Synthesis and Structure of Geminally Activated Nitroethenes of the Indole Series

Article abstract of DOI:10.1134/S1070363219050037

A series of 2-(indol-3-yl)-1-nitroethenes containing an ester, acetyl, benzoyl, or cyano group in the geminal position with respect to the nitro group have been synthesized, and their structure has been studied by ¹H, ¹³C?{¹

Full text of DOI:10.1134/S1070363219050037

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 5, pp. 870–880. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 5, pp. 671–683.
Synthesis and Structure of Geminally Activated Nitroethenes
of the Indole Series1
R. I. Baichurina, A. A. Fedorushchenkoa, N. I. Aboskalovaa, L. V. Baichurinab,
A. V. Felgendlerb, and S. V. Makarenkoa*
a Herzen State Pedagogical University of Russia, nab. r. Moiki 48, St. Petersburg, 191186 Russia
*e-mail: kohrgpu@yandex.ru
b Kirov Military Medical Academy, St. Petersburg, Russia
Received December 13, 2018; revised December 13, 2018; accepted December 20, 2018
Abstract—A series of 2-(indol-3-yl)-1-nitroethenes containing an ester, acetyl, benzoyl, or cyano group in the
geminal position with respect to the nitro group have been synthesized, and their structure has been studied by
1H, 13C–{1H} NMR, IR, and UV spectroscopy.
Keywords: indole, gem-ethoxycarbonylnitroethene, gem-acetylnitroethene, gem-benzoylnitroethene, gem-
cyanonitroethene
DOI: 10.1134/S1070363219050037
β-Nitrostyrenes and their furan and thiophene
analogs containing an ester, acyl, or cyano group in the
geminal position with respect to the nitro group are
reactive compounds and convenient intermediate
products for the synthesis of various linear and cyclic
structures [1–4], many of which (α-amino acids,
α-amino ketones, 1,2,3-triazoles, dihydrofurans,
dihydro-1,5-benzothiazepines, etc.) possess practically
useful properties.
features of nitroethenes of the indole series containing
an ester, acyl, or cyano group in the geminal position
with respect to the nitro group are of undoubted
interest.
It is known that in most cases the condensation of
aldehydes with nitro-substituted CH acids in the
presence of bases gives no desired geminally activated
(het)aryl-substituted nitroethenes but leads to the
formation of 2,4-dinitroglutaric acid derivatives, sub-
stituted (dihydro)isoxazole N-oxides [18–22], or 5-hyd-
roxy-6-oxo-1,2-oxazine-3-carboxylates (isolated as
salts) [23]. Furthermore, base-catalyzed reactions of
aldehydes with nitroacetone involved only the methyl
group of the latter [24], whereas nitroacetophenone
readily decomposed in the presence of strong bases
[25].
On the other hand, an important position among
biologically active compounds is occupied by those
containing a pharmacophoric indole ring [5–9]. For
example, medicines of the indole series, such as
vinprocetine, indometacin, α-methyltryptamine, bo-
pindolol, umifenovir, etc., are widely used in medical
practice [10, 11]. Preparatively accessible indole
compounds are widely used in organic synthesis [12].
Interest in 3-(2-nitrovinyl)indoles has increased in
recent years [13–17]. However, published data on
geminally functionalized nitroethenes containing an
indole fragment are mainly concerned with α-
nitroacrylates. Only a few synthetic procedures and
scattered spectral characteristics are available for their
acyl and cyano analogs. Nevertheless, structural
Some geminally activated nitroethenes could be
obtained from Schiff bases or acetals. For example,
ethyl β-(1-acetylindol-3-yl)-α-nitroacrylate [19, 20]
and methyl β-(indol-3-yl)-α-nitroacrylate [26, 27] were
synthesized from nitroacetic acid esters. Direct
alkenylation of nitroacetic acid ester with (hetero)
aromatic aldehydes in anhydrous CCl4–THF in the
presence of TiCl4 and N-methylmorpholine (pyridine)
was also successful [28–30]. The condensation of
indole-3-carbaldehyde and its analogs with ethyl nitro-
acetate, nitroacetone, and nitroacetophenone in ethanol
1
Supplementary materials are available for this article at
doi 10.1134/S1070363219050037 and are accessible for
authorized users.
870

SYNTHESIS AND STRUCTURE OF GEMINALLY ACTIVATED NITROETHENES
871
Scheme 1.
