2-Dicyanomethylidene-3-ethoxymethylidene-2,3-dihydroindole in the synthesis of fused tri-and tetracyclic systems

Article abstract of DOI:10.1007/s11172-010-0059-6

The reactions of 2-dicyanomethylidene-3-ethoxymethylidene-2,3-dihydroindole with hydrazine hydrate and phenylhydrazine afforded 2,3-diamino-4- cyanopyrido[4,3-b]indole and 3-amino-2-anilino-4-cyanopyrido[4,3-b]indole, respectively, and the reactions of th

Full text of DOI:10.1007/s11172-010-0059-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 177—185, January, 2010
177
2ꢀDicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroindole
in the synthesis of fused triꢀ and tetracyclic systems
O. B. Smirnova,a T. V. Golovko,a L. M. Alekseeva,a V. V. Chernyshev,b and V. G. Granika
aState Scientific Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Eꢀmail: vggranik@mail, smirolia@mail.ru
bDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3654. Eꢀmail: Vladimir@struct.chem.msu.ru
The reactions of 2ꢀdicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroindole with hyꢀ
drazine hydrate and phenylhydrazine afforded 2,3ꢀdiaminoꢀ4ꢀcyanopyrido[4,3ꢀb]indole and
3ꢀaminoꢀ2ꢀanilinoꢀ4ꢀcyanopyrido[4,3ꢀb]indole, respectively, and the reactions of the latter
compounds with dimethylformamide diethyl acetal were studied. The reactions of 2,3ꢀdiamiꢀ
noꢀ4ꢀcyanopyrido[4,3ꢀb]indole with benzaldehyde, ethyl acetoacetate, and acetylacetone were
investigated. First representatives of new heterocyclic systems, viz., [1,2,4]triazolo[1´,5´:1,6]ꢀ
pyrido[4,3ꢀb]indole and pyrazolo[1´,5´:1,2]pyrido[4,3ꢀb]indole, were synthesized. The strucꢀ
ture of ethyl 6ꢀcyanoꢀ5ꢀ[(E)ꢀ(dimethylamino)methylideneamino]ꢀ2ꢀmethylꢀ7Hꢀpyrazoloꢀ
[1´,5´:1,2]pyrido[4,3ꢀb]indoleꢀ1ꢀcarboxylate was established by Xꢀray diffraction.
Key words: hydrazine hydrate, phenylhydrazine, pyrido[4,3ꢀb]indoles (γꢀcarbolines), dimꢀ
ethylformamide diethyl acetal, amidines, heterocyclization, ethyl acetoacetate, benzaldehyde,
acetylacetone, [1,2,4]triazolo[1´,5´:1,6]pyrido[4,3ꢀb]indole, alkylation, pyrazolo[1´,5´:1,2]ꢀ
pyrido[4,3ꢀb]indole, Xꢀray diffraction study.
Compounds containing the pyrido[4,3ꢀb]indole fragꢀ
ment have a broad spectrum of biological activities. Comꢀ
pounds of this class, for example, the neuroleptic agent
Carbidinum (or Stobadine), the antihistaminic agents
Dimebonum and Diazolinum (or Omeril), and the gasꢀ
troenterological agent Alosetron (or Lotronex),1,2 have
found use as drugs. Substituted γꢀcarboline 1 is a selective
5HT3 serotonin receptor inhibitor.3
In this series of compounds, there are not only pharꢀ
macologically active compounds, but also chemotheraꢀ
peutic agents. Thus the natural alkaloid isocryptolepine
possesses strong antibacterial, antimalarial, and antituꢀ
mor activities, which has provoked considerable interest
in the synthesis of its analogs.4—12
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 174—181, January, 2010.
1066ꢀ5285/10/5901ꢀ0177 © 2010 Springer Science+Business Media, Inc.

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Smirnova et al.
1ꢀAminoꢀsubstituted pyrido[4,3ꢀb]indoles 2 were shown
spectra provide evidence that the reaction products have
structures 7a,b rather than the isomeric structures 6a,b.
For compound 7a, its monohydrochloride 8 was obtained.
The 1H NMR spectrum of compound 8 shows signals for
two NH2 groups (δ 6.91 (N(3)H2) and 8.54 (N(2)H2),
both br.s, 2 H each) along with a broadened signal for the
indole proton at δ 12.84.
to possess antitumor activity.13 A series of substituted
annulated γꢀcarboline derivatives 3 and 4 was syntheꢀ
sized.14,15 Many of the latter compounds exhibit citotoxꢀ
icity and possess antitumor activity. Compound 3 with
R1 = H, R2 = CH2CH2CH2N(CH3)2, and R3 = OH known
as Intoplicine is an antitumor agent and a topoisomerase
inhibitor.
