Reduction of 2-amino-1-(4-nitrophenyl)-1i/-pyrido[3,2-b]indole- 3-carbonitrile by sodium borohydride and sodium cyanoborohydride

Article abstract of DOI:10.1007/s11172-009-0068-5

The reduction of pyridoindole derivative 1 by sodium borohydride in methanol gives, 5-dihydropyridoindole 2. On treatment of 5i/-pyrido[3,2-b] indolium chloride 3 with sodium cyanoborohydride in methanol in the presence of hydrogen chloride, reduction of

Full text of DOI:10.1007/s11172-009-0068-5

Russian Chemical Bulletin, International Edition, Vol. 58, No. 3, pp. 634—639, March, 2009
634
Reduction of 2ꢀaminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ1Hꢀpyrido[3,2ꢀb]indoleꢀ
3ꢀcarbonitrile by sodium borohydride and sodium cyanoborohydride
S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik
State Scientific Center on Antibiotics,
3a Nagatinskaya ul., 117003 Moscow, Russian Federation.
Fax: +7 (499) 611 1548. Eꢀmail: syuryabova@yandex.ru
The reduction of pyridoindole derivative 1 by sodium borohydride in methanol gives
4,5ꢀdihydropyridoindole 2. On treatment of 5Hꢀpyrido[3,2ꢀb]indolium chloride 3 with sodium
cyanoborohydride in methanol in the presence of hydrogen chloride, reduction of the pyridine
ring is accompanied by reduction of the CN group, resulting in the formation of tetrahydroꢀ
pyridoindole 4. Compound 4 reacts with DMF dimethyl acetal to yield amidine 6, and refluxing
of 4 with acetic anhydride results in tetrahydropyridine ring cleavage yielding indolylacrylonitrile 9.
The hydrochloride and chloride of compounds 4 and 6 were obtained
Key words: dihydropyridoindole, tetrahydropyridoindole, reduction, amidine, acetylation,
indolylacrylonitrile.
Previously, we developed approaches to the synꢀ
pyrido[3,2ꢀb]indole series. However, no data on the
synthesis of 4,5ꢀdihydropyrido[3,2ꢀb]indoles by the
reduction of pyrido[3,2ꢀb]indoles have been reported.
Our work deals with the reduction of 1ꢀarylꢀδꢀcarboline
derivatives exemplified by the reduction of 2ꢀaminoꢀ
1ꢀ(4ꢀnitrophenyl)ꢀ1Hꢀpyrido[3,2ꢀb]indoleꢀ3ꢀcarbonitrile
(1a), which is a 2ꢀiminoꢀ2,5ꢀdihydropyrido[3,2ꢀb]indole
1b derivative in a tautomeric form (see Refs 1, 2, 7), with
sodium borohydride and sodium cyanoborohydride. These
reducing agents do not tend8,9 to reduce nitro and cyano
groups in the absence of catalysts, although some excepꢀ
tions still have been reported. Thus it was shown, for
thesis of diverse 1ꢀarylꢀsubstituted pyrido[3,2ꢀb]indoles
(δꢀcarbolines) from 3ꢀarylaminoindoles and studied some
properties of the obtained compounds, in particular, a
method was found for converting 2ꢀiminoꢀ2,5ꢀdihydroꢀ
pyridoindole to 2ꢀdimethylaminoꢀ4,5ꢀdihydropyridoꢀ
indole derivatives.1,2 Many indole derivatives are pharmaꢀ
ceutical agents used in medical practice,3,4 and 1,4ꢀdiꢀ
hydropyridine derivatives exhibit biological activities.5,6
Therefore, combination of these fragments in one molecule
may prove to be of interest as regards the search of comꢀ
pounds with new biological properties in the 4,5ꢀdihydroꢀ
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 617—622, March, 2009.
1066ꢀ5285/09/5803ꢀ0634 © 2009 Springer Science+Business Media, Inc.

1ꢀ(4ꢀNitrophenyl)ꢀ1Hꢀpyrido[3,2ꢀb]indol
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 3, March, 2009
635
Scheme 2
Previously we have shown that pyridoindole 1 is easily
protonated in concentrated hydrochloric acid being conꢀ
verted into chloride 3.12 Therefore, it is more expedient
to introduce the chloride 3 rather than the proper comꢀ
pound 1 into reduction by sodium cyanoborohydride in
methanol in the presence of hydrogen chloride. Under
these conditions, the reaction was shown to give the product
of more extensive reduction than in the previous case.