H
H
NO2
X
R2
O
NO2
X
+
R2
N
N
R1
R1
6−22
1−5
R1 = R2 = H (1); R1 = Me, R2 = H (2); R1 = Bn, R2 = H (3); R1 = R2 = Me (4); R1 = C(O)Me, R2 = H (5); X = C(O)OEt: R1 =
Bn, R2 = H (6); R1 = R2 = Me (7); R1 = C(O)Me, R2 = H (8); X = C(O)Me: R1 = R2 = H (9); R1 = Me, R2 = H (10); R1 = Bn,
R2 = H (11); R1 = R2 = Me (12); X = C(O)Ph : R1 = R2 = H (13); R1 = Me, R2 = H (14); R1 = Bn, R2 = H (15); R1 = R2 =
Me (16); R1 = C(O)Me, R2 = H (17); X = CN: R1 = R2 = H (18); R1 = Me, R2 = H (19); R1 = Bn, R2 = H (20); R1 = R2 =
Me (21); R1 = C(O)Me, R2 = H (22).
in the presence of aprotic and protic acids also seems
promising [19, 31, 32]; it made it possible to obtain a
wide series of (hetero)aryl-substituted nitroethenes
[33–35]. Various geminal alkoxycarbonyl- and benzoyl-
nitroethenes (including indole-containing analogs)
were synthesized by heating aldehydes and the cor-
responding CH acids in boiling benzene in the
presence of acetic acid and β-alanine or ε-amino-
Table 1. 1H NMR spectra of (E)-benzoyl(cyano)nitroethenes 13–18 and 20–24a
H
NO2
H
H
NO2
β
α
β
α
X
R2
R2
N
N
R1
R1
23, 24
13−18, 20−22
δ, ppm, J, Hz
Compound
no.
X
R1
R2
Hα (Hβ)
R1
Harom
13
14
C(O)Ph
C(O)Ph
H
H
H
8.80 s
8.77 s
12.33 s
3.76 s
7.10–8.0 m
Me
7.30–7.94 m
15
C(O)Ph
C(O)Ph
C(O)Ph
CH2Ph
Me
H
8.69 s
8.70 s
8.59 s
5.24 s
3.69 s
2.52 s
6.90–7.90 m
6.95–8.00 m
7.40–8.44 m
16b
Me
H
17
C(O)Me
18
20
CN
CN
H
H
H
8.93 s
9.08 s
13.06 s
5.68 s
7.27 m, 7.53, 8.00 m, 8.54 m
CH2Ph
7.31–7.33 m, 7.66 m, 8.13 m, 8.80 m
21c
22
23
CN
CN
–
Me
Me
H
8.78 s
9.09 s
3.81 s
2.70 s
5.18 s
7.32–7.40 m, 7.67 m, 8.14 m
7.42–7.47 m, 8.14 m, 8.33 m, 8.80 m
7.19–7.43 m
C(O)Me
CH2Ph
H
8.13 d (7.61 d)
Jαβ = 14.0
24
–
C(O)Me
H
8.17 d (7.81 d)
2.71 s
7.40–7.87 m, 8.48–8.52 m
Jαβ = 13.7
a
b
c
The 1H NMR spectra of 13, 18, and 20–22 were recorded in DMSO-d6, and of 14–17, 23, and 24, in CDCl3.
2-Me: δ 2.57 ppm.
2-Me: δ 2.60 ppm.
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BAICHURIN et al.
Table 2. 13C–{1H} NMR spectra of (E)-benzoyl(cyano)nitroethenes 13–18 and 20–22a
H
NO2
X
β
α
R2
N
R1
13−18, 20−22
δC, ppm (J, Hz)
R1
Comp.
no.
X
R1
R2
Cα
Cβ
X
13
14
15
16
17
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
H
H
138.40
139.14
140.01
138.98
144.02
132.77
131.04
130.13
134.02
129.04
–
190.41 (C=O)
190.29 (C=O)
189.43 (C=O)
189.70 (C=O)
188.80 (C=O)
CH3
H
34.01
CH2Ph
CH3
H
51.28 (СН2)
CH3
H
30.66
C(O)CH3
23.82 (СН3),
168.53 (С=О)
18
20
21
22
CN
CN
CN
CN
H
H
115.31
115.92
113.95
111.00
142.58
141.90
142.43
141.70
–
114.70 (CN, 3JCNHβ = 10.4)
114.44 (CN, 3JCNHβ = 10.6)
114.96 (CN, 3JCNHβ = 10.1)
113.38 (CN)
CH2Ph
CH3
H
51.12 (СН2)
31.93
CH3
H
C(O)CH3
24.38 (СН3),
170.40 (С=О)
The 13C–{1H} NMR spectra of 13, 18, and 20–22 were recorded in DMSO-d6, and of 14–17, in CDCl3. Carbon atoms of the benzene and
indole ring resonated in the region δC 107.28–157.43 ppm; the 2-Me signal was located at δC 11.94 (16) or 12.22 ppm (21).
a
caproic acid [34–38]. The condensation of aldehydes
with nitroacetonitrile successfully afforded geminal
cyanonitroethenes in the presence of AlkNH2·HCl +
Na2CO3, β-alanine, or propylamine as condensing agent,
on silica gel, under microwave irradiation [4, 39, 40]
or without a catalyst [41]. Some geminal cyanonitro-
ethenes were obtained in this way using crude nitro-
acetonitrile [19, 31, 39]. It should be noted that the
reaction of (hetero)aromatic aldehydes with nitro-
acetonitrile at a ratio of 1:2 in the presence of an
equimolar amount of a base (diethylamine or sodium
acetate) led to the formation of 2,4-dinitroglutaronitrile
salts which were converted to the corresponding cyano-
nitroethenes by the action of acids [42, 43].
agent2 (18–22; method b). Compounds 6, 8, and 15–17
were synthesized by heating the reactants in boiling
benzene in the presence of β-alanine and acetic acid
with simultaneous removal of liberated water (method c).
