2-[(3,5-Diamino-1H-pyrazol-4-yl)methylidene]-1,2-dihydro-3H-indol-3-ones: Synthesis and properties

Article abstract of DOI:10.1007/s11172-009-0269-y

Reactions of 3-acetoxy-2-(2,2-dicyanovinyl)indole with hydrazine hydrate and methyl-and phenylhydrazines afforded new indolin-3-one derivatives, namely, 2-[(3,5-diaminopyrazol-4-yl)methylidene]indolin-3-ones. Reactions of the compounds obtained with acetic anhydride and DMF and DMAA dimethyl acetals were studied. Cyclization of 2-[(3,5-diamino-1H-pyrazol4-yl)methyridene]-1,2-dihydro- 3 H-indolinone gave 3-amino-1,5-dihydropyrazolo-[4',3':5,6]pyrido[3,2-b]indole, a representative of a novel heterocyclic system.

Full text of DOI:10.1007/s11172-009-0269-y

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1973—1980, September, 2009
1973
2ꢀ[(3,5ꢀDiaminoꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ
1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀones: synthesis and properties
N. S. Masterova,a S. Yu. Ryabova,a L. M. Alekseeva,a A. S. Shashkov,b V. V. Chernyshev,c and V. G. Granika
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117003 Moscow, Russian Federation.
Fax: +7 (499) 611 1548. Eꢀmail: syuryabova@yandex.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119899 Moscow, Russian Federation.
Fax: +7 (495) 939 3654. Eꢀmail: vladimir@struct.chem.msu.ru
Reactions of 3ꢀacetoxyꢀ2ꢀ(2,2ꢀdicyanovinyl)indole with hydrazine hydrate and methylꢀ and
phenylhydrazines afforded new indolinꢀ3ꢀone derivatives, namely, 2ꢀ[(3,5ꢀdiaminopyrazolꢀ
4ꢀyl)methylidene]indolinꢀ3ꢀones. Reactions of the compounds obtained with acetic anhydride
and DMF and DMAA dimethyl acetals were studied. Cyclization of 2ꢀ[(3,5ꢀdiaminoꢀ
1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ1,2ꢀdihydroꢀ3Hꢀindolinone gave 3ꢀaminoꢀ1,5ꢀdihydropyrazoloꢀ
[4´,3´:5,6]pyrido[3,2ꢀb]indole, a representative of a novel heterocyclic system.
Key words: 3ꢀacetoxyꢀ2ꢀ(2,2ꢀdicyanovinyl)indole, hydrazines, 2ꢀ[(3,5ꢀdiaminoꢀ
1Hꢀpyrazolꢀ4ꢀyl)methylidene]indolinꢀ3ꢀones, acetylation, Xꢀray diffraction analysis, DMF
and DMAA dimethyl acetals, cyclization, pyrazolo[4´,3´:5,6]pyrido[3,2ꢀb]indole.
Earlier,1,2 we have reported that 3ꢀacetoxyꢀ2ꢀ(2,2ꢀdiꢀ
cyanovinyl)indole (1) reacts with primary and secondary
aliphatic and aromatic amines to give, through interꢀ
mediate ammonium salts 2, 2ꢀ(3,3ꢀdiaminoꢀ2ꢀcyanopropꢀ
2ꢀenylidene)indolinꢀ3ꢀones (hereafter diene diamines) 3
(Scheme 1) with pronounced antihypertensive activity.1—3
Using diene diamines 3 as starting materials, we
developed an approach to the synthesis of new pyrroloꢀ
[1,2ꢀa]indoles4 and obtained the novel heterocyclic
system pyrimido[5´,4´:5,6]pyrido[3,2ꢀb]indole.5
In the present work, we studied reactions of dicyanoꢀ
vinylindole 1 with hydrazine hydrate, methylhydrazine,
and phenylhydrazine.
We assumed that these reactions would proceed as
with amines1 to give salts 4a—c undergoing dissociation
to hydroxyindole 5 and the corresponding hydrazine
(Scheme 2). The high acidity of the 3ꢀhydroxy group in
compound 5 would favor the activation of the CN group
and tautomerization into imino ketene 6. Rapid and irreꢀ
versible addition of hydrazines to imino ketene 6 would
yield amidines 7a—c, which are stable as tautomers
8a—c. Thus, we expected to obtain 2ꢀ(3ꢀaminoꢀ2ꢀcyanoꢀ
3ꢀhydrazinopropꢀ2ꢀenylidene)indolinꢀ3ꢀones (8a—c) as
the final products (see Scheme 2).
Scheme 1
It turned out that dicyanovinylindole 1 reacts with
hydrazine hydrate in isopropyl alcohol even at room
temperature to give hydrazinium salt 4a identified by IR
1
and H NMR spectroscopy and mass spectrometry (see
Experimental).
Subsequent reflux of a solution of salt 4a in the same
solvent gave a product containing no CN groups (its IR
spectrum does not show the corresponding absorption
Conditions and reagents: i, RR´NH, C6H6; ii, RR´NH, C6H6 or
PriOH, Δ; iii, Δ.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1911—1918, September, 2009.
1066ꢀ5285/09/5809ꢀ1973 © 2009 Springer Science+Business Media, Inc.

1974
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Masterova et al.
