Synthesis of substituted indazole-5,6-dicarbonitriles

Article abstract of DOI:10.1134/S107042801212010X

Methods have been developed for the synthesis of previously unknown N-substituted 1H-indazole-5,6-dicarbonitriles from 4-methyl-5- nitrophthalonitrile.

Full text of DOI:10.1134/S107042801212010X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 12, pp. 1557–1560. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © Zh.V. Chirkova, V.S. Sharunov, S.I. Filimonov, I.G. Abramov, S.I. Firgang, G.A. Stashina, 2012, published in Zhurnal
Organicheskoi Khimii, 2012, Vol. 48, No. 12, pp. 1586–1589.
Synthesis of Substituted Indazole-5,6-dicarbonitriles
Zh. V. Chirkovaa, V. S. Sharunova, S. I. Filimonova, I. G. Abramova,
S. I. Firgangb, and G. A. Stashinab
a Yaroslavl State Technical University, Moskovskii pr. 88, Yaroslavl, 150023 Russia
e-mail: filimonovsi@ystu.ru
b Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
e-mail: galina_stashina@chemical-block.com
Received May 15, 2012
Abstract—Methods have been developed for the synthesis of previously unknown N-substituted 1H-indazole-
5,6-dicarbonitriles from 4-methyl-5-nitrophthalonitrile.
DOI: 10.1134/S107042801212010X
Heterocyclic systems containing an indazole frag-
ment are efficient bioisosters of indole and benzimid-
azole derivatives possessing diverse biological activity,
in particular antitumor [1], antimicrobial [2], and anti-
inflammatory [3]. The presence of two cyano groups in
the ortho position with respect to each other makes
indazole-5,6-dicarbonitriles convenient building blocks
for the synthesis of various phthalocyanines that are
chromophoric compounds promising for use in optics
[4], nonlinear optics [5], electronic power transmission
systems [6], light-emitting diodes [7], and supramolec-
ular chemistry [8]. Different synthetic approaches to
indazoles have been reported, including those based on
nucleophilic substitution reactions [9, 10]; however,
we have found no published data on the synthesis of
1H-indazole-5,6-dicarbonitriles.
In the present article we describe two methods of
synthesis of new N-substituted 1H-indazole-5,6-dicar-
bonitriles starting from 4-methyl-5-nitrophthalonitrile
(I) [11] (Scheme 1). The first method (a) implies re-
duction of I with SnCl2 to the corresponding amine II
according to [12], followed by treatment of II with
sodium nitrite in glacial acetic acid. Intramolecular
azo coupling involving the activated methyl group of
the substrate led to the formation of indazole IIIa in
65% yield.
Following the second procedure (b), initial com-
pound I was heated for 3 h in excess dimethylform-
amide dimethyl acetal. Dimethylaminoethenyl deriv-
ative IV thus obtained was oxidized with sodium per-
iodate under stirring in 50% aqueous THF for 4 h at
55–65°C [13]. The product was 4-formyl-5-nitro-
Scheme 1.
Me
CN
CN
Me
CN
CN
CN
NaNO2, AcOH
N
a
N
O2N
H2N
CN
R
I
II
IIIa–IIId
b
NaOH
NaIO4
THF–H2O
RNHNH2
VIb–VId
Me2N
CN
CN
CN
CN
RNH
CN
CN
N
O
O2N
O2N
O2N
VIIb–VIId
IV
V
R = H (a), Ph (b), 4-MeOC6H4 (c), 4-MeC6H4 (d).
1557

CHIRKOVA et al.
1558
Scheme 2.
RBr (VIIIa, VIIIb)
K2CO3
NC
NC
NC
NC
NC
N
N
+
N
R
N
N
N
NC
H
R
IIIa
IXa, IXb
Xb
R = 3,4-Me2C6H3C(O)CH2 (a), PhCH2 (b).
phthalonitrile V (63%). Its condensation with substi-
tuted hydrazines VIb–VId in alcohol at 70–80°C gave
the corresponding hydrazones VIIb–VIId which un-
derwent intramolecular heterocyclization on heating in
4% alcoholic sodium hydroxide. As a result, N-substi-
tuted indazole-5,6-dicarbonitriles IIIb–IIId were iso-
lated in 72–76% yield.
vent as reference (δ 2.50 ppm). The elemental com-
positions were determined on a CHN-1 analyzer. The
IR spectra were measured on a Perkin Elmer RX-1
spectrometer from samples dispersed in mineral oil
and placed between KBr plates. The mass spectra
(electron impact, 70 eV) were obtained on a Finnigan
MAT INCOS-50 GC–MS system (ion source tempera-
ture 100–220°C).