Scheme 1
Thus, γꢀcarbolines are promising subjects for investiꢀ
gation of their biological activity. Hence, the synthesis of
various derivatives of this series is topical and expedient.
Previously,16 we have synthesized 2ꢀdicyanomethꢀ
ylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroindole (5) manꢀ
ifesting high reactivity toward nucleophilic agents.17
With the aim of synthesizing new γꢀcarboline deriꢀ
vatives and investigating their chemical and biological
properties, in the present study we examined the reacꢀ
tions of compound 5 with hydrazine hydrate and phenylꢀ
hydrazine.
R = H (a), Ph (b)
Reagents and conditions: for 7a: NH2NH2•H2O, PriOH;
for 7b: NH2NHPh, PriOH, Δ.
It was found that the reaction of compound 5 with
hydrazines does not stop at the step of formation of bicyꢀ
clic derivatives 6a,b and leads to the pyridine ring closure
giving rise to substituted γꢀcarbolines 7a,b (Scheme 1), as
was observed in the reactions of compound 1 with some
amines.17 Thus the reaction of compound 5 with hydrꢀ
azine hydrate (pKa = 8.07) in isopropyl alcohol proceeds
even at room temperature to give 2,3ꢀdiaminoꢀ4ꢀcyanoꢀ
pyrido[4,3ꢀb]indole (7a) in virtually quantitative yield
(98%) in 1 h. The reaction of compound 5 with much less
basic phenylhydrazine (pKa = 5.21) in isopropyl alcohol
does not proceed at room temperature, and 3ꢀaminoꢀ2ꢀ
anilinoꢀ4ꢀcyanopyrido[4,3ꢀb]indole (7b) could be obtained
only upon refluxing. The 1H NMR spectra of compounds
7a and 7b show signals for aromatic protons and protons
in position 1 along with signals for two NH2 groups (δ 6.36
(s) and 7.26 (br.s), 2 H each) for compound 7a or signals
for NH (δ 9.52 (br.s, 1 H)) and signals for NH2 groups
(δ 7.50 (br.s, 2 H)) for compound 7b. Thus, the 1H NMR
It should be noted that the protonation of compound
7a occurs at one nitrogen atom in position 2. This is atꢀ
tributed to the formation of the energetically favorable
aromatic cation of salt 8.
Due to the presence of two amino groups in the adjaꢀ
cent positions (2 and 3), diamines 7a,b have considerable
promise in the synthesis of tetracyclic systems containing
the pyrido[4,3ꢀb]indole fragment. The synthesis of polyꢀ
heterocycles having a planar structure and containing
a basic center are of particular interest, because compounds
of this class can act as intercalators2 and, after cerꢀ
tain modifications, can exhibit antiviral and (or) antituꢀ
mor activity.
Amide acetals are widely used in the synthesis of variꢀ
ous heterocyclic compounds.18 In this connection, we
studied the reactions of diamines 7a,b with dimethylforꢀ
mamide diethyl acetal (9). Refluxing of 7a in dry toluene
with an excess of acetal 9 results in the triazole ring cloꢀ
sure giving rise to compound 10a. The latter is a represenꢀ

Fused triꢀ and tetracyclic systems
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
179
tative of a new heterocyclic system, viz., [1,2,4]triazoloꢀ
[1´,5´:1,6]pyrido[4,3ꢀb]indole, which can exist in three
tautomeric forms (A, B, and C) (Scheme 2).
To elucidate the scheme of formation of tetracyꢀ
clic compound 10a, we made an attempt to prepare inꢀ
termediates. However, no reaction occurred even upon
prolonged storage (5 days) of diamine 7a in an excess
of acetal 9 in the presence of a catalytic amount of pyrꢀ
rolidine (TLC data), and product 10a formed only upon
heating.
The reaction of compound 7b with an excess of acetal
9 in dry toluene gave amidine 11, whereas the triazole ring
closure (as in the case of diamine 7a) did not occur.
The storage of compound 11 in saturated methanolic
ammonia at room temperature resulted in transamination
giving rise to compound 12 rather than in the cyclization
to tetracyclic compound 13. The IR spectrum of the reacꢀ
tion product contains an absorption band at 2218 cm–1
(C≡N group) and a broad band at 3250 cm–1 (NH2 group).
The 1H NMR spectrum contains a signal for the proton of
the N=CH group at δ 8.73 (t, 1 H).
