Two-step synthesis of ferrocenyl esters of vanillic acid

Article abstract of DOI:10.1134/S107036321703015X

Successive reactions of vanillin with aromatic aldehydes at the phenol group and ferroceneboronic acid at the carbonyl group catalyzed with various N-heterocyclic carbenes afforded the corresponding ferrocenyl esters. In these reactions copper(II) sulfate

Full text of DOI:10.1134/S107036321703015X

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 3, pp. 463–469. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.S. Denisov, A.A. Gorbunov, V.O. Nebogatikov, L.V. Pavlogradskaya, V.A. Glushkov, 2017, published in Zhurnal Obshchei
Khimii, 2017, Vol. 87, No. 3, pp. 457–464.
Two-Step Synthesis of Ferrocenyl Esters of Vanillic Acid
M. S. Denisov*, A. A. Gorbunov, V. O. Nebogatikov,
L. V. Pavlogradskaya, and V. A. Glushkov
Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
ul. Akademika Koroleva 3, Perm, 614013 Russia
*e-mail: m189@mail.ru
Received October 27, 2016
Abstract—Successive reactions of vanillin with aromatic aldehydes at the phenol group and ferroceneboronic
acid at the carbonyl group catalyzed with various N-heterocyclic carbenes afforded the corresponding
ferrocenyl esters. In these reactions copper(II) sulfate, cinnamic aldehyde, and air oxygen act as oxidants. The
resulting ferrocenyl esters of vanillic acid were tested for cytotoxicity.
Keywords: hydroxyferrocene, vanillin, organocatalysis, N-heterocyclic carbenes, cytotoxicity
DOI: 10.1134/S107036321703015X
Benzimidazolium and imidazolium salts are pre-
cursors of N-heterocyclic carbenes, which are NHC
organocatalysts for the oxidative esterification
reactions of aldehydes [1], including the synthesis of
ferrocenyl esters, which are potential biologically
active compounds [2]. A number of ferrocene-
substituted compounds have been known as biosensors
based on adducts of ferrocene with nucleic acids [3]
and nucleic bases [4], and other adducts [5, 6],
chemosensors [7, 8], antitumor drugs [9–17] and
compounds with other biological activity [4, 18].
Previously, we have studied ferrocene-substituted
derivatives of lupane for cytotoxic activity [19], which
is an actual direction in the study of biological activity
[20–22]. Vanillin esters exhibit biological activity even
without ferrocenyl fragment. In particular, vanillin
ester of nicotinic acid was patented as an active
substance against Alzheimer's disease, which prevents
formation of amyloid plaques [23]. The substance has
been prepared from nicotinic acid and vanillin in a
yield of only 9%. Vanillin esters have been widely
studied in detail. For example, vanillin esters of
vanillic [24], benzoic [25], acetic [26], p-nitrobenzoic
[27], naphthoic [28], fumaric [29], p-bromobenzoic,
and cinnamic [30], 2-thiophenecarboxylic [31],
cyclohexanecarboxylic [32], nicotinic [23], and
isonicotinic [33] acids have been reported.
reactions. The esterification of vanillin by the reduc-
tion mechanism has been reported in [34] by the
example of conversion of vanillin to 3-methoxy-4-
hydroxybenzyl ester. Earlier we have obtained vanillin
esters by the oxidative mechanism through the con-
version of vanillin to the vanillic acid esters. This
mechanism has been described in [35, 36] by the
example of other aldehydes. Iron [37–39], manganese
[40–42], and palladium compounds [39, 43, 44], cyclic
ketones [45, 46] are used as oxidants in the esteri-
fication reactions.
We have prepared a wide series of ferrocenyl esters
from aromatic aldehydes using the NHC catalysis
method [2]. A feature of this NHC-catalyzed reaction
is the use of air oxygen as an oxidizing agent.