The molecule of 1H-indazole-5,6-dicarbonitrile
(IIIa) possesses a fairly reactive NH group which
could give rise to prototropic tautomerism [14], it is
also capable of acting as nucleophile in nucleophilic
substitution reactions. This was confirmed by success-
ful alkylation of indazole IIIa with 3,4-dimethyl-
phenacyl bromide (VIIIa) and benzyl bromide
(VIIIb). The reactions were carried out in DMF in the
presence of K2CO3 at 40–60°C (reaction time 1–2 h).
In the reaction with more active bromide VIIIa we
isolated 1-substituted isomer IXa as the major product,
whereas the reaction with benzyl bromide gave a mix-
ture of 1- and 2-substituted isomers IXb and Xb at
a ratio of 5:3 (Scheme 2).
1H-Indazole-5,6-dicarbonitrile (IIIa). A solution
of 0.3 g (4.4 mmol) of sodium nitrite in 0.6 ml of water
was added in one portion under vigorous stirring to
a suspension of 0.3 g (1.9 mmol) of 4-amino-5-
methylphthalonitrile (II) in 5 ml of glacial acetic acid.
The mixture was stirred for 40 min at room tempera-
ture and diluted with an equal volume of water, and the
precipitate was filtered off, washed with water on
a filter, and dried. Yield 0.207 g (65%), mp 185–
187°C. IR spectrum, ν, cm–1: 3270 (NH), 2231 (C≡N),
1
1611 (C=Carom). H NMR spectrum, δ, ppm: 8.38 s
(1H, 4-H), 8.41 s (1H, 7-H), 8.64 s (1H, 3-H), 14.15 s
(1H, NH). Found, %: C 64.09; H 2.35; N 33.10.
C9H4N4. Calculated, %: C 64.28; H 2.40; N 33.32.
The structure of the newly synthesized compounds
1
was determined on the basis of their IR, H NMR, and
4-Formyl-5-nitrophthalonitrile (V). Sodium per-
iodate, 1.278 g (6 mmol), was dissolved in 10 ml of
water, a solution of 0.484 g (2 mmol) of 4-[(E)-2-(di-
methylamino)vinyl]-5-nitrophthalonitrile (IV) [13] in
THF was added, and the mixture was stirred for 3–4 h
at 50–60°C and extracted with methylene chloride. The
extract was washed with water and subjected to chro-
matography on silica gel using methylene chloride–
hexane (1:2) as eluent. The eluate was evaporated, and
the precipitate was filtered off, washed with alcohol,
and dried. Yield 0.253 g (63%), mp 155–157°C. IR
spectrum, ν, cm–1: 2233 (C≡N); 1670 (C=O); 1616
1
mass spectra. The key signals in the H NMR spectra
of IIIa–IIId were singlets belonging to 4-H and 7-H,
as well as to 3-H, in the region δ 8.0–8.8 ppm, which
indicated formation of five-membered nitrogen-con-
taining heterocycle. Compound V characteristically
displayed a signal from the aldehyde proton at
δ 10.22 ppm. The structure of indazoles IXa, IXb, and
Xb was determined using NOESY spectroscopy. Sub-
stitution at the N1 atom in compounds IXa and IXb
followed from the presence of cross peaks between
protons in the CH2 group of the R substituent and 7-H
and between 3-H and 4-H. The NOESY spectrum of
2-substituted isomer Xb showed cross peaks between
the NCH2 protons and 3-H and between 3-H and 4-H.
1
(C=Carom); 1557, 1351 (NO2). H NMR spectrum, δ,
ppm: 8.63 s (1H, 3-H), 9.02 s (1H, 6-H), 10.22 s (1H,
CHO). Found, %: C 53.60; H 1.43; N 20.78.
C9H3N3O3. Calculated, %: C 53.74; H 1.50; N 20.89.