Scheme 2
R = H (a), Me (b), Ph (c)
bands at 2200 cm–1). Therefore, both the cyano groups
are involved in the reaction.
corresponding to diene diamine 8c)*. Further reflux of
compound 8c in isopropyl alcohol for 2 h resulted in
closure of a pyrazole ring and hence the formation of
compound 9c. Structures 9b,c were confirmed by 1H NMR,
IR, and mass spectra (see Experimental and Table 1).
Thus, we demonstrated that the reactions of dicyanoꢀ
vinylindole 1 with hydrazines and amines are similar.
Addition of a hydrazine to one cyano group of compound
1 is promoted by its own acidic 3ꢀhydroxy group and thus
no catalysts are required (as noted earlier6). However, the
presence of the group —NHNH2 in compounds 8a—c
allows the formation of a pyrazole ring, yielding the new
indole derivatives 2ꢀ[(3,5ꢀdiaminopyrazolꢀ4ꢀyl)methylꢀ
idene]indolinꢀ3ꢀones 9a—c.
It should be noted that analogous pyrazoleꢀcontaining
compounds have been obtained earlier by reactions of
hydrazine with 3ꢀdicyanovinylquinoline7 and 3ꢀdicyanoꢀ
vinylindole.8
Structures 9 seem to be suitable for cyclization involvꢀ
ing the indoline CO group and the pyrazole NH2 group
(formation of a pyridine ring).
We assumed that the formation of compound 8a is
followed by its cyclization through the second cyano
group and the amino group of the hydrazine fragment.
Thus, the final product is 2ꢀ[(3,5ꢀdiaminoꢀ1Hꢀpyrazolꢀ
4ꢀyl)methylidene]ꢀ1,2ꢀdihydroꢀ3Hꢀindolinꢀ3ꢀone (9a),
a new indolinꢀ3ꢀone derivative.
The mass spectrum of compound 9a contains a moꢀ
lecular ion peak, which corresponds to its molecular mass.
The 1H NMR spectrum shows signals for the vinylic proꢀ
ton, the protons of the benzene ring, the NH protons in
the pyrazole (δ 10.65) and pyrrole rings (δ 9.28), and the
protons of two primary amino groups (δ 5.28, 4 H). The
presence of both the indolinone fragment and the pyrazole
ring is confirmed by correlation peaks in the HMBC NMR
spectrum: the signal for N(1)H (δ 9.28) correlates with
the signal for C(3) (δ 183.3) and the signal for CH (δ 6.80)
correlates with the signals for C(3), C(3´), and C(5´)
(δ 150.8).
A reaction of dicyanovinylindole 1 with methylꢀ
hydrazine in isopropyl alcohol occurs much more easily
than that with hydrazine hydrate: even at room temperaꢀ
ture, we obtained 2ꢀ[(1ꢀmethylpyrazolꢀ4ꢀyl)methylꢀ
idene]indolinꢀ3ꢀone 9b in 58% yield without isolating
intermediate salt 4b. This is probably due to the fact that
intermediate methylhydrazinium salt 4b is less stable than
hydrazinium salt 4a. Destabilizing steric effects facilitate
the decomposition of salt 4b and increase the rates of all
subsequent reactions.
A reaction of dicyanovinylindole 1 with phenylhydrꢀ
azine in isopropyl alcohol at room temperature, as well as
in boiling isopropyl alcohol, produced a complex mixture
of inseparable compounds. The same reagents in boiling
benzene reacted to give a product containing a CN group
(its IR spectrum shows an absorption band at 2191 cm–1
and its mass spectrum contains a molecular ion peak
However, attempted cyclization of compounds 9a,b
in boiling acetic anhydride gave only diꢀ (10a) and
monoacetyl derivatives (10b) (Scheme 3).
Acetylation of compound 9a can occur at both the
pyrazole N atom and the primary amino groups. The mass
spectrum of the compound obtained contains an intense
molecular ion peak corresponding to diacetylated prodꢀ
1
uct 10a. Unlike the H NMR spectrum of the starting
compound 9a, the spectrum of product 10a does not show
the signal for the pyrazole NH proton at δ 10.65, but it
contains signals for the NH2 group (δ 7.00, 2 H), the
* The 1H NMR spectrum of compound 8c was not recorded
because of its transformation into compound 9c upon dissoluꢀ
tion in DMSO. After 3—4 h, the spectrum of the resulting soluꢀ
tion showed signals for compound 9c only.