The reaction of diamine 7a with ethyl acetoacetate
under reflux in propanꢀ2ꢀol proceeds differently and very
unexpectedly. Thus we isolated compound 14, which is
the first representative of a new heterocyclic system, viz.,
pyrazolo[1´,5´:1,2]pyrido[4,3ꢀb]indole (Scheme 3). The
IR spectrum of compound 14 shows absorption bands of
C=O (1683 cm–1) and CN (2212 cm–1) groups and inꢀ
tense absorption bands at 3295 and 3414 cm–1 assigned to
NH2 and NH vibrations, respectively. The 1H NMR specꢀ
trum of compound 14: δ 1.38 (t, 3 H, COCH2CH3, J =
= 7.5 Hz); 2.58 (s, 3 H, CH3); 4.42 (q, 2 H, COCH2CH3,
J = 7.5 Hz); 7.12 and 7.21 (both t, 1 H each), 7.49 and
7.89 (both d, 1 H each) (H(8)—H(11)); 7.79 (s, 2 H,
NH2); 12.02 (br.s, 1 H, NH). Apparently, the condensaꢀ
tion of ethyl acetoacetate involves the amino group in the
pyridine ring in position 2 to form the imino intermediate
A. The latter is transformed into aminocrotonate B, which
is typical of the reactions of ethyl acetoacetate with amines.
Aminocrotonate B undergoes cyclization to the dihydroꢀ
pyrazole derivative D, which is oxidized into energetically
favorable aromatic tetracyclic compound 14 under the reꢀ
action conditions (see Scheme 3).
Then we studied the condensation of diamine 7a with
carbonyl compounds, such as benzaldehyde, ethyl aceꢀ
toacetate, and acetylacetone.
Refluxing of diamine 7a with benzaldehyde in dry tolꢀ
uene in the presence of a catalytic amount of pꢀtolueneꢀ
sulfonic acid monohydrate afforded triazolopyridoindole
10b in good yield (73%).
To confirm the presence of the primary amino group
in position 5, we performed the reaction of compound 14
with acetal 9 giving rise to the corresponding amidine 15.
We obtained crystals of compound 15, and the strucꢀ
ture of this compound was established by Xꢀray diffraction
(Fig. 1). All geometric parameters of molecule 15 have
Scheme 2
Reagents and conditions: i. for 10a and 11: (EtO)2CHNMe2 (9), toluene, Δ; ii. for 10b: PhCHO, pꢀtoluenesulfonic acid•H2O, toluene, Δ;
iii. for 10c: AcCH2Ac, PriOH, Δ or AcOH, Δ.

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Smirnova et al.
Scheme 3
values similar to the corresponding parameters found in
the Cambridge Structural Database.19 In the crystals, the
cyano and amino groups are involved in intermolecular
hydrogen bonds (Table 1), through which the molecules
are linked into centrosymmetric dimers.
In connection with the unexpected formation of tetraꢀ
cyclic compound 14 in the reaction of 7a with ethyl aceꢀ
toacetate, we studied the analogous reaction with another
dicarbonyl compound, viz., acetylacetone. The reaction
of compound 7a with acetylacetone in dry toluene affordꢀ
ed a mixture of two compounds (TLC data), but only
product 10c was isolated in the individual state (recrystalliꢀ
zation of the reaction mixture from 67% aqueous DMF) (see
Scheme 2). However, the mass spectrum of the crude prodꢀ
uct contains molecular ion peaks of the major compound
(248 [247 + H]+, 270 [247 + Na]+, 495 [2×247 + H]+)
along with a molecular ion peak at 304 [303 + H]+, which
can be assigned to product 16 that is formed analogously
1
to compound 14 (Scheme 4). The H NMR spectrum of
Scheme 4
C(11)
C(10)
C(9)
C(12)
i. AcCH2Ac, toluene.
N(8)
C(7)
N(24)
C(21)
C(13)
Table 1. Geometric parameters of the hydrogen
bonds in the structure of 15
C(14)
C(15)
C(6)
C(5)
Parameter
Bond
Value
O(23)
C(16)
N(17)
C(26)
d/Å
N(4)
C(22)
C(28)
N(8)—H(8)
H(8)...N(24)
N(8)...N(24)
0.86
2.10
2.938(5)
C(20)
C(1)
N(3)
N(19)
O(18)
C(25)
C(2)
C(27)
C(29)
Angle
ω/deg
N(8)—H(8)...N(24)
166
Fig. 1. Molecular structure of 15. Nonhydrogen atoms are repꢀ
resented by displacement ellipsoids at the 50% probability level.
Note. Symmetry code: N(8)—H(8)...N(24),
1 – x, 2 – y, 1 – z.

Fused triꢀ and tetracyclic systems
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
181
Scheme 5
the crude product shows signals for protons of compound
10c along with signals that can be assigned to protons of
compound 16: 2.60 and 2.62 (both s, 1 H each, 2 Me);
7.12—7.27 (m, 4 H, H(6)—H(9); 7.82 (s, 2 H, NH2);
12.04 (br.s, 1 H, NH).
group (δ 6.33), the NOEDIFF spectrum contains signals
for the protons of the phenyl group (δ 7.74, 8.18, both d,
2 H each) and a doublet for the proton in position 9
(δ 7.74, d, 1 H).
