Reactions of α-nitrocinnamic acids esters with indole and its derivatives

Article abstract of DOI:10.1134/S107036321103025X

Reactions of α-nitrocinnamic acids esters with indole and its derivatives lead to the formation of the products of alkylation at the C ₃-reaction center of the heterocycle. The hydrogenation of the adduct of 1-methylindole and α-nitro-β-phenyla

Full text of DOI:10.1134/S107036321103025X

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 3, pp. 586–590. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © L.V. Baichurina, N.I. Aboskalova, E.V. Trukhin, V.M. Berestovitskaya, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81,
No. 3, pp. 491–495.
Reactions of α-Nitrocinnamic Acids Esters
with Indole and Its Derivatives
L. V. Baichurina, N. I. Aboskalova, E. V. Trukhin, and V. M. Berestovitskaya
Herzen Russian State Pedagogical University, nab. r. Moiki 48, St. Petersburg, 191186 Russia
e-mail: kohrgpu@yandex.ru
Received June 17, 2010
Abstract—Reactions of α-nitrocinnamic acids esters with indole and its derivatives lead to the formation of the
products of alkylation at the C3-reaction center of the heterocycle. The hydrogenation of the adduct of 1-
methylindole and α-nitro-β-phenylacrylate on the Raney nickel catalyst afforded indolylaminopropanoate, that
was used for the synthesis of ethyl 2-acetylamino-3-(1-methylindol-3-yl)-3-phenylpropanoate, a precursor of
the methylated in the indole ring phenyl-substituted tryptophan.
DOI: 10.1134/S107036321103025X
The preparatively accessible α-nitrocinnamic esters
are promising starting reagents for the construction of
potential biologically active structures with the desired
carbon skeleton. It suffices to say that the esters of α-
nitrocinnamic acids can be converted into α-amino
acids by the hydrogenation and subsequent hydrolysis
[1]. The study of the reactions aimed at the
introduction of such pharmacophore moiety as indole
into the β-aryl-α-nitroacrylate molecule is of
undoubted interest [2]. It is known that indole
derivatives are both key structures in the composition
of many substances of natural origin and synthetic
drugs. In particular, compounds related to them are the
essential α-amino acid tryptophan, a mediator of nerve
impulses serotonin, the biogenic amine tryptamine, and
the widely used in medical practice antiinflammatory
R1
R1
N
R3
HA NO2
R2
NO2
COOC2H5
HB
R3
COOC2H5
N
R2
I−III
IV−XIII
(CH3CO)2O,
pyridin
HA
HA
NHCOCH3
NH2
H2, Ni/Re
R3 = H
HB
HB
R1
R2 = CH3
=
COOC2H5
COOC2H5
N
N
CH3
CH3
XV
XIV
R1 = H (I), CH3O (II), Cl (III). R1 = H: R2 = R3 = H (IV), R2 = CH3, R3 = H (V), R2 = C2H5, R3 = H (VI), R2 = H, R3 =
CH3 (VII); R1 = CH3O: R2 = R3 = H (VIII), R2 = CH3, R3 = H (IX), R2 = C2H5, R3 = H (X), R2 = H, R3 = CH3 (XI); R1 = Cl:
R2 = R3 = H (XII), R2 = CH3, R3 = H (XIII).
586

REACTIONS OF α-NITROCINNAMIC ACIDS ESTERS
587
Table 1. Yields, melting points, and spectral data for indolylnitropropanoates IV–XIIIа
IR spectrum (СHCl3), ν, cm–1
1Н NMR spectra (СDCl3), δ, ppm, J, Hz
Comp. mp, °С
Yield,
%
OCH2CH3
(OCH3)
NCH3 (N–
CH2CH3)
[C–CH3]
–
no.