Veratraldehyde-derived ferrocenyl ester has been also
obtained. However we failed to synthesize ferrocenyl
ester from vanillin probably due to the presence of the
phenol group, which can also be subjected to
esterification. The aim of this work was to develop a
method for NHC-catalyzed vanillin esterification at the
phenol group followed by the esterification of the
resulting products using the known method [2] to
ferrocenyl esters of vanillic acid, as well as to identify
compounds showing antitumor activity.
The esterification of phenols with cinnamaldehyde
has been reported in [47]. This procedure was op-
timized for vanillin esterification. The most significant
The present work consists in the synthesis of ferro-
cene and vanillin derivatives by oxidation-reduction
463

464
DENISOV et al.
Scheme 1.
N
I
N
O
O
O
O
OH
K2CO3
+
MW, 120oC, 0.5 h, toluene
O
O
O
1 (66%)
Scheme 2.
N
I
N
O
O
O
O
O
R
OH
CuSO4, DABCO
+
MW, 110_135oC, 1_2 h, toluene
O
O
R
2 (55%)
3 (21%)
R = 3-pyridyl (2), p-trifluoromethylphenyl (3).
changes were the use of potassium carbonate as a base
instead of diazabicycloundecene (DBU) and micro-
wave activation. The used catalyst {1,3-dimethyl-1H-
benzimidazol-3-ylium iodide [48] (10 mol %)} and the
solvent (toluene) were the same. Thus, compound 1
was prepared in a yield of 66% (Scheme 1).
Cinnamaldehyde acts as an oxidizing agent, and the
reaction turns out to be applicable only to it. For other
aldehydes, an external oxidant is required.
than in the patent [23]. Saxena and Akella used
nicotinic acid, but in our case benzoic acids did not
enter into the esterification reaction. However,
aliphatic acids can apparently enter into this reaction.
Thus, the use of copper(II) acetate allowed the isola-
tion of vanillin acetate (1%) by column chromato-
graphy. This can not be a preparative synthesis; acyla-
tion of vanillin as a side reaction in the esterification of
vanillin with aromatic aldehydes does not allow the
use of copper(II) acetate as an oxidizing agent.
The aforementioned procedures using various
oxidants we tested for the esterification of vanillin, but
the product either did not form at all or was formed in
trace amounts, which were recorded by GC-MS. We
developed a new method for vanillin esterification at
the phenol group using the NHC catalysis and copper
sulfate as an oxidizing agent (Scheme 2). Examples of
the esters preparation in the presence of copper
compounds have been known [49], but the starting
compounds were carboxylic acids and olefins. Use of
microwave activation was found to be effective in
esterification of vanillin. The reaction of vanillin with
nicotinic aldehyde in the presence of copper(II) sulfate
as an oxidizing agent and 1,4-diazabicyclo[2.2.2]-
octane (DABCO) as the base in toluene in a
microwave pressure reactor at 120°C for 1 h afforded
compound 2 in a yield of 55%, which is much larger
Copper(II) sulfate was proved to be the best
oxidant. The ester of vanillin and p-trifluoromethyl-
benzoic acid 3 has not been previously described. The
synthesis of compound 3 was carried out in a
microwave pressure reactor in toluene at 135°C for 2 h
with the use of copper(II) sulfate and DABCO
(30 mol %). Yet the yield of the desired product was
low (21%).
Aliphatic aldehydes did not enter into the studied
reaction. The reaction of vanillin with isobutyric al-
dehyde led to isobutyration of vanillin resulting in the
formation of two isomers registered by GC-MS method.
Compounds 1–3 were used as aldehydes in the
reaction with ferroceneboronic acid according to the
procedure described previously [2] (Scheme 3). The
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465
TWO-STEP SYNTHESIS OF FERROCENYL ESTERS OF VANILLIC ACID
Scheme 3.