(Diaminopyrazolꢀ4ꢀylmethylidene)indolinꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1975
Table 1. Yields, melting points, elemental analysis data, and mass and IR spectra of the compounds obtained
Comꢀ
pound (%)
Yield
M.p./°С
(solvent for
М
Molecular
formula
Found
Calculated
IR,
max/cm–1
MS,
m/z
(%)
ν
recrystallization)
С
Н
N
8c
18
220—224
(Me2CO)
317
C
18H15N5O
67.83 4.54 21.85
68.14 4.76 22.07
1651 (CO),
2191 (CN),
3196, 3300,
3439 (NH, NH2) 657 [2 M + Na]+,
952 [3 M + H]+
318 [M + H]+,
340 [M + Na]+,
635 [2 M + H]+,
9a
9b
61
58
188—192
(PriOH)
241
255
C12H11N5O
C13H13N5O
59.99 4.60
59.74 4.60
—
1647 (CO),
3153
3163(NH2)
242 [M + H]+,
280 [M + K]+,
483[2 M + H]+,
521 [2 M + K]+
256 [M + H]+,
278 [M + Na]+,
511[2 M + H]+,
533 [2 M + Na]+,
766 [3 M + H]+,
788 [3 M + Na]+
318 [M + H]+,
635 [2 M + H]+,
252—258
(MeOH : DMF,
2 : 1)
61.04 5.36 27.41
61.17 5.13 27.43
1668 (CO),
3151, 3300,
3369 (NH2)
9c
67
69
210—214
(PriOH)
317
325
C18H15N5O
67.83 4.45 21.87
68.13 4.76 22.07
1668 (CO),
3182,
3304 (NH, NH2) 952 [3 M + H]+
1714 (CO),
3252,
3433 (NH2)
10a
274—276
(DMF : H2O,
2 : 1)
С16H15N5O3 59.81 4.69 21.53
59.07 4.65 21.53
326 [M + H]+,
348 [M + Na]+,
364 [M + K]+,
651[2 M + H]+,
689 [2 M + K]+,
673 [2 M + Na]+,
976 [3 M + H]+,
998 [3 M + Na]+
10b
65
280—284
(DMF : H2O,
3:1)
297
C15H15N5O2 60.49 5.23 23.20
60.60 5.09 23.56
1653, 1707 (CO), 298 [M + H]+,
3209, 3300,
595 [2 M + H]+,
3427 (NH, NH2) 892 [3 M + H]+
3132, 3348,
208 [M + H – 16]+,
11
20
75
>320
223
351
C12H9N5
64.57 4.23 31.52
64.56 4.06 31.37
61.41 5.90 27.52
61.52 6.02 27.90
3416 (NH, NH2) 224 [M + H]+
1670 (CO), 3055, 262 [M + H – 90]+,
3138, 3174 (NH) 307 [M + H – 45]+,
352 [M + H]+,
12a
212—220
(EtOH)
C18H21N7O
374 [M + Na]+,
703 [2 M + H]+
12b
12c
83
51
162—166
(hexane : PriOH,
2 : 1)
137—138
(CH3Cl : hexane,
2 : 1)
365
379
C19H23N7O
C20H25N7O
62.43 6.49 26.58
62.45 6.34 26.83
1668 (CO)
1668(CO)
366 [M + H]+,
731 [2 M + H]+
63.26 6.42 25.91
63.30 6.64 25.84
290 [M + H – 90]+,
380 [M + H]+,
402 [M + Na]+,
760 [2 M + H]+
proton of the indole NH group (δ 8.68), and the proton of
the NHCOCH3 group (δ 9.98). Acetylation of 2ꢀ[(3,5ꢀdiꢀ
aminoꢀ1ꢀmethylpyrazolꢀ4ꢀyl)methylidene]indolinꢀ3ꢀone
9b under similar conditions gave monoacetyl derivative
10b. Note that compounds 10a,b can be represented by
either structure A or B (Scheme 3).
ined them by Xꢀray diffraction and obtained unambiguꢀ
ous evidence for structure B (Figs 1, 2).
Crystal structures 10a and 10b were determined by
powder Xꢀray diffraction analysis.9 Powder patterns were
recorded in a Huber Imaging Plate Camera G670 with
a bent Ge monochromator. The positions of the first
30 peaks were refined and used for indexing the powder
patterns in a triclinic cell with the TREOR90 program.10
Since 1H, 13C, and HMBC NMR data are insufficient
for accurate determination of structures 10a,b, we examꢀ

1976
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Masterova et al.
Scheme 3
a
C(21)
C(19)
O(9)
N(17)
C(12)
C(2)
C(1)
C(7)
C(5)
C(4)
O(20)
C(11)
C(14)
N(18)
N(15)
C(6)
C(13)
N(10)
C(3)
C(8)
N(16)
C(22)
C(24)
O(23)
R = COCH3 (a), CH3 (b)
10a
240000
a
b
O(9)
C(4)
C(21)
C(19)
N(17)
C(2)
C(5)
C(7)
C(12)
O(20)
C(11)
1
C(6)
C(14)
N(10)
N(18)
C(1)
C(3)
0
C(8)
2
N(15)
C(13)
10 20 30 40 50 60 70 80 2θ/deg
N(16)
170000
b
C(22)
10b
Fig. 2. Molecular structures 10a (a) and 10b (b) with atomic
numbering. For the nonꢀhydrogen atoms, their thermal disꢀ
placement spheres (50% probability) are indicated.
refinement11 of the powder patterns with the MRIA
program12 (Table 2).
Crystal structures 10a and 10b were solved using the
simulated annealing algorithm16 for the centrosymmetric
space group P1. The structures found for a DFTꢀoptiꢀ
mized (with the PRIRODA program17) 3D model were
refined by the Rietveld method with the MRIA program;
the peak profiles were approximated with the modified
Voigt function.18 In the refinement, permissible variations
of the interatomic distances in the structures and the ring
planarity were restrained. The parameters of the thermal
vibrations of the nonꢀhydrogen atoms were refined isoꢀ
tropically. The hydrogen atoms were located geometriꢀ
cally and their positions were not refined. Selected crysꢀ
tallographic parameters and the data collection statistics
for compounds 10a and 10b are summarized in Table 2.