The yields reached 93%. Compounds 7, 12, 16, 17, 21,
and 22 were not reported previously. The properties of
compounds 6, 8, and 15 (method c) were consistent
with those of samples prepared previously by other
methods [20, 29, 31].
The structure of nitroethenes 6–223 was studied by
1
IR, UV, and H and 13C–{1H} NMR spectroscopy,
1
1
1
including H–13C HMQC, H–13C HMBC, and H–1H
NOESY experiments. The 1H NMR spectra of benzoyl
and cyano derivatives 13–18 and 20–224 indicated
their stereochemical homogeneity (Table 1). The
olefinic proton resonated at δ 8.59–9.09 ppm, i.e.,
shifted downfield than the corresponding proton in
In this work, we performed condensation of indole-
3-carbaldehydes 1–5 with ethyl nitroacetate,
nitroacetone, nitroacetophenone, and nitroacetonitrile
and obtained 3-(2-nitrovinyl)indoles 6–22 containing
an ester, acetyl, benzoyl, or cyano group in the geminal
position with respect to the nitro group (Scheme 1).
The reactions were carried out in anhydrous ethanol in
the presence of thionyl chloride or phosphoryl chloride
(7, 9–15; method a) or in the absence of a condensing
2
Crude nitroacetonitrile [44] was used.
3
Structurally related compounds used as models were considered
as indole-containing geminally substituted 1-nitroethenes.
4
The 1H and 13C–{1H} NMR, IR, and electronic absorption
spectra of cyano analog 19 were given in [45].
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SYNTHESIS AND STRUCTURE OF GEMINALLY ACTIVATED NITROETHENES
873
Table 3. Electronic absorptiona and IRb spectra of (E)-benzoyl(cyano)nitroethenes 13–18 and 20–24
H
NO2
β
α
X
R2
N
R1
13−18, 20−22
Comp.
no.
C=O
(CN) [NH]
X
R1
R2 λmax, nm ε, L mol–1 cm–1
NOO– (NO2)
C=C, C=N+
13
14
15
16
C(O)Ph
H
H
422
430
426
440
17300
17000
16400
18500
1277, 1228,
1220
1670
[3337 sh]
1606, 1580
1620, 1608
1620, 1608
1601, 1579
C(O)Ph
C(O)Ph
C(O)Ph
CH3
H
1288, 1244,
1229
1672
1672
1668
CH2Ph
CH3
H
1321, 1292,
1176
CH3
1286, 1260,
1229
17
18
20
21
22
C(O)Ph
CN
C(O)CH3
H
H
386
440
440
439
407
12800
30000
36200
39330
18840
1321, 1231,
1202
1724,
1676
1632, 1546
1593, 1575
1591, 1576
1593, 1580
1611, 1601
H
1278, 1262,
1238
(2219)
[3352 sh]
CN
CH2Ph
CH3
H
1297, 1274,
1167
(2219)
CN
CH3
H
1300, 1285,
1237
(2211)
CN
C(O)CH3
(1524, 1324)
(2227)
1728
23
24
–
–
CH2Ph
Н
Н
397
354
17900
19000
1310, 1265
1513, 1337
–
1625, 1500
1623
C(O)CH3
1723
a
The UV spectra of 13–17, 21–23 were recorded in acetonitrile, and of 18, 20, and 24, in ethanol; given are long-wavelength bands in the
region λ > 300 nm.
The IR spectra of 14–17, 23, and 24 were recorded in chloroform, and of 13, 18, and 20–22, in KBr.
b
model E-nitroethenes5; this suggests E configuration of
the exocyclic double bond in 13–18 and 20–22 (Table 1).
presumably due to anisotropic effect of the cyano
1
group [49]. The H–13C coupling constant between the
olefinic proton and carbon nucleus of CN group
(3JCH = 10.1–10.6 Hz) confirmed their trans orienta-
tion, in keeping with published data [39, 50].
The 13C–{1H} NMR spectra of 13–18 and 20–22
displayed signals of all carbon atoms present in their
molecules (Table 2). In the spectra of 13–17, the
carbon atom linked to the nitro and benzoyl groups
shifted downfield (δC 138.40–144.02 ppm) than that of
cyano analogs 18 and 20–22 (δC 111.00–115.92 ppm),
The E configuration of the exocyclic double bond
1
in 13–18 and 20–22 assigned on the basis of the H
NMR data is also consistent with the electronic
absorption spectra of these compounds (Table 3). In
fact, introduction of a benzoyl or cyano group into
indolylnitroethene molecules induces a red shift of the
long-wavelength absorption band.