N
N
O
O
Mes
Mes
Cl
R2
O
R2
O
OH
O
R2
Cs2CO3
R1
R1
B
+
+
toluene, air, 70oС, 6 h
O
O
O
O
R1
OH
O
O
5, 8, 10
6, 7, 9, 11
R1 = ferrocenyl, R2 = phenylethyl (5, 6); R1 = ferrocenyl, R2 = 3-pyridyl (7); R1 = ferrocenyl, R2 = p-trifluoromethylphenyl
(8, 9); R1 = p-tolyl, R2 = phenylethyl (10, 11).
Scheme 4.
O
N
O
O
O
Fe
Fe
Fe
O
O
O
O
12
13
14
aldehydes reacted with ferroceneboronic acid in
toluene in air at 70°C for 6 h; 1,3-bis(2,4,6-trimethyl-
phenyl)-4,5-dihydro-1H-imidazole-3-ylium chloride and
cesium carbonate were used as the catalyst and the
base, respectively. Air oxygen was the oxidant. Com-
pound 1 was found to be the most reactive, and the
desired product 5 was isolated in the highest yield (24%).
Compounds 3, 5, 6, 8, and 10 were obtained for the
first time.
The reaction with tolylboronic acid was carried out
for comparison (Scheme 3). The product of trans-
esterification prevailed over the esterification product:
55% (11) versus 5% (10). Probably, the nature of
boronic acid affects the reaction chemoselectivity.
The formation of ferrocenyl esters of vanillic and
nicotinic acids was not even confirmed by GC-MS,
although this method is reliable for identification of
ferrocene compounds [50]. Ferrocenyl ester 8 was
isolated in a yield of 12%. For comparison, the esters
of hydroxyferrocene (not vanillin derived) [2] have
been previously obtained with yields of 17–76%;
veratraldehyde-derived ferrocenyl ester 14 has been
obtained in 76% yield. In all cases, the formation of
transesterification products was observed (NHC can
catalyze the transesterification reaction [51]), which
were isolated in 6–15% yields. Due to the trans-
esterification reaction, vanillin was also recovered with
yields of 9, 60, and 24% when vanillin esters 1–3 were
prepared. We assumed that the absence of ferrocenyl
esters of vanillic and nicotinic acids and the increased
recovery of vanillin may be due to the decomposition
of the desired product immediately after formation.
Instability of ferrocenyl ester of nicotinic acid 7 has
been previously shown in [2]: the substance decom-
poses significantly when stored at room temperature
for a week.
Cytotoxic activity of the obtained compounds 5–9
and compounds 12–14 prepared earlier [2] was
studied. All the compounds do not exhibit cytotoxic
activity to both rhabdomyosarcoma cells (RD TE 32)
and colon carcinoma cells (HCT116), the IC50 con-
centrations calculated for them exceed 200 μM [52].
In summary, ferrocenyl esters of vanillic acid were
first obtained. NHC-Organocatalysis was proved to be
suitable for their preparation in low yields. The
compounds obtained showed no cytotoxic activity.
EXPERIMENTAL
IR spectra were recorded on a VERTEX 80v
Fourier spectrophotometer from mulls in minerale oil
1
or a thin film. H and 13C NMR spectra of CDCl3
solutions were obtained on a Varian Mercury Plus 300
instrument operating at 300 and 75 MHz, respectively,
internal reference HMDS (1H) or residual signals of
the solvent. Melting points were determined on a PTP
instrument. Column chromatography was performed
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

466
DENISOV et al.
with the use of silica gel 60 (Alfa Aesar, 0.032–0.070
mm) and petroleum ether–ethyl acetate as eluent,
increasing polarity from 20 : 0 to 20 : 1 (9), 10 : 1 (6,
8, 11), 5 : 1 (3, 5, and 10), 3 : 1 (1, 4 and 7), 1 : 1 (2).