Experimental powder patterns and the difference curves
1
0
2
10 20 30 40 50 60 70 80 2θ/deg
Fig. 1. Powder patterns of structures 10a (a) and 10b (b) refined
by the Rietveld method: (1) experimental curves, (2) difference
curves between the experimental and calculated powder patterns
upon the refinement, and (3) calculated positions of the peaks.
For compound 10b, two weak peaks with interplanar
spacings of 8.311 and 6.108 Å were unfit for the triclinic
cell and assigned to an unknown impurity. The correctꢀ
ness of the determined unit cells was verified by the Pawley

(Diaminopyrazolꢀ4ꢀylmethylidene)indolinꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1977
Table 2. Crystallographic parameters of structures 10a and 10b
obtained upon the Rietveld refinement are shown in
Fig. 1.
Parameter
10a
10b
All the geometrical parameters in crystal structures
10a and 10b (see Fig. 2) have common values comparable
with those found in the Cambridge Crystallographic
Data Collection.19 In the crystal, the molecules of comꢀ
pound 10b are linked by intermolecular hydrogen bonds
Molecular formula
Crystal system
Space group
a/Å
b/Å
c/Å
C16H15N5O3
Triclinic
P1
C15H15N5O2
Triclinic
P1
9.186(2)
11.938(2)
7.4320(16)
94.643(15)
100.217(18)
109.31(2)
748.4(3)
49
8.2631(19)
12.306(2)
7.2252(15)
98.779(12)
93.904(15)
70.448(11)
684.1(2)
31
...
N—H O (Table 3). For compound 10a, similar hydroꢀ
...
gen bonds N—H O are supplemented with weak conꢀ
α/deg
β/deg
...
tacts C—H O; their parameters are given in Table 3.
γ/deg
Thus, compounds 9a,b are acetylated in boiling acetic
anhydride only at the amino group in position 3 of the
pyrazole ring. The selectivity of this acylation reaction
can be interpreted in terms of basicity:20 introduction
of one and two amino groups into a pyrazole molecule
(pKa = 2.47) increases its basicity to pKa = 6.16 and 8.59,
respectively. It seems logical that the strong base 9a in
acetic anhydride abstracts the proton from the endocyclic
NH group of a second molecule of this compound to give
cation C and anion D (Scheme 4). Acetylation of the
latter yields the corresponding Nꢀacetylpyrazole E, which
undergoes further acetylation at one of the NH2 groups
(Scheme 4).
V/Å3
M20
*
F30
Z
*
72 (0.009, 57) 47 (0.010, 76)
2
2
Dx (g cm–3
Radiation
(λ/Å)
)
1.444
1.443
CuKα1
1.54059
CuKα1
1.54059
Powder pattern:
2θmin – 2θ
(scan step/deg)
4.00 – 100.00
(0.01)
4.00 – 100.00
(0.01)
max
Rp*
0.0234
0.0180
Rwp
*
0.0297
0.0246
Rexp
χ *
*
0.0086
11.992
0.0072
11.669
2
Since the basicity of 5ꢀNH2 group in intermediate E
is sharply lowered by a strong negative mesomeric effect
* The figures of merit M20 and F30 were defined in Refs 13
and 14, respectively; Rp, Rwp, Rexp, and χ were defined in Ref. 15.
2
Table 3. Parameters of the hydrogen bonds in structures 10a and 10b
D—H...A H...A
Compound
D—H
D...A
D—H...A
/deg
Å
10a
10b
N(10)—H(10)...O(20)i
N(17)—H(17)...O(9)ii
C(24)—H(24B)...O(23)iii
N(10)—H(10)...O(20)i
N(16)—H(16A)...O(9)ii
N(17)—H(17)...O(9)iii
0.86
0.86
0.96
0.86
0.86
0.86
2.24
1.94
2.41
2.27
2.38
2.10
3.021(6)
2.794(6)
3.273(6)
3.011(4)
3.057(4)
2.937(5)
150
172
150
145
136
164
Symmetry operation codes: (i) –x, –y, –z; (ii) 1 – x, –y, 1 – z; (iii) –1 – x, –y, –z for compound
10a and (i) –x, 1 – y, 1 – z; (ii) x – 1, y, z; (iii) 1 – x, 1 – y, 2 – z for compound 10b.
Scheme 4

1978
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Masterova et al.
of the O atom (see Scheme 4, structure F), subsequent
acetylation occurs at the more basic 3ꢀNH2 group to give
compound 10a(B). As a result, the basicity of the 5ꢀNH2
group decreases still more, which prevents its acetylation.
Analogously, monoacetyl derivative 10b(B) is obtained
from compound 9b.
Scheme 6
or PPA
It should be recollected that a reaction of 3,5ꢀdiaminoꢀ
4ꢀphenylꢀ1Hꢀpyrazole with acetic anhydride also gives a
1ꢀacetylꢀ3ꢀacetylamino derivative.21 Its formation is posꢀ
sible only if the acetylation at the NH group of the pyrazole
ring is dominant in the first step of the process. Further
acetylation at the 3ꢀNH2 (rather than 5ꢀNH2) group is
explained by a negative mesomeric effect of the 4ꢀphenyl
substituent lowering the basicity of the 5ꢀNH2 group
(Scheme 5).