Chloride 3 is reduced at the N+(1)=C(2) bond. TLC
monitoring of the reaction mixture during reduction indiꢀ
cates that, first, the reaction gives dihydro derivative 2,
which exists apparently as hydrochloride 2•HCl in
the acid medium and occurs in equilibrium typical of
enamines with intermediate A protonated at the βꢀposiꢀ
tion of the enediamine fragment. The presence of the
protonated species in the equilibrium system of 2•HCl
and A facilitates electron transfer from the reducing agent
to the CN group, resulting in its irreversible reduction to
an aminomethyl group to afford 1ꢀ[2ꢀiminoꢀ1ꢀ(4ꢀnitroꢀ
phenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[3,2ꢀb]indolꢀ
3ꢀyl]methanamine (4), which was also isolated as hydroꢀ
chloride 5 (Scheme 2).
The fact that the CN group has been reduced can be
proven by the IR spectra of compounds 4 and 5, which do
not exhibit absorption bands at ~2200 cm–1. The ESI and
EI mass spectra of base 4 are not characteristic, as they
contain no molecular ion peaks, but the ESI mass specꢀ
trum of hydrochloride 5 has a peak [M + H – HCl]+,
which attests to addition of six hydrogen atoms to the
initial molecule 3, and this is fully consistent with the
NMR data (see the spectrum of hydrochloride 5). Note
that the lack of the signal of NH2 group in the spectrum of
4 is apparently due to the fact that basic aliphatic amines
are more prone for exchange with water present in the
solvent than aromatic amines, which are weaker bases.
Hydrochloride 5 is protonated at the amino group giving
example, that treatment of epoxides having two geminal
cyano groups in the ring with sodium borohydride results
in reduction of one cyano group to aminomethyl group.10
Sodium borohydride, which is used most often for the
reduction of C=N bonds, reduces the N(5)=C(5a) bond
in δꢀcarboline 1 (or the C(2)=NH bond in tautomer 1а)
to give intermediate A (or В). The subsequent proton
migration yields 2ꢀaminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ4,5ꢀdihydroꢀ
1Hꢀpyrido[3,2ꢀb]indoleꢀ3ꢀcarbonitrile (2) (Scheme 1).
The reduction was carried out in methanol using a twoꢀ
fold excess of sodium borohydride.
The structure of the reduction product as a 4,5ꢀdiꢀ
hydroꢀ1Hꢀpyrido[3,2ꢀb]indoleꢀ3ꢀcarbonitrile derivative 2
was confirmed by the IR spectrum (CN absorption band
at 2175 cm–1) and the 1H NMR spectrum, which exhibits,
in addition to aromatic proton signals, a signal of H2C(4)
(δ 3.85) and signals of the 2ꢀNH2 and N(5)H groups
(δ 5.24 and 10.87).
Compound 2 represents darkꢀcherry crystals readily
soluble in acetone and acetonitrile. During recrystallizaꢀ
tion of 2 from acetonitrile, impurities appeared, and a
mixture of the starting compound 1 with reduction prodꢀ
uct 2 (TLC) was isolated from the mother liquor. The IR
spectrum of this mixture exhibited absorption bands for
both the starting and final compounds.* Thus, it was
concluded that 4,5ꢀdihydropyridoindole 2 is unstable
being readily dehydrogenated to give aromatic tricyclic
product 1.
Compound 1 is actually a cyclic enediamine. It is
known that enamines are readily reduced by sodium
cyanoborohydride in acid medium11 to give iminium salts.
*IR spectrum (ν/cm–1) of compound 1: 3320, 2200, 1620, 1600,
1580. IR spectrum (ν/cm–1) of compound 2: 3466, 3443, 3385,
3366, 3292, 3194, 2175, 1620, 1600, 1580. IR spectrum (ν/cm–1
)
of a mixture of compounds 1 and 2: 3466, 3443, 3385, 3366,
3392, 3320, 3194, 2200, 2175, 1620, 1600, 1580.

636
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 3, March, 2009
Ryabova et al.