1
It should be noted that the H NMR spectra of comꢀ
Compound 10c was prepared also under other conꢀ
ditions, viz., by refluxing compound 7a in acetic acid.
Samples of compound 10c isolated in different experiꢀ
ments are identical in the spectroscopic and physical data.
It can be suggested that in this case the reactions of 7a
with benzaldehyde and acetic acid proceed according to
Scheme 5.
The alkylation of compounds 10a—c with phenacyl
bromide in dry DMF in an argon atmosphere in the presꢀ
ence of sodium hydride affords the corresponding derivaꢀ
tives 17a—c in good yields (Scheme 6). The structures of
the resulting Nꢀsubstituted tetracyclic compounds were
confirmed based on the NOEDIFF spectrum of compound
17a. After the saturation of the signal for the methylene
pounds 10a—c and 17a—c contain signals for the protons
H(5) at δ 10.01—10.24. Such a substantial downfield shift
of these signals is apparently attributed to the strong elecꢀ
tronꢀwithdrawing effect of the annulated triazole ring.
Attempts to prepare fused γꢀcarboline 18 by the Thorꢀ
pe—Ziegler cyclization of compound 17a failed (Scheme 7).
After the prolonged reflux of compound 17a with potassiꢀ
um tertꢀbutoxide in tertꢀbutanol, with sodium ethoxide in
anhydrous ethanol, and with potassium tertꢀbutoxide in
pyridine, only the starting compound was isolated (in 45,
67, and 85% yields, respectively). Apparently, the Thorꢀ
Scheme 7
Scheme 6
Reagents and conditions: ButOH, ButOK, refluxing; EtOH,
EtONa, refluxing; ButOK, pyridine.
R = H (a), R = Ph (b), R = Me (c)

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Smirnova et al.
was refluxed for 2 h 30 min, and an additional portion of the
acetal (1.03 mL, 0.89 g, 6 mmol) was added. Then the reaction
mixture was refluxed for 2 h and cooled to 0 °C. The precipitate
was filtered off, washed with propanꢀ2ꢀol and diethyl ether,
and dried. Compound 10a was obtained in a yield of 2.36 g.
1H NMR, δ: 7.31 (t, 1 H), 7.51 (m, 2 H), 8.24 (d, 1 H) (H(6)—H(9),
J0 = 7.5 Hz); 8.46 (s, 1 H, H(2)); 10.14 (s, 1 H, H(5)); 12.52
(br.s, 1 H, NH).
pe—Ziegler cyclization of these γꢀcarbolines is hindered
due to the formation of tetracyclic system 18 containing
two fused fiveꢀmembered rings. An unsuccessful attempt
to perform cyclization under analogous conditions has
been described previously17,20 for the fiveꢀmembered ring.
To sum up, we performed a series of transformations
of 2ꢀdicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihyꢀ
droindole and synthesized pyrido[4,3ꢀb]indole derivatives
and the first representatives of new fused tetracyclic sysꢀ
tems, viz., [1,2,4]triazolo[1´,5´:1,6]pyrido[4,3ꢀb]indole
and pyrazolo[1´,5´:1,2]pyrido[4,3ꢀb]indole.
10Hꢀ (10bA), 3Hꢀ (10bB), or 1Hꢀ2ꢀphenylꢀ11ꢀcyano[1,2,4]ꢀ
triazolo[1´,5´:1,6]pyrido[4,3ꢀb]indole (10bC). A mixture of comꢀ
pound 7a (0.68 g, 3.05 mmol), benzaldehyde (0.93 mL, 0.97 g,
9.15 mmol), pꢀtoluenesulfonic acid monohydrate (0.05 g,
0.26 mmol), and dry toluene (7 mL) was refluxed for 8 h 30 min.
Then more benzaldehyde (0.50 mL, 0.52 g, 4.9 mmol) was addꢀ
ed. The reaction mixture was refluxed additionally for 7 h, kept
at room temperature for 15 h, refluxed for 4 h, and cooled to
0 °C. The precipitate was filtered off, washed with propanꢀ2ꢀol
and diethyl ether, and dried. Compound 10b was obtained in
Experimental
The 1H NMR spectra were recorded on Bruker ACꢀ300 and
Bruker DRXꢀ500 spectrometers in a DMSOꢀd6 + CCl4 mixture.
The mass spectra were obtained on a Waters Micromass ZQ 2000
mass spectrometer in an ESI+ mode. The IR spectra were meaꢀ
sured on a Perkin—Elmer 457 instrument in Nujol mulls. The
melting points were determined on a Boetius hotꢀstage apparatus.
The yields, melting points, and the data from elemental analꢀ
ysis, mass spectrometry, and IR spectroscopy are given in Table 2.
2ꢀDicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroinꢀ
dole (5) was synthesized according to a procedure described preꢀ
viously.17
1
a yield of 0.69 g. H NMR, δ: 7.34 (t, 1 H), 7.54 (m, 5 H), 8.26
(m, 3 H) (H(6)—H(9), Ph, J0 = 7.5 Hz); 10.08 (s, 1 H, H(5));
12.53 (br.s, 1 H, NH).
2ꢀAnilinoꢀ4ꢀcyanoꢀ3ꢀdimethylaminomethylideneaminopyridoꢀ
[4,3ꢀb]indole (11). A mixture of compound 7b (0.42 g, 1.41 mmol),
acetal 5 (0.36 mL, 0.31 g, 2.11 mmol), and dry toluene (5 mL)
was refluxed for 1 h 30 min. More acetal (0.15 mL) was added,
and the reaction mixture was refluxed for 1 h and cooled to 0 °C.
The precipitate was filtered off, washed with propanꢀ2ꢀol and
diethyl ether, and dried. Compound 11 was obtained in a yield of
2,3ꢀDiaminoꢀ4ꢀcyanopyrido[4,3ꢀb]indole (7a). A mixture of
compound 5 (2.60 g, 11 mmol), hydrazine hydrate (3.84 g,
77 mmol), and propanꢀ2ꢀol ((30 mL) was stirred at room temꢀ
perature for 1 h. Then the reaction mixture was cooled to 0 °C.
The precipitate was filtered off, washed with propanꢀ2ꢀol and
diethyl ether, and dried. Compound 7a was obtained in a yield of
1
0.23 g. H NMR, δ: 3.39 (s, 6 H, N(CH3)2); 7.04 (m, 2 H),
7.36 (m, 3 H), 7.57 (t, 2 H), 7.95 (d, 2 H) (H(6)—H(9), Ph, J0 =
= 7.5 Hz); 8.70 (s, 1 H, N=CH); 9.23 (s, 1 H, H(1)); 11.37
(s, 1 H, NH)).
3ꢀAminomethylideneaminoꢀ2ꢀanilinoꢀ4ꢀcyanopyrido[4,3ꢀb]ꢀ
indole (12). A mixture of compound 11 (0.36 g, 1.02 mmol) and
saturated methanolic ammonia (10 mL) was kept at room temꢀ
perature for 45 h. The precipitate was filtered off and washed
with diethyl ether. Compound 12 was obtained in a yield of 0.18 g.
1H NMR, δ:* 7.03 (t, 1 H), 7.12 (t, 1 H), 7.39 (m, 2 H), 7.57 (t, 2 H),
7.85 (d, 1 H), 7.95 (d, 2 H) (H(6)—H(9), Ph, J0 = 7.5 Hz); 8.73
(t, 1 H, N=CH, J0 = 11.6 Hz), 9.26 (s, 1 H, H(1)), 11.31 (br.s,
1 H, NH)).
Ethyl 5ꢀaminoꢀ6ꢀcyanoꢀ2ꢀmethylꢀ7Hꢀpyrazolo[1´,5´:1,2]ꢀ
pyrido[4,3ꢀb]indoleꢀ1ꢀcarboxylate (14). A mixture of compound
7a (1.35 g, 6.05 mmol), ethyl acetoacetate (0.78 mL, 0.80 g,
6.12 mmol), and propanꢀ2ꢀol (20 mL) was refluxed for 6 h 30 min
and kept at room temperature for 15 h. Then more ethyl aceꢀ
toacetate (0.78 mL) was added, the reaction mixture was reꢀ
fluxed for 7 h and kept at room temperature for 15 h, and a new
portion of ethyl acetoacetate (0.78 mL) was added. The reaction
mixture was refluxed for 2 h and cooled to 0 °C. The precipitate
was filtered off, washed with propanꢀ2ꢀol and diethyl ether, and
dried. Compound 14 was obtained in a yield of 1.15 g.
1
2.40 g. H NMR, δ: 6.36 (s, 2 H, N(3)H2); 6.96 (t), 7.26 (t),
7.38 (d), 7.85 (d) (all 1 H each, H(6)—H(9), J0 = 7.5 Hz); 7.26
(br.s, 2 H, NH2); 8.47 (s, 1 H, H(1)).
3ꢀAminoꢀ2ꢀanilinoꢀ4ꢀcyanopyrido[4,3ꢀb]indole (7b). A mixꢀ
ture of compound 5 (0.60 g, 2.53 mmol), phenylhydrazine (0.55 g,
5.06 mmol), and propanꢀ2ꢀol (7 mL) was stirred at room temꢀ
perature for 1 h under argon. Then the reaction mixture was
heated to reflux, stirred for 40 min, and cooled to 0 °C. The
precipitate was filtered off, washed with propanꢀ2ꢀol and diethyl
ether, and dried. Compound 7b was obtained in a yield of 0.68 g.
