (40%).
Isopropyl cinnamate (3), colorless oil, IR (KBr, cm-1), 1,712 (C=O), 1,637
(C=C), 1,180, 1,108 (C–O–C), 1H NMR (600 MHz, CDCl3, d ppm), d 7.614–7.587
(1H, d, J = 16.2 Hz, =CH), 7.463–7.430 (2H, m, ArH), 7.331–7.306 (3H, m, ArH),
6.367–6.340 (1H, d, J = 16.2 Hz, =CH), 5.106–5.044 (1H, m, CH), 1.254–1.243
(6H, d, J = 6.6 Hz, (CH3)2), MS (m/z, %), 190 (M?, 30%), 147 (80%), 131 (100%),
103 (50%), 77 (40%).
Methyl p-hydroxycinnamate (4), white solid, mp 129–130 °C, IR (KBr, cm-1),
3,378 (O–H), 1,686 (C=O), 1,633 (C=C), 1,197, 1,170 (C–O–C), 1H NMR
(600 MHz, CDCl3, d ppm), d 7.588–7.561 (1H, d, J = 16.2 Hz, =CH), 6.363–6.349
(2H, d, J = 8.4 Hz, ArH), 6.799–6.784 (2H, d, J = 9.0 Hz, ArH), 6.246–6.219 (1H,
d, J = 16.2 Hz, =CH), 5.927 (1H, s, OH), 3.735 (3H, s, CH3), MS (m/z): 178 (M?,
75%), 147 (100%), 119 (40%).
Ethyl p-hydroxycinnamate (5), white solid, mp 70–71 °C, IR (KBr, cm-1), 3,286
1
(O–H), 1,683 (C=O), 1,632 (C=C), 1,190, 1,168 (C–O–C), H NMR (600 MHz,
CDCl3, d ppm), 7.578–7.551 (1H, d, J = 16.2 Hz, =CH), 7.361–7.346 (2H, d,
J = 9.0 Hz, ArH), 6.795–6.781 (2H, d, J = 8.4 Hz, ArH), 6.241–6.215 (1H, d,
J = 15.6 Hz, =CH), 5.96 (1H, s, OH), 4.211–4.175 (2H, q, J = 7.2 Hz, CH2),
1.279–1.255 (3H, t, J = 7.2 Hz, CH3), MS (m/z): 192 (M?, 50%), 147 (100%).
Isopropyl p-hydroxycinnamate (6), pale yellow solid, mp 80–81 °C, IR (KBr,
cm-1), 3,357 (O–H), 1,679 (C = O), 1,632 (C=C), 1,203, 1,170 (C–O–C), 1H NMR
(600 MHz, CDCl3, d ppm), 7.557–7.530 (1H, d, J = 16.2 Hz, = CH), 7.351–7.337
(2H, d, J = 8.4 Hz, ArH), 6.784–6.770 (2H, d, J = 8.4 Hz, ArH), 6.222–6.195
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(1H, d, J = 16.2 Hz, =CH), 5.952 (1H, s, OH), 5.089–5.047 (1H, m, CH),
1.248–1.237 (6H, d, J = 6.6 Hz, (CH3)2), MS (m/z, %):206 (M?, 45%), 164 (50%),
147 (100%).
Methyl p-methoxycinnamate (7), pale yellow solid, mp 88–89 °C, IR (KBr,
1
cm-1), 1,717 (C=O), 1,637 (C=C), 1,206, 1,170 (C–O–C), H NMR (600 MHz,
CDCl3, d ppm), 7.596–7.570 (1H, d, J = 15.6 Hz, =CH), 7.415–7.401 (2H, d,
J = 8.4 Hz, ArH), 6.843–6.829(2H, d, J = 8.4 Hz, ArH), 6.256–6.230 (1H, d,
J = 15.6 Hz, = CH), 3.769 (3H, s, OCH3), 3.724 (3H, s, OCH3), MS (m/z, %):192
(M?, 100%), 161 (90%), 133 (25%).
