Mild reaction of primary alcohols with ferulic acid

Full text of DOI:10.1134/S1070428016030258

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 3, pp. 441–443. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © L.A. Bakholdina, A.I. Khlebnikov, V.P. Sevodin, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 3,
pp. 449–451.
SHORT
COMMUNICATIONS
Mild Reaction of Primary Alcohols with Ferulic Acid
L. A. Bakholdinaa, A. I. Khlebnikovb, and V. P. Sevodina
a Biisk Institute of Technology (Branch), Polzunov Altai State Technical University,
ul.Trofimova 27, Biisk, 659305, Altai Krai, 659305 Russia
e-mail: ljuba27@mail.ru
b Tomsk National Research Polytechnical University, pr. Lenina 30, Tomsk, 634050 Russia
Received December 11, 2015
DOI: 10.1134/S1070428016030258
Until present, much data have been reported on the
antioxidant activity of ferulic acid and its derivatives
[1–11]; foods containing ferulic acid bound to glycerol
[4], oligosaccharides [1], and sterols (γ-oryzanol) [10,
11] are used in the prophylactics of intestinal cancer. In
the first two cases, substituents in the ferulic acid
molecule are hydrophilic, and in the latter, hydro-
phobic. The mechanism of antioxidant action of ferulic
acid is not completely clear, which may be related to
difficult synthesis of its conjugates with mono- and
oligosaccharides, as well as with sugar alcohols.
Therefore, development of simple procedures for the
preparation of ferulic acid derivatives under mild
conditions is an important problem.
is no need of protecting hydroxy groups in polyols and
sugars [13]. The presence of a catalytic amount of
a strong acid considerably increases the yield [14].
We tried 4-O-acetylferulic acid (1) [15] as acylating
agent toward various primary alcohols 2a–2e. The
reactions of alcohols 2a–2e with acid 1 were carried
out in pyridine in the presence of DCC and p-toluene-
sulfonic acid (TsOH). The esterification conditions
were optimized using the reaction of 1 with benzyl
alcohol (2a) (see table). The optimal ratio 1‒2a‒DCC‒
pyridine was 0.01:0.011:0.012:49 (mol:mol:mol:mL).
Benzyl alcohol was taken in slight excess (run no. 1),
and further increase of the amount of 2a did not affect
the yield of ester 3a to an appreciable extent (run
no. 2). If acid 1 was taken in excess, the yield of 3a
decreased (run no. 3), and unreacted acid 1 was
isolated together with target ester 3a. Raising the
amount of DCC above 20% also did not improve the
yield (run no. 4).
The most common approach is based on the
acylation of alcohols with ferulic acid chlorides where
the 4-hydroxy group is protected. A drawback of this
approach is the necessity of protecting hydroxy groups
in the substrates [12]. Acylation of alcohols and sugars
with ferulic acid can be accomplished using N,N′-di-
cyclohexylcarbodiimide (DCC) as condensing agent.
In this case, selective acylation is achieved, and there
The selected esterification procedure ensures easy
isolation of the product by acidification of the mixture
at 2‒5°C and subsequent extraction with chloroform.
O
O
DCC, TsOH
MeO
MeO
AcO
+
RCH2OH
OH
O
R
AcO
1
2a–2e
MeO
HO
3a–3e
O
NaOH
O
Ph
R = Ph
4a
R = Ph (a), PhCH2 (b), CH2=CH (c), 5-formylfuran-2-yl (d), oxolan-2-yl (e).
441

BAKHOLDINA et al.
442
cm–1: 2951 (C–H), 1756 and 1707 (C=O), 1634 (C=C).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.26 s (3H,
CH3CO), 3.82 s (3H, CH3O), 5.24 s (2H, CH2), 6.80 d
(1H, CH, Ј = 16.0 Hz), 7.13 d (1H, Harom, Ј = 8.1 Hz),
7.30 d (1H, Harom, Ј = 8.4 Hz), 7.37‒7.43 m (5H,
Harom), 7.52 s (1H, Harom), 7.71 d (1H, CH, Ј =
16.0 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 20.37,
38.69, 38.96, 39.24, 39.52, 39.79, 40.07, 40.35, 55.99,
65.72, 111.93, 118.14, 121.68, 123.22, 128.21, 128.49,
133.00, 136.17, 141.06, 144.28, 151.16, 166.10, 168.39.