Scheme 5
It turned out that compounds 9a,b react with DMF
and DMAA dimethyl acetals to give the corresponding
bisamidines 12a—c (Scheme 7).
Scheme 7
It is worth noting that acidꢀcatalyzed acetylation of
3,5ꢀdiaminopyrazole in hot acetic acid most likely does
not involve the formation of an amide anion at position 1,
thus yielding 3,5ꢀdiacetylaminopyrazole.22
Thus, the attempted closure of a pyridine ring in comꢀ
pounds 9a,b in acetic anhydride failed. This objective was
achieved by using strong acid agents for activation of the
indole C=O group. For instance, a reaction of compound
9a with trifluoroacetic or polyphosphoric acid (PPA) gave
3ꢀaminopyrazolo[4´,3´:5,6]pyrido[3,2ꢀb]indole 11, which
is a representative of a novel heterocyclic system.
Since the reaction was carried out in an acidic
medium and compound 11 is likely to be a fairly strong
base*, we additionally treated the reaction mixture with
NaOH to prevent salt formation (e.g., trifluoroacetate
salts) (Scheme 6).
12
a
b
R
H
Me
H
R´
H
H
c
Me
Structures 12a—c were determined from IR, 1H NMR,
and mass spectra; they agree with elemental analysis data
(see Experimental and Table 1).
The yield of 3ꢀaminoꢀ1,5ꢀdihydropyrazolo[4´,3´:5,6]ꢀ
pyrido[3,2ꢀb]indole (11) was 20% in CF3COOH and only
3% in PPA.
Because the aforesaid acetylation of diamino derivaꢀ
tives 9a,b involved only one primary amino group, we
studied reactions of these compounds with DMF and
DMAA dimethyl acetals.24
Experimental
IR spectra were recorded on an FSMꢀ1201 instrument
(Nujol). Mass spectra were measured on a Waters ZQꢀ2000
mass spectrometer (ESI, direct inlet probe). 1H NMR spectra
were recorded on Bruker DRXꢀ500 and Bruker ACꢀ300 specꢀ
trometers with DMSOꢀd6 as a standard. The crystallographic
* The basicity constant pKa of Nꢀmethylpyrido[3,2ꢀb]indole is
10.77 (see Ref. 23).

(Diaminopyrazolꢀ4ꢀylmethylidene)indolinꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1979
parameters of structures 10a,b have been deposited with the
Cambridge Crystallographic Data Center (CCDC 710 828 and
710 829, respectively). The course of the reactions was moniꢀ
tored, and the purity of the products was checked, by TLC on
60 F254 plates (Merck) in chloroform—methanol (10 : 1). Spots
were visualized under UV light. The yields, melting points,
elemental analysis data, and mass and IR spectra of the comꢀ
pounds obtained are given in Table 1.
Hydrazinium 2ꢀ(2,2ꢀdicyanovinyl)indolꢀ3ꢀolate (4a). Hydrꢀ
azine hydrate (3 mL, 60 mmol) was added to a suspension
of dicyanovinylindole 1 (3 g, 12 mmol) in isopropyl alcohol
(70 mL). The suspension was stirred at room temperature for
2.5 h. The precipitate was filtered off, washed with isopropyl
alcohol, and dried. The yield of salt 4a was 2.2 g (76%),
m.p. 158—164 °C, M 241. IR, ν/cm–1: 1620 (CO), 2175, 2196
(CN), 3348, 3416 (NH2). 1H NMR (DMSOꢀd6), δ*: 6.47 (s,
1 H, CH); 6.70 (t, 1 H, H(5)); 7.13 (d, 1 H, H(7)); 7.26 (t, 1 H,
H(6)); 7.43 (d, 1 H, H(4)); 10.14 (s, 1 H, N(1)H). MS, m/z:
210 [M + H]+, 232 [M + Na]+, 248 [M + K]+, 419 [2 M + H]+,
441 [2 M + Na]+, 457 [2 M + K]+.
2ꢀ[(3,5ꢀDiaminoꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ1,2ꢀdihydroꢀ
3Hꢀindolꢀ3ꢀone (9a). A suspension of salt 4a (2.2 g) in isopropyl
alcohol (40 mL) was refluxed with stirring for 3 h. The precipiꢀ
tate was filtered off hot, washed with isopropyl alcohol and
ether, and dried. The yield of compound 9a was 1.37 g. The
mother liquor was concentrated in vacuo to a viscous suspension
and the resulting precipitate was filtered off. An additional crop
of compound 9a was 0.38 g. 1H NMR (DMSOꢀd6), δ: 5.28 (br.s,
4 H, 2 NH2); 6.80 (s, 1 H, CH); 6.82 (t, 1 H, H(5)); 7.06 (d,
1 H, H(7)); 7.39 (t, 1 H, H(6)); 7.51 (d, 1 H, H(4)); 9.28 (s, 1 H,
N(1)H); 10.65 (br.s, 1 H, N(1´)H). 13C NMR (DMSOꢀd6), δ:
89.8 C(4´); 107.2 (CH); 112.4 (C(7)); 118.2 (C(5)); 121.8
(C(3a)); 123.2 (C(4)); 129.6 (C(2)); 134.2 (C(6)); 150.0 (C(3´)),
C(5´)); 151.0 (C(7a)); 183.1 (C(3)). HMBC NMR (DMSOꢀd6),
δ: 6.82/121.8 (H(5)/C(3a)); 7.06/121.8 (H(7)/C(3a)); 9.28/
121.8 ((N(1)H)/C(3a)); 9.28/129.6 ((N(1)H)/C(2)); 9.28/151.0
((N(1)H)/C(7a)); 9.28/183.1 ((N(1)H)/C(3)); 7.51/151.0
(H(4)/C(7a)); 7.51/183.1 (H(4)/C(3)); 7.39/151.0 (H(6)/C(7a));
6.80/183.1 ((CH)/C(3)); 6.80/150.0 (CH/C(3´), C(5´)).
