Synthesis of cinnamic acid derivatives in a water-insoluble ionic liquid

Article abstract of DOI:10.3184/174751911X13236869868941

A number of cinnamic acid derivatives have been synthesised from commercially available aromatic aldehydes and propanedioic acid in a water-insoluble ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]PF₆) in high yields in the presence of small catalytic amounts of piperidine. The ionic liquid can be reused at least five times.

Full text of DOI:10.3184/174751911X13236869868941

JOURNAL OF CHEMICAL RESEARCH 2011
DECEMBER, 723–725
RESEARCH PAPER 723
Synthesis of cinnamic acid derivatives in a water-insoluble ionic liquid
Wensheng Zhang*, Wenjing Xu, Mei Liu, Yuerong Yan, Yuezhi Sun and Sheli Zhang
School of Biological and Chemical Engineering, JiaozuoTeachers’ College, Shanyang Road 998, Jiaozuo 454001, P. R. China
A number of cinnamic acid derivatives have been synthesised from commercially available aromatic aldehydes and
propanedioic acid in a water-insoluble ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]PF6)
in high yields in the presence of small catalytic amounts of piperidine. The ionic liquid can be reused at least five
times.
Keywords: cinnamic acid, synthesis, aromatic aldehyde, propanedioic acid, piperidine, Knoevenagel reaction, ionic liquid,
recycling
Cinnamic acid (3-phenylprop-2-enoic acid) is the parent com-
pound of a relatively large family of organic acids. In nature,
cinnamic acid derivatives are important metabolic building
blocks in the production of lignins for higher plants. Cinnamic
acids have shown a broad spectrum of antibacterial, antifungal
and antiparasitic abilities. A derivative of cinnamic acid is an
important pharmaceutical for high blood pressure and stroke
Results and discussion
The condensation reaction of aromatic aldehydes and pro-
panedioic acid in an ionic liquid was carried out at 85 °C. We
focused on the condensation in water-insoluble ionic liquids
mainly due to the good solubility of the desired cinnamic acids
in basic aqueous solution. Thus, extraction of the reaction
mixtures with NaOH (10%) followed by acidification of the
aqueous layers using 10% HCl under stirring afforded the
products in high yields. 4-Methylbenzaldehyde was initially
chosen as a model using propanedioic acid (3 equiv.), small
catalytic amounts of piperidine (0.1 equiv.) and 10 mL of the
ionic liquid as reaction solvent. A series of water-insoluble
ionic liquids including 1-butyl-3-methylimidazolium hexaflu-
1
,2
prevention and possesses antitumour activity. Cinnamic acid
derivatives are extensively studied not only due to their potent
biological activity, but also because of their wide scope of
applications in macromolecular synthesis as important build-
ing blocks for various classes of polymers having attractive
3
properties, especially a high photoreactivity. In addition,
orophosphate ([bmim]PF ), 1-hexyl-3-methylimidazolium
tetrafluoroborate ([hmim]BF ), 1-ethyl-3-methylimidazolium
6
cinnamic acid derivatives are valuable and versatile synthetic
4
precursors in the stereoselective synthesis of (E)-arylvinyl
4–15
16–23
bis[(trifluoromethyl)sulfonyl]imide ([emim]TF
-methylimidazolium trifluoromethanesulfonate ([bmim]OTF)
were screened. According to the results summarised in Table 1,
bmim]PF was selected as the best solvent in terms of solvent
N) and 1-butyl-
2
halides
and (Z)-arylvinyl halides.
For their use in
3
perfume production, the food industry, pharmaceuticals,
medicinal organic synthesis and technical applications,
cinnamic acids are synthesised on a commercial scale. A wide
range of methodologies are available, including the Perkin
[
6
cost and yield of the product. The recovered ionic liquids could
be reused at least five runs without obvious decline in yield
24–26
27
reaction,
Doebner reaction and the Heck reaction.
the Claisen condensation, the Knoevenagel-
(
Table 1, entry 5).