5
The spectral parameters of model nitroethene 26 were given in
[46]. Model compounds 23–25 were synthesized as described in
[47, 48]; their spectral characteristics were measured in this
work.
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874
BAICHURIN et al.
predominated (Table 4). The presence of two isomers
Scheme 2.
N O
of 6–8 and 10–12 is also supported by their electronic
spectra which showed two absorption bands in the
long-wavelength region (Table 4).
O
NOO−
H
N
H
X
X
It should be noted that α-nitro-β-(indol-3-yl)
acrylates and their N-methyl analogs synthesized
previously were also isolated as equilibrium mixtures
of Z and E isomers [51]. Only the Z isomer of methyl
α-nitro-β-(1-acetyl-indol-3-yl)acrylate was isolated in
the pure state [52].
R2
R2
+
N
R1
R1
X = C(O)Ph, CN.
The 13C–{1H} NMR spectra of 6–8 and 10–12 are
given in Table 5. The carbonyl carbon nuclei resonated
in the region δC 159.32–195.31 ppm. As in the spectra
of benzoyl analogs 13–17 (Table 2), signals of Cα were
located downfield (δC 134.49–144.43 ppm) from the
signals of Cβ (δC 126.59–134.10 ppm).
The IR spectra of (E)-benzoyl(cyano)nitroethenes
13–18, 20, and 21 (Table 3) are similar to the spectra
of model (E)-nitroethenes. They lacked absorption
bands typical of a covalently bonded nitro group but
contained bands at 1546–1632 (C=C, C=N+) and 1167–
1321 cm–1 (NOO–). This spectral pattern suggests high
degree of polarization of molecules 13–18, 20, and 21
due to efficient p,π-conjugation involving electron pair
on the indole nitrogen atom, C=C bond, and nitro
group (Scheme 2). A similar spectral pattern was
observed previously for geminal cyanonitroethenes
containing a pyrrole, N-methylpyrrole, thiophene, or
furan ring [39, 41]. Unlike compounds 13–18, 20, and
21, the IR spectrum of N-acetylindole 22 showed
absorption bands typical of a covalently bonded nitro
group (1524, 1324 cm–1).
The IR spectra of Z/E isomer mixtures 6–8 and 10–
17 were fairly complex, but we were able to
distinguish therein absorption bands due to covalently
bonded nitro group of the Z isomers. Effective
conjugation between the lone electron pair on the
indole nitrogen atom, C=C bond, and carbonyl group
of the acetyl (ester) fragment of the Z isomer is likely
to induce reduction of the intensity of the carbonyl
stretching band in comparison to the C=C stretching
band (Scheme 3), whereas characteristics of the NO2
stretching bands remain almost unchanged.
1
According to the H NMR data, among geminal
The conformation with respect to the C3–Cβ bond
of some indolylnitroethenes was determined by
ethoxycarbonyl- and acetylnitroethenes, only
compound 9 was obtained as a single stereoisomer
1
analysis of the NOESY data. The H–1H NOESY
1
(Table 4). In the H NMR spectrum of 9, the olefinic
spectrum of 21 (DMSO-d6) showed cross-peaks
between β-H and 2-Me protons, indicating s-trans
conformation of the molecule. On the other hand, in
proton resonated at δ 7.75 ppm, i.e., shifted upfield
than the corresponding proton of model (E)-
nitrovinylindole 25 (δ 8.38 ppm in DMSO-d6).
Therefore, compound 9 was assigned Z configuration
1
the H–1H NOESY spectra of 20 and 22 (DMSO-d6)
1
we observed a correlation between β-H and 4-H, which
is possible for the s-cis conformation. A similar pattern
was typical of benzoylnitroethene 14 in CDCl3,
whereas its analog 16 was assigned s-trans configura-
tion in the same solvent (Scheme 4).
of the exocyclic double bond. The H NMR spectra of
the other compounds (6–8 and 10–12) displayed two
sets of signals. In particular, the olefinic proton signals
were located at δ 7.74–8.01 (Z isomer) and 8.22–
8.62 ppm (E isomer); in most cases, the Z isomer
Scheme 3.
Me
Me
O−
H
H
O
NO2
NO2
+
N
..
