A new approach to the synthesis of pyrido[4,3-b]indole derivatives (γ-carbolines) via cyclization of enamino dinitriles

Article abstract of DOI:10.1007/s11172-008-0344-9

Reactions of 2-dicyanomethylidene-3-ethoxymethylidene-2,3-dihydroindole with various amines afforded enamino dinitriles and the corresponding pyrido[4,3-b]indoles (γ-carbolines). 3-Amino-4-cyano-5H-pyrido[4,3-b] indole reacted with cyclohexanone to give pentacyclic 13-amino-2,3,4,12- tetrahydro-1H-benzo[b]indolo[2,3-f]-1,8-naphthyridine. Alkylation of pyrido[4,3-b]indoles with various alkylating agents was studied.

Full text of DOI:10.1007/s11172-008-0344-9

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2410—2417, November, 2008
2410
A new approach to the synthesis of pyrido[4,3ꢀb]indole derivatives
(γꢀcarbolines) via cyclization of enamino dinitriles
O. B. Smirnova,a T. V. Golovko,a L. M. Alekseeva,a A. S. Shashkov,b and V. G. Granika
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Phone: +7 (499) 611 2031. Eꢀmail: vggranik@mail.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Phone: +7 (499) 135 5328
Reactions of 2ꢀdicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroindole with various
amines afforded enamino dinitriles and the corresponding pyrido[4,3ꢀb]indoles (γꢀcarbolines).
3ꢀAminoꢀ4ꢀcyanoꢀ5Hꢀpyrido[4,3ꢀb]indole reacted with cyclohexanone to give pentacyclic
13ꢀaminoꢀ2,3,4,12ꢀtetrahydroꢀ1Hꢀbenzo[b]indolo[2,3ꢀf]ꢀ1,8ꢀnaphthyridine. Alkylation of
pyrido[4,3ꢀb]indoles with various alkylating agents was studied.
Key words: enamino dinitriles, heterocyclization, pyrido[4,3ꢀb]indoles (γꢀcarbolines),
DMF diethyl acetal, amidines, phosphoryl chloride, alkylation.
It is well known that a considerable part of drugs are
structurally based on polycyclic compounds. Among those
systems, triꢀ, tetraꢀ, and pentacycles containing the
indole fragment are very important. Particular examples
of such drugs include Carbidine (neuroleptic), Pyrazidol,
Tetrindol, Incazan (antidepressants), Ondansetron (antiꢀ
emetic), Dimebon, Diazolin (antihistamine (antiallergic)
drugs), and Mitomycin (antitumor antibiotic).1,2
An attractive route to such annulated indole systems
involves indolinꢀ2ꢀone (oxindole) derivatives as starting
materials.
Recently, a new class of analgesics, antiinflammatory
drugs, and antiarthritic agents has been discovered among
oxindole derivatives.3 One of those substances has already
been patented as the drug Tenidap.
While searching for new highly reactive compounds
among oxindoles, Robinson et al.4 obtained a representaꢀ
tive of the fused heterocyclic system 1,3,5ꢀoxadiazino[3,2ꢀa]ꢀ
indole from a Tenidap derivative (Scheme 1).
One can state that the use of oxindole and its deriꢀ
vatives for the design of various fused heterocycles is a
Some investigations dealing with oxindole derivatives
are aimed at the synthesis of such important compounds
as Physostigmine and its analogs (Eseroline and Deoxyꢀ
eseroline). Physostigmine is a highly reactive cholineꢀ
sterase inhibitor used for treatment of glaucoma and as an
antidote against organophosphorus intoxication. Physoꢀ
stigmine may also be effective against Alzheimer´s
disease.1,2
Scheme 1
Tenidap
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2361—2368, November, 2008.
1066ꢀ5285/08/5711ꢀ2410 © 2008 Springer Science+Business Media, Inc.

A new route to pyrido[4,3ꢀb]indoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2411
Scheme 2
fruitful and promising area of heterocyclic chemistry. The
potential of oxindole derivatives for heterocyclization is
far from being exhausted; their application remains an
attractive synthetic approach to new polycyclic indoleꢀ
based systems and is of considerable interest for synthetic
and theoretical organic chemistry.
Earlier,5 we have developed a new method for the
synthesis of pyrido[4,3ꢀb]indoles (γꢀcarbolines) and
obtained some representatives of this class. We found that
2ꢀdicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroꢀ
indole (1) (see Ref. 5) is more reactive toward nucleoꢀ
philes than the enamine we have used before (2ꢀdicyanoꢀ
methylideneꢀ3ꢀdimethylaminomethylideneꢀ2,3ꢀdihydroꢀ
indole). Note that enol ethers have already been reported
to be more reactive than enamines.6
for 2a,b
For this reason, here we used 2ꢀdicyanomethylideneꢀ
3ꢀethoxymethylideneꢀ2,3ꢀdihydroindole (1) as the starting
reagent for the synthesis of various enamino dinitriles 2
and further heterocyclization reactions.
for 3b
Compound 1 smoothly reacted with 3,4ꢀdimethoxyꢀ
aniline, pꢀ and oꢀanisidines, and tertꢀbutylamine to give
the corresponding enamino dinitriles 2a—d (Scheme 2).
However, shortꢀtime heating during attempted recrystalꢀ
lization of compounds 2a (50% aqueous DMF) and 2b
(acetonitrile) resulted in pyridine ring formation leading
to the corresponding pyrido[4,3ꢀb]indoles 3a and 3b in
good yields. This cyclization is very sensitive to steric
factors, not occurring when the benzene ring in the aniline
fragment contains an orthoꢀsubstituent (compound 2c) or
when such a bulky substituent as tertꢀbutyl is attached to
the secondary NH group (compound 2d). Because of this,
our attempts to obtain the corresponding pyrido[4,3ꢀb]ꢀ
indoles from enamino dinitriles 2c and 2d failed: even on
prolonged reflux in acetonitrile, the starting compounds
were recovered intact.