Ethyl p-methoxycinnamate (8), pale yellow oil, IR (KBr, cm-1), 1,709 (C=O),
1,633 (C=C), 1,205, 1,173 (C–O–C), 1H NMR (600 MHz, CDCl3, d ppm),
7.572–7.546(1H, d, J = 15.6 Hz, =CH), 7.409–7.398 (2H, d, J = 6.6 Hz, ArH),
6.835–6.824 (2H, d, J = 6.6 Hz, ArH), 6.238–6.211 (1H, d, J = 16.2 MHz, =CH),
4.187–4.152 (2H, q, J = 6.9 Hz, CH2), 3.749 (3H, s, OCH3), 1.260–1.237 (3H, t,
J = 6.9 Hz, CH3), MS (m/z, %), 206 (M?, 100%), 161 (70%), 134 (20%).
Isopropyl p-methoxycinnamate (9), yellow oil IR (KBr, cm-1), 1,706 (C=O),
1,634 (C=C), 1,204, 1,172 (C–O–C), 1H NMR (600 MHz, CDCl3, d ppm),
7.565–7.539 (1H, d, J = 15.6 Hz, =CH), 7.410–7.3969 (2H, d, J = 8.4 Hz, ArH),
6.836–6.822 (2H, d, J = 8.4 Hz, ArH), 6.232–6.205 (1H, d, J = 16.2 Hz, =CH),
5.080–5.039 (1H, m, CH), 3.765 (3H, s, OCH3), 1.241–1.231 (6H, d, J = 6.0 Hz,
(CH3)2), MS (m/z,%), 220 (M?, 100%), 161 (40%), 134 (60%).
Methyl ferulate (10), white solid, mp, 64–65 °C, IR (KBr, cm-1), 3,407 (O–H),
1
1,703 (C=O), 1,633 (C=C), 1,269, 1,167 (C–O–C), H NMR (600 MHz, CDCl3, d
ppm), 7.557–7.531 (1H, d, J = 15.6 Hz, =CH), 7.024–6.948 (2H, m, ArH),
6.859–6.848 (1H, d, J = 6.6 Hz, ArH), 6.252–6.227 (1H, d, J = 15 Hz, =CH),
5.853 (1H, s, OH), 3.870 (3H, s, OCH3), 3.719 (3H, s, OCH3), MS (m/z, %), 208
(M?, 100%), 177 (75%).
Ethyl ferulate, pale yellow solid, mp, 59–60 °C, IR (KBr, cm-1), 3,411 (O–H),
1
1,700 (C=O), 1,631 (C=C), 1,265, 1,163 (C–O–C), H NMR (600 MHz, CDCl3, d
ppm), 7.558–7.532 (1H, d, J = 15.6 Hz, =CH), 7.027–6.962 (2H, m, ArH),
6.854–6.841 (1H, d, J = 7,8 Hz, ArH), 6.234–6.208 (1H, d, J = 15.6 Hz, =CH),
5.835 (1H, s, OH), 4.204–4.170 (2H, q, J = 6.9 Hz, CH2), 3.854 (3H, s, OCH3),
1.277–1.254 (3H, t, J = 6.9 Hz, CH3), MS (m/z, %), 222 (M?, 100%), 177 (50%),
150 (25%).
Isopropyl ferulate, white solid, mp, 79–80 °C, IR (KBr, cm-1), 3,391 (O–H),
1
1,691 (C=O), 1,628 (C=C), 1,184, 1,096 (C–O–C), H NM (600 MHz, CDCl3, d
ppm), 7.538–7.511 (1H, d, J = 16.2 Hz, =CH), 7.029–6.961 (2H, m, ArH),
6.850–6.836 (1H, d, J = 8.4 Hz, ArH), 6.215–6.189 (1H, d, J = 15.6 Hz, =CH),
5.827 (1H, s, OH), 5.085–5.044 (1H, m, CH), 3.850 (3H, s, OCH3), 1.244–1.234
(6H, d, J = 6.0 Hz, (CH3)2), MS (m/z, %), 236 (M?, 100%), 177 (25%), 150
(20%).
Acknowledgments This study was supported by the National Natural Science Foundation of China
(Grant no. 20702016).
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One-pot preparation of phenylpropanoid esters
213
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