Synthesis and Some Transformations of 7-(Fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]benzothiazole

Article abstract of DOI:10.1134/S1070363218030088

N-Methylation of 5-nitro-1H-indazole in a KOH–DMSO system resulted in a mixture of 1-methyl-5(6)-nitroindazoles in a ratio of 1: 2. Reduction of the isomers with tin in concentrated hydrochloric acid afforded pure 1-methyl-1H-indazole-6-amine. Condensation of the latter with furoyl chloride in 2-propanol yielded N-(1-methylindazol-6-yl)furan-2-carboxamide, treatment of which with an excess of P2S5 in anhydrous pyridine gave the corresponding carbothioamide. 7-(Fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]benzothiazole was synthesized by Jacobson oxidation of N-(1-methylindazol-6-yl) furan-2-carbothioamide with potassium ferricyanide in an alkaline medium. Some transformations of 7-(fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]- benzothiazole such as formylation and acylation were performed.

Full text of DOI:10.1134/S1070363218030088

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 3, pp. 425–429. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © M.M. El’chaninov, A.A. Aleksandrov, V.F. Stepanov, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 3, pp. 397–
4
01.
Synthesis and Some Transformations
of 7-(Fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]benzothiazole
M. M. El’chaninov*, A. A. Aleksandrov, and V. F. Stepanov
Platov South-Russian State Polytechnic University (NPI), pr. Prosveshcheniya 132, Novocherkassk, 346428 Russia
*
e-mail: elchaninov22@gmail.com
Received October 19, 2017
Abstract—N-Methylation of 5-nitro-1H-indazole in a KOH–DMSO system resulted in a mixture of 1-methyl-
(6)-nitroindazoles in a ratio of 1 : 2. Reduction of the isomers with tin in concentrated hydrochloric acid
afforded pure 1-methyl-1H-indazole-6-amine. Condensation of the latter with furoyl chloride in 2-propanol
yielded N-(1-methylindazol-6-yl)furan-2-carboxamide, treatment of which with an excess of P in anhydrous
5
2 5
S
pyridine gave the corresponding carbothioamide. 7-(Fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]benzothiazole
was synthesized by Jacobson oxidation of N-(1-methylindazol-6-yl) furan-2-carbothioamide with potassium
ferricyanide in an alkaline medium. Some transformations of 7-(fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]-
benzothiazole such as formylation and acylation were performed.
Keywords: 5-nitroindazole, oxidation, 1-methyl-1H-5(6)-nitroindazole, potassium ferricyanide, electrophilic
substitution reactions, formylation, acylation
DOI: 10.1134/S1070363218030088
Among the fields of heterocyclic chemistry, chemistry
cyclic systems [5], due to fast annular tautomerism of
1-methyl-1H-indazole a mixture of two N-methyl
derivatives 5-nitro-1-methyl-1H- (1) and 6-nitro-1-
methyl-1H-indazoles (2) were obtained in a 1 : 2 ratio
(Scheme 1). It should be noted that the annulation of
the thiazole ring to non-alkylated indazole did not
proceed.
of bihetaryl compounds consisting of two hetero-
aromatic fragments connected by a single bond has
attracted considerable attention. These compounds are
used as pharmaceuticals and pesticides. The mutual
influence of heterocyclic fragments in bihetaryls both
in terms of their structure and reactivity is an
interesting and still insufficiently studied problem.
Unfortunately, nitro compounds 1 and 2 could not
be separated due to a slight difference in their
chromatographic mobility, however, each of the
There is practically no information on the pre-
paration and reactivity of thiazoles containing the
furan fragment annelated with the indazole ring. At the
same time, bisheterocyclic compounds of this type are
of interest as potential biologically active substances
1, 2] and organic phosphors [3]. In this regard, of
interest is to develop or select a convenient method of
annelation of 2-(fur-2-yl)thiazole fragment to 1-methyl-
1
isomers in the mixture is easily identified by the H
NMR spectroscopy data (Tables 1, 2).
When compounds 1 and 2 were reduced with tin in
concentrated hydrochloric acid followed by
decomposition of the tin salt with KOH in 2-propanol,
a mixture of 5(6)-amines was obtained, upon recrys-
tallization of which from 2-propanol one pure isomer
was unexpectedly isolated in 49% yield (Scheme 2).
[
1
H-indazole. To this end, we tried to apply the
Jacobson method of obtaining benzothiazoles [4] by
cyclization of benzene thioamides in aqueous alkali
medium in the presence of potassium ferricyanide.
Scheme 1.
Methylation of commercial 5-nitro-1H-indazole was
successfully carried out in a KOH–DMSO system
using an equivalent amount of methyl iodide. The
yield of target compound was close to quantitative.
Like the previously studied unsymmetrical hetero-
_
O N
MeI KOH
DMSO
2
N
O N
2
N
N
N
1, 2
4
25