Scheme 3
rise to a signal of N+H3 in the spectrum, while the signals
of =NH and N(5)H are retained. This explanation was
subsequently confirmed by smooth reactions of comꢀ
pounds 4 and 5 with DMF dimethyl acetal to give amidine
6 and its hydrochloride 7 (Scheme 3).
Scheme 4
The reduction of 4,5ꢀdihydropyrido[3,2ꢀb]indole 2
under similar conditions followed by treatment with HCl
results in hydrochloride 5 whose physicochemical charꢀ
acteristics are identical to those for the compound
obtained from chloride 3.
We studied some properties of compounds 4 and 5, in
particular, the reaction with DMF dimethyl acetal and
acylation with acetic anhydride.
On heating with excess acetal in methanol, base 4 and
hydrochloride 5 are readily converted to Nꢀ{[2ꢀiminoꢀ
1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[3,2ꢀb]ꢀ
indolꢀ3ꢀyl]methylimino)methyl}ꢀNꢀmethylmethanamine
(6), which was also isolated as chloride 7. The structure of
compounds 6 and 7 was confirmed by 1H NMR data.
Base 4 and hydrochloride 5 are readily acetylated with
acetic anhydride at room temperature (Scheme 4), the
tetrahydropyridoindole structure being retained and acetylꢀ
aminomethyl derivative 8 being formed as the final product.
Heating of compounds 4 and 5 in acetic anhydride
affords a complex mixture of compounds. 2ꢀ(Diacetylꢀ
aminomethyl)ꢀ3ꢀ[3ꢀ(4ꢀnitrophenylamino)ꢀ1Hꢀindolꢀ
2ꢀyl]acrylonitrile (9) resulting from tetrahydropyridine
ring cleavage was the only product to be isolated from this
mixture (in a low yield) and characterized (see Scheme 4).
This structure of compound 9 is supported by the data
of IR spectrum, in which a CN absorption band appears
at 2225 cm–1 as compared with the spectra of initial comꢀ
pounds 4 and 5. The mass spectrum exhibits a molecular
Scheme 5

1ꢀ(4ꢀNitrophenyl)ꢀ1Hꢀpyrido[3,2ꢀb]indol
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 3, March, 2009
637
ZQꢀ2000 spectrometer; the sample was injected, bypassing the
chromatographic column. 1H NMR spectra were run on Bruker
ACꢀ300 and Bruker DRXꢀ500 spectrometers. The reactions
were monitored and the product purity was checked using
Merck 60 F254 plates and chloroform—methanol, 10 : 1, and
ethyl acetate—isopropyl alcohol—ammonia, 5 : 3 : 1, systems.
The yields, melting points, and data of elemental analysis, mass
spectra and IR spectra for the synthesized compounds are
summarized in Tables 1 and 2.
2ꢀAminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrido[3,2ꢀb]ꢀ
indoleꢀ3ꢀcarbonitrile (2). Sodium borohydride (0.19 g, 5 mmol)