1H NMR, δ: 6.62 (d, 2 H), 6.95 (m, 2 H), 7.26 (m, 3 H), 7.41
(d, 1 H), 7.86 (d, 1 H) (H(6)—H(9) Ph, J0 = 7.5 Hz); 7.50 (br.s,
2 H, NH2); 8.50 (s, 1 H, H(1)), 9.52 (br.s, 1 H, NH).
2,3ꢀDiaminoꢀ4ꢀcyanopyrido[4,3ꢀb]indole hydrochloride (8).
A mixture of compound 7a (0.32 g, 1.44 mmol), concentrated
hydrochloric acid (0.3 mL), and methanol (6 mL) was stirred at
room temperature for 2 h. Then the reaction mixture was cooled
to 0 °C. The precipitate was filtered off, washed with propanꢀ2ꢀ
ol and diethyl ether, and dried. Compound 8 was obtained in
Ethyl 6ꢀcyanoꢀ5ꢀ[(E)ꢀ(dimethylamino)methylideneamino]ꢀ2ꢀ
methylꢀ7Hꢀpyrazolo[1´,5´:1,2]pyrido[4,3ꢀb]indoleꢀ1ꢀcarboxyꢀ
late (15). A mixture of compound 14 (0.77 g, 2.31 mmol), acetal
9 (0.43 mL, 0.37 g, 2.54 mmol), and dry toluene (15 mL) was
refluxed for 1 h 30 min. Then a new portion of the acetal
(0.43 mL) was added, and the reaction mixture was refluxed for
1
a yield of 0.19 g. H NMR, δ: 6.91 (br.s, 2 H, N(3)H2); 7.35
(t, 1 H), 7.55 (m, 2 H), 8.17 (d, 1 H) (H(6)—H(9), J0 = 7.5 Hz);
8.54 (br.s, 2 H, N(2)H2); 9.29 (s, 1 H, H(1)); 12.84 (br.s, 1 H, NH).
10Hꢀ (10aA), 3Hꢀ (10aB), or 1Hꢀ11ꢀcyano[1,2,4]triazoloꢀ
[1´,5´:1,6]pyrido[4,3ꢀb]indole (10aC). A mixture of compound
7a (2.52 g, 11 mmol), acetal 9 (2.06 mL, 1.77 g, 12 mmol), and
dry toluene (25 mL) was refluxed for 2 h. Then more acetal
(2.06 mL) was added, the reaction mixture was refluxed for 3 h,
a new portion of the acetal (2.06 mL) was added, the mixture
* The chemical shifts of the signals for the NH2 group overlap
with those of the signals for H(6)—H(9) and Ph.

Fused triꢀ and tetracyclic systems
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
183
Table 2. Yields, melting points, data from elemental analysis, mass spectrometry, and IR spectroscopy for compounds 7a,b, 8, 10a—c,
11, 12, 14, 15, and 17a—c
Comꢀ Yield
pound (%)
M.p.
/°C
Solvent
Found
Calculated
Molecular
formula
MS, m/z
IR, νmax/cm–1
(%)
C≡N
NH,
NH2
C
H
N
(C=O)
7a
7ba
8
98
90
51
250
50%
aqueous
DMF
63.91 4.35 31.51 C12H9N5
64.56 4.06 31.98
224 [M + H]+,
447 [2 M + H]+
2209
2118
2228
3175,
3316,
3362
3206,
3308,
3392
3248,
3362
(with decomp.)
260—263 DMF : PriOH, 67.56 5.31 22.44 C21H20N6O 300 [M + H]+,
1 : 3
67.64 5.43 22.63
322 [M + Na]+,
599 [2 M + H]+
284—285
>350
90%
aqueous
PriOH
—
—
—
C12H10N5Clb 208 [M + H – NH2]+,
224 [M + H]+,
447 [2M + H]+
10a
92
73
75%
aqueous
DMF
67.20 3.60 29.98 C13H7N5
66.94 3.03 30.03
234 [M + H]+,
256 [M + Na]+,
272 [M + K]+,
467 [2 M + H]+,
489 [2 M + Na]+
310 [M + H]+,
619 [2M + Н]+
2220
3115
(br.)
10b
10с
11
>350
>350
60%
aqueous
DMF
73.90 3.58 22.96 C19H11N5
73.77 3.59 22.64
2222
2224
3200
(br.)
A 32
B 30
67%
68.58 3.64 28.09 C14H9N5
68.00 3.67 28.33
248 [M + H]+,
270 [M + Na]+,
495 [2M + H]+
310 [M + H – NMe2]+, 2170
355 [M + H]+,
709 [2M + H]+
327 [M + H]+,
349 [M + Na]+,
365 [M + K]+,
653 [2 M + H]+,
675 [2 M + Na]+
3252
aqueous
DMF
PriOH
46
54
180—182
229—231
71.57 5.16 23.35 C21H18N6
71.17 5.12 23.72
3200
(
br.)