4
26
EL’CHANINOV et al.
a
Table 1. Melting points, elemental analysis data and yields of compounds 1–10
Found, %
Calculated, %
H
Comp.
no.
Yield, %
mp, °С
Formula
С
Н
N
C
N
1
3
4
5
6
7
8
9
1
+2
89
49
78
72
32
67
29
11
68
126–127
117–118
176–177
154–155
174–175
190–191
153–154
233–234
239–240
53.98
65.47
64.93
60.73
61.37
59.17
60.73
59.91
67.11
3.73
6.23
4.47
4.49
3.39
2.98
3.59
4.12
3.49
23.79
28.39
17.19
16.17
16.55
15.09
13.87
12.17
11.73
С
С
С
С
С
С
С
С
С
8
Н
Н
7
N
3
3
O
2
54.24
65.29
64.72
60.68
61.16
59.35
60.59
60.17
66.84
3.98
6.16
4.60
4.31
3.55
3.20
3.73
3.86
3.65
23.72
28.55
17.42
16.33
16.46
14.83
14.13
12.38
11.69
8
9
N
13
13
13
14
15
17
20
Н
11
11
N
N
3
3
3
О
2
Н
Н
Н
Н
Н
Н
OS
9
N
ОS
9
N
3
O
2
S
11
13
13
N
3
3
3
O
O
O
2
3
2
S
N
N
S
S
0
a
The results of elemental analysis for the content of C, H and N correspond to the calculated values within ±0.34%.
1
Table 2. The IR and H NMR spectral data for compounds 1–10
Comp.
no.
–
1
ν, cm
δ, ppm (J, Hz)
7
6
1
1540 [νas(NO
2
)]
4.11 s (3Н, NCH ), 7.83 d (1Н, Н Ar, J = 9.0), 8.21 d (1Н, Н Ar, J = 9.0), 8.36 s (1Н,
3
3
4
Н
pyrazole), 8.80 s (1Н, Н Ar)
4
7
3
2
3
4
1382 [ν
s
(NO
2
)]
)],
)]
)],
)]
4.23 s (3Н, NCH
(1Н, Н Ar, J = 9.0)
3.69 s (3Н, NCH
3
), 7.74 d (1Н, Н Ar, J = 9.0), 7.98 s (1Н, Н Ar), 8.74 s (1Н, Н pyrazole), 8.85 d
5
1
540 [νas(NO
2
7
5
1382 [ν
s
(NO
2
3
), 6.59 s (2Н, NH
2
), 6.77 s (1Н, Н Ar), 6.86 d (1Н, Н Ar, J = 8.4), 7.38 d
4
3
3
376 [νas(NН
2
(1Н, Н Ar, J = 8.4), 8.08 s (1Н, Н pyrazole
3
), 6.69–6.70 m (1Н, Н furan), 7.32 d (1Н, Н furan, J = 3.6), 7.49 d (1Н, Н Ar,
J = 9.0), 7.65 s (1Н, Н Ar), 7.77 d (1Н, Н Ar, J = 9.0), 7.92 d (1Н, Н furan, J = 1.2), 8.10 s
)
4
3
5
3203 [ν (NН
s
2
4.07 s (3Н, NCH
7
4
5
3
(
1Н, Н pyrazole), 10.01 s (1Н, NH)
), 6.69–6.70 m (1Н, Н furan), 7.38 d (1Н, Н furan, J = 3.0), 7.49 d (1Н, Н Ar,
4
3
4
5
1689 (С=О),
263 (NH)
4.09 s (3Н, NCH
J = 9.0), 7.68 s (1Н, Н Ar), 7.82 d (1Н, Н Ar, J = 9.0), 7.99 d (1Н, Н furan, J = 1.2), 8.13 s
3
7
4
5
3
3
(
1Н, Н pyrazole), 11.52 s (1Н, NH)
), 6.76–6.78 m (1Н, Н furan), 7.30 d (1Н, Н furan, J = 3.3), 7.82 d (1Н, Н Ar,
4
3
4
6
7
8
9
1235 (С=S),
360 (NН)
4.14 s (3Н, NCH
J = 9.0), 7.99 d (1Н, Н furan, J = 0.9), 8.01 d (1Н, Н Ar, J = 9.0), 8.37 s (1Н, Н pyrazole
3
5
5
3
3
)
5
4
1658 s (С=О)
3
4.09 s (3Н, NCH ), 7.48 d (1Н, Н Ar, J = 9.0), 7.54 d (1Н, Н furan, J = 3.6), 7.68 d (1Н,
3
4
3
Н
furan, J = 3.6), 7.69 d (1Н, Н Ar, J = 9.0), 8.13 s (1Н, Н pyrazole), 9.76 s (1Н, СНО)
2.70 s (3Н, CH ), 4.10 s (3Н, NCH ), 7.46 d (1Н, Н furan, J = 3.6), 7.58 d (1Н, Н furan, J =
3 3
3.6), 7.86 d (1Н, Н Ar, J = 8.9), 8.06 d (1Н, Н Ar, J = 9.0), 8.29 s (1Н, Н pyrazole
2.49 s (3Н, CH ), 4.12 s (3Н, NCH ), 6.22 d (1Н, Н , J = 1.4), 6.80 d (1Н, Н
d (1Н, Н furan, J = 3.6), 7.60 d (1Н, Н furan, J = 3.6), 7.89 d (1Н, Н Ar, J = 8.9), 8.09 d (1Н,
3
4
1678 s (С=О)
4
5
3
1
639 s (С=О),
)
1675 s (С=О)
3
3
α
β
, J = 2.2), 7.48
3
4
4
5
3
Н
Ar, J = 9.0), 8.30 s (1Н, Н pyrazole
)
3
4
1
0
1685 s (С=О)
3
4.11 s (3Н, NCH ), 7.42 d (1Н, Н furan, J = 3.8), 7.56 d (1Н, Н furan, J = 3.8), 7.60 t (3Н,
3
,4,5
4
5
2,6
Н
Ar, J = 7.8), 7.84 d (1Н, Н Ar, J = 9.0), 8.01 d (1Н, Н Ar, J = 9.0), 8.14 d (1Н, Н Ar
,
3
J = 7.8), 8.30 s (1Н, Н pyrazole
)
Apparently, the second isomer was too soluble in
alcohol and therefore was lost. According to H NMR
proton of the aromatic ring was registered in a rather
strong field at 6.81 ppm because of the effect of two
electron donating groups NH and NCH , while the
1
data, 1-methyl-1H-indazole-6-amine 3 was isolated. In
2
3
1
7
4
the H NMR spectrum, the singlet signal of the H
analogous singlet of the H proton deshielded by a
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018