R2
N
R2
R1
R1
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SYNTHESIS AND STRUCTURE OF GEMINALLY ACTIVATED NITROETHENES
875
Table 4. 1H NMR and electronic absorption spectra of ethoxycarbonyl(acetyl)nitroethenes 6–12, 25, and 26a
H
NO2
H
H
NO2
X
β
α
β
α
R2
R2
N
N
R1
R1
6−12
25, 26
δ, ppm (J, Hz)
Z/E
ratio
X
R1
R2
R1
(NH)
OCH2Me
(Me)
α-H (β-H)
Harom
6
COOCH2Me PhCH2
COOCH2Me Me
H
~1.1:1
Z
7.96 s
8.49 s
5.27 s
5.31 s
4.37 q, 1.37 t 7.13–7.82 m 358b
(3J = 7.2)
5600
E
4.34 q, 1.30 t 7.06–7.94 m 411b
(3J = 7.2)
6400
7c
8
Me ~1:1.2
Z
E
7.90 s
8.43 s
3.70 s 4.369 q, 1.37 t
(3J = 7.2)
3.73 s 4.368 q, 1.23 t
344
429
7340
7.15–7.45 m
16280
(3J = 7.2)
COOCH2Me C(O)Me
H
~3.3:1
Z
E
7.74 s
8.22 d
2.60 s
2.64 s
4.36 q, 1.34 t 7.30–8.40 m 332
11470
(3J = 7.2)
4.39 q, 1.33 t 8.18–8.40 m 385 sh 5900
(4Jβ,2 = 0.7)
(3J = 7.2)
9
C(O)Me
C(O)Me
H
H
H
100:0
7.75 s
(12.37 s)
3.85 s
(2.52 s)
7.30–8.05 m 390
6300
10
Me
~5:1
Z
8.01 s
(2.50 s)
7.22–7.90 m 367
8.29 s
15500
E
Z
8.44 s
7.94 s
3.88 s
5.34 s
(2.49 s)
(2.48 s)
7.22–7.80 m 430
8200
11
C(O)Me
PhCH2
H
~1.6:1
7.10–7.85 m 366
7.93 s, 8.66 s 429
20000
E
Z
E
8.62 s
7.94 s
8.42 s
5.40 s
3.73 s
(2.55 s)
(2.46 s)
8300
11500
8300
12d C(O)Me
Me
H
Me ~2.9:1
360
7.08–7.37 m
440
3.73 s
(2.63 s)
–
25
–
–
H
0:100
8.38 d
(7.98 d)
(12.23)
7.22–8.22 m 400b 22300
3Jαβ = 13.4
26e
Me
Me
0:100
8.32 d
(7.75 d)
3.77 s
–
7.27–8.02 m 415
20200
3Jαβ = 13.1
a
b
c
d
e
The 1H NMR spectra of 6–8, 11, 12, and 26 were recorded in CDCl3, and of 9, 10, and 25, in DMSO-d6.
The UV spectrum was recorded in ethanol.
2-Me: δ 2.53 (Z), 2.55 ppm (E).
2-Me: δ 2.56 (Z), 2.54 ppm (E).
2-Me: δ 2.57 ppm.
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BAICHURIN et al.
Table 5. 13C NMR spectra of ethoxycarbonyl(acetyl)nitroethenes 6–8 and 10–12a
HA
NO2
X
β
α
R2
N
R1
6−8, 10−12
Comp.
no.
X
R1
R2
H
Isomer
Cα
Cβ
R1
X
6
7b
8
СООСН2СН3
СН2Ph
Z
E
134.49 126.59 51.22 (СН2) 14.31 (СН3), 62.44
(СН2), 60.46 (С=О)
135.42 130.77 51.22 (СН2) 13.99 (СН3), 62.58
(СН2), 162.81 (С=О)
СООСН2СН3
СООСН2СН3
CH3
CH3
H
Z
E
134.42 130.54 30.49 (СН3) 14.36 (СН3), 62.30
(СН2), 161.36 (С=О)
136.20 133.27 30.60 (СН3) 13.87 (СН3), 62.50
(СН2), 163.16 (С=О)
COCH3
Z
E
139.26 127.71 23.86 (СН3) 14.13 (СН3), 63.19
168.8 (С=О) (СН2), 159.32 (С=О)
140.65 128.73 23.90 (СН3) 13.92 (СН3), 63.22
168.8 (С=О) (СН2), 161.57 (С=О)
10
11
С(О)СН3
С(О)СН3
С(О)СН3
CH3
СН2Ph
CH3
H
H
Z
E
144.43 127.27
141.49 131.99
34.00
34.27
25.62 (СН3), 188.25
(С=О)
30.35 (СН3), 194.99
(С=О)
Z
E
143.42 127.07 51.50 (СН2) 26.11 (СН3), 188.55
(С=О)
142.30 133.02 56.65 (СН2) 30.41 (СН3), 194.41
(С=О)
12c
CH3
Z
E
142.66 130.99
141.70 134.10
29.94
29.94
26.45 (СН3), 189.19
(С=О)
30.68 (СН3), 195.31
(С=О)
The 13C–{1H} NMR spectra of 6–8, 11, and 12 were recorded in CDCl3, and of 10, in DMSO-d6. Carbon atoms of the benzene and indole
a
rings resonated in the region δC 105.38–148.51 ppm.