The purity of the obtained compounds was monitored
by GC-MS using an Agilent Technologies 6890N/5975B
chromatograph-mass spectrometer (column HP-5ms,
30000 × 0.25 mm, 0.25 μm, evaporator temperature
260–300°C, temperature programming at the heating
rate 20–40 deg/min, carrier gas helium, 1 mL/min,
electron impact ionization, 70 eV). Microwave heating
was carried out in the microwave pressure reactor
Discover (USA).
(1Н, 5-Ar, 3JHH = 5.6, 3.2 Hz), 7.11 d.d (1Н, 6-Ar, 3JHH
=
3
5.6, 3.2 Hz), 7.52 d.d (1Н, 5-Py, JHH = 7.0, 1.7 Hz),
3
7.56 s (1Н, 2-Ar), 8.19 d (1Н, 4-Py, JHH = 7.0 Hz),
3
8.86 d (1Н, 6-Py, JHH = 1.7 Hz), 9.10 s (1Н, 2-Py),
10.12 s (1Н, HCO). Mass spectrum, m/z (Irel, %): 257
(14) [M]+, 107 (7), 106 (100) [PyCO]+, 79 (6), 78 (39)
[C5H4N]+, 51 (13).
4-Formyl-2-methoxyphenyl 4-(trifluoromethyl)ben-
zoate (3) was prepared from 0.440 g (2.87 mmol) of
vanillin, 0.500 mL (3.73 mmol) of p-trifluorobenzal-
dehyde, 0.709 g (6.32 mmol) of DABCO, 1.470 g
(5.74 mmol) of CuSO4, 0.273 g (0.86 mmol) of 1,3-
dimethyl-1Н-benzimidazol-3-ylium iodide and 10 mL
of toluene; the reaction was carried out at 135°С for
2 h. Yield 21% (0.196 g), pale yellow oil crystallizing
when stored at room temperature in capped container
for one month. Crystallization of oily substance from
petroleum ether afforded colorless crystals, mp 83–85°C.
IR spectrum, ν, cm–1: 699, 734, 769, 780, 861, 1017,
1032, 1071, 1113, 1130, 1147, 1172, 1202, 1261, 1326,
Ferroceneboronic acid was obtained by a known
method [53].
General procedure for the synthesis of com-
pounds 1–4. A mixture of vanillin, aldehyde, base,
CuSO4, 1,3-dimethyl-1H-benzimidazol-3-ylium iodide
[48], and anhydrous toluene was charged into a
microwave pressure reactor. The reaction was carried
out for 0.5–2 h at a temperature of 110–135°C. After
the reaction completion the mixture was filtered and
the solvent was distilled off on a rotary evaporator.
The products were purified by column chromatography.
1
1391, 1412, 1424, 1467, 1503, 1602, 1704, 1749. H
NMR spectrum (CDCl3), δ, ppm: 3.89 s (3H, OCH3),
3
7.36 d (1Н, 5-Ar, JHH = 8.1 Hz), 7.51 d.d (1Н, 6-Ar,
5
3JHH = 8.1, 1.8 Hz), 7.55 s (1Н, 2-Ar, JHH = 1.8 Hz),
7.79 d (2Н, 3,5-Ar, 3JHH = 8.3 Hz), 8.32 d (2Н, 2,6-Ar,
13
3JHH = 8.3 Hz), 9.99 s (1H, HCO). С NMR spectrum
4-Formyl-2-methoxyphenyl 3-phenylpropanoate
(1) [32] was prepared from 0.279 g (1.83 mmol) of
vanillin, 0.300 mL (2.38 mmol) of p-trifluorobenzal-
dehyde, 0.507 g (3.67 mmol) of K2CO3, 0.050 g
(0.183 mmol) of 1,3-dimethyl-1H-benzimidazol-3-
ylium iodide and 5 mL of toluene; the reaction was
carried out at 120°C for 0.5 h. Yield 66% (0.346 g),
(CDCl3), δС, ppm: 51.92, 121.58, 124.29, 124.85,
124.89, 125.53, 125.56, 125.60, 125.64, 129.35, 129.46,
134.98, 135.31, 138.25, 165.33, 190.39. Mass spectrum,
m/z (Irel, %): 324 (8) [M]+, 174 (9), 173 (100)
[CF3C6H4CO]+, 145 (34) [CF3C6H4]+.