12
67%
aqueous
DMF
69.37 4.17 26.21 C19H14N6
69.92 4.32 25.75
2218
3250,
3493
14
57
89
90
53
219—220
295—297
318—321
>350
PriOH
DMF
64.51 4.54 21.30 C18H15N5O2 334 [M + H]+,
64.85 4.54 21.01
2212
(1683)
3295,
3414
667 [2M + H]+,
689 [2 M + Na]+,
1000 [3M + H]+
15
64.85 5.06 21.84 C21H20N6O2 389 [M + H]+,
64.93 5.19 21.64
2222
(1697)
3256
—
411 [M + Na]+,
777 [2M + H]+,
1165 [3M + H]+
17a
17b
67%
aqueous
DMF
71.80 3.66 20.15 C21H13N5O 352 [M + H]+,
71.78 3.73 19.94
2218
(1692)
374 [M + Na]+,
703 [2 M + H]+,
725 [2 M + Na]+
428 [M + H]+,
450 [M + Na]+,
855 [2 M + H]+,
877 [2 M + Na]+,
1282 [3 M + H]+
366 [M + H]+,
388 [M + Na]+,
731 [2 M + H]+,
753 [2 M + Na]+
80%
aqueous
DMF
75.91 3.94 16.57 C27H17N5
75.86 4.01 16.39
O
2214
(1691)
—
17c
45
325
80%
aqueous
DMF
72.40 3.95 19.36 C22H15N5
72.31 4.14 19.17
O
2216
(1645)
—
1
a The H NMR spectrum of compound 7b shows signals for one molecule of DMF (δ): 7.92 (s, 1 H, CH); 3.20 and 2.50 (both s,
1 H each, NMe2).
b Found (%): Cl, 13.20. Calculated (%): Cl, 13.20.

184
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Smirnova et al.
4 h and cooled to 0 °C. The precipitate was filtered off, washed
with propanꢀ2ꢀol and diethyl ether, and dried. Compound 15
was obtained in a yield of 0.8 g. 1H NMR, δ: 1.31 (t, 3 H,
CH2CH3); 4.37 (q, 2 H, CH2CH3); 2.46 (s, 3 H, CH3); 3.15 and
3.20 (both s, 3 H each, N(CH3)2); 7.13 (t), 7.23 (t), 7.50 (d), 7.81
(d) (1 H each, H(8)—H(11), J0 = 7.5 Hz); 8.84 (s, 1 H, N=CH).
10Hꢀ (10cA), 3Hꢀ (10cB), or 1Hꢀ2ꢀmethylꢀ11ꢀcyano[1,2,4]ꢀ
triazolo[1´,5´:1,6]pyrido[4,3ꢀb]indole (10cC) and 1ꢀacetylꢀ5ꢀ
aminoꢀ6ꢀcyanoꢀ2ꢀmethylꢀ7Hꢀpyrazolo[1´,5´:1,2]pyrido[4,3ꢀb]ꢀ
indole (16). A. A mixture of compound 7a (0.8 g, 3.59 mmol),
acetylacetone (0.41 mL, 0.39 g, 3.59 mmol), and propanꢀ2ꢀol
(10 mL) was refluxed for 1 h. Then more acetylacetone (0.41 mL)
was added, and the reaction mixture was refluxed for 2 h, kept at
room temperature for 15 h, refluxed for 2 h, and cooled to 0 °C.
The precipitate was filtered off, washed with propanꢀ2ꢀol and
diethyl ether, and dried. A mixture of compounds 10c and 16
was obtained in a yield of 0.54 g. The recrystallization of this
mixture (0.25 g) from 67% aqueous DMF afforded compound
10c in a yield of 0.08 g.
B. A mixture of compound 7a (0.30 g, 1.35 mmol) and acetic
acid (3 mL) was refluxed for 2 h, kept at room temperature for
15 h, refluxed for additional 7 h, and cooled to 0 °C. The precipꢀ
itate was filtered off, washed with propanꢀ2ꢀol and diethyl ether,
and dried. Compound 10c was obtained in a yield of 0.1 g.
1H NMR, δ: 2.50 (s, 3 H, CH3); 7.34 (t, 1 H), 7.52 (m, 2 H), 8.25
(d, 1 H) (H(6)—H(9), J0 = 7.5 Hz); 10.01 (s, 1 H, H(5)); 12.52
(br.s, 1 H, NH).