(1 tablet) was added to a suspension of pyridoindole 1 (0.82 g,
2.5 mmol) in methanol (50 mL). Hydrogen evolution was
accompanied by the formation of a solution and then the
formation of a new precipitate. After NaBH4 has been completely
converted, the reaction mixture was stirred for an additional
30—40 min, and the precipitate was filtered off, washed
with methanol, water, and again methanol to give 0.62 g of
4,5ꢀdihydropyrido[3,2ꢀb]indole 2. 1H NMR (DMSOꢀd6), δ: 3.85
(s, 2 H, H2C(4)); 5.24 (br.s, 2 H, NH2); 5.91 (d, 1 H, H(9),
J = 8.4 Hz); 6.61 (t, 1 H, H(8), J = 8.4 Hz); 6.90 (t, 1 H, H(7),
J = 8.4 Hz); 7.22 (d, 1 H, H(6), J = 8.4 Hz); 7.70, 8.35 (A2В2,
4 H, C6H4NO2); 10.87 (s, 1 H, NH).
1ꢀ[2ꢀIminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyridoꢀ
[3,2ꢀb]indolꢀ3ꢀyl]methaneamine (4). Method A. NaBH3(CN)
(0.3 g, 5 mmol) was added to a suspension of 2ꢀaminoꢀ3ꢀcyanoꢀ
1ꢀ(4ꢀnitrophenyl)ꢀ5Hꢀpyrido[3,2ꢀb]indole chloride (3) (0.59 g,
1.6 mmol) in methanol (10 mL). Then ~2.8 mL of a saturated
(7%) solution of hydrogen chloride in ethyl acetate was added
dropwise with stirring over a period of 2 h. The reaction mixture
was stirred for 16 h at room temperature. The inorganic
precipitate was filtered off and washed with methanol. The
solvent was evaporated in vacuo, the residue was dissolved in
ion peak corresponding to its molecular weight. The strucꢀ
ture of compound 9 is also confirmed by the H NMR
1
spectrum. Additional evidence for the structure of comꢀ
pound 9 is the absence of highꢀfield signals from five
protons, which are present in the 1H NMR spectra of
tetrahydropyridoindole derivatives 4—8.
Cleavage of the tetrahydropyridine ring induced by
acetic anhydride is unusual. The isolated yield of product
9 is fairly low (19%), hence acetylation is accompanied
by a series of parallel reactions, and the mechanism of
formation of 9 is difficult to discuss without special invesꢀ
tigation. However, the presence of dehydrogenation step
of the same type as observed during recrystallization of
dihydro derivative 2 to give δꢀcarboline 1 (see above) in
the process scheme appears obvious.
Note that chromatographic analysis of the reaction mixꢀ
ture obtained on heating of compound 8 in acetic anhyꢀ
dride showed the presence of acrylonitrile derivative 9.
The possible ways of ring cleavage in the acetylation of
compounds 4 and 5 involving intermediate formation
of tricyclic compound 8, are shown in Scheme 5.
Acetylation may involve both the acetamide group
and the amidine NH group followed by migration of
the acetyl group. Certainly, other options also cannot be
ruled out.
Experimental
IR spectra were recorded on an FSMꢀ1201 instrument
in mineral oil. ESI mass spectra were recorded on a Waters
Table 1. Yields, melting points,a and elemental analysis datab for synthesized compounds
Comꢀ
pound
Yield
(%)
M.p./°С Molecular
Found
Calculated
Molecular formula
(%)
N
weight
С
H
Н2О
—
2
4
5
6
7
8
9
75
275—277
90—92
331
335
64.75
64.38
64.50
64.53
55.46
55.90
63.80
63.86
58.60
58.34
62.33
62.46
63.49
63.30
3.80
4.05
5.34
5.30
5.17
5.30
5.34
5.74
5.39
5.50
4.92
5.18
4.45
4.59
20.63
20.86
19.52
20.23
17.97
17.80
20.32
21.28
18.87
19.44
17.58
18.21
16.54
16.77
C18H13N5O2•0.25 H2O
с
83 (А)
93 (B)
70 (А)
84 (B)
86
—
С18Н17N5O2
190—195
111—113
178—190
140—142
193—194
371.8
390
4.62
3.80
—
С18Н18СlN5O2•Н2О
C21H22N6O2•0.25 H2O
C21H23ClN6O2•0.3 Н2О
C20H19N5O3•0.4 Н2О
C22H19N5O4
64
426.9
377
1.32
1.25
2.32
1.87
—
84 (А)
99 (B)
19 (А)
14 (B)
417
a
Compounds 4—8 are amorphous and resisted recrystallization. On melting, they liquify over a broad temperature
range.
b
The results of analysis were obtained for noncrystallized substances and include water.
c According to 1H NMR spectrum, the compound contains 0.15 mol of ethyl acetate, which was taken into account in
the analysis.

638
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 3, March, 2009
Ryabova et al.
Table 2. Data of mass and IR spectra for synthesized compounds
0.09 g of the same product. The total yield of hydrochloride 5
was 0.42 g. 1H NMR (DMSOꢀd6), δ: 3.12 (m, 4 H, H2C(4),
3
CH2N+H3), 3.75 (qt, 1 H, H(3), JH,H = 6.5 Hz); 6.68, 8.00
Comꢀ
pound
MS m/z
(Irel(%))
IR,
max/cm–1
(A2В2, 4 H, C6H4NO2); 6.99 (t, 1 H), 7.13 (m, 2 H), 7.42 (d, 1
H) (H(6)—H(9), Jо = 7.8 Hz); 8.52 (br.s, 3 H, N+H3); 8.91 (s, 1
H, =NH); 11.43 (br.s, 1 H, N(5)H).