1
4-Formyl-2-methoxyphenyl acetate (4) [26] was
prepared from 0.300 g (1.92 mmol) of vanillin, 0.332 g
(2.96 mmol) of DABCO, 0.466 g (2.56 mmol) of
Cu(OAc)2, 0.054 g (0.20 mmol) of 1,3-dimethyl-1Н-
benzimidazol-3-ylium iodide and 5 mL of toluene; the
reaction was carried out at 130°С for 2 h. Yield 1%
yellow liquid. H NMR spectrum (CDCl3), δ, ppm:
2.93 t (2H, CH2, 3JHH = 7.4 Hz), 3.09 t (2H, CH2, 3JHH
7.4 Hz), 3.85 s(3Н, ОСН3), 7.13 d (1Н, 5-Ar, JHH
=
=
3
8.4 Hz), 7.21–7.35 мm (5Н, Ph), 7.43 d (1Н, 6-Ar,
3JHH = 8.4 Hz), 7.47 s (1Н, 2-Ar). Mass spectrum, m/z
(Irel, %): 284 (2) [M]+, 153 (16), 152 (100) [vanillin]+,
151 (20) [vanillin – H]+, 133 (9), 106 (6), 105 (76)
[PhC2H4]+, 104 (6), 103 (9), 92 (6), 91 (73) [PhCH2]+,
79 (11), 78 (6), 77 (14) [Ph]+, 65 (10), 51 (8).
1
(0.04 g). H NMR spectrum (CDCl3), δ, ppm: 2.36 s
3
(3Н, Ас), 3.93 s (3Н, OMe), 7.24 d (1Н, 5-Ar, JHH
=
8.0 Hz), 7.49 d.d (1Н, 6-Ar, 3JHH = 8.0, 1.6 Hz), 7.52 d
5
(1Н, 2-Ar, JHH = 1.6 Hz), 9.97 s (НСО). Mass spec-
trum, m/z (Irel, %): 194 (5) [M]+, 153 (9), 152 (100)
[vanillin]+, 151 (79) [vanillin – Н]+, 123 (6), 109 (7),
81 (6), 79 (5), 52 (5), 51 (7), 43 (23) [Ac]+.
4-Formyl-2-methoxyphenyl pyridine-3-carboxylate
(2) [23] was prepared similarly from 0.653 g (4.29 mmol)
of vanillin, 0.500 mL (5.58 mmol) of nicotinic al-
dehyde, 1.059 g (9.44 mmol) of DABCO, 2.194 g
(8.58 mmol) of CuSO4, 0.118 g (0.43 ммоль) of 1,3-
dimethyl-1Н-benzimidazol-3-ylium iodide and 10 mL
of toluene; the reaction was carried out at 110°С for
General procedure for the synthesis of com-
pounds 5–9. To a solution of 0.105 g (0.5 mmol) of
ferroceneboronic acid [54] and 0.017 g (0.05 mmol) of
1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol-
3-ylium chloride [48] in 5 mL of toluene was added
1
1 h. Yield 55% (0.609 g), colorless oil. H NMR
spectrum (CDCl3), δ, ppm: 3.42 s (3H, CH3), 6.97 d.d
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467
3-methoxy-4-{[4-(trifluoromethyl)
TWO-STEP SYNTHESIS OF FERROCENYL ESTERS OF VANILLIC ACID
0.65 mmol of the corresponding aldehyde 1–3 and
0.244 g (0.75 mmol) of Cs2CO3. The reaction mixture
was stirred in air at 70°C for 6 h. The solvent was
distilled from the reaction mixture. The transesteri-
fication products (6, 7, 9), the esterification products
(5, 8) and the starting aldehydes were isolated by
column chromatography.