R = 3,4ꢀ(MeO)2C6H3 (2a, 3a), 4ꢀMeOC6H4 (2b, 3b),
2ꢀMeOC6H4 (2c), R = But (2d), Et2N(CH2)2 (3c), Me(CH2)2 (3d),
3,4,5ꢀ(MeO)3C6H2 (3e), 5ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀyl (3f)
Reagents and conditions: i. For 2a: 3,4ꢀ(OMe)2C6H3NH2,
MeCN. For 2b: pꢀanisidine, MeCN, 0 °C.
For 2c: oꢀanisidine, MeCN, 35 °C.
For 2d: ButNH2, boiling MeCN;
To extend the range of substituted pyrido[4,3ꢀb]ꢀ
indoles, we carried out reactions of ethoxymethylidene
dinitrile 1 with 2ꢀdiethylaminoethylamine, propylamine,
3,4,5ꢀtrimethoxyaniline, and 3ꢀaminoꢀ5ꢀmethylpyrazole.
In no cases were intermediate enamino dinitriles isolated
because their formation is followed by rapid and irreversꢀ
ible cyclization into the corresponding γꢀcarbolines 3c—f
(see Scheme 2).
ii. For 3c: NH2(CH2)2N(C2H5)2, MeCN.
For 3d: NH2(CH2)2Me, MeCN, 60 °C.
For 3e: 3,4,5ꢀ(OMe)3C6H2NH2, boiling MeCN.
For 3f: 3ꢀaminoꢀ5ꢀmethylpyrazole, MeCN;
iii. For 3a: reflux of compound 2a in 50% aqueous DMF.
For 3b: reflux of compound 2b in MeCN;
iv. Me2NCH(OEt)2 (4), boiling toluene.
1
The H NMR spectra of enamino dinitriles 2 and
H(3´) and N(3″)H protons (JAB = 12 Hz) typical of such
compounds.
δꢀCarbolines were also reported7 to exist in a tautoꢀ
meric form like A for pyrido[4,3ꢀb]indoles 3 (Scheme 3).
pyrido[4,3ꢀb]indoles 3 show some differences that allow
structure determination of the products obtained. The
spectra of compounds 3 contain, apart from the signals
for the aromatic protons and the substituents in position
2, a signal for the NH2 group (δ 6.67—7.62), while the
spectra of compounds 2 exhibit signals for the N(1)H
(δ 11.43—11.60) and N(3″)H protons (δ 8.53—10.37).
It should be noted that the chemical shift of the signal for
the N(3″)H proton (mostly a broadened singlet) widely
varies with the substituent at the N(3″) atom. Only the
spectrum of compound 2d shows an AB system for the
Scheme 3

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Smirnova et al.
Scheme 4
Reagents and conditions: i. MeI, DMF; ii. Me2NCH(OEt)2 (4), toluene, reflux; iii. NH3/MeOH;
iv. MeOH (or H2O), reflux.
To confirm the presence of a primary amino group in
position 3, we converted compound 3b*, via a reaction
with DMF diethyl acetal (4), into amidine 5**.
Roomꢀtemperature alkylation of tricyclic compound
6 with methyl iodide in DMF gave monomethyl derivaꢀ
tive 8 (Scheme 4). Its structure was determined from the
NOEDIFF spectrum. Saturation of the signal for the
methyl group (δ 3.93) resulted in a resonance with
the singlet for the H(1) proton (δ 9.35) (NOE = 7%).
Roomꢀtemperature alkylation of tricyclic compound
7 with methyl iodide in DMF yielded monomethyl
derivative 9, which was converted into tetracycle 10 by
treatment with a saturated solution of ammonia in methaꢀ
nol. Compound 10 was also obtained from compound 8
and DMF diethyl acetal (4) in boiling toluene. The
resulting precipitate of amidine 9 was treated in situ with a
saturated solution of ammonia in methanol (see Scheme 4).
The 1H NMR spectrum of a mixed sample of products 10
obtained in alternative ways shows a single set of signals.
1H NMR (DMSOꢀd6—CCl4), δ: 4.12 (s, 3 H, CH3);
7.28 (t, 1 H, Jo = 7.5 Hz), 7.47 (t, 1 H, Jo = 7.5 Hz),
7.78 (d, 1 H, Jo = 7.5 Hz), 8.16 (d, 1 H, Jo = 7.5 Hz)
(H(7)—H(10)); 8.56, 9.34 (both s, 1 H each, H(3), H(6));
8.59, 9.49 (both br.s, 1 H each, NH2). The presence of
two broadened signals at δ 8.59 and 9.49 is probably due
to an equilibrium between tautomers 10A and 10B (both
18πꢀelectron aromatic systems); the shift of the equilibꢀ
rium to tautomer 10A can be promoted by bases. That is
why addition of amide acetal 4 (as rigorously proved,8 the
ethoxy anion is present in equilibrium) to the system leads
to the formation of amidine 11 through condensation at
The structures of compounds 2d and 3c were conꢀ
firmed by complete assignment of the signals in their
HSQC, HMBC, and NOESY spectra (see Experimental).
The spectrum of compound 2d contains two lowꢀfield
signals at δ 138.4 and 158.3 for the C(7a) and C(2) atoms,
respectively, while the spectrum of compound 3c shows
lowꢀfield signals at δ 152.4, 156.1, and 156.1 due to
three quaternary atoms: C(3), C(5a), and C(4a). The corꢀ
relation peak (H(3´)/H(4) = 8.68/7.93) in the NOESY
spectrum of compound 2d suggests its existence as a
Z isomer.
Previously5 obtained 3ꢀaminoꢀ4ꢀcyanoꢀ5Hꢀpyridoꢀ
[4,3ꢀb]indole (6) and 4ꢀcyanoꢀ3ꢀdimethylaminomethylideneꢀ
aminoꢀ5Hꢀpyrido[4,3ꢀb]indole (7) are promising starting
materials for subsequent synthesis of various γꢀcarbolines.