Under the optimised ionic liquid and reaction time, a range
28
29–31
Amongst these
methodologies, the condensation of aromatic aldehydes with
propanedioic acid, known as the Knoevenagel reaction is
arguably the most direct synthetic approach. The traditional
Knoevenagel reaction, however, needs to use not only unpleas-
ant pyridine as the reaction solvents but also a large amount of
hydrochloric acid to acidify the reaction mixtures in order to
isolate the products from the reaction system.
of aromatic aldehydes 1 gave the corresponding cinnamic acid
compounds 2 in good yields (Table 2). Isolated yields of the
products are excellent and the IL could be reused for at least
five times. These results indicate that the present reaction can
be used for the synthesis of cinnamic acid compounds carrying
either an electron-donating group (Table 2, entries 1–5) or an
electron-withdrawing group (Table 2, entries 6–7) in 89–95%
yields. This method proved to be applicable for aromatic alde-
hydes bearing ortho groups, the corrosponding cinnamic acid
compounds 2h and 2i were obtained in 88% and 83% yields,
respectively (Table 2, entries 8 and 9). In the case of nicotinal-
dehyde, the cinnamic acid derivative 2j was also isolated in a
yield of 85% (Table 2, entry 10).
Ionic liquids have become solvents of choice in many appli-
32
cations. Dai’s group reported a method for the synthesis of
α,β-unsaturated carboxylic acids employing ionic liquids
[
bmim]BF and [bpy]BF as environmentally benign media
4
4
3
3
with catalysts by pyridine. In this paper, to avoid the use of
toxic organic solvents, we have developed a facile method
for the synthesis of cinnamic acid derivatives 2 from commer-
cially available aromatic aldehydes and propanedioic acid in a
water-insoluble ionic liquid (1-butyl-3-methylimidazolium
Conclusion
In summary, we have developed a facile method for the synthe-
sis of cinnamic acid derivatives from aromatic aldehydes in a
hexafluorophosphate, [bmim]PF ) (Scheme 1).
6
Scheme 1 Synthesis of cinnamic acid derivatives in the water-insoluble ionic liquid [bmim]PF
6
.
*
Correspondent. E-mail: tongjizws@163.com

7
24 JOURNAL OF CHEMICAL RESEARCH 2011
Table 1 Screen on optimal conditions for the reaction of
-methylbenzaldehyde and propanedioic acid in water-insoluble
ionic liquid
Experimental
4
Melting points were recorded using WRS-1B digital melting point
apparatus and were uncorrected. IR spectra were obtained on a Perkin-
Elmer FT-IR spectrophotometer. H NMR spectra were recorded
1
Entry
Ionic liquid
Reaction
time/h
Yields of
a,b
using a Bruker DPX-400 spectrometer with SiMe as an internal stan-
2a/%
4
dard. All reactions were monitored by TLC with HuanghaiGF254 silica
gel coated plates. Column chromatography was carried out using
300–400 mesh silica gel at medium pressure.
1
2
3
4
5
6
7
8
[bmim]PF
[hmim]BF
[emim]TF
[bmim]OTF
6
8
8
93
89
86
87
4
2
N
8
8
Synthesis of cinnamic acids 2; general procedure
To the stirred solution of aldehyde 1 (214 mg, 1 mmol) and propane-
dioic acid (312 mg, 3 mmol) in the water-insoluble ionic liquid
c
[bmim]PF
[bmim]PF
[bmim]PF
[bmim]PF
6
6
6
6
6
93, 93, 91, 90, 91
3
85
90
91
5
(
10 mL) was added piperidine (9 mg, ~0.1 mmol) with syringe. The
10
reaction mixture was stirred at 85 °C for 6 h. After the completion
of the reaction screened by TLC, the mixture was cooled to room
temperature, and extracted with 10% NaOH (10 × 3 mL). The ionic
liquid layer was collected and dried under reduced pressure at 80 °C
for 6 h before reuse. To the combined aqueous layer was added 10%
HCl under stirring to a pH of 5. The precipitate was filtered, washed
with water and dried in a vacuum desiccator. Recrystallisation of
the precipitate from EtOAc-hexane yielded the pure product 2. All
a
Reaction conditions: 4-methylbenzaldehyde, 1 mmol; pro-
o
panedioic acid, 3 mmol; piperidine, 10 mol%; IL, 10 mL, 85 C.