EXPERIMENTAL
Hydrazonomethylphthalonitriles VIIb–VIId
(general procedure). Substituted hydrazine VIb–VId,
3 mmol, was added to a solution of 0.426 g (2 mmol)
of compound V in 5 ml of alcohol. The mixture was
1
The H NMR spectra were recorded at 30°C on
a Bruker DRX-500 instrument from solutions in
DMSO-d6 using the residual proton signal of the sol-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 12 2012

SYNTHESIS OF SUBSTITUTED INDAZOLE-5,6-DICARBONITRILES
1559
stirred for 1 h at 70–78°C, and the precipitate was
filtered off, washed with alcohol, and dried.
spectrum, ν, cm–1: 2235 (C≡N); 1610, 1518 (C=Carom);
1258, 1117, 1023 (C–O–C); 825 (δC6H4-1,4). H NMR
1
spectrum, δ, ppm: 3.86 s (3H, OMe), 7.18 d (2H, 3′-H,
5′-H, J = 8.9 Hz), 7.72 d (2H, 2′-H, 6′-H, J = 8.9 Hz),
8.58 s (1H, 3-H), 8.69 s (1H, 7-H), 8.81 s (1H, 4-H).
Mass spectrum, m/z (Irel, %): 274 (100) [M]+, 259 (39),
231 (40), 204 (11), 178 (14), 64 (15). Found, %:
C 69.04; H 2.83; N 15.03. C16H10N4O. Calculated, %:
C 70.07; H 3.67; N 20.43. M 274.28.
4-Nitro-5-[(E)-phenylhydrazonomethyl]phthalo-
nitrile (VIIb). Yield 0.43 g (74%), mp >300°C. IR
spectrum, ν, cm–1: 3276 (NH); 2230 (C≡N); 1605
1
(C=Carom); 1541, 1330 (NO2). H NMR spectrum, δ,
ppm: 6.94 t (1H, 4′-H, J = 7.2 Hz), 7.28 m (4H, Ph),
8.17 s (1H, CH), 8.73 s (1H, 3-H), 11.55 s (1H, NH).
Found, %: C 61.70; H 3.05; N 23.95. C15H9N5O2. Cal-
culated, %: C 61.86; H 3.11; N 24.04.
1-(4-Methylphenyl)-1H-indazole-5,6-dicarbo-
nitrile (IIId). Yield 0.392 g (76%), mp 224–225°C. IR
spectrum, ν, cm–1: 2229 (C≡N); 1610, 1518 (C=Carom);
4-[(E)-(4-Methoxyphenyl)hydrazonomethyl]-
5-nitrophthalonitrile (VIIc). Yield 0.514 g (80%),
mp 259–260°C (decomp.). IR spectrum, ν, cm–1: 3280
(NH); 2233 (C≡N); 1604, 1487 (C=Carom); 1541, 1330
(NO2); 1255, 1235, 1029 (OMe). 1H NMR spectrum, δ,
ppm: 3.73 s (3H, OMe), 6.91 d (2H, 3′-H, 5′-H, J =
9.0 Hz), 7.21 d (2H, 2′-H, 6′-H, J = 9.0 Hz), 8.12 s
(1H, CH), 8.94 s (1H, 3-H), 9.17 s (1H, 6-H), 11.56 s
(1H, NH). Mass spectrum, m/z (Irel, %): 321 (69) [M]+,
274 (66) [M – HNO3]+, 259 (39), 231 (40), 204 (11),
178 (14), 64 (15). Found, %: C 59.64; H 3.38;
N 21.70. C16H11N5O3. Calculated, %: C 59.81; H 3.45;
N 21.80. M 321.29.
1
831 (δC6H4-1,4). H NMR spectrum, δ, ppm: 2.43 s
(3H, Me), 7.24 d (2H, 3′-H, 5′-H, J = 7.7 Hz), 7.69 d
(2H, 2′-H, 6′-H, J = 7.7 Hz), 8.61 s (1H, 3-H), 8.68 s
(1H, 7-H), 8.78 s (1H, 4-H). Mass spectrum, m/z
(Irel, %): 258 (100) [M]+, 230 (17), 91 (44), 77 (27), 65
(41). Found, %: C 74.23; H 3.83; N 21.58. C16H10N4.
Calculated, %: C 74.41; H 3.90; N 21.69. M 258.25.
1- and 2-Substituted indazole-5,6-dicarbonitriles
IXa, IXb, and Xb (general procedure). Bromide
VIIIa or VIIIb, 3 mmol, and potassium carbonate,
0.414 g (3 mmol), were added to a solution of 0.504 g
(3 mmol) of compound IIIa in 5 ml of DMF. The mix-
ture was stirred for 1–2 h at 40–60°C and diluted with
water, and the precipitate was filtered off, washed with
alcohol, and dried.
