One-Step Synthesis of ortho-Hydroxycinnamaldehyde

Article abstract of DOI:10.1081/SCC-120030309

An improved and convenient one-step procedure for the large scale synthesis of ortho-hydroxycinnamaldehyde (3a) using ortho-hydroxybenzaldehyde and vinyl acetate is described.

Full text of DOI:10.1081/SCC-120030309

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One‐Step Synthesis of ortho‐Hydroxycinnamaldehyde
Jong Han Kim a , Sangku Lee a , Mu‐Gil Kwon b , Yong Soo Park b , Sung‐Kyu Choi a &
Byoung‐Mog Kwon a
a Korea Research Institute of Bioscience and Biotechnology , 52 Uendong, Yusunggu,
Taejon, 305‐600, Republic of Korea
b Kunwha Pharmaceutical, Ltd. , Choongnam, Republic of Korea
Published online: 21 Aug 2006.
To cite this article: Jong Han Kim , Sangku Lee , Mu‐Gil Kwon , Yong Soo Park , Sung‐Kyu Choi & Byoung‐Mog Kwon (2004)
One‐Step Synthesis of ortho‐Hydroxycinnamaldehyde, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:7, 1223-1228, DOI: 10.1081/SCC-120030309
To link to this article: http://dx.doi.org/10.1081/SCC-120030309
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 7, pp. 1223–1228, 2004
One-Step Synthesis of
ortho-Hydroxycinnamaldehyde
Jong Han Kim,1 Sangku Lee,1 Mu-Gil Kwon,2
Yong Soo Park,2 Sung-Kyu Choi,1 and
Byoung-Mog Kwon1,
*
1Korea Research Institute of Bioscience and Biotechnology,
Taejon, Republic of Korea
2Kunwha Pharmaceutical, Ltd., Choongnam,
Republic of Korea
ABSTRACT
An improved and convenient one-step procedure for the large scale
synthesis of ortho-hydroxycinnamaldehyde (3a) using ortho-hydroxy-
benzaldehyde and vinyl acetate is described.
Key Words: Cinnamaldehyde, Cross aldol condensation; ortho-Hydro-
xycinnamaldehyde; One-step procedure.
*
Correspondence: Byoung-Mog Kwon, Korea Research Institute of Bioscience and
Biotechnology, 52 Uendong, Yusunggu, Taejon 305-600, Republic of Korea;
Fax: 82-42-8612675; E-mail: kwonbm@kribb.re.kr.
1223
DOI: 10.1081/SCC-120030309
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Kim et al.
INTRODUCTION
ortho-Hydroxycinnamaldehyde (3a) was isolated from the stem bark of
Cinnamomum cassia Blume.[1] This plant has been used as a traditional medicine
for various diseases including hypertension and indigestion in China and Korea.
ortho-Hydroxycinnamaldehyde (3a) and its derivatives have been reported to
exhibit a broad range of biological activities including farnesyl protein transfer-
ase inhibitory activity,[1] anti-angiogenic activity,[2] anti-tumor activity,[3]
immunomodulatory effects,[4] and cyclindependent kinases inhibitory activity.[5]
We previously reported an approach to ortho-hydroxycinnamaldehyde
(3a) based on the functional group transformation of carboxylic acid to
aldehyde.[2] However, the approach involved three reaction steps and expens-
ive reagents such as diisobutylaluminum hydride. As we were interested in in
vivo activities of 3a, we needed to have a simple and convenient synthetic
method that would bring a large quantity of 3a.
Cross aldol condensation between two different carbonyl compounds has
long provoked interest to organic chemists due to its effectiveness for carbon–
carbon bond formations.[6,7] The condensation reaction has traditionally been
carried out by mixing two different carbonyl units under protic conditions in
the presence of an acid or base as a catalyst. Recently, Junjappa et al. reported
the generation of acetaldehyde enolate from vinyl acetate (2) by cleaving the
acetyl group with barium hydroxide or potassium t-butoxide.[8] They also
prepared several aromatic enals by the reaction of substituted benzaldehydes
with acetaldehyde enolate generated in situ by cleaving vinyl acetate in high
yields.[8] However, we could not detect ortho-hydroxycinnamaldehyde (3a)
from ortho-hydroxybenzaldehyde (1a) under the same conditions as Junjappa
et al. described.
In order to effect the condensation of ortho-hydroxybenzaldehyde with
vinyl acetate as a precusor of acetaldehyde enolate, we screened bases and sol-
vents (Table 1). When potassium carbonate was used as a base, ortho-hydroxy-
cinnamaldehyde (3a) was obtained in 34% yield together with a trace amount of
coumarin (4) and unidentified side products. Interestingly, upon heating a mix-
ture of ortho-hydroxybenzaldehyde and vinyl acetate in the presence of KHCO3
or Na2CO3 as a base, only coumarin (4) was isolated and no 3a was detected.
Having successfully demonstrated the utility of potassium carbonate as a
base, we examined the condensation of ortho-hydroxybenzaldehyde with vinyl
acetate by changing solvents in order to improve the yield of 3a (Table 2). How-
ever, all attempts were not rewarding. The feasibility of potassium carbonate/
acetonitrile in the condensation reaction of substituted benzaldehydes (1a–f)
with vinyl acetate as a source of acetaldehyde enolate was examined (Table 3).
Among the tested benzaldehydes, ortho-methoxybenzaldehyde (1b) and para-
hydroxybenzaldehyde (1f) did not provide the corresponding enals.