1
* Compound 3b, H NMR (DMSOꢀd6—CCl4), δ: 3.86 (s, 3 H,
OCH3); 6.83 (br.s, 2 H, NH2); 7.00 (t, 1 H, Jo = 7.5 Hz), 7.17
(m, 2 H), 7.30 (t, 1 H, Jo = 7.5 Hz), 7.43 (d, 1 H, Jo = 7.5 Hz),
7.53 (m, 2 H), 7.89 (d, 1 H, Jo = 7.5 Hz) (H(6)—H(9),
—C6H4OCH3)); 8.54 (s, 1 H, H(1)).
** Compound 5, 1H NMR (DMSOꢀd6—CCl4), δ: 2.78, 3.12
(both s, 3 H each, N(CH3)2); 3.84 (s, 3 H, OCH3); 7.07 (m,
3 H), 7.38 (m, 3 H), 7.56 (d, 1 H, Jo = 7.5 Hz), 8.01 (d, 1 H,
Jo = 7.5 Hz) (H(6)—H(9), —C6H4OCH3)); 8.13, 8.83 (both s,
1 H each, H(1), N=CH).

A new route to pyrido[4,3ꢀb]indoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2413
Scheme 6
the primary amino group.* Hydrolysis of the amidine fragꢀ
ment in boiling water allows compound 10 to be recovered.
The presence of the primary amino group in the orthoꢀ
position relative to the cyano group in the pyridine ring of
compound 6 makes it possible to annulate the pyridine
ring for the synthesis of heteropentacyclic derivative 12,
the first representative of the novel heterocyclic system,
viz., benzo[b]indolo[2,3ꢀf]ꢀ1,8ꢀnaphthyridine (Scheme 5).
Scheme 5
i. POCl3, Et3N•HCl, ii. RNH2; R = (CH2)2NMe2
Alkylation of compound 7 with chloroacetonitrile and
2ꢀbromoacetophenone in dry DMF in the presence of
NaH occurs at the indole NH group, giving the correꢀ
sponding derivatives 16a,b (Scheme 7). Attempts to
obtain fused γꢀcarboline 17a by the Thorpe—Ziegler
cyclization of compound 16a failed because of the
hydrolysis of one cyano group under the reaction condiꢀ
tions (ButOK, ButOH, reflux). For reliable proof of strucꢀ
ture 16c (not 18), we conducted an independent synthesis
by alkylating compound 7 with chloroacetamide. Unsucꢀ
cessful were our attempts at cyclization of compound
16b, which is highly reactive in such reactions because
of the strong electronꢀwithdrawing effect of the phenacyl
group. On prolonged reflux of compound 16b with potasꢀ
sium tertꢀbutoxide in ButOH, or with sodium ethoxide
in anhydrous EtOH, or with potassium tertꢀbutoxide in
pyridine, we recovered only the starting compound in 95,
Previously5 obtained 4ꢀcyanoꢀ5Hꢀ2,3ꢀdihydropyridoꢀ
[4,3ꢀb]indolꢀ3ꢀone (13) can also be regarded as a promisꢀ
ing starting material for the synthesis of γꢀcarbolines.
Reflux of compound 13 with phosphoryl chloride gave
chloro derivative 14, which reacted with N,Nꢀdimethylꢀ
ethylenediamine to yield amino derivative 15 (Scheme 6).
1
* Compound 11, H NMR (DMSOꢀd6), δ: 3.27, 3.38 (both s,
3 H each, N(CH3)2); 4.12 (s, 3 H, OCH3); 7.24, 7.43, 7.72, 8.09
(t, t, d, d, 1 H each, H(7)—H(10), Jo = 7.5 Hz); 8.72, 8.81, 9.27
(all s, 1 H each, H(3), N=CH), H(6)).
Scheme 7
for 16a,b
for 16a
R = CN (a), COPh (b), CONH2 (c)
Reagents and conditions: i. For 16a: 1) NaH, DMF; 2) ClCH2CN. For 16b: 1) NaH, DMF; 2) BrCH2COPh.
For 16c: 1) NaH, DMF; 2) ClCH2CONH2. ii. ButOH, ButOK, reflux.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Smirnova et al.
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀ(3,4ꢀdimethoxyphenyl)pyrido[4,3ꢀb]ꢀ
indole (3a) and 3ꢀaminoꢀ4ꢀcyanoꢀ2ꢀ(4ꢀmethoxyphenyl)pyridoꢀ
[4,3ꢀb]indole (3b) were obtained by attempted recrystallization
of compounds 2a (from 50% aqueous DMF) and 2b (from
acetonitrile), respectively. Compound 3a. 1H NMR (DMSOꢀd6—
CCl4), δ: 3.84, 3.89 (both s, 3 H each, OCH3, OCH3); 6.67
(br.s, 2 H, NH2); 6.99 (t, 1 H, Jo = 7.5 Hz), 7.08—7.17 (m,
3 H), 7.29 (t, 1 H, Jo = 7.5 Hz), 7.42 (d, 1 H, Jo = 7.5 Hz), 7.81
(d, 1 H, Jo = 7.5 Hz) (H(6)—H(9), —C6H3(OCH3)2); 8.36 (s,
1 H, H(1)).
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀ(2ꢀdiethylaminoethyl)pyrido[4,3ꢀb]ꢀ
indole (3c). A. A mixture of compound 1 (0.05 g, 0.21 mmol)
and N,Nꢀdiethylethylenediamine (0.03 g, 0.25 mmol) was stirred
in acetonitrile (3 mL) at room temperature for 20 min and then
cooled to 0 °C. The precipitate that formed was filtered off. The
yield of compound 3c was 0.04 g.
82, and 71% yields, respectively. Apparently, the Thorpe—
Ziegler cyclization for these γꢀcarbolines is impeded by
the formation of a strained tetracyclic system of the type
17 containing two fused fiveꢀmembered rings. A similar
failure in the cyclization has been reported earlier.9
Experimental
NMR spectra were recorded on Bruker ACꢀ300 and Bruker
DRXꢀ500 spectrometers. Mass spectra were measured on a
Waters Micromass ZQ 2000 mass spectrometer in the ESI+
mode. IR spectra were recorded on a Perkin—Elmer 457 instruꢀ
ment in Nujol. Melting points were determined on a Boetius
hot stage.