ν
2
332 [M + H]+,
370 [M + K]+,
683 [2 M + H]+
—
3466 (NH, NH2),
2175 (CN)
Method B. The product was obtained from dihydropyridoꢀ
indole 2 (0.33 g, 1 mmol), NaBH3(CN) (0.12 g, (2 mmol), and
methanol (10 mL) as described for the synthesis of 4 by method
A (except that the reaction was carried out under argon). The
hydrochloride was isolated as in method A to give 0.3 g of hydroꢀ
chloride 5 identical to the compound obtained by method A.
Nꢀ{[2ꢀIminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
pyrido[3,2ꢀb]indolꢀ3ꢀyl]methyliminomethyl}ꢀNꢀmethyl
methanamine (6). A solution of tetrahydropyridoindole 4
(0.05 g, 0.15 mmol) and DMF dimethyl acetal (0.045 mL,
0.3 mmol) in methanol (1 mL) was stirred at reflux for 0.5 h.
The solvent was evaporated to dryness. The residue was trituꢀ
rated with water. The precipitate was filtered off, washed with
water, and dried in a vacuum dessicator over КOH to give 0.05 g
of amidine 6. 1H NMR (DMSOꢀd6+CCl4), δ: 2.72 (s, 6 H,
N(CH3)2); 3.00—3.30 (m, 5 H, H2C(4), CH2NH2, H(3)); 6.62,
7.96 (A2В2, 4 H, C6H4NO2); 6.96 (t, 1 H), 7.12 (m, 2 H), 7.37
(d, 1 H) (H(6)—H(9), Jо = 7.8 Hz); 7.34 (s, 1 H, N=CH); 8.68
(s, 1 H, =NH); 11.21 (br.s, 1 H, N(5)H).
Nꢀ{[2ꢀIminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
pyrido[3,2ꢀb]indolꢀ3ꢀyl]methyliminomethyl}ꢀN,Nꢀdimethyl
methanammonium chloride (7). A solution of hydrochloride 5
(0.37 g, 1 mmol) and DMF dimethyl acetal (0.3 mL, 2 mmol) in
methanol (6 mL) was stirred at reflux for 0.5 h. The solvent was
evaporated to dryness. The oily residue was triturated with 5 mL
of water with addition of 1 drop of concentrated ammonia
(рH 8). Amidine 6 was filtered off, washed with water, dissolved
in ethyl acetate, and dried with K2CO3. The solution was filꢀ
tered and acidified with a 7% solution of HCl in ethyl acetate.
The precipitate was filtered off, washed with ethyl acetate,
and dried in air to give 0.27 g of compound 7. For analysis,
compound 7 was purified in the following way: the compound
was dissolved in acetone, the solution was clarified by activated
carbon and concentrated, the residue was triturated with
ethyl acetate, and the precipitate was filtered off. 1H NMR
(DMSOꢀd6), δ: 3.00, 3.13 (both s, 3 H each, N(CH3)2); 3.08
(m, 2 H, H2C(4)), 3.63 (t, 2 H, CH2NH2), 3.85 (qt, 1 H, H(3))
(3JH,H = 6.0—6.5 Hz); 6.70, 7.94 (A2В2, 4 H, C6H4NO2); 6.94
(т, 1 H), 7.10 (m, 2 H); 7.39 (d, 1 H) (H(6)—H(9), Jо = 7.8 Hz);
8.38 (d, 1 H, NH—CH, JNHCH = 12.9 Hz); 8.93 (s, 1 H, =NH);
10.03 (m, 1 H, NH—CH); 11.47 (br.s, 1 H, N(5)H).