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ortho-Hydroxycinnamaldehyde
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Table 1. Condensation of ortho-hydroxybenzaldehyde (1a) with vinyl acetate (2).
Base
Yield (%) of 3a
K2CO3
34a
KHCO3
Ba(OH)2
Na2CO3
t-BuOK
Side productsb
No reactiona
Side productsb
No reactionc
aCH3CN at reflux.
bCoumarin (4).
cTHF at 708C.
Table 2. Effects of solvent on condensation of 1a and 2 using K2CO3 as
a base.
Solvent
Temperature (8C)
Yield (%) of 3a
CH3CN
Toluene
THF
80–85
110–115
65–70
34
No reaction
No reaction
Side producta
No reaction
DMF
1,4-Dioxane
155–160
100–105
aCoumarin (4) was only isolated product.
In conclusion, we have successfully employed potassium carbonate as a
base for the cross aldol condensation of ortho-hydroxybenzaldehyde (1a) with
vinyl acetate (2) to yield ortho-hydroxycinnamaldehyde (3a). This synthetic
method was easily amenable to large scale in one pot chemical reaction step.
EXPERIMENTAL
General
Analytical TLC was performed on Kiesel gel 60 F254 (precoated silica
gel plate, Merck, Art. 105715, NMRC, Palo Alto, CA). NMR spectra were

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Kim et al.
Table 3. Condensation of substituted benzaldehydes and vinyl acetate in K2CO3/
CH3CN.
Entry
R1
OH
R2
R3
Time (hr)
Yield (%)a
1a
1b
1c
1d
1e
1f
H
H
40
40
40
40
40
40
34
No reactionb
40
OCH3
Cl
Br
H
H
H
H
H
H
40
43
H
OH
H
H
OH
H
No reactionb
aYields refer to isolated products.
bNo cinnamaldehydes 3b, f were detected.
obtained on a Varian UNITY 300 MHz instrument. Column chromatography
was performed on Merck silica gel 60 (230–400 mesh).
General Procedure for the Synthesis of 3
A mixture of benzaldehyde (1 mol) and vinyl acetate (1.1 mol) in CH3CN
(300 mL) was added by dropwise using dropping funnel to a stirred suspension
of K2CO3 (1.2 mol) and H2O (catalytic amount) in CH3CN. The reaction
mixture was refluxed for 40 hr. The reaction mixture after cooling was poured
into cold water and diluted with EtOAc : n-hexane (2 : 1) mixture. The organic
layer was washed with 10% NaOH solution, and the aqueous layer was
separated, acidified with 10% HCl solution, and extracted with CH2Cl2. The
resultant organic layer (CH2Cl2) was dried over MgSO4 and concentrated
in vacuo. The dark residue was purified by column chromatography on silica
gel eluting with n-hexane-EtOAc to afford the cinnamaldehyde 3. The
following compounds were obtained.
ortho-Hydroxycinnamaldehyde (3a). m.p.: 129–1318C, [lit.[1] m.p.
1
131–1328C]. H NMR (300 MHz, acetone-d6): d 9.68 (1H, d, J ¼ 7.8 Hz),
7.89 (1H, d, J ¼ 16.2 Hz), 7.63 (1H, dd, J ¼ 7.7, 1.5 Hz), 7.30 (1H, dd,
J ¼ 7.7, 1.5 Hz), 7.00 (1H, d, J ¼ 7.8 Hz), 6.92 (1H, dd, J ¼ 7.5, 1.1 Hz),
6.84 (1H, dd, J ¼ 7.8, 16.2 Hz).