Ferrocenyl
benzoyl]oxy}benzoate (8). Yield 12%, brown oil. IR
spectrum, ν, cm–1: 699, 748, 770, 861, 1017, 1032,
1072, 1132, 1174, 1199, 1267, 1326, 1413, 1464,
1503, 1546, 1582, 1599, 1728, 1744, 2855, 2928,
2960. 1Н NMR spectrum (CDCl3), δ, ppm: 3.94 s (3H,
OMe), 4.05 s (2H, Fс), 4.30 s (5H, Fс), 4.62 s (2H,
3
Fс), 7.32 d (1Н, 5-Ar, JHH = 8.4 Hz), 7.74 s (1Н, 2-
Ferrocenyl 3-methoxy-4-[(3-phenylpropanoyl)oxy]-
benzoate (5). Yield 24%, yellow crystals, mp 97–98°C
(СН2Сl2). IR spectrum, ν, cm–1: 490, 700, 753, 798,
819, 934, 1002, 1031, 1079, 1121, 1172, 1200, 1233,
1267, 1287, 1323, 1369, 1413, 1454, 1506, 1604,
1736, 1766. 1Н NMR spectrum (CDCl3), δ, ppm: 2.93 t
Ar), 7.79 d (1Н, 6-Ar, 3JHH = 8.4 Hz), 7.82 d (2Н, 3,5-
3
3
Ar, JHH = 7.6 Hz) 8.37 d (2Н, 2,6-Ar, JHH = 7.6 Hz).
13С NMR spectrum (CDCl3), δC, ppm: 55.69, 60.35,
62.85, 64.63, 68.90, 113.37, 115.77, 122.08, 122.40,
122.47, 125.09, 125.12, 125.16, 128.35, 130.22,
130.26, 143.45, 150.83, 162.52. Mass spectrum, m/z
(Irel, %): 525 (13) [M + 1]+, 524 (44) [M]+, 324 (5), 323
(28) [CF3C6H4COOC6H3(OCH3)CO]+, 202 (5), 174
(9), 173 (100) [CF3C6H4CO]+, 145 (21) [CF3C6H4]+,
121 (16) [C5H5Fe]+.
3
3
(2H, CH2, JHH = 7.5 Hz), 3.09 t (2H, CH2, JHH
=
7.4 Hz), 3.86 s (3Н, ОСН3), 4.03 s (2Н, Fe), 4.28 s
3
(5H, Fс), 4.59 s (2H, Fс), 7.06 d (1Н, 6-Ar, JHH
=
8.1 Hz), 7.21–7.34 m (5Н, Ph), 7.66 s (1Н, 2-Ar), 7.71
d (1Н, 6-Ar, JHH = 8.1 Hz). 13С NMR spectrum
3
(CDCl3), δС, ppm: 30.78, 35.43, 56.01, 60.83, 63.31,
69.36, 113.57, 116.16, 122.82, 126.34, 128.28, 128.32,
128.48, 140.02, 143.94, 151.13, 164.08, 170.29. Mass
spectrum, m/z (Irel, %): 485 (16) [M + 1]+, 484 (50) [M]+,
203 (6), 202 (45) [FcOH]+, 152 (9), 151 (100) [vanillin –
H]+, 121 (15) [C5H5Fe]+, 105 (8), 91 (12) [C7H7]+.
Ferrocenyl 4-trifluoromethylbenzoate (9) [2].