The yields, melting points, elemental analysis data, mass
spectra, and IR spectra of the compounds obtained are given in
Table 1.
B. A mixture of compound 1 (0.41 g, 1.73 mmol) and
N,Nꢀdiethylethylenediamine (1.65 g, 14 mmol) was stirred at
room temperature for 20 min and then cooled to 0 °C. The
precipitate that formed was filtered off and washed with light
petroleum. The yield of compound 3c was 0.46 g.
2ꢀDicyanomethylideneꢀ3ꢀethoxymethylideneꢀ2,3ꢀdihydroꢀ
indole (1) was prepared as described earlier.5
Synthesis of enamino dinitriles 2a—d (general procedure).
A mixture of compound 1 and an appropriate amine in a molar
ratio of 1 : 1 was stirred in acetonitrile at 20 (for 2a, 1 h), 0 (for
2b, 1 h), and 35 °C (for 2c, 2 h), as well as in boiling acetonitrile
(for 2d, 2 h). The reaction mixture was cooled to 0 °C and the
precipitate that formed was filtered off. In the case of compound
2c, the reaction with freshly distilled oꢀanisidine was carried out
under argon and the product was recrystallized twice from
acetonitrile.
2ꢀDicyanomethylideneꢀ3ꢀ(3,4ꢀdimethoxyphenylamino)ꢀ
methylideneꢀ2,3ꢀdihydroindole (2a). 1H NMR (DMSOꢀd6—
CCl4), δ: 3.80, 3.84 (both s, 3 H each, OCH3); 6.96—7.24 (m,
6 H), 8.09 (d, 1 H, Jo = 7.5 Hz) (H(4)—H(7), —C6H3(OCH3)2);
8.92 (s, 1 H, =CHNH); 10.10 (br.s, 1 H, =CHNH); 11.44 (br.s,
1 H, N(1)H).
1H NMR (DMSOꢀd6), δ: 0.83 (t, 6 H, (CH2CH3)2, J = 7.2 Hz);
2.49 (q, 4 H, (CH2CH3)2, Jo = 7.2 Hz); 2.73, 4.25 (both t, 2 H
each, (CH2)2, J = 5.1 Hz); 7.03 (t, 1 H), 7.29 (t, 1 H), 7.41 (d,
1 H), 7.82 (d, 1 H) (H(6)—H(9), Jo = 7.5 Hz); 7.62 (br.s, 2 H,
NH2); 8.48 (s, 1 H, H(1)).
13C NMR (DMSOꢀd6), δ: 11.7, 46.6, 51.4, 52.0 (CH2CH2ꢀ
N(CH2CH3)2); 72.5 (C(4)); 116.5 (CN); 116.6, 118.8, 119.7,
126.6 (C(6)—C(9)); 117.4 (C(9b)); 124.5 (C(9a)); 134.2 (C(1));
152.4 (C(3)); 156.1 (C(5a), C(4a)). HMBS (DMSOꢀd6), δ: 72.5
(C(4), [H(1)]); 117.4 (C(9b), [H(1)]); 124.5 (C(9a), [H(1), H(6),
H(8)]); 152.4 (C(3), [H(1)]); 156.1 (C(5a), [H(7), H(9)]); 156.1
(C(4a), [H(1)]).
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀpropylpyrido[4,3ꢀb]indole (3d). A mixꢀ
ture of compound 1 (0.46 g, 1.94 mmol) and propylamine
(0.12 g, 0.16 mL, 1.94 mmol) was stirred in acetonitrile (5 mL)
at room temperature for 1 h and then at 60 °C for 30 min. On
cooling to 0 °C, the precipitate that formed was filtered off and
washed with light petroleum. The yield of compound 3d was
0.45 g.
1H NMR (DMSOꢀd6—CCl4), δ: 0.93 (t, 3 H, CH2CH2CH3,
J = 7.2 Hz); 1.77 (m, 2 H, CH2CH2CH3); 4.15 (t, 1 H,
CH2CH2CH3, J = 7.2 Hz); 7.02 (t, 1 H), 7.29 (t, 1 H), 7.41 (d,
1 H), 7.84 (d, 1 H) (H(6)—H(9), Jo = 7.5 Hz); 7.27 (br.s, 2 H,
NH2); 8.60 (s, 1 H, H(1)).
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀ(3,4,5ꢀtrimethoxyphenyl)pyrido[4,3ꢀb]ꢀ
indole (3e). A mixture of compound 1 (0.55 g, 2.32 mmol) and
3,4,5ꢀtrimethoxyaniline (0.43 g, 2.35 mmol) was stirred in
acetonitrile (10 mL) at room temperature for 40 min and then
refluxed for 30 min. On cooling to 0 °C, the precipitate that
formed was filtered off and washed with light petroleum. The
yield of compound 3e was 0.86 g.
2ꢀDicyanomethylideneꢀ3ꢀ(4ꢀmethoxyphenylamino)ꢀ
methylideneꢀ2,3ꢀdihydroindole (2b). 1H NMR (DMSOꢀd6), δ:
3.78 (s, 3 H, OCH3); 7.04 (m, 2 H), 7.14—7.40 (m, 3 H), 7.42
(m, 2 H), 8.13 (d, 1 H, Jo = 7.5 Hz) (H(4)—H(7), —C6H4OCH3);
8.85 (s, 1 H, =CHNH); 10.37 (br.s, 1 H, =CH NH); 11.60 (br.s,
1 H, N(1)H).
2ꢀDicyanomethylideneꢀ3ꢀ(2ꢀmethoxyphenylamino)ꢀ
methylideneꢀ2,3ꢀdihydroindole (2c). 1H NMR (DMSOꢀd6—
CCl4), δ: 4.00 (s, 3 H, OCH3); 6.89—7.49 (m, 7 H), 7.78 (d,
1 H, Jo = 7.5 Hz) (H(4)—H(7), —C6H4OCH3); 8.96 (s, 1 H,
=CHNH); 9.21 (br.s, 1 H, =CHNH); 11.52 (br.s, 1 H, N(1)H).