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ortho-Hydroxycinnamaldehyde
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ortho-Chlorocinnamaldehyde (3c). m.p.: 53–548C, [lit.[9] m.p.
51–538C]. 1H NMR (300 MHz, acetone-d6): d 9.79 (1H, d, J ¼ 7.5 Hz), 8.01
(1H, d, J ¼ 15.9 Hz), 7.91 (1H, t, J ¼ 7.2 Hz), 7.54 (1H, d, J¼ 7.5 Hz), 7.48
(1H, dd, J ¼ 7.2, 1.8 Hz), 7.42, (1H, dd, J ¼ 7.2, 1.5 Hz), 6.80 (1H, dd,
J ¼ 7.5, 15.9 Hz).
ortho-Bromocinnamaldehyde (3d). m.p.: 63–658C, [lit.[10] m.p.
1
65–678C]. H NMR (300 MHz, CDCl3): d 9.75 (1H, d, J ¼ 7.5 Hz), 7.87
(1H, d, J ¼ 15.9 Hz), 7.63 (2H, d, J ¼ 7.8 Hz), 7.35 (1H, t, J ¼ 7.5 Hz),
7.27 (1H, dd, J ¼ 7.2, 1.8 Hz), 6.80 (1H, dd, J ¼ 7.5, 15.9 Hz).
meta-Hydroxycinnamaldehyde (3e). m.p.: 119–1208C, [lit.[11] m.p.
1
118–1208C]. H NMR (300 MHz, acetone-d6): d 9.69 (1H, d, J ¼ 7.8 Hz),
7.60 (1H, d, J ¼ 15.9 Hz), 7.29 (1H, t, J ¼ 7.8 Hz), 7.20 (1H, s), 7.16 (1H,
d, J ¼ 2.4 Hz), 6.96 (1H, dd, J ¼ 8.25, 2.4 Hz), 6.69 (1H, dd, J ¼ 7.8,
15.9 Hz).
REFERENCES
1. Kwon, B.M.; Cho, Y.K.; Nam, J.Y.; Lee, S.H.; Bok, S.H.; Chun, S.K.;
Kim, J.A.; Lee, I.R. 20-Hydroxycinnamaldehyde from Cinnamomum
cassia Blume. Planta Media 1996, 62, 183–184.
2. Kwon, B.M.; Lee, S.H.; Cho, Y.K.; Bok, S.H.; So, S.H.; Youn, M.R.;
Chang, S.I. Synthesis and biological activity of cinnamaldehydes as
angiogenesis inhibitors. Bioorg. Med. Chem. Letters 1997, 7, 2473–2476.
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differentiation. Int. J. Immunpharm. 1998, 20, 643–660.
5. Jeong, H.W.; Kim, M.R.; Son, K.H.; Han, M.Y.; Ha, J.H.; Garnier, M.;
Meijer, L.; Kwon, B.M. Cinnamaldehydes inhibit cyclin dependent
kinase 4/cyclin D1. Bioorg. Med. Chem. Letters 2000, 10, 1819–1822.
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9. Nudelman, A.; Binnes, Y.; Shmueli-Broide, N.; Odessa, Y.; Hieble, J.P.;
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Received in Poland September 29, 2003

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