Yield 15%, red powder, mp 106–107°С (CH2Cl2). IR
spectrum, ν, cm–1: 3117, 1735, 1695, 1412, 1334,
1307, 1281, 1238, 1161, 1115, 1107, 1095, 1069,
1019, 1001, 927, 859, 814, 768, 698, 662, 592, 513,
1
484. Н NMR spectrum (CDCl3), δ, ppm: 4.01 t (2Н,
3
Fc, JHH = 1.8 Hz), 4.25 s (5H, Fc), 4.57 s (2Н, Fc,
Ferrocenyl 3-phenylpropanoate (6). Yield 9%,
yellow oil. IR spectrum, ν, cm–1: 488, 699, 753, 820,
865, 924, 943, 1002, 1023, 1030, 1052, 1078, 1106,
1136, 1186, 1232, 1288, 1368, 1413, 1454, 1497,
3
3JHH = 1.8 Hz), 7.74 d (2Н, 3,5-Ar, JHH = 8.1 Hz),
8.72 d (2Н, 2,6-Ar, 3JHH = 8.1 Hz). 13С NMR spectrum
(CDCl3), δC, ppm: 60.84, 63.46, 69.42, 99,95, 125.45,
125.55, 130.22. Mass spectrum, m/z (Irel, %): 375 (12)
[M + 1]+, 374 (49) [M]+, 201 (6), 174 (9) [CF3C6H4CO +
1]+, 173 (100) [CF3C6H4CO]+, 171 (6), 147 (8), 145
(32) [CF3C6H4]+, 126 (6), 121 (37) [C5H5Fe]+, 95 (6),
56 (9).
1
1604, 1756, 2854, 2926, 2956, 3028, 3063, 3088. Н
NMR spectrum (CDCl3), δ, ppm: 2.74 t (2H, CH2, 3JHH
=
3
7.1 Hz), 3.00 t (2H, CH2, JHH = 7.1 Hz), 3.91 s (2Н,
Fс), 4.15 s (5H, Fс), 4.37 s (2H, Fс) 7.22–7.31 m (5Н,
Ph). 13С NMR spectrum (CDCl3), δС, ppm: 30.39,
35.00, 55.53, 60.36, 62.83, 68.89, 113.04, 122.03,
122.17, 127.88, 128.04, 128.06. Mass spectrum, m/z
(Irel, %): 334 (16) [M]+, 203 (14) [FcOH + 1]+, 202
(100) [FcOH]+, 200 (6), 121 (17) [C5H5Fe]+, 91 (7).
p-Tolyl
3-methoxy-4-(3-phenylpropanoyloxy)
benzoate (10). A mixture of 0.22 g (0.65 mmol) of 4-
formyl-2-methoxyphenyl-3-phenylpropionate, 0.068 g
(0.5 mmol) of p-tolylboronic acid, 0.244 g (0.75 mmol)
of cesium carbonate and 0.017 g (0.05 mmol) of 1,3-
bis(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol-3-
ylium chloride [48] in 5 mL of toluene was stirred in
air for 3 h at 60°C. Yield 5%, cream powder, mp 106–
111°С (СН2Сl2). IR spectrum, ν, cm–1: 502, 517, 699,
754, 787, 824, 860, 882, 918, 973, 1031, 1077, 1121,
1171, 1196, 1229, 1267, 1287, 1323, 1367, 1413,
1454, 1464, 1503, 1605, 1620, 1733, 1765, 2869,
Ferrocenyl pyridine-3-carboxylate (7) [55]. Yield
9%, brown crystals, mp 69–76°C (СН2Сl2). IR spec-
trum, ν, cm–1: 1730, 1679, 1279, 1235, 1103, 1086,
1
1038, 1027, 835, 809, 700, 516, 506, 492. Н NMR
spectrum (CDCl3), δ, ppm: 4.03 s (2H, Fc), 4.27 s (5H,
Fc), 4.58 s (2H, Fc), 7.48 br.s (1H, Py-5), 8.37 d (1H,
3
Py-4, JHH = 6.9 Hz), 8.88 br.s (1H, Py-6), 9.36 s (1H,
Py-2). 13С NMR spectrum, δС, ppm: 60.42, 63.01,
68.98, 115.52, 123.12, 129.21 136.77, 150.69, 153.26,
163.18. Mass spectrum, m/z (Irel, %): 308 (17) [M + 1]+,
307 (86) [M]+, 305 (5) [M – 2]+, 201 (7), 199 (7), 173
(6), 147 (11), 121 (54) [C5H5Fe]+, 107 (8), 106 (100)
[C5H4NCO]+, 78 (25) [C5H4N]+, 56 (18) [Fe]+, 51 (11).