3ꢀtertꢀButylaminomethylideneꢀ2ꢀdicyanomethylideneꢀ
2,3ꢀdihydroindole (2d). 1H NMR (DMSOꢀd6—CCl4), δ: 1.44
(s, 9 H, C(CH3)3); 7.12 (m, 2 H), 7.23 (d, 1 H, Jo = 7.5 Hz),
7.93 (d, 1 H, Jo = 7.5 Hz) (H(4)—H(7)); 8.53 (br.d, 1 H,
=CHNH, J = 12.0 Hz); 8.68 (d, 1 H, =CHNH, J = 12.0 Hz);
11.43 (br.s, 1 H, N(1)H). 13C NMR (DMSOꢀd6), δ: 28.8, 56.4
(C(CH3)3); 99.4 (C(3)); 110.6, 119.6, 121.6, 124.0 (C(4)—C(7));
120.2 (CN); 124.5 (C(3a)); 138.4 (C(7a)) 145.9 (C(3´); 158.3
(C(2)). HMBS (DMSOꢀd6), δ*: 99.4 (C(3), [H(3´)]); 124.5
(C(3a), [H(3´), H(5), H(7)]); 138.4 (C(7a), [H(4), H(6)]); 158.3
(C(2), [H(3´)]).
1H NMR (DMSOꢀd6—CCl4), δ: 3.79 (s, 3 H), 3.85 (s, 6 H)
(OCH3)3; 6.80 (br.s, 2 H, NH2); 6.90 (s, 2 H), 6.99 (t, 1 H,
Jo = 7.5 Hz), 7.29 (t, 1 H, Jo = 7.5 Hz), 7.42 (d, 1 H, Jo = 7.5 Hz),
7.82 (d, 1 H, Jo = 7.5 Hz) (H(6)—H(9), —C6H2(OCH3)3); 8.40
(s, 1 H, H(1)).
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀ(5ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀyl)pyrido[4,3ꢀb]ꢀ
indole (3f). A mixture of compound 1 (0.28 g, 1.18 mmol) and
97% 3ꢀaminoꢀ5ꢀmethylpyrazole (0.12 g, 1.18 mmol) was stirred
in acetonitrile (5 mL) at room temperature for 1 h. On cooling
* The protons showing correlation peaks with the corresponding
quaternary C atom are enclosed in square brackets.

A new route to pyrido[4,3ꢀb]indoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2415
Table 1. Yields, melting points, elemental analysis data, mass spectra, and IR spectra for compounds 2a—d, 3a—f, 5, 8—12, 12a, 14,
15, and 16a—c
Comꢀ Yield
pound (%)
M.p./°C
Found
Molecular
formula
MS,
IR, νmax/cm–1
(%)
(solvent)
Calculated
m/z
C≡N
(C=O)
NH,
NH2
C
H
—
N
—
2aa
2ba
2c
82
69
85
92
185
—
—
C20H16N4О2 345 [M + H]+, 367 [M + Na]+,
689 [2 M + H]+, 711 [2 M + Na]+
2172,
2207
2172,
2201
2172,
2209
2174,
3223,
3349
3260,
3389
3188,
3401
3192,
3306
195—197
—
—
C19H14N4O 315 [M + H]+, 629 [2 M + H]+,
651 [2 M + Na]+
191
(МеСN)
235
72.47 4.44 17.15
72.60 4.49 17.83
73.15 6.00 21.18
72.70 6.10 21.20
C19H14N4O 315 [M + H]+, 629 [2 M + H]+
2d
C16H16N4
265 [M + H]+, 287 [M + Na]+,
(МеСN)
551 [2 M + Na]+, 815 [3 M + Na]+, 2203
1079 [4 M + Na]+
3a
56
76
253—254
(50%aqueous
DMF)
258—259
(МеСN)
190—191
(МеСN)
269—271
(МеСN)
309
69.78 4.59 16.05
69.96 4.41 16.32
C20H16N4О2 345 [M + H]+, 367 [M + Na]+,
689 [2 M + H]+, 711 [2 M + Na]+
2214
3277—
3300,
3430
3b
3c
3d
3e
72.02 4.31 17.81
72.60 4.49 17.83
70.19 6.76 22.53
70.33 6.89 22.78
71.98 5.50 22.57
71.98 5.64 22.39
65.49 5.06 14.38
C19H14N4O 315 [M + H]+, 629 [2 M + H]+,
651 [2 M + Na]+
C18H21N5
2199
2195
2199
2214
3431
62 (A)
87 (B)
93
308 [M + H]+, 330 [M + Na]+,
615 [2 M + H]+, 637 [2 M + Na]+
251 [M + H]+, 273 [M + Na]+,
501 [2 M + H]+, 523 [2 M + Na]+
3311
3448
C15H14N4
98
95
C21H18N4O3• 375 [M + H]+, 397 [M + Na]+,
3206,
3376
(75% aqueous 65.78 4.99 14.61
DMF)
•0.5 H2Ob
749 [2 M + H]+, 771 [2 M + Na]+
3f
273—275
66.06 3.99 28.49
66.65 4.20 29.15
C16H12N6
289 [M + H]+, 311 [M + Na]+,
577 [2 M + H]+, 599 [2 M + Na]+,
865 [3 M + H]+
2212
3318,
3418
(PriOH)
5
8
85
54
244—246
71.45 5.51 18.87
C22H19N5
O
370 [M + H]+, 392 [M + Na]+,
739 [2 M + H]+
2210
2234
—
(CH3—C6H5) 71.52 5.18 18.96
311—312
(H2O)
44.67 3.16 16.05
44.59 3.17 16.00
C13H11N4Ic
223 [M – HJ + H]+,
3192,
3291,
3333
3376
445 [2 (M – HJ) + H]+,
537 [2 M – HJ + H]+
9
62
275—277
(H2O)
348—350
47.53 4.12 17.57
47.42 3.98 17.28
67.25 4.41 27.73
C16H16N5Id 278 [M – HJ + H]+,
555 [2 (M – HJ) + H]+
C14H11N5
2214
—
10
93 (A)
250 [M + H]+, 272 [M + Na]+,
3295
—
31 (B) (75% aqueous 67.45 4.45 28.10
DMF)
288 [M + K]+, 499 [2 M + H]+,
521 [2 M + Na]+
11
65
250
66.59 5.04 27.48
C17H16N6
C18H16N4
260 [M – NMe2 + H]+,
—
(CH3—C6H5) 67.09 5.30 27.61
305 [M + H]+, 609 [2 M + H]+
289 [M + H]+, 599 [2 M + Na]+
289 [M + H]+, 311 [M + Na]+,
12a
12a
67
89
>350
>350
—
—
—
—
—
3362
—
63.10 5.76 16.54
63.06 5.59 16.34
63.30 2.79 18.74
63.31 2.66 18.46
68.39 6.59 25.02
68.79 6.14 25.07
67.60 5.09 27.65
C18H16N4•
(MeOH)
>350
•HCl•H2Oe 599 [2 M + Na]+
14
79
78
51
C12H6N3Cl
C16H17N5
C17H14N6
228 [M + H]+
2230
3119
3374
—
(PriOH)
218
15
280 [M + H]+, 559 [2 M + H]+,
597 [2 M + K]+
2209
(PriOH)
254
16a
303 [M + H]+, 325 [M + Na]+,
341 [M + K]+, 605 [2 M + H]+,
627 [2 M + Na]+, 643 [2 M + K]+,
929 [3 M + Na]+
2206br.