4-[(E)-4-Methylphenylhydrazonomethyl]-
5-nitrophthalonitrile (VIId). Yield 0.476 g (78%),
mp 245–247°C (decommp.). IR spectrum, ν, cm–1:
3279 (NH); 2231 (C≡N); 1605 (C=Carom); 1541, 1329
1
(NO2). H NMR spectrum, δ, ppm: 2.25 s (3H, CH3),
1-[2-(3,4-Dimethylphenyl)-2-oxoethyl)-1H-inda-
zole-5,6-dicarbonitrile (IXa). Yield 0.593 g (65%),
7.08 d (2Н, 3′-H, 5′-H, J = 8.5 Hz), 7.12 d (2Н, 2′-H, 6′-H,
J = 8.5 Hz), 8.14 s (1Н, CH) , 8.65 s (1Н, 3-H), 8.77 s (1Н,
6-H), 11.47 s (1Н, NH). Found, %: C 62.78; H 3.57;
N 22.81. Mass spectrum: m/z 305 [M]+. C16H11N5O2.
Calculated, %: C 62.95; H 3.63; N 22.94. M 305.30.
1
mp 234–235°C. H NMR spectrum, δ, ppm: 2.34 s
(6H, Me), 6.29 s (2H, CH2), 7.38 d (1H, 5′-H, J =
7.9 Hz), 7.82 d.d (1H, 6′-H, J = 7.9, 1.8 Hz), 7.87 d
(1H, 2′-H, J = 1.8 Hz), 8.52 s (1H, 3-H), 8.71 s (1H,
7-H), 8.73 s (1H, 4-H). Mass spectrum, m/z (Irel, %):
314 (3) [M]+, 134 (10), 133 (100), 105 (18), 77 (16).
Indazole-5,6-dicarbonitriles IIIb–IIId (general
procedure). Sodium hydroxide, 0.168 g (3 mmol), was
added to a solution of 2 mmol of compound VIIb–
VIId in a mixture of 4 ml of alcohol and 1 ml of DMF.
The mixture was stirred for 1 h at room temperature,
and the precipitate was filtered off, washed with
alcohol, and dried.
1-Benzyl-1H-indazole-5,6-dicarbonitrile (IXb).
1
Yield 0.488 g (63%) (in a mixture with Xb). H NMR
spectrum, δ, ppm: 5.67 s (2H, CH2), 7.22 d (2H, 2′-H,
6′-H, J = 7.8 Hz), 7.35 t (2H, 3′-H, 5′-H, J = 7.8 Hz),
7.41 t (1H, 4′-H), 7.82 s (1H, 7-H), 8.26 s (2H, 3-H,
4-H). Mass spectrum, m/z (Irel, %): 258 (41) [M]+,
91 (100).
1-Phenyl-1H-indazole-5,6-dicarbonitrile (IIIb).
Yield 0.342 g (70%), mp >300°C. IR spectrum, ν,
cm–1: 2238 (C≡N); 1609, 1520 (C=Carom); 1258.
1H NMR spectrum, δ, ppm: 7.70 m (5H, Ph), 8.75 m
(3H, NH, 4-H, 7-H). Found, %: C 73.60; H 3.23;
N 22.83. Mass spectrum: m/z 244 [M]+. C15H8N4. Cal-
culated, %: C 73.76; H 3.30; N 22.94. M 244.26.
2-Benzyl-2H-indazole-5,6-dicarbonitrile (Xb).
Yield 0.286 g (37%) (in a mixture with IXb). 1H NMR
spectrum, δ, ppm: 5.67 s (2H, CH2), 7.33–7.36 m (4H,
2′-H, 3′-H, 5′-H, 6′-H, J = 7.8 Hz), 7.40 t (1H, 4′-H,
J = 7.8 Hz), 8.16 s (1H, 3-H), 8.21 s (1H, 4-H), 8.24 s
(1H, 7-H). Mass spectrum, m/z (Irel, %): 258 (41) [M]+,
91 (100).
1-(4-Methoxyphenyl)-1H-indazole-5,6-dicarbo-
nitrile (IIIc). Yield 0.406 g (74%), mp 229°C. IR
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CHIRKOVA et al.
7. Díaz, D.D., Bolink, H.J., Cappelli, L., Claessens, C.G.,
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