1
2825, 2937, 3029, 3062, 3083. Н NMR spectrum
(CDCl3), δ, ppm: 2.45 s (3Н, Ме), 2.99 t (2Н, СН2,
3
3JHH = 7.7 Hz), 3.16 t (2Н, СН2, JHH = 7.6 Hz), 3.91 s
(3Н, ОМе), 7.11–7.89 m (12Н, Ar, Ph, Tol). 13С NMR
spectrum (CDCl3), δС, ppm: 20.98, 31.02, 35.63, 56.24,
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468
DENISOV et al.
4. Snegur, L.V., Simenel, A.A., Rodionov, A.N., and
Boev, V.I., Russ. Chem. Rev., 2014, vol. 63, no. 1, p. 26.
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doi 10.1016/j.snb.2005.07.011
114.09, 121.44, 121.45, 123.05, 123.38, 126.54, 128.48,
128.51, 128.57, 128.58, 129.08, 130.10, 130.11, 135.67,
151.40, 170.44. Mass spectrum, m/z (Irel, %): 390 (0.4)
[M]+, 258 (7), 152 (9), 151 (100) [PhCH2CH2C(OH)2]+,
122 (6), 105 (9), 91 (14) [PhCH2]+, 77 (5). In addition,
the transesterification product p-tolyl 3-phenylpro-
panoate (11) [56] was isolated. Yield 55%, red liquid.
1Н NMR spectrum (CDCl3), δ, ppm: 2.40 s (3H CH3),
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2.93 t (2H, СH2, 3JHH = 7.6 Hz), 3.14 t (2Н, СH2, 3JHH
=
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7.6 Hz), 6.94–7.40 m (9H, Ph, Tol). Mass spectrum,
m/z (Irel, %): 240 (9) [M]+, 109 (8), 108 (100) [TolOH]+,
107 (10) [TolO]+, 105 (29) [PhCH2CH2]+, 91 (37)
[PhCH2]+, 79 (8), 78 (6), 77 (16) [Ph]+, 65 (5).
The cytotoxic activity of compounds 5–14 was
studied using a MTT test for human cell cultures:
colon carcinoma (HCT116) and rhabdomyosarcoma
(RD TE 32). Cell cultures were grown in DMEM
medium supplemented with 10% fetal calf serum, 2
mM L-glutamine and 1% gentamicin at 37°C and 5%
CO2 in a humid atmosphere. After 24 h incubation
cells were treated with obtained compounds in con-
centration from 10–4 to 10–6 M. After 72 h a MTT dye
was added to the treated cell cultures. The formazan
crystals were dissolved in 100 μL of DMSO. The
optical density was determined using a FLUOstar
Optima plate spectro-photometer (BMG Labtech,
GmbH), calculating IC50 value, the concentration of
the substance toxic to 50% of the cells [52].
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Korman, D.B., Bluchterova, N.V., Fomina, M.M.,
Rikova, V.A., Goldberg, V.M., Abzaeva, K.A.,
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Gumenyuk, V.V., Nekrasov, Yu.S., Ostrovskaya, L.A.,
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ACKNOWLEDGMENTS
The authors are grateful to I.A. Borisova for
recording the IR spectra, O.A. Maiorova and
I.G. Mokrushin for recording NMR spectra, as well as
to N.A. Polezhaeva for her help in finding literature.
This work was supported by the Russian Founda-
tion for Basic Research (grant no. 16-33-00147-mol-a)
in the frame of the Program of the Ural Branch of the
Russian Academy of Sciences “Biomolecular Chemistry
and Organic Synthesis” (no. 15-21-3-2).
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