4
5
3350, (NH),
1633 (C=N)
3360 (NH, NH2),
1600 (C=N)
336 [M + H – HCl]+,
358 [M – HCl + Na]+,
374 [M – HCl + K]+,
671 [2 M – 2 HCl + H]+,
693 [2 M – 2 HCl + Na]+
391 [M + H – HCl]+,
781 [2 M + H – 2 HCl]+
391 [M + H – HCl]+,
781 [2M + H – 2 HCl]+
378 [M + H]+,
6
7
8
3352 (NH),
1647, 1597 (C=N)
3176 (NH),
1707, 1599 (C=N)
3346 (NH),
1662 (CO)
400 [M + H + Na]+,
416 [M + H + K]+,
777 [2 M + Na]+,
793 [2 M + K]+
9
440 [M + Na]+,
3379, 3304 (NH),
2210 (CN),
1712, 1689 (CO)
456 [M + К]+,
857 [2 M + Na]+
water (~30 mL) and alkalified with a concentrated ammonia
solution (~0.5 mL). The precipitate was filtered off, washed
with water, squeezed out on the filter, and dissolved in ethyl
acetate. The solution was dried with Na2SO4, clarified by
activated carbon, and concentrated to dryness. The residue was
dried in a vacuum desiccator over P2O5 to give 0.45 g of
1
tetrahydropyridoindole 4. H NMR (DMSOꢀd6+CCl4), δ: 2.76
(m, 2 H, H2C(4)), 2.99 (d, 2 H, CH2NH2), 3.12 (qt, 1 H, H(3))
(3JH,H = 6.5—7.5 Hz); 6.63, 7.96 (A2В2, 4 H, C6H4NO2); 6.96
(t, 1 H), 7.12 (m, 2 H), 7.37 (d, 1 H) (H(6)—H(9), Jо = 7.8 Hz);
8.68 (s, 1 H, =NH); 11.18 (br.s, 1 H, N(5)H).
Method B. A solution of hydrochloride 5 (0.19 g, 0.5 mmol)
(see below) in water (20 mL) was alkalified by two drops of
concentrated ammonia. The precipitate was filtered off, washed
with water, and dried in a vacuum dessicator over КOH to give
0.16 g of base 4. The melting point of a mixed sample with the
compound obtained by method A was undepressed.
1ꢀ[2ꢀIminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyridoꢀ
[3,2ꢀb]indolꢀ3ꢀyl]methanamine hydrochloride (5). Method A. The
product was obtained from chloride 3 (0.59 g, 1.6 mmol) as
described for the synthesis of 4 by method A. Drying and
clarification of the ethyl acetate solution was followed (without
isolation of compound 4) by acidification with a 7% solution
of hydrogen chloride in ethyl acetate (~1 mL) and stirring for
2—2.5 h at 20 °C. The precipitate was filtered off, washed with
ethyl acetate, and dried in air* to give 0.33 g of hydrochloride 5.
The mother liquor was concentrated to dryness. The oily
precipitate was triturated with ethyl acetate. The precipitate was
filtered off and washed with ethyl acetate to give additionally
Nꢀ{[2ꢀIminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
pyrido[3,2ꢀb]indolꢀ3ꢀyl]methyl}acetamide (8). Method A.
A solution of pyridoindole 4 (0.34 g, 1 mmol) in acetic anhyꢀ
dride (2.5 mL) was allowed to stand for 20 h at 20 °C. Acetic
anhydride was evaporated to dryness, and the residue was trituꢀ
rated with water. The precipitate was filtered off, washed
with water, and dried in air to give 0.32 g of compound 8. For
analysis, the compound was purified by column chromatograꢀ
phy (SiO2, elution with chloroform, chloroform—methanol,
10 : 0.25; chloroform, chloroform—methanol, 10 : 1). 1H NMR
(DMSOꢀd6+CCl4), δ: 1.85 (s, 3 H, COCH3); 2.97 (d, 2 H,
H2C(4)), 3.29 (t, 2 H, CH2NH2), 3.39 (qt, 1 H, H(3))
(3JH,H = 6.0—7.5 Hz); 6.64, 7.94 (A2В2, 4 H, C6H4NO2); 6.95
(t, 1 H), 7.09 (t, 1 H), 7.14 (d, 1 H), 7.36 (d, 1 H) (H(6)—H(9),
* If the hydrochloride does not precipitate, the solvent is evapoꢀ
rated in vacuo, the residue is triturated with ethyl acetate with
heating, and the precipitate is filtered off.

1ꢀ(4ꢀNitrophenyl)ꢀ1Hꢀpyrido[3,2ꢀb]indol
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 3, March, 2009
639
Jо = 7.8 Hz); 8.29 (t, 1 H, NH, JNH,CH = 6.4 Hz); 8.62 (s, 1 H,
=NH); 11.19 (br.s, 1 H, N(5)H).
References
2
Method B. Acetic anhydride (0.2 mL) was added to a
suspension of hydrochloride 5 (0.05 g, 0.14 mmol) in benzene
(1 mL), and the mixture was stirred at reflux for 4 h. The product
was isolated as in method A to give 0.05 g of acetamide 8.