2-Me: δC 11.60 (Z), 11.67 ppm (E).
2-Me: δC 11.77 (Z), 12.13 ppm (E).
b
c
Both isomers of α-nitroacrylate 7 displayed in the
fragment was observed for the Z isomer of 10, which
corresponds to s-trans conformation of the enone
fragment (Scheme 6). Likewise, the Z isomer of 12 in
CDCl3 was assigned s-trans configuration of both
vinylindole and enone fragments.
1H–1H NOESY spectrum (CDCl3) cross-peaks between
β-H and 2-Me [δ 7.90/2.53 (Z) and 8.43/2.55 ppm (E)],
which suggests s-trans configuration of the vinylindole
fragment in both Z-7 and E-7 (Scheme 5).
1
The H–1H NOESY spectrum of 10 (DMSO-d6)
In summary, we have synthesized a series of indolyl-
substituted nitroethenes containing an acetyl, benzoyl,
ethoxycarbonyl, or cyano group geminal to the nitro
group by condensation of indole-3-carbaldehydes with
the corresponding CH acids. The proposed procedure
showed cross-peaks between β-H and 4-H of both
isomers, indicating s-cis conformation of the
vinylindole fragment therein. In addition, a cross-peak
between β-H and methyl protons of the acetyl
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS AND STRUCTURE OF GEMINALLY ACTIVATED NITROETHENES
877
University of Russia. The 1H, 13C–{1H}, 1H–13C
HMQC, and 1H–13C HMBC NMR spectra were
recorded on a Jeol JNM-ECX400A spectrometer at
399.78 (1H) and 100.53 MHz (13C) using CDCl3 or
DMSO-d6 as solvent; the chemical shifts were measured
relative to the residual proton and carbon signals of the
solvent. The IR spectra were recorded on a Shimadzu
IR Prestige-21 spectrometer with Fourier transform
from solutions in chloroform (c = 40 mg/mL) or KBr
pellets. The electronic absorption spectra were
measured in ethanol or acetonitrile on a Shimadzu UV
2401PC spectrophotometer using quartz cells with a
cell path length l of 1.01 mm. The elemental analyses
were obtained on a EuroVector EA 3000 CHN Dual
analyzer.
Scheme 4.
NOE
NOE
α NO2
α NO2
H
H
β
β
H
H
CN
H
CN
H
4
7
4
7
3
3
5
5
6
2
2
6
NOE
N
N
NOE
CH2
C⎯CH3
O
Ph
20
22
Scheme 5.
NO2
α
COOEt
α
EtOOC
Ethyl 3-(1-benzyl-1H-indol-3-yl)-2-nitroprop-2-
enoate (6). A mixture of 0.67 g (5 mmol) of ethyl
nitroacetate, 1.17 g (5 mmol) of 1-benzyl-1H-indole-3-
carbaldehyde (3), 0.19 g of β-alanine, and 0.8 mL of
glacial acetic acid in 20 mL of anhydrous benzene was
refluxed for 5 h in a flask equipped with a Dean–Stark
trap. After cooling, the mixture was washed with brine,
the organic phase was dried over calcined MgSO4, the
solvent was removed, and the residue was subjected to
chromatography on silica gel. Elution with benzene
gave 1.42 g (81%) of 6 as red–orange oil, Rf 0.53
(hexane–acetone, 3:1). Found, %: N 7.89. C20H18N2O4.
Calculated, %: N 8.00.
β
O2N
β
H
H
NOE
NOE
4
5
4
3
3
5
CH3
2
6
7
CH3
2
6
7
N
N
CH3
CH3
s-trans-Е-7
s-trans-Z-7
Scheme 6.
NOE
H3C
NOE
NOE
O
NO2
H
α NO2
H
β
α
H
β
H
Z
E
Ethyl 3-(1,2-dimethyl-1H-indol-3-yl)-2-nitroprop-
2-enoate (7). Thionyl chloride (2 drops) was added to
a suspension of 0.35 g (2 mmol) of 1,2-dimethyl-1H-
indole-3-carbaldehyde (4) and 0.25 mL (2 mmol) ethyl
nitroacetate in 2 mL of anhydrous ethanol. The
mixture was heated until it became homogeneous and
was left to stand for 24 h at room temperature. The
precipitate was filtered off and dried. Yield 0.42 g
(73%), yellow crystals, mp 107–108°C (from EtOH).
Found, %: N 9.85. C15H16N2O4. Calculated, %: N 9.72.
4
C(O)CH3
3
4
5
5
3
2
6
2
6
7
7
N
N
CH3
CH3
s-cis-E-10
s-cis-Z-10
is characterized by high efficiency and preparative
convenience. Analysis of spectral parameters of the
synthesized compounds showed that geminal benzoyl-
and cyanonitroethenes have E configuration of the
exocyclic double bond and that most acetyl and
ethoxycarbonyl analogs are mixtures of E and Z
isomers, the latter prevailing. The configuration of
some nitroethenes with respect to the C3–Cβ bond has
been determined on the basis of the 1H–1H NOESY data.