Reaction of 4-acetoxyferulic acid (1) with benzyl alcohol
(2a) in the presence of DCC
Amounts of reactants, mol
Run
no.
Yield
of 3a, %
1
2a
DCC
1
2
3
4
0.010
0.010
0.011
0.010
0.011
0.015
0.010
0.011
0.012
0.012
0.012
0.020
55±12
56±10
41±11
57±11
2-Phenylethyl (2E)-3-(4-acetoxy-3-methoxy-
phenyl)prop-2-enoate (3b). Yield 45%, mp 108‒
110°C, Rf 0.88. UV spectrum, λmax, nm: 210, 282. IR
spectrum, ν, cm–1: 2957 (C–H), 1759 and 1719 (C=O),
After recrystallization from 96% ethanol, esters 3a–3e
were isolated as white crystalline substances. Their
1
structure was confirmed by IR and H NMR spec-
1
1
troscopy. The H NMR spectra of 3a–3e contained
1639 (C=C). H NMR spectrum (DMSO-d6), δ, ppm:
signals from protons on the double-bonded carbon
atoms as doublets at δ 6.76‒6.81 and 7.29‒7.32 ppm
with a coupling constant 3J of ~16 Hz, which is typical
of trans configuration of the C=C double bond. The
singlet from protons of the acetyl protecting group
(δ 2.26 ppm) disappeared after deprotection, and
a singlet at δ 9.68 ppm (OH) appeared instead. The IR
spectrum of 4a showed a medium-intensity absorption
band at 3511 cm–1 due to O–H stretching vibrations.
No signals assignable to carboxy groups were ob-
served in the IR and NMR spectra of 3a–3e and 4a.
2.26 s (3H, CH3CO), 2.95 t (2H, CH2, Ј = 13.5 Hz),
3.82 s (3H, CH3O), 4.38 t (2H, OCH2, Ј = 13.2 Hz),
6.69 d (1H, CH, Ј = 16.0 Hz), 7.12 d (1H, Harom, Ј =
8.1 Hz), 7.27 d (1H, Harom, Ј = 8.4 Hz), 7.30‒7.22 m
(5H, Harom), 7.52 s (1H, Harom), 7.64 d (1H, CH, Ј =
16.0 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 20.40,
34.44, 38.69, 38.97, 39.24, 39.52, 39.80, 40.08, 40.35,
56.03, 64.61, 111.89, 118.22, 121.71, 123.23, 126.43,
128.43, 128.88, 132.99, 137.99, 141.05, 144.07,
151.19, 166.22 168.41.
Prop-2-en-1-yl (2E)-3-(4-acetoxy-3-methoxy-
phenyl)prop-2-enoate (3c). Yield 42%, mp 60‒62°C,
Rf 0.89. UV spectrum, λmax, nm: 233, 282. IR spectrum,
ν, cm–1: 2925 (C–H), 1764 and 1708 (C=O), 1633 and
(E)-3-(4-Acetoxy-3-methoxyphenyl)prop-2-enoic
acid (1) was synthesized from 4-acetoxyvanillin which
was prepared in turn according to the procedure de-
scribed in [16]. mp 196°C. UV spectrum, λmax, nm:
278, 215. IR spectrum, ν, cm–1: 3013 (OH), 2945
(C–H), 1763 (C=O) [15].
1
1601 (C=C). H NMR spectrum (DMSO-d6), δ, ppm:
2.27 s (3H, CH3CO), 3.45 s (3H, CH3O), 4.69 d (2H,
CH2, Ј = 5.1 Hz), 5.25 d (1H, CH2, Ј = 10.2 Hz),
5.37 d (1H, CH2, Ј = 17.1 Hz), 5.99 m (1H, CH),
6.74 d (1H, CH, Ј = 16.2 Hz), 7.12 d (1H, Harom, Ј =
8.1 Hz), 7.30 d (1H, Harom, Ј = 8.1 Hz), 7.68 d (1H,
CH, Ј = 16.2 Hz). 13C NMR spectrum (CDCl3), δC,
ppm: 20.38, 38.69, 38.96, 39.24, 39.51, 39.79, 40.06,
40.34, 56.00, 64.59, 111.96, 117.95, 118.07, 124.63,
123.23, 132.78, 133.00, 141.05, 144.20, 151.17,
165.88, 168.40.