b
c
Isolated yields based on 4-methylbenzaldehyde. Yields for
recycling reaction for five times.
products are white powders.
Table 2 Synthesis of cinnamic acid derivatives in [bmim]PF
6
34
(
E)-3-p-Tolylacrylic acid (2a): M.p. 198.1–200.1 °C (lit. 196–198
Products 2a
°C). IR (KBr): 2920, 2594 (br), 1686, 1632, 1568, 1515, 1421, 1311,
1286, 937, 813 cm . H NMR (400 MHz, DMSO-d ): δ 2.33 (3H, s),
6
Entry aldehydes 1
Yields of
−1 1
b
2
/%
6
.46 (1H, d, J = 16.0 Hz), 7.23 (2H, d, J = 7.6 Hz), 7.55 (1H, d,
J = 16.0 Hz), 7.57 (2H, d, J = 7.6 Hz), 12.29 (1H, s).
E)-3-m-Tolylacrylic acid (2b): M.p. 116.1–117.5 °C (lit. 116 °C).
IR (KBr): 2917, 2560 (br), 1682, 1633, 1430, 1324, 1247, 944, 787
93, 93,
1
2a 91, 90,
34
(
c
91
−
1
1
cm . H NMR (400 MHz, DMSO-d ): δ 2.33 (3H, s), 6.50 (1H, d,
6
J = 16.0 Hz), 7.23 (1H, d, J = 7.6 Hz), 7.30 (1H, t, J = 7.0 Hz), 7.46
2
3
4
2b
2c
2d
92
95
90
(
(
1H, d, J = 7.6 Hz), 7.50 (1H, s), 7.55 (1H, d, J = 16.0 Hz), 12. 35
1H, s).
(
E)-3-(4-Methoxyphenyl)acrylic acid (2c): M.p. 172.2–172.9 °C
34
(
lit. 173.5 °C). IR (KBr): 2939, 2844 (br), 1686, 1624, 1598, 1514,
−
1 1
1
257, 1217, 1174, 1027, 826 cm . H NMR (400 MHz, DMSO-d ):
6
δ 3.80 (3H, s), 6.37 (1H, d, J = 16.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.54
(
1H, d, J = 16.0 Hz), 7.64 (2H, d, J = 8.8 Hz), 12.19 (1H, s).
(E)-3-(3-Methoxyphenyl)acrylic acid (2d): M.p. 117.0–119.2 °C
34
(
1
lit. 116–119 °C). IR (KBr): 2965, 2840 (br), 1682, 1632, 1607,
−
1
1
578, 1489, 1456, 1280, 1050, 945, 781 cm . H NMR (400 MHz,
DMSO-d ): δ 3.79 (3H, s), 6.55 (1H, d, J = 16.0 Hz), 6.98 (1H, dd,
J = 8.4, 6.0 Hz), 7.23–7.35 (3H, m), 7.56 (1H, d, J = 16.0 Hz), 12.37
5
6
7
2e
2f
89
90
93
6
(
1H, s).