(a:b)
NO2
C=O
NH
НА (НВ)
NH
Ar, Het
IVb
142–144
55
91
1565, 1375 1740
3410
5.92 d (5.37 d)
J(HAHB) 11.77
5.92 d (5.36 d)
J(HAHB) 10.30
5.87 d (5.36 d)
J(HAHB) 11.77
5.92 5.37 d
0.95 t, 3.98 q
0.91 t, 3.99 q
0.99 t, 4.03 q
8.13 s 6.99–7.73 m
–
Vа
3.74 s
3.76 s
124–126
(1:1)
1570, 1375 1755
–
6.97–7.61 m
–
Vb
VIа
VIb
VIIb
VIIIа
VIIIb
IX
0.99 t, 4.08 q (1.45 t, 4.12 q)
0.85 t, 3.97 q (1.42 t, 4.09 q)
–
108–110
(1:1)
J(HAHB) 11.03
5.90 ( 5.37 d)
J(HAHB) 11.77
6.31 d (5.28 d)
J(HAHB) 11.18
5.85 d (5.33 d)
J(HAHB) 11.03
5.87 d (5.31 d)
J(HAHB) 11.77
5.84 d (5.32 d)
J(HAHB) 11.03
5.84 d (5.31 d)
J(HAHB) 11.03
5.85 d (5.29 d)
J(HAHB) 11.77
6.27 d (5.23 d)
J(HAHB) 11.90
6.24 d (5.29 d)
J(HAHB) 12.21
5.84 d (5.33 d)
J(HAHB) 10.78
5.86 d (5.33 d)
J(HAHB) 11.31
5.83 d (5.33 d)
J(HAHB) 11.29
5.85 d (5.32 d)
J(HAHB) 11.60
66
20
1565, 1375 1765
1565, 1375 1750
–
7.03–7.61 m
–
137–139
3470
1.06 t, 4.12 q
[2.47 s]
7.85 s 7.07–7.68 m
8.10 s
1.05 t, 4.07 q
(3.74 s)
–
–
164–166
(2:1)
54
43
1565, 1375 1745
1565, 1375 1750
3330
–
6.73–7.65 m
8.10 s
0.93 t, 3.99 q
(3.75 s)
138–140
1.04 t, 4.02 q
(3.75 s)
3.74 s
–
–
6.73–7.60 m
Xа
1.01 t, 4.02 q (1.44 t, 4.11 q)
(3.73 s)
99–101
(6:1)
20
54
32
54
1565, 1375 1750
1560, 1375 1750
1565, 1375 1750
1565, 1375 1750
–
6.78–7.45 m
Xb
1.03 t, 4.05 q (1.35 t, 4.14 q)
(3.73 s)
–
XIа
XIb
XIIа
XIIb
XIIIа
XIIIb
1.12 t, 4.13 q
(3.73 s)
[2.43 s]
[2.42 s]
–
7.87 s
7.87 s
8.14 s
8.14 s
–
136–138
(8:1)
3470
3475
–
6.78–7.87 m
7.05–7.52 m
7.06–7.55 m
1.12 t, 4.12 q
(3.73 s)
1.05 t, 4.00 q
128–130
(1:8)
0.93 t, 3.98 q
1.04 t, 4.05 q
0.92 t, 4.03 q
–
3.75 s
3.74 s
110–112
(5:1)
–
a
Diastereomers with lower spin–spin coupling constant between methyne protons НА and НВ are designated as “a,” and with greater, as
“b.” b The IR spectra of compounds IV and VII were recorded in mineral oil.
and analgesic agent indomethacin, the antiarrhythmic
and antihypertensive drug bopindalol, the antihyper-
tensive diuretic Arifon, the hypolipidemic drug ator-
vastatin, and others. [3].
the fusion of equimolar amounts of the initial com-
pounds in the solvent-free conditions, without addi-
tional catalytic agents, to form C3-adducts with yields
up to 91%.
The study of the reaction of α-nitroacrylates I–III
with indole and its alkyl-substituted derivatives
showed that these reactions occur most efficiently at
The structure of compounds IV–XIII is confirmed
by the spectral data (Table 1). Thus, the IR spectra
contain the intense absorption bands of stretching
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

588
BAICHURINA et al.