Esters 3a–3e (general procedure). Acid 1,
0.01 mol, alcohol 2a–2e, 0.011 mol, and p-toluenesul-
fonic acid, 0.09 g, were dissolved in 49 mL of pyri-
dine, 0.012 mol of DCC was added, and the mixture
was kept for 24 h at room temperature in the dark.
Acetic acid, 0.01 mol, was then added, and the mixture
was cooled to 4°C and left overnight. The mixture was
filtered, the precipitate was washed with cold pyridine,
80 g of ice was added to the filtrate, and the mixture
was acidified with 5 M aqueous HCl and extracted
with chloroform (3×80 mL). The combined extracts
were washed with water, aqueous sodium hydrogen
carbonate, and water again, dried, and evaporated
under reduced pressure, and the residue was recrystal-
lized from ethanol.
(5-Formylfuran-2-yl)methyl (2E)-3-(4-acetoxy-3-
methoxyphenyl)prop-2-enoate (3d). Yield 40%,
mp 80‒87°C, Rf 0.87. UV spectrum, λmax, nm: 199,
216, 232, 281. IR spectrum, ν, cm–1: 2945 (C–H), 1760
1
and 1711 (C=O), 1668 (C=C). H NMR spectrum
(DMSO-d6), δ, ppm: 2.26 s (3H, CH3CO), 3.81 s (3H,
CH3O), 5.32 s (2H, CH2), 6.78 d (1H, CH, Ј =
15.9 Hz), 7.12 d (1H, Harom, Ј = 7.8 Hz), 7.31 d (1H,
Harom, Ј = 8.7 Hz), 7.54 s (2H, CH), 7.71 d (1H, CH,
Ј = 15.9 Hz), 9.61 s (1H, CHO). 13C NMR spectrum
Benzyl (2E)-3-(4-acetoxy-3-methoxyphenyl)-
prop-2-enoate (3a). Yield 55%, mp 76‒78°C, Rf 0.90.
UV spectrum, λmax, nm: 210, 233, 282. IR spectrum, ν,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

MILD REACTION OF PRIMARY ALCOHOLS WITH FERULIC ACID
443
(CDCl3), δC, ppm: 20.40, 38.69, 38.97, 39.24, 39.52,
39.80, 40.07, 40.35, 56.03, 57.71, 112.01, 113.18,
117.50, 121.89, 123.29, 123.90, 132.94, 141.24, 145.03,
151.22, 152.55, 155.46, 165.72, 168.48, 178.54.
spectrophotometer. The IR spectra (500‒4000 cm–1)
were recorded in KBr on an InfraLYuM FT-01 spec-
trometer with Fourier transform. The 1H and 13C NMR
spectra were obtained on a Bruker AV 300 instrument
at 300 and 75 MHz, respectively, using tetramethyl-
silane as internal standard.
(Oxolan-2-yl)methyl (2E)-3-(4-acetoxy-3-me-
thoxyphenyl)prop-2-enoate (3e). Yield 45%,
mp 106–108°C, Rf 0.9. UV spectrum, λmax, nm: 214,
281. IR spectrum, ν, cm–1: 2950 (C–H), 1760 and 1705
(C=O), 1633 (C=C). 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.92 m (4H, CH2), 2.26 s (3H, CH3CO), 3.66 t
(2H, CH2, Ј = 21.0 Hz), 3.83 s (3H, CH3O), 4.13 m
(3H, CH, CH2, Ј = 26.7 Hz), 6.73 d (1H, CH, Ј =
16.0 Hz), 7.12 d (1H, Harom, Ј = 8.1 Hz), 7.30 d (1H,
Harom, Ј = 8.1 Hz), 7.53 s (1H, Harom), 7.65 d (1H, CH,
Ј = 16.0 Hz). 13C NMR spectrum (CDCl3), δC, ppm:
20.40, 25.23, 27.54, 38.70, 38.97, 39.25, 39.53, 39.80,
40.08, 40.35, 56.74, 66.06, 67.46, 75.93, 111.89,
118.18, 121.71, 123.23, 133.01, 141.04, 144.13,
151.17, 166.19, 168.41.
This study was financially supported in part by the
Nauka state assignment (project no. 4.1991.2014/K).
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