(E)-3-(4-Hydroxyphenyl)acrylic acid (2e): M.p. 209.2–209.8 °C
34
(
lit. 210–213 °C). IR (KBr): 3384, 2961, 2837 (br), 1672, 1628,
−1 1
1
602, 1590, 1512, 1450, 1245, 1214, 1173, 979, 834 cm . H NMR
2g
(
400 MHz, DMSO-d ): δ 6.29 (1H, d, J = 16.0 Hz), 6.79 (2H, d,
6
J = 8.6 Hz), 7.50 (1H, d, J = 16.0 Hz), 7.51 (2H, d, J = 8.6 Hz) , 9.95
(
1H, s), 12.11 (1H, s).
8
9
2h
88
(E)-3-(4-Chlorophenyl)acrylic acid (2f): M.p. 248.5–249.1 °C
34
(
1
lit. 248–250 °C). IR (KBr): 2968 (br), 1684, 1626, 1591, 1569,
−
1
1
490, 1427, 1305, 1284, 1085, 821, 715 cm . H NMR (400 MHz,
DMSO-d ): δ 6.55 (1H, d, J = 15.6 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.58
(1H, d, J = 16.0 Hz), 7.73 (2H, d, J = 8.4 Hz), 12.41 (1H, s).
6
2i
2j
83
85
(
E)-3-(4-Bromophenyl)acrylic acid (2g): M.p. 260.2–261.9 °C
34
(
1
lit. 260–265 °C). IR (KBr): 2927, 2830 (br), 1683, 1626, 1586,
488, 1425, 1305, 1284, 1070, 817 cm . H NMR (400 MHz,
−
1
1
10
DMSO-d ): δ 6.57 (1H, d, J = 16.0 Hz), 7.57 (1H, d, J = 16.0 Hz),
6
7
.61 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 12.43 (1H, s).
a
Reaction conditions: aromatic aldehyde, 1 mmol; propanedioic
(E)-3-(2-Chlorophenyl)acrylic acid (2h): M.p. 208.5–209.8 °C
o
34
acid, 3 mmol; piperidine, 10 (mol)%; [bmim]PF
h.
6
, 10 mL, 85 C,
(lit. 208–210 °C). IR (KBr): 2836 (br), 1686, 1622, 1590, 1566,
6
−1 1
1
6
7
470, 1441, 1278, 984, 755 cm . H NMR (400 MHz, DMSO-d ): δ
.61 (1H, d, J = 16.0 Hz), 7.38-7.46 (2H, m), 7.54 (1H, d, J = 8.0 Hz),
.88 (1H, d, J = 16.0 Hz), 7.92 (1H, d, J = 6.8 Hz), 12.61 (1H, s).
6
b
Isolated yields based on aromatic aldehyde.
Yields for recycling reaction for five times.
c
34
(
E)-3-(2-Bromophenyl)acrylic acid (2i): M.p. 217.1–218.3 °C (lit.
2
1
17–219 °C). IR (KBr): 2831 (br), 1686, 1622, 1562, 1466, 1275,
−1 1
223, 983, 755 cm . H NMR (400 MHz, DMSO-d ): δ 6.57 (1H, d,
6
J = 16.0 Hz), 7.34-7.46 (2H, m), 7.71 (1H, d, J = 8.0 Hz), 7.85 (1H,
d, J = 16.0 Hz), 7.90 (1H, d, J = 8.0 Hz), 12.64 (1H, s).
water-insoluble ionic liquid (bmim]PF ) in high yields,
6
avoiding the use of toxic organic solvents. The ionic liquid as
a green solvent can be reused for at least five times without
obvious decrease in yield. In addition, this method is efficient
not only because of its convenient separation procedure for the
products but also because of the ease of recycling of the ionic
liquid.
34
(
E)-3-(Pyridin-3-yl)acrylic acid (2j): M.p. 231.1–231.9 °C (lit.
32–235 °C). IR (KBr): 2926, 2449 (br), 1703, 1636, 1580, 1418,
−1
1
311, 1284, 975, 811 cm . H NMR (400 MHz, DMSO-d ): δ 6.69
6

JOURNAL OF CHEMICAL RESEARCH 2011 725
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