Table 2. The 1Н NMR spectral data of indolylnitropropanoates (XIV, XV)a
1Н NMR spectra (СDCl3), δ, ppm, J, Hz
OCH2 CH3 (N–CH3) СОСН3
Comp. no.
НА (НВ)
NH (NH2)
(1.57 s)
Ar, Ind
XIVа
XIVb
XVа
4.67 d (4.20 d), J(HAHB) 6.00
4.04 q 1.06 t (3.75 s)
4.00 q 0.97 t (3.77 s)
4.06 q 1.09 t (3.78 s)
3.91 q 0.93 t (3.78 s)
–
–
6.98–7.47 m
4.63 d (4.18 d), J(HAHB) 6.80
(1.57 s)
5.44 d.d (4.88 d), J(HAHB) 5.00, J(HANH) 8.80
5.30 d.d (4.68 d), J(HAHB) 8.33, J(HANH) 9.00
1.95 s 5.99 d, J(NHHA) 8.8
1.89 s 5.74 d, J(NHHA) 9.0
6.90–7.38 m
XVb
a
Diastereomers with a lower spin–spin coupling constant between methyne protons НА and НВ are designated as “а,” and with greater,
as “b.”
vibrations of non-conjugated nitro- (1560–1570,
1375 cm–1) and carbonyl (1740–1765 cm–1) groups. In
the spectra of compounds IV, VII, VIII, XI, XII there
are absorption bands belonging to the vibrations of
NH-groups of indole rings (3330–3475 cm–1).
The hydrogenation of compound V on a skeletal
nickel catalyst at room temperature led to the indolyl-
aminopropanoate XIV isolated as an oily substance in
~94% yield. The acylation of the latter with acetic
anhydride in pyridine yields ethyl 2-acetylamino-3-(1-
methylindol-3-yl)-3-phenylpropanoate XV (45%), the
precursor of phenyl-substituted tryptophan methylated
by the nitrogen of the indole ring.
1
In the H NMR spectra of indolylnitropropanoates
IV–XIII the signals of protons of all the structural
fragments are present. The 1H NMR spectra of
compounds V, VI, VIII, X–XIII contain a double set
of the proton signals, indicating the existence in the
chloroform-d solution of a mixture of diastereomers.
The adducts IV, VII, IX were isolated as individual
The structure of the synthesized amino ester XIV
and N-acetylamino ester XV was confirmed by the
spectroscopic methods. Thus, the IR spectrum (KBr)
of compound XV contains no absorption bands of the
stretching vibrations of nitro groups, and there are
intense absorption bands of stretching vibrations of
carbonyl groups of ester and amide fragments at 1735
and 1675 cm–1, respectively. The absorption band at
3430 cm–1 can be assigned to the stretching vibrations
of amide NH-group.
1
diastereomers. Thus, in the H NMR spectrum of IV
there are two clear doublets of the methine protons НА
and НB at 5.92 and 5.37 ppm respectively with a spin-
spin coupling constant 3J(HAHB) 11.77 Hz. Methyl and
methylene protons in OCH2CH3-fragment appear as a
triplet and a quadruplet at 0.95 and 3.98 ppm, respec-
tively. The protons of phenyl and indole rings are
recorded as multiplets in the region of 6.99–7.73 ppm.
The NH proton of indole ring resonates at 8.13 ppm.
1
The H NMR spectra of amino ester XIV and N-
acetylamino ester XV contain the signals of all the
structural fragments of the molecules (Table 2). The
double set of the proton signals indicates the existence
in a solution in chloroform-d of diastereomeric
It should be noted that recently the reaction was
studied of β-aryl-α-nitroacrylate derivatives with
indole and its derivatives in the presence of chiral
metal complex catalysts in methylene chloride (toluene)
at 0°C over 60–130 h [4]. The spectral characteristics
of compound VIII and the adduct (anti-form) syn-
thesized from indole and ethyl 2-nitro-3-(4-methoxy-
phenyl)propenoate described in [4] are very close.