(50% aqueous 67.53 4.67 27.80
DMF)
16b
16c
48
305—310
72.28 5.17 18.69
C23H19N5O 382 [M + H]+, 404 [M + Na]+,
420 [M + K]+, 763 [2 M + H]+,
2214
—
(75% aqueous 72.42 5.02 18.36
DMF)
(1682)
785 [2 M + Na]+, 801 [2 M + K]+
66 (A)
300
62.23 4.61 25.30
C17H15N6O• 321 [M + H]+, 343 [M + Na]+,
2216
(1615)
3212,
3385
94 (B) (50% aqueous 62.18 4.91 25.60
•0.5 H2Of
641 [2 M + H]+, 663 [2 M + Na]+
DMF)
a Data for crude products.
b Found (%): H2O, 2.35. Calculated (%): H2O, 2.92.
c Found (%): I, 36.24. Calculated (%): I, 36.24.
d Found (%): I, 31.33. Calculated (%): I, 31.32.
e Found (%): H2O, 4.81. Calculated (%): H2O, 5.25.
f Found (%): H2O, 2.55. Calculated (%): H2O, 2.74.

2416
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Smirnova et al.
to 0 °C, the precipitate that formed was filtered off and washed
with light petroleum. The yield of compound 3f was 0.36 g.
1H NMR (DMSOꢀd6), δ: 2.34 (s, 3 H, CH3); 6.44 (s, 1 H,
H(4)); 7.25 (br.s, 2 H, NH2); 7.03 (t, 1 H), 7.32 (t, 1 H), 7.44
(d, 1 H), 7.94 (d, 1 H) (H(6)—H(9), Jo = 7.5 Hz); 8.63 (s, 1 H,
H(1); 13.18 (br.s, 1 H, N(H)).
4ꢀCyanoꢀ3ꢀdimethylaminomethylideneaminoꢀ2ꢀ(4ꢀmethoxyꢀ
phenyl)pyrido[4,3ꢀb]indole (5). A mixture of compound 3b
(0.21 g, 0.67 mmol) and acetal 4 (0.17 mL, 0.15 g, 0.99 mmol)
was refluxed in toluene (5 mL) for 2 h. On cooling to 0 °C, the
precipitate that formed was filtered off to give compound 5 (0.21 g).
3ꢀAminoꢀ4ꢀcyanoꢀ5Hꢀpyrido[4,3ꢀb]indole (6) was obtained
as described earlier.5
13ꢀAminoꢀ2,3,4,12ꢀtetrahydroꢀ1Hꢀbenzo[b]indolo[2,3ꢀf]ꢀ
1,8ꢀnaphthyridine (12). A mixture of compound 6 (1.09 g,
5.24 mmol) and molten ZnCl2 (0.72 g, 5.29 mmol) was refluxed
in cyclohexanone (25 mL) for 40 min. On cooling to 0 °C, the
precipitate (2.07 g) was filtered off, washed with light petroleum,
and dissolved in water (300 mL). Sodium hydroxide (ca. 4.9 g)
was added for complete precipitation. The precipitate was
filtered off and washed successively with water, methanol, and
light petroleum to give compound 12 (1.01 g).
13ꢀAminoꢀ2,3,4,12ꢀtetrahydroꢀ1Hꢀbenzo[b]indolo[2,3ꢀf]ꢀ
1,8ꢀnaphthyridine hydrochloride (12a). A 18% solution of HCl in
ethanol (0.5 mL) was added dropwise to compound 12 (0.5 g,
1.74 mmol) in methanol (10 mL). The reaction mixture was
stirred at room temperature for 30 min. The precipitate
was filtered off to give compound 12a (0.5 g).
4ꢀCyanoꢀ3ꢀdimethylaminomethylideneaminoꢀ5Hꢀpyridoꢀ
[4,3ꢀb]indole (7) was obtained as described earlier.5
1
3ꢀAminoꢀ4ꢀcyanoꢀ2ꢀmethylꢀ5Hꢀpyrido[4,3ꢀb]indolꢀ2ꢀium
iodide (8). A mixture of compound 6 (1.03 g, 4.95 mmol) and
methyl iodide (0.5 mL) was stirred in dry DMF (15 mL) at room
temperature for 6 h, while adding another portion of methyl
iodide (0.5 mL) every 2 h (in all, four times). The reaction
mixture was kept at room temperature for an additional 15 h and
cooled to 0 °C. The precipitate that formed was filtered off to
give compound 8 (0.93 g).