Ethyl 3-(1-acetyl-1H-indol-3-yl)-2-nitroprop-2-
enoate (8) was synthesized as described above for
compound 6 from 1-acetyl-1H-indole-3-carbaldehyde
(5) and ethyl nitroacetate; reaction time 2 h. The
solvent was evaporated to 1/3 of the initial volume,
and the yellow solid was filtered off and dried. Yield
55%, mp 137–138°C (from EtOH); published data
[20]: mp 140–141°C (from EtOH).
EXPERIMENTAL
Physicochemical studies were performed using the
equipment of the Center for Collective Use of the
Faculty of Chemistry of the Herzen State Pedagogical
4-(1H-Indol-3-yl)-3-nitrobut-3-en-2-one (9). A
mixture of 0.206 g (2 mmol) of nitroacetone, 0.29 g
(2 mmol) of 1H-indole-3-carbaldehyde (1), and
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878
BAICHURIN et al.
2 drops of phosphoryl chloride in 3 mL of anhydrous
ethanol was heated until it became homogeneous and
was left to stand for 24 h at room temperature. The
solution was poured onto crushed ice, and the
precipitate was filtered off and washed with ethanol on
a filter. Yield 0.3 g (65%), yellow crystals, mp 157–
158°C (from EtOH); published data [31]: mp 159–
160°C (from EtOH).
3-(1-Benzyl-1H-indol-3-yl)-2-nitro-1-phenylprop-
2-en-1-one (15). a. The procedure was analogous to
the synthesis of 14. Yield 76%, orange crystals, mp
116–118°C (from i-PrOH). Found, %: C 75.35; H 4.85;
N 7.25. C24H18N2O3. Calculated, %: C 75.39; H 4.71;
N 7.32.
b. A mixture of 0.82 g (5 mmol) of nitroaceto-
phenone, 1.17 g (5 mmol) of aldehyde 3, 0.19 g of
β-alanine, and 4 mL of glacial acetic acid in 40 mL of
anhydrous benzene was refluxed for 4 h in a flask
equipped with a Dean–Stark trap. After cooling, the
mixture was washed with water and dried over
calcined MgSO4, the solvent was removed, and the
precipitate was filtered off and dried. Yield 1.62 g
(85%), orange crystals, mp 124–126°C (from i-PrOH).
The product showed no depression of the melting point
on mixing with a sample prepared as described in a.
4-(1-Methyl-1H-indol-3-yl)-3-nitrobut-3-en-2-
one (10) was synthesized as described above for
compound 7 from 1-methyl-1H-indole-3-carbaldehyde
(2) and nitroacetone. After 24 h, the mixture was
poured onto crushed ice. Yield 93%, yellow crystals,
mp 154–155°C (from MeCN). Found, %: C 63.75; H
4.84; N 11.53. C13H12N2O3. Calculated, %: C 63.93; H
4.92; N 11.48.
4-(1-Benzyl-1H-indol-3-yl)-3-nitrobut-3-en-2-one
(11) was synthesized as described above for compound
10 from 1-benzyl-1H-indole-3-carbaldehyde (3) and
3-(1,2-Dimethyl-1H-indol-3-yl)-2-nitro-1-phenyl-
prop-2-en-1-one (16) was synthesized as described
above for compound 15 (b) from aldehyde 4 and nitro-
acetophenone; reaction time 4.5 h. Yield 58%, orange
crystals, mp 183–184°C (from PhH). Found, %: C
71.35; H 5.20; N 8.60. C19H16N2O3. Calculated, %: C
71.25; H 5.0; N 8.75.
nitroacetone. Yield 80%, orange crystals, mp 137–
.
138°C (from i-PrOH). Found, %: C 71.36; H 5.23; N
8.63. C19H16N2O3. Calculated, %: C 71.25; H 5.00; N 8.75.
4-(1,2-Dimethyl-1H-indol-3-yl)-3-nitrobut-3-en-2-
one (12) was synthesized as described above for
compound 10 from aldehyde 4 and nitroacetone. Yield
64%, yellow crystals, mp 170–171°C (from EtOH).
Found, %: C 64.96; H 5.57; N 10.70. C14H14N2O3.
Calculated, %: C 65.10; H 5.42; N 10.85.