1
mixtures (~1:1). In the H NMR spectrum of XV the
protons NH, HA and HB of the three-spin ABC system
are registered at 5.99, 5.44 and 4.88 ppm (diastereomer
a) and at 5.74, 5.30 and 4.68 ppm (diastereomer b),
respectively. Methyl and methylene protons in
ОСН2СН3-fragment appear as a triplet and quadruplet
at 9.1, 4.06 ppm (diastereomer a) and at 0.93, 3.91
ppm (diastereomer b), respectively. The methyl group
protons in the indole ring resonate at 3.78 ppm. Indole
and phenyl ring protons are recorded as multiplets at
6.9–7.38 ppm.
The synthesized indolylnitropropanoates IV–XIII
may be recommended as the initial reagents in the
synthesis of aryl-substituted tryptophans. The principal
possibility of their transformation into the modified
analogs of tryptophan we showed by the example of
reduction of the adduct of 1-methylindole and ethyl α-
nitrocinnamate V.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

REACTIONS OF α-NITROCINNAMIC ACIDS ESTERS
589
EXPERIMENTAL
Ethyl 3-(1-methylindol-3-yl)-3-(4-methoxyphenyl)-
2-nitropropanoate (IX). Yield 43%, individual dia-
stereomer, mp 138–140°С (ethanol). Found N, %:
7.37. C21H22N2O5. Calculated N, %: 7.33.
1
The Н NMR spectra were recorded on a Bruker
WM-400 (400 MHz) and Jeol JNM-ECX400A
(400 MHz) spectrometers in chloroform-d. Chemical
shifts (δ) were measured in ppm using residual CHCl3
as an internal reference.
Ethyl 3-(4-methoxyphenyl)-2-nitro-3-(1-ethylindol-
3-yl)propanoate (X). Yield 20%, diastereomers mix-
ture (a:b = 6:1), mp 99–101°С (ethanol). Found N, %:
N 6.64. C22H24N2O5. Calculated N, %: N 7.07.
The IR spectra were taken on a Shimadzu IR
Prestige-21 and InfraLum FT-02 spectrometers from
the samples in chloroform (с 0.1–0.001 mol l–1) or
mineral oil. The elemental analysis was performed on
a Eurovector EA3028 analyzer.
Ethyl 3-(2-methylindol-3-yl)-3-(4-methoxyphenyl)-
2-nitropropanoate (XI). Yield 54%, diastereomers
mixture (a:b ~8:1), mp 136–138°С (ethanol). Found,
%: C 66.34, H 5.90, N 7.17. C21H22N2O5. Calculated,
%: C 65.96, H 5.80, N 7.33.
The mass spectra were registered on a МKh 1321
mass spectrometer with a direct injection of the sample
into the ion source. Measuring conditions: ionizing
voltage 70V, ionizing source temperature 180°С).
Ethyl 3-(indol-3-yl)-2-nitro-3-(4-chlorophenyl)pro-
panoate (XII). Yield 32%, diastereomers mixture (a:b
~1:8), mp 128–130°С (ethanol). Found N, %: 7.09.
C19H17N2O4. Calculated N, %: N 7.51.
Ethyl 3-(indol-3-yl)-2-nitro-3-phenylpropanoate
(IV). A mixture of 0.221 g (1 mmol) of ethyl 2-nitro-3-
phenylpropenoate I and 0.12 g (1 mmol) of indole was
heated up to melt under stirring and allowed to stand
for 3 days at room temperature in the dark. The
reaction mixture was treated with ethanol and filtered.
Yield 0.187 g (55%), white crystals (individual dia-
stereomer), mp 142–144°С (ethanol). Found N, %:
8.23. C19H18N2O4. Calculated N, %: 8.28.
Ethyl 3-(1-methylindol-3-yl)-2-nitro-3-(4-chloro-
phenyl)propanoate (XIII). Yield 54%, diastereomers
mixture (a:b ~5:1), mp. 110–112°С (ethanol). Found,
%: C 62.17, H 4.95, N 7.32. C20H19СlN2O4. Calculated
N, %: C 62.10, H 4.95, N 7.24.