2ꢀ(Diacetylaminomethyl)ꢀ3ꢀ{3ꢀ[(4ꢀnitrophenyl)amino]ꢀ1Hꢀ
indolꢀ2ꢀyl}acrylonitrile (9). Method A. A solution of 3ꢀaminoꢀ
methyltetrahydropyridoindole 4 (0.35 g, 1 mmol) in acetic
anhydride (5 mL) was refluxed for 6 h and kept at 20 °C for 16 h.
Acetic anhydride was distilled off in vacuo and the residue was
triturated with water. The precipitate was filtered off, washed
with water, and dissolved in ethyl acetate, and the solution was
clarified by activated carbon, and dried with Na2SO4. The solvent
was evaporated in vacuo to dryness. The residue (0.35 g) was
triturated with methanol (5 mL), and the suspension was heated
to reflux. The red precipitate was filtered hot and washed with
methanol and ether to give 0.06 g (14.5%) of compound 9.
Column chromatography of the mother liquor (SiO2, elution
with chloroform, chloroform—methanol, 100 : 1) gave addiꢀ
tionally 0.02 g of the same compound. The overall yield of
compound 9 was 0.08 g. For analysis, product 9 was recrystallized
from DMF. 1H NMR (DMSOꢀd6+CCl4), δ: 2.36 (s, 6 H, (COCH3)2);
4.68 (s, 2 H, CH2); 6.71, 8.02 (A2В2, 4 H, C6H4NO2); 7.05 (t,
1 H), 7.26 (m, 2 H), 7.59 (d, 1 H) (H(6)—H(9), Jо = 7.8 Hz);
7.21 (s, 1 H, CH=C(CN)); 9.05 (br.s, 1 H, NHC6H4NO2);
11.00 (br.s, 1 H, N(5)H).
1. S. Yu. Ryabova, L. M. Alekseeva, V. G. Granik, Mendeleev
Commun., 1995, № 3, 107.
2. S. Yu. Ryabova, L. M. Alekseeva, V. G. Granik, Khim.ꢀ
Farm. Zhurn., 1996, 30, No. 9, 29 [Pharm. Chem. J. (Engl.
Transl.), 1996, 579].
3. M. D. Mashkovskii, Lekarstvennye sredstva [Medicinal
Agents], issue 13, Torgsin, Kharґkov, 1997 (in Russian).
4. V. G. Granik, Lekarstva. Farmakologicheskii, biokhimicheskii
i khimicheskii aspekty [Drugs. Pharmocological, Biochemical,
and Chemical Aspects], Vuzovskaya kniga, Moscow, 2001,
406 pp. (in Russian).
5. A. Sausins, G. Duburs, Heterocycles, 1988, 27, 269.
6. A. Sausins, G. Duburs, Khim. Geterotsikl. Soedinen., 28,
1992, 435 [Chem. Heterocycl. Compd. (Engl. Transl.), 1992].
7. S. Yu. Ryabova, L. M. Alekseeva, V. G. Granik, Khimiya
Geterotsikl. Soedinen., 2001, 1086 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2001, 37].
8. H. C. Brown, S. Krishnamurthy, Tetrahedron, 1979, 35, 567.
9. C. F. Lane, Synthesis, 1975, 135.
10. J. Mauger, A. Robert, J. Chem. Soc., Chem. Commun., 1986,
395.
11. L. Fieser, M. Fieser, Reagents for Organic Synthesis, Wiley,
New York, 1979, 7, 377.
12. S. Yu. Ryabova, L. M. Alekseeva, V. G. Granik, Khimiya
Geterotsikl. Soedinen., 2000, 362 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2000, 36, 301].
Method B. A solution of chloride 5 (0.19 g, 0.5 mmol) in
acetic anhydride (2 mL) was refluxed for 6 h and kept at 20 °C
for 16 h. The reaction mixture was poured in water (20 mL) and
washed for 2 h at 20 °C. The precipitate was filtered off, washed
with water, and dissolved in ethyl acetate, and the solution was
clarified by activated carbon and dried with Na2SO4. The solvent
was evaporated in vacuo to dryness. The residue was dissolved in
chloroform and purified by column chromatography as described
above to give 0.03 g of compound 9.
Received September 3, 2008;
in revised form November 12, 2008