Table 3. Crystallographic data for compound 15
Parameter
Characteristics
Molecular formula
Crystal system
Space group
C21H20N6O2
Моноклинная
P21/с
Unit cell parameters
a/Å
b/Å
c/Å
β/deg
V/Å3
Z
dcalc (g cm–3
μ/mm–1
7.4365(12)
9.474(3)
27.474(5)
92.132(15)
1953.4(8)
4
)
1.321
0.726
Radiation
CuKα
θ
69.93o
3561
max
Number of independent reflections
R(F)
Rw(F2)
GOOF
0.0626
0.1902
1.01
precipitate was filtered off, washed with ipropanꢀ2ꢀol and diethꢀ
yl ether, and dried. Compound 17c was obtained in a yield of
1
0.32 g. H NMR, δ: 2.50 (s, 3 H, CH3); 6.30 (s, 2 H, CH2Ph);
10ꢀBenzoylmethylꢀ11ꢀcyano[1,2,4]triazolo[1´,5´:1,6]pyꢀ
rido[4,3ꢀb]indole (17a). Sodium hydride (0.82 g, 21 mmol) as
a 60% suspension in Vaseline oil was added portionwise to a soluꢀ
tion of compound 10a (3.32 g, 14 mmol) in dry DMF (25 mL)
under argon. The reaction mixture was stirred for 2 h and phenꢀ
acyl bromide (4.18 g, 20 mmol) was added. The reaction mixture
was stirred at room temperature for 2 h, kept at room temperaꢀ
ture for 15 h, and cooled to 0 °C. The precipitate was filtered off,
washed with propanꢀ2ꢀol and diethyl ether, and dried. Comꢀ
7.30—7.88 (m, 6 H), 8.17 (d, 2 H), 8.32 (d, 1 H) (H(6)—H(9),
Ph, J0 = 7.5); 10.08 (s, 1 H, H(5)).
Xꢀray diffraction study. The crystal structure of 15 was estabꢀ
lished by Xꢀray diffraction. The Xꢀray diffraction data were colꢀ
lected on a singleꢀcrystal fourꢀcircle CADꢀ4 diffractometer
(CuKα radiation, graphite monochromator) at room temperaꢀ
ture. The structure was solved by direct methods with the use of
the SHELXS97 program package21 and refined with anisotropic
displacement parameters for nonhydrogen atoms using the
SHELXL97 program package.21 The hydrogen atoms were posiꢀ
tioned geometrically and refined using a riding model. The crysꢀ
tal structure of 15 was deposited with the Cambridge Crystalloꢀ
graphic Data Centre;19 the CCDC reference number is 714418.
Principal crystallographic parameters are given in Table 3. The
geometric parameters of the hydrogen bonds are listed in Table 1.
1
pound 17a was obtained in a yield of 2.35 g. H NMR, δ: 6.33
(s, 2 H, CH2Ph); 7.34—7.75 (m, 6 H), 8.18 (d, 2 H), 8.34 (d, 1 H)
(H(6)—H(9), Ph, J0 = 7.5 Hz); 8.44 (s, 1 H, H(2)); 10.24
(s, 1 H, H(5)).
10ꢀBenzoylmethylꢀ11ꢀcyanoꢀ2ꢀphenyl[1,2,4]triazoloꢀ
[1´,5´:1,6]pyrido[4,3ꢀb]indole (17b). Sodium hydride (0.08 g,
2.18 mmol) as a 60% suspension in Vaseline oil was added porꢀ
tionwise to a solution of compound 10b (0.45 g, 1.46 mmol) in
dry DMF (6 mL) under argon. The reaction mixture was stirred
for 40 min and phenacyl bromide (0.43 g, 2.18 mmol) was addꢀ
ed. The reaction mixture was stirred at room temperature for
6 h, kept at room temperature for 15 h, and cooled to 0 °C. The
precipitate was filtered off, washed with propanꢀ2ꢀol and diethyl
ether, and dried. Compound 17b was obtained in a yield of 0.33
g. 1H NMR, δ: 6.33 (s, 2 H, CH2Ph); 7.37—7.76 (m, 9 H), 8.19
(d, 2 H), 8.26 (d, 2 H), 8.34 (d, 1 H) (H(6)—H(9), CH2Ph, Ph,
J0 = 7.5 Hz); 10.22 (s, 1 H, H(5)).
10ꢀBenzoylmethylꢀ11ꢀcyanoꢀ2ꢀmethyl[1,2,4]triazoloꢀ
[1´,5´:1,6]pyrido[4,3ꢀb]indole (17c). Sodium hydride (0.11 g,
2.91 mmol) as a 60% suspension in Vaseline oil was added porꢀ
tionwise to a solution of compound 10c (0.48 g, 1.94 mmol) in
dry DMF ((5 mL) under argon. The reaction mixture was stirred
for 40 min and phenacyl bromide (0.48 g, 2.91 mmol) was addꢀ
ed. The reaction mixture was stirred at room temperature for
2 h, kept at room temperature for 15 h, and cooled to 0 °C. The
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Received January 28, 2009;
in revised form June 29, 2009