Compound 12a. H NMR (DMSOꢀd6), δ: 1.85 (m, 4 H),
2.57 (m, 2 H), 2.94 (m, 2 H) (H2C(1—4)); 7.39 (t, 1 H, Jo = 7.5 Hz),
7.56 (t, 1 H, Jo = 7.5 Hz), 7.80 (d, 1 H, Jo = 7.5 Hz), 8.33 (d,
1 H, Jo = 7.5 Hz) (H(8 )—H(11)); 8.28 (br.s, 2 H, NH2); 9.61 (s,
1 H, H(7)); 13.29, 13.75 (br.s, 1 H each, N(12)H, N+H).
4ꢀCyanoꢀ5Hꢀ2,3ꢀdihydropyrido[4,3ꢀb]indolꢀ3ꢀone (13) was
obtained as described earlier.5
3ꢀChloroꢀ4ꢀcyanoꢀ5Hꢀpyrido[4,3ꢀb]indole (14). A mixture
of compound 13 (0.3 g, 1.44 mmol), triethylamine hydrochloꢀ
ride (0.21 g, 1.44 mmol), and phosphoryl chloride (4 mL) was
refluxed for 8 h and then kept at room temperature for an addiꢀ
tional 15 h. The precipitate that formed was filtered off and
washed successively with water, an aqueous solution of K2CO3,
again water, and diethyl ether to give compound 14 (0.26 g).
1H NMR (DMSOꢀd6—CCl4), δ: 7.35 (t, 1 H, Jo = 7.5 Hz),
7.56 (m, 2 H), 8.24 (d, 1 H, Jo = 7.5 Hz) (H(6)—H(9)); 9.27 (s,
1 H, H(1)); 12.85 (br.s, 1 H, N(5)H).
4ꢀCyanoꢀ3ꢀ[2ꢀ(dimethylamino)ethylamino]ꢀ5Hꢀpyridoꢀ
[4,3ꢀb]indole (15). A mixture of compound 14 (0.22 g,
0.97 mmol) and 2ꢀdimethylaminoethylamine (2 mL) was reꢀ
fluxed for 3 h and then kept at room temperature for an addiꢀ
tional 15 h. The excess amine was removed, the residue was
triturated with isopropyl alcohol, and the resulting precipitate
was filtered off to give compound 15 (0.21 g).
1H NMR (DMSOꢀd6), δ: 3.93 (s, 3 H, CH3); 7.34—8.05 (m,
4 H, H(6)—H(9)); 8.55 (br.s, 2 H, NH2); 9.35 (s, 1 H, H(1));
13.01 (br.s, 1 H, N(5)H).
4ꢀCyanoꢀ3ꢀdimethylaminomethylideneaminoꢀ2ꢀmethylꢀ5Hꢀ
pyrido[4,3ꢀb]indolꢀ2ꢀium iodide (9). A mixture of compound 7
(0.36 g, 1.36 mmol) and methyl iodide (0.6 mL) was stirred in
dry DMF (7 mL) at room temperature for 6 h. Another portion
of methyl iodide (0.5 mL) was added and the mixture was kept at
room temperature for two days. Then methyl iodide (2×0.5 mL)
was added every 4 h. The precipitate that formed was filtered off
and washed with diethyl ether to give compound 9 (0.34 g).
1H NMR (DMSOꢀd6), δ: 3.19, 3.29 (both s, 3 H each,
N(CH3)2); 3.99 (s, 3 H, CH3); 7.47 (t, 1 H, Jo = 7.5 Hz), 7.60
(m, 2 H), 8.19 (d, 1 H, Jo = 7.5 Hz) (H(6)—H(9)); 8.48, 9.66
(both s, 1 H each, N=CH, H(1)); 13.34 (br.s, 1 H, NH).
1ꢀAminoꢀ5ꢀmethylpyrimido[5´,4´:5,6]pyrido[4,3ꢀb]indole
(10). A. A mixture of compound 9 (0.35 g, 0.86 mmol) and a
saturated solution of ammonia (11 mL) in methanol was kept
at room temperature for 5 days. The precipitate that formed
was filtered off and washed with diethyl ether to give compound
10 (0.2 g).
B. A mixture of compound 7 (0.46 g, 1.31 mmol) and acetal
4 (0.34 mL, 0.29 g, 1.97 mmol) was refluxed in toluene (3 mL)
for 1 h and then kept at room temperature for 16 h. Another
portion of acetal 4 (0.1 mL, 0.09 g, 0.58 mmol) was added and
the reaction mixture was refluxed for 1 h. On cooling to 0 °C,
the precipitate (0.47 g) that formed was filtered off and kept in a
saturated solution of ammonia (5 mL) in methanol at room
temperature for two days. The precipitate that formed was filtered
off and washed with diethyl ether to give compound 10 (0.1 g).
1ꢀDimethylaminomethylideneaminoꢀ5ꢀmethylpyrimidoꢀ
[5´,4´:5,6]pyrido[4,3ꢀb]indole (11). A mixture of compound 10
(0.1 g, 0.4 mmol) and acetal 4 (0.07 mL, 0.06 g, 0.42 mmol) was
refluxed in toluene (5 mL) for 2 h. Another portion of acetal 4
(0.05 mL, 0.04 g, 0.29 mmol) was added and the reaction mixꢀ
ture was refluxed for 1 h. On cooling to 0 °C, the precipitate that
formed was filtered off and washed with diethyl ether to give
compound 11 (0.08 g).
1H NMR (DMSOꢀd6—CCl4), δ*: 2.24 (s, 6 H, N(CH3)2);
3.56 (m, 2 H, CH2); 6.49 (t, 1 H, NH, Jo = 5.1 Hz); 7.15 (t,
1 H), 7.28 (t, 1 H), 7.40 (d, 1 H), 7.91 (d, 1 H) (H(6)—H(9),
Jo = 7.5 Hz); 8.85 (s, 1 H, H(1)); 11.84 (br.s, 1 H, N(5)H).
4ꢀCyanoꢀ5ꢀcyanomethylꢀ3ꢀdimethylaminomethylideneaminoꢀ
pyrido[4,3ꢀb]indole (16a). Sodium hydride (0.08 g, 2.08 mmol)
as a 60% suspension in Vaseline oil was added under argon
to compound 7 (0.55 g, 2.08 mmol) in dry DMF (10 mL).