Ethyl 2-amino-3-(1-methylindol-3-yl)-3-phenyl-
propanoate (XIV). A solution of 1.1 g (0.3 mmol) of
ethyl 3-(1-methylindol-3-yl)-2-nitro-3-phenylpropanoate
V in 25 ml of methanol was charged into the flask for
hydrogenation with a Raney nickel pre-saturated with
hydrogen. The hydrogenation was carried out in
methanol at shaking (atmospheric pressure) to com-
plete absorption of the calculated amount of hydrogen
(2 h). After the catalyst separating and solvent
removal, the compound XIV was obtained (0.91 g,
94%) as a pale-green oil, which is a mixture of dia-
Compounds V–XIII were similarly prepared from
the corresponding α-nitrocinnamic acids esters and
indole or its derivatives.
Ethyl 3-(1-methylindol-3-yl)-2-nitro-3-phenylpro-
panoate (V). Yield 91%, diastereomers mixture (a:b
~1:1), mp 124–126°С (ethanol). Found N, %: N 7.92.
C20H20N2O4. Calculated N, %: 7.95.
Ethyl 2-nitro-3-phenyl-3-(1-ethylindol-3-yl)pro-
panoate (VI). Yield 66%, diastereomers mixture
(a:b = 1:1), mp 108–110°С (ethanol). Found N, %: C
68.65, H 5.89, N 7.65. C21H22N2O4. Calculated, %: C
68.84, H 6.05, N 7.65. Mass spectrum, m/z: 366 [M+],
Мcalc 366.
1
stereomers a:b in a ratio of ~1:1 according to the H
NMR spectroscopy. The obtained compound XIV was
used without further purification in the acylation
reaction.
Ethyl
2-acetylamino-3-(1-methylindol-3-yl)-3-
phenylpropanoate (XV). To a solution of 0.9 g
(0.25 mmol) of ethyl 2-amino-3-(1-methylindol-3-yl)-
3-phenylpropanoate XIV in 4 ml of pyridine was
added 4 ml of acetic anhydride. The mixture was kept
for 3 days. Then it was poured into ice, the solid was
filtered off. Yield 0.455 g (45%), diastereomers mix-
ture (1:1), mp 96–98°С (ethanol). Found, %: C 72.60,
H 6.53, N 7.51. C22H24N2O3. Calculated, %: C 72.50,
H 6.64, N 7.69.
Ethyl 2-nitro-3-phenyl-3-(2-methylindol-3-yl)pro-
panoate (VII). Yield 20%, diastereomers mixture
(a:b = 1:1), mp 137–139°С (ethanol). Mass spectrum,
m/z: 352 [M+], Мcalc 352.
Ethyl 3-(indol-3-yl)-3-(4-methoxyphenyl)-2-nitro-
propanoate (VIII). Yield 54%, diastereomers mixture
(a:b = 2:1), mp 164–166°С (ethanol). Found N, %:
7.86. C20H20N2O5. Calculated N, %: 7.61.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

590
BAICHURINA et al.
Modification of Heterocycles. Chemistry of Synthetic
REFERENCES
Indole Systems), Moscow: IBS Press, 2004, vol. 3,
p. 34.
1. Perekalin, V.V. and Temp, A.A., USSR Inventor’s
Certificate no. 209465, 1968; Byull. Izobret., 1968,
vol. 45, no. 5, p. 33.
2. Berstovitskaya, V.M., Aboskalova, N.I., and
Makarenko, S.V., in: Izbrannye metody sinteza i modi-
fikatsii geterotsiklov. Khimiya sinteticheskikh indol’-
nykh system (Selected Methods for Synthesis and
3. Mashkovskii, M.D. Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2007, pp. 162, 173, 171, 267,
470.
4. Sui, Y., Liu, Li, Zhao, J.-L., Wang, D., and Chen, Y.-J.,
Tetrahedron, 2007, vol. 63, no. 24, p. 5173.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011