2ꢀ[(3,5ꢀDiaminoꢀ1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ
1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (9b). Methylhydrazine (5.26 mL,
0.1 mol) was added to a suspension of dicyanovinylindole 1 (5 g,
0.02 mol) in isopropyl alcohol (160 mL). The suspension was
stirred at room temperature for 2 h. The precipitate was filtered
off and washed with isopropyl alcohol and ether. The yield of
compound 9b was 2.98 g. 1H NMR (DMSOꢀd6—CCl4), δ: 3.40
(s, 3 H, NCH3); 4.59 (br.s, 2 H, NH2); 5.88 (s, 2 H, NH2); 6.75
(s, 1 H, CH); 6.78 (t, 1 H, H(5)); 7.00 (d, 1 H, H(7)); 7.33 (t,
1 H, H(6)); 7.50 (d, 1 H, H(4)); 9.15 (s, 1 H, N(1)H).
cooling, the precipitate that formed was filtered off and washed
with isopropyl alcohol and ether. The yield of compound 9c
was 0.08 g. 1H NMR (DMSOꢀd6), δ: 4.96 (br.s, 2 H, NH2); 5.88
(br.s, 2 H, NH2); 6.82 (m, 2 H, CH, H(5)); 7.05 (d, 1 H, H(7));
7.24 (t, 1 H, H(6)); 7.31—7.60 (m, 6 H, Ph, H(4)); 8.99 (s, 1 H,
N(1)H).
2ꢀ[(1ꢀAcetylꢀ3ꢀacetylaminoꢀ5ꢀaminoꢀ1Hꢀpyrazolꢀ4ꢀyl)
methylidene]ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (10a). A mixture of
compound 9a (0.5 g, 2.1 mmol) and acetic anhydride (6 mL)
was refluxed with stirring for 30 min. The precipitate that formed
was filtered off hot, washed with isopropyl alcohol and ether,
and dried. The yield of compound 10a was 0.46 g. 1H NMR
(DMSOꢀd6), δ: 2.04, 2.53 (both s, 3 H each, COCH3); 6.53 (s,
1 H, CH); 6.87 (t, 1 H, H(5)); 7.00 (br.s, 2 H, NH2); 7.04 (d,
1 H, H(7)); 7.46 (t, 1 H, H(6)); 7.53 (d, 1 H, H(4)); 8.68 (s, 1 H,
N(1)H); 9.98 (br.s, 1 H, NHCOCH3). 13C NMR (DMSOꢀd6),
δ: 93.0 C(4´); 102.1 (CH); 112.7 (C(7)); 119.2 (C(5)); 121.4
(C(3a)); 123.6 (C(4)); 133.2 (C(2)); 135.4 (C(6)); 147.9 (C(5´));
148.4 (C(3´)); 153.0 (C(7a)); 169.0, 172.7 (COCH3); 184.8
(C(3)). HMBC NMR (DMSOꢀd6), δ: 7.00/93.0 (NH2/C(4´));
6.87/121.4 (H(5)/C(3a)); 7.04/121.4 (H(7)/C(3a)); 8.68/121.4
(N(1)H/C(3a)); 8.68/133.2 (N(1)H/C(2)); 8.68/153.0 (N(1)H/
C(7a)); 8.68/184.8 (N(1)H/C(3)); 6.53/147.9 (CH/(C(5´));
6.53/148.4 (CH/(C(3´)); 6.53/184.8 (CH/C(3)); 7.53/153.0
(H(4)/C(7a)); 7.53/184.8 (H(4)/C(3)); 7.46/153.0 (H(6)/C(7a));
2.04/169.0 (COCH3/COCH3); 2.53/172.7 (COCH3/(COCH3).
2ꢀ[(3ꢀAcetylaminoꢀ5ꢀaminoꢀ1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
methylidene]ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (10b). A mixture of
compound 9b (1 g, 3.9 mmol) and acetic anhydride (15 mL) was
refluxed with stirring for 30 min. The precipitate that formed
was filtered off hot, washed with isopropyl alcohol and ether,
and dried. The yield of compound 10b was 0.63 g. 1H NMR
(DMSOꢀd6), δ: 1.97 (s, 3 H, COCH3); 3.55 (s, 3 H, NCH3);
5.83 (br.s, 2 H, NH2); 6.58 (s, 1 H, CH); 6.83 (t, 1 H, H(5));
7.02 (d, 1 H, H(7)); 7.39 (t, 1 H, H(6)); 7.50 (d, 1 H, H(4));
8.51 (s, 1 H, N(1)H); 9.48 (br.s, 1 H, NHCOCH3).