The reaction mixture was heated to 70 °C, stirred for
30 min, and cooled to room temperature. Chloroacetonitrile
(0.24 g, 0.2 mL, 3.18 mmol) in dry DMF (5 mL) was
added and the mixture was stirred at room temperature for 3 h
and left for 15 h. The precipitate that formed was filtered
off and washed with isopropyl alcohol to give compound 16a
(0.32 g).
1H NMR (DMSOꢀd6—CCI4), δ: 3.11, 3.23 (both s, 3 H
each, N(CH3)2); 5.80 (s, 2 H, CH2CN), 7.34 (t, 1 H), 7.50 (t,
1 H), 7.76 (d, 1 H), 8.10 (d, 1 H) (H(6)—H(9), Jo = 7.5 Hz);
8.79, 9.03 (both s, 1 H each, N=CH, H(1)).
* The signal for the second methylene group is masked with the
signal of the solvent.

A new route to pyrido[4,3ꢀb]indoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2417
4ꢀCyanoꢀ3ꢀdimethylaminomethylideneaminoꢀ5ꢀphenacylpyridoꢀ
[4,3ꢀb]indole (16b). Sodium hydride (0.1 g, 2.72 mmol) as a
60% suspension in Vaseline oil was added under argon to comꢀ
pound 7 (0.48 g, 1.81 mmol) in dry DMF (6 mL). The reaction
mixture was heated to 70 °C, stirred for 30 min, and cooled to
room temperature. 2ꢀBromoacetophenone (0.54 g, 2.72 mmol)
was added and the mixture was stirred at room temperature for
an additional 2 h. The precipitate was filtered off and washed
with isopropyl alcohol to give compound 16b (0.33 g).
1H NMR (DMSOꢀd6—CCl4), δ: 3.11, 3.19 (both s, 3 H
each, N(CH3)2); 6.26 (s, 2 H, CH2); 7.30 (t, 1 H, Jo = 7.5 Hz),
7.41 (t, 1 H, Jo = 7.5 Hz), 7.62 (m, 3 H), 7.74 (m, 1 H), 8.15
(m, 3 H) (Ph, H(6)—H(9)); 8.77, 9.01 (both s, 1 H each,
N=CH, H(1)).
5ꢀCarbamoylmethylꢀ4ꢀcyanoꢀ3ꢀdimethylaminomethylideneꢀ
aminopyrido[4,3ꢀb]indole (16c). A. Sodium hydride (0.07 g,
1.71 mmol) as a 60% suspension in Vaseline oil was added under
argon to compound 7 (0.3 g, 1.13 mmol) in dry DMF (4 mL).
The reaction mixture was heated to 70 °C, stirred for 30 min,
and cooled to room temperature. Chloroacetamide (0.16 g,
1.71 mmol) was added and the reaction mixture was stirred at
room temperature for 3 h and left for 15 h. The precipitate that
formed was filtered off and washed with isopropyl alcohol to
give compound 16c (0.24 g).
B. A mixture of compound 16a (0.50 g, 1.66 mmol), potasꢀ
sium tertꢀbutoxide (0.17 g, 1.77 mmol), and tertꢀbutyl alcohol
(7.86 g) was refluxed for 75 min. On cooling to room temperaꢀ
ture, the mixture was stirred with anhydrous ethanol (5 mL) for
an additional 30 min. The precipitate that formed was filtered
off and washed with ethanol to give compound 16c (0.5 g).
1H NMR (DMSOꢀd6—CCl4), δ: 3.17, 3.22 (both s, 3 H each,
N(CH3)2); 5.22 (s, 2 H, CH2); 7.28 (t, 1 H, Jo = 7.5 Hz), 7.44
(m, 2 H), 8.08 (d, 1 H, Jo = 7.5 Hz) (H(6)—H(9)); 7.25, 7.66
(both br.s, 1 H each, CONH2); 8.77, 9.00 (both s, 1 H each,
N=CH, H(1)).
2. V. G. Granik, Lekarstva. Farmakologicheskii, biokhimicheskii
i khimicheskii aspekty [Drugs: Pharmacological, Biochemical,
and Chemical Aspects], Vuzovskaya Kniga, Moscow, 2001,
407 pp. (in Russian).
3. M. PorcsꢀMakkay, G. Simig, J. Heterocycl. Chem., 2001,
38, 451.
4. R. P. Robinson, L. A. Reiter, W. B. Barth, A. M. Campeta,
K. Cooper, B. J. Cronin, R. Destito, K. M. Donahue, F. C.
Falkner, E. F. Fiese, D. L. Johnson, A. V. Kuperman, T. E.
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S. L. Shamblin, C. F. Wright, J. Med. Chem., 1996, 39, 10.
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Smirnova, M. I. Evstratova, S. S. Kiselev, V. G. Granik, Izv.
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Ed., 2008, 57, 177].
6. V. G. Granik, E. N. Dozorova, N. B. Marchenko, L. I.
Budanova, V. A. Kuzovkin, R. G. Glushkov, Khim.ꢀFarm.
Zh., 1987, 21, 10, 1249 [Pharm. Chem. J., 1987, 21, 10, 1249
(Engl. Transl.)].
7. S. Yu. Ryabova, L. M. Alekseeva, V. G. Granik, Khim.
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2001, 1086 (Engl. Transl.)].
8. V. G. Granik, Organicheskaya khimiya: Reaktsiya Nenitsesku.
Izbrannye glavy kursa organicheskoi khimii na baze odnoi
imennoi reaktsii [Organic Chemistry: The Nenitzescu Reaction.
Selected Chapters from the Course of Organic Chemistry
Concerned with a Particular Named Reaction], Vuzovskaya
Kniga, Moscow, 2003, 384 pp. (in Russian).
9. N. I. Smetskaya, Ph.D. (Chem.) Thesis, Novokuznetskii
nauchnoꢀissledovatel´skii khimikoꢀfarmatsevticheskii institut,
Novokuznetsk, 1985, 142 pp. (in Russian).
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Received June 11, 2008