3-(1-Acetyl-1H-indol-3-yl)-2-nitro-1-phenylprop-
2-en-1-one (17) was synthesized as described above
for compound 15 (b) from aldehyde 5 and nitro-
acetophenone; reaction time 2 h. Yield 73%, yellow
crystals, mp 142–143°C (from i-PrOH). Found, %: N
8.51. C19H14N2O3. Calculated, %: N 8.38.
3-(1H-Indol-3-yl)-2-nitro-1-phenylprop-2-en-1-
one (13). Phosphoryl chloride (2 drops) was added to a
mixture of 0.72 g (5 mmol) of aldehyde 1 and 0.82 g
(5 mmol) nitroacetophenone in 3 mL of anhydrous
ethanol. The mixture was heated until it became
homogeneous. After 24 h, the mixture was poured into
an ice–water mixture and extracted with diethyl ether.
The extract was dried over calcined Na2SO4, and the
solvent was removed. Yield 1.35 g (93%), mp 131–
132°C (from EtOH); published data [31]: mp 131–
132°C (from EtOH).
3-(1H-Indol-3-yl)-2-nitroprop-2-enenitrile (18).
A suspension of 1.45 g (10 mmol) of aldehyde 1 in
15 mL of anhydrous ethanol was added to 0.86 g
(10 mmol) of crude nitroacetonitrile. The mixture
turned dark, and an orange crystalline solid separated
on slight heating. The mixture was left to stand for
24 h at room temperature, and the precipitate was
filtered off and dried. Yield 1.86 g (87%), mp 219–
220°C (from MeNO2); published data [31]: mp 215°C
(from MeNO2).
3-(1-Methyl-1H-indol-3-yl)-2-nitro-1-phenylprop-
2-en-1-one (14). A mixture of 0.41 g (2.5 mmol) of
nitroacetophenone, 0.4 g (2.5 mmol) of aldehyde 2,
and 2 drops of thionyl chloride in 2 mL of anhydrous
ethanol was heated until it became homogeneous and
was left to stand for 24 h at room temperature. The
precipitate was filtered off and dried. Yield 0.62 g
(81%), orange crystals, mp 191–192°C (from MeCN).
Found, %: C 70.50; H 4.72; N 9.28. C18H14N2O3.
Calculated, %: C 70.59; H 4.58; N 9.15.
3-(1-Methyl-1H-indol-3-yl)-2-nitroprop-2-enenitrile
(19) was synthesized in a similar way from aldehyde 3
and nitroacetonitrile. Yield 66%, mp 190–191°C (from
MeNO2). Found, %: C 63.58; H 4.05; N 18.48.
C12H9N3O2. Calculated, %: C 63.44; H 3.96; N 18.50.
3-(1-Benzyl-1H-indol-3-yl)-2-nitroprop-2-enenitrile
(20) was synthesized in a similar way from aldehyde 3
and nitroacetonitrile; reaction time 3 h. Yield 51%, mp
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS AND STRUCTURE OF GEMINALLY ACTIVATED NITROETHENES
879
11. Mashkovskii, M.D., Lekarstvennye sredstva
213–214°C (MeNO2); published data [31]: mp 211°C
(from MeNO2).
(Medicines), Moscow: Novaya Volna, 2012, 16th ed.
12. Zhungietu, G.I., Budylin, V.A., and Kost, A.N.,
Preparativnaya khimiya indola (Preparative Indole
Chemistry), Kishinev: Shtiintsa, 1975
13. Baron, M., Metay, E., Lemaire, M., and Popowycz, F.,
J. Org. Chem., 2012, vol. 77, no. 7, p. 3598. doi
10.1021/jo2026096
3-(1,2-Dimethyl-1H-indol-3-yl)-2-nitroprop-2-
enenitrile (21) was synthesized in a similar way from
aldehyde 4 and nitroacetonitrile; reaction time 3 h.
Yield 78%, mp 191–192°C (from MeNO2). Found, %:
N 17.51. C13H11N3O2. Calculated, %: N 17.43.
14. Aksenov, A.V., Aksenov, N.A., Skomorokhov, A.A.,
Aksenova, I.V., Gryaznov, G.D., Voskressensky, L.G.,
and Rubin, M.A., Chem. Heterocycl. Compd., 2016,
vol. 52, no. 11, p 923. doi 10.1007/s10593-017-1988-x
15. Abdelwaly, A., Salama, I., Gomaa, M.S., and Helal, M.A.,
Med. Chem. Res., 2017, vol. 26, no. 12, p. 3173. doi
10.1007/s00044-017-2011-x
16. Wang, Y.-C., Wang, J.-L., Burgess, K.S., Zhang, J.-W.,
Zheng, Q.-M., Pu, Y.-D., Yan, L.-J., and Chen, X.-B.,
RSC Adv., 2018, vol. 8, no. 11, p. 5702. doi 10.1039/
c7ra13207g
3-(1-Acetyl-1H-indol-3-yl)-2-nitroprop-2-enenitrile
(22) was synthesized in a similar way from aldehyde 5
and nitroacetonitrile. Yield 78%, mp 201–202°C (from
MeNO2). Found, %: N 16.38. C13H9N3O3. Calculated,
%: N 16.47.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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