3ꢀAminoꢀ1,5ꢀdihydropyrazolo[4´,3´:5,6]pyrido[3,2ꢀb]indole
(11). A mixture of compound 9a (0.6 g, 2.5 mmol) and trifluoroꢀ
acetic acid (7 mL) was refluxed with stirring for 3 h. The
solution was cooled and evaporated to dryness. The residue was
refluxed in water (60 mL) for 30 min and filtered to remove
mechanical impurities. On cooling, the solution was alkalized
with 5 M NaOH (12 mL) to pH 14. The precipitate that formed
was filtered off, washed with water, and dried. The yield of a
crude product was 0.35 g. The product was refluxed in acetone
(100 mL) to almost complete homogenization and purified by
adding charcoal. The solution was filtered and concentrated
until first signs of suspension formation appeared. On cooling,
the precipitate that formed was filtered off and dried. The yield
of compound 11 was 0.1 g. 1H NMR (DMSOꢀd6), δ: 5.31 (br.s,
2 H, NH2); 7.12, 7.43, 8.16 (all m, 1 H each, 2 H and 1 H,
H(6)—H(9)); 7.44 (m, 2 H, CH, H(6)); 8.11 (s, 1 H, H(4));
10.96 (br.s, 1 H, N(5)H); 11.46 (br.s, 1 H, N(1)H).
2ꢀ[3ꢀAminoꢀ2ꢀcyanoꢀ3ꢀ(2ꢀphenylhydrazino)propꢀ2ꢀenylꢀ
idene]ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (8c). Phenylhydrazine
(1 mL, 10 mmol) was added to a suspension of dicyanovinylꢀ
indole 1 (1.28 g, 5.1 mmol) in benzene (30 mL). The suspension
was refluxed for 1.5 h. The resulting precipitate was filtered off
hot and washed with benzene, acetone, and ether. The yield of
compound 8c was 0.25 g.
2ꢀ[(3,5ꢀDiaminoꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ
1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (9c). A suspension of diene diamine
8c (0.12 g) in isopropyl alcohol (7 mL) was refluxed for 2 h. On
2ꢀ{[3,5ꢀBis(N,Nꢀdimethylamino)methylideneaminoꢀ1Hꢀ
pyrazolꢀ4ꢀyl]methylidene}ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (12a).
Dimethylformamide dimethyl acetal (0.3 mL, 2.5 mmol) was
added to a stirred suspension of compound 9a (0.3 g, 1.25 mmol)
in isopropyl alcohol (10 mL) or in DMF (7 mL). The reaction
mixture was refluxed for 30 min or kept at 20 °C (in DMF). The
precipitate that formed was filtered off hot, washed with isoproꢀ
pyl alcohol and ether, and dried (the solution in DMF was
* For all compounds, Jo = 7.5 Hz.

1980
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Masterova et al.
concentrated and the residue was triturated with hexane and, on
decantation, with isopropyl alcohol). The yield of compound
12a was 0.33 g. 1H NMR (DMSOꢀd6), δ: 3.09 (br.s, 6 H,
N(CH3)2); 6.71 (s, 1 H, CH); 6.77 (t, 1 H, H(5)); 6.89 (d, 1 H,
H(7)); 7.37 (t, 1 H, H(6)); 7.50 (d, 1 H, H(4)); 7.99, 8.20
(both s, 1 H each, N=CH); 11.63 (s, 1 H, N(1)H); 11.80 (br.s,
1 H, N(1´)H). 13C NMR (DMSOꢀd6), δ: 39.5 (N(CH3)2); 99.4
(C(4´)); 105.8 (CH); 111.0 (C(7)); 117.5 (C(5)); 121.0 (C(3a));
123.6 (C(4)); 130.5 (C(2)); 134.5 (C(6)); 149.9 (C(7a)); 153.7,
154.8 (N=CH); 183.1 (C(3)). HMBC NMR, δ: 6.77/121.0
(H(5)/C(3a)); 6.89/121.0 (H(7)/C(3a)); 11.63/121.0 (N(1)H/
C(3a)); 11.63/130.5 (N(1)H/C(2)); 11.63/149.9 (N(1)H/C(7a));
11.63/183.1 (N(1)H/C(3)); 7.50/149.9 (H(4)/C(7a)); 7.50/
183.1 (H(4)/C(3)); 7.37/149.9 (H(6)/C(7a)); 3.09/153.7, 154.8
(N(CH3)2/N=CH); 7.99, 8.20/183.1 (N=CH C(3)).
2ꢀ{[3,5ꢀBis(N,Nꢀdimethylamino)methylideneaminoꢀ1ꢀmethylꢀ
1Hꢀpyrazolꢀ4ꢀyl]methylidene}ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (12b).
Dimethylformamide dimethyl acetal (2.5 mL, 0.19 mol) was
added to a stirred suspension of compound 9b (1.6 g, 0.063 mol)
in isopropyl alcohol (50 mL). The reaction mixture was refluxed
for 1 h, cooled, and concentrated. The residue was triturated
with a mixture of ether and a small amount of isopropyl alcohol.
The precipitate was filtered off and washed with ethyl acetate
and ether, and dried. The yield of compound 12b was 1.91 g.
1H NMR (DMSOꢀd6), δ: 3.09—3.17 (all s, 3 H each, N(CH3)2);
3.55 (s, 3 H, NCH3); 6.28 (s, 1 H, CH); 6.74 (t, 1 H, H(5)); 6.86
(d, 1 H, H(7)); 7.35 (t, 1 H, H(6)); 7.46 (d, 1 H, H(4)); 7.73,
8.19 (both s, 1 H each, N=CH); 11.66 (s, 1 H, N(1)H).
2. RF Pat. 2 008 308; Byull. Izobret., 1994, 83.
3. RF Pat. 2 026 287; Byull. Izobret., 1995, 161.
4. S. Yu. Ryabova, L. M. Alekseeva, E. A. Lisitsa, N. S.
Masterova, S. S. Kiselev, M. I. Evstratova, V. G. Granik,
Izv. Akad. Nauk, Ser. Khim., 2006, 55, 2186 [Russ. Chem.
Bull., Int. Ed., 2006, 55, 2271].
5. S. Yu. Ryabova, L. M. Alekseeva, N. S. Masterova, V. G.
Granik, Izv. Akad. Nauk, Ser. Khim., 2007, 1529 [Russ. Chem.
Bull., Int. Ed., 2007, 56, 1588].
6. R. S. Garigipati, Tetrahedron Lett., 1990, 31, 1969.
7. N. M. Fathy, G. H. Elgemele, J. Chem. Eng. Data, 1988,
33, 218.
8. S. Hiremath, A. Ullagaddi, K. R. Sekhar, M. G. Purohit,
Indian J. Chem., 1988, 27B, 758.
9. V. V. Chernyshev, Izv. Akad. Nauk, Ser. Khim., 2001, 50,
2174 [Russ. Chem. Bull., Int. Ed., 2001, 50, 2273].
10. P.ꢀE. Werner, L. Eriksson, M. Westdahl, J. Appl. Crystallogr.,
1985, 18, 367.
11. G. S. Pawley, J. Appl. Crystallogr., 1981, 14, 357.
12. V. B. Zlokazov, V. V. Chernyshev, J. Appl. Crystallogr., 1992,
25, 447.
13. P. M. de Wolff, J. Appl. Crystallogr., 1968, 1, 108.
14. G. M. Smith, R. L. Snyder, J. Appl. Crystallogr., 1979, 12, 60.
15. R. A. Young, D. B. Wiles, J. Appl. Crystallogr., 1982, 15, 430.
16. S. G. Zhukov, V. V. Chernyshev, E. V. Babaev, E. J.
Sonneveld, H. Schenk, Z. Kristallogr., 2001, 216, 5.
17. D. N. Laikov, Yu. A. Ustynyuk, Izv. Akad. Nauk, Ser. Khim.,
2005, 54, 804 [Russ. Chem. Bull., Int. Ed., 2005, 54, 820].
18. H. Toraya, J. Appl. Crystallogr., 1986, 19, 440.
19. F. H. Allen, Acta Crystallogr., Sect. B, 2002, B58, 380.
20. G. Dedichen, Ber., 1906, 39, 1831.
2ꢀ({3,5ꢀBis[1ꢀ(N,Nꢀdimethylamino)ethylidene]aminoꢀ1Hꢀ
pyrazolꢀ4ꢀyl}methylidene)ꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀone (12c).
Dimethylacetamide dimethyl acetal (0.18 mL, 1.25 mmol) was
added to a stirred suspension of compound 9a (0.3 g, 1.25 mmol)
in isopropyl alcohol (10 mL). The reaction mixture was refluxed
for 2 h, another portion of DMAA (0.18 mL) was added, and the
reflux was continued for an additional 30 min. The solvent was
removed and the residue was triturated with ether. The yield
21. G. Zvilichovky, D. Mordechai, J. Chem. Soc., Perkin
Trans. 1, 1983, 11.
22. M. H. Elnagdi, E. M. Kandeel, E. M. Zayed, Z. E. Kandil,
J. Prakt. Chem., 1978, 320 (4), 533.
23. R. A. Abramovich, K. A. N. Adams, A. D. Notation, Can.
J. Chem., 1960, 38, 2152.
1
of compound 12c was 0.24 g. H NMR (DMSOꢀd6), δ: 2.02 (s,
6 H, 2 CH3); 3.12 (s, 12 H, 2 N(CH3)2); 6.37 (s, 1 H, CH); 6.78
(t, 1 H, H(5)); 6.91 (d, 1 H, H(7)); 7.39 (t, 1 H, H(6)); 7.50 (d,
1 H, H(4)); 10.43 (br.s, 1 H, N(1)H); 11.40 (br.s, 1 H, N(H´)).
24. V. G. Granik, Atsetali amidov i laktamov [Acetals of Amides
and Lactams], Vuzovskaya Kniga, Moscow, 2008, 579 pp.
(in Russian).
References
1. S. Yu. Ryabova, Yu. I. Trofimkin, L. M. Alekseeva, I. F.
Kerbnikova, G. Ya. Shvarts, V. G. Granik, Khim.ꢀFarm.
Zh., 1995, 29, No. 9, 22 [Pharm. Chem. J. (Engl. Transl.),
1995, 29, No. 9, 610].
Received December 17, 2008;
in revised form April 22, 2009