SYNTHESIS AND SOME TRANSFORMATIONS
427
Scheme 2.
Sn
O N
2
N
N
HCl
N
N
H N
2
1, 2
3
Scheme 3.
S
N
N
K
3
[Fe(CN)
]
6
N
KOH
N
S
O
H
O
N N
5
6
Scheme 4.
N
S
_
N
S
(
CH ) N Ac O
2
6
4
2
_
PhCO H PPA
2
O
O
O
N
N
N
N
R
6
7_10
2
R = H (7), Me (8), CH COMe (9), Ph (10).
pyridine nitrogen atom in the 5-amino derivative
would be detected in a weaker field (Table 2).
is apparently due to the influence of the steric factor on
the spatial orientation of the S-substituent formed by
oxidation with the complex ion.
Condensation of amine 3 with 2-furoyl chloride in
2
-propanol gave N-(1-methyl-1H-indazol-6-yl)furan-2-
Further, compound 6 was subjected to medium-
strength electrophiles: urotropine in polyphosphoric
acid (PPA), acetic anhydride and benzoic acid in PPA
(Scheme 4).
carboxamide 4 in 78% yield, which when heated in
anhydrous pyridine with an excess of phosphorus
pentasulfide in 72% yield afforded 6-carbothioamide 5
(
Scheme 3). Subsequent oxidation of compound 5 with
Recently, the formyl group was introduced into the
furan core of isomeric 1-methyl-2-(2-furyl)-1H-benz-
imidazole [6] by the action of urotropine in PPA. For
compound 6, this method was also successful. The
yield of aldehyde 7 was 67%.
a 20% aqueous solution of K [Fe(CN) ] furnished
7
thiazole 6 with a yield of 32%.
3
6
-(fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]benzo-
1
In the H NMR spectrum of compound 6, the
signals of the aromatic ring were registered not as
singlets, which would confirm the 5,6-annelation of
Taking into account the deactivating effect of the
pyrazolobenzothiazole fragment on the reactivity of
the furan ring, acetylation of compound 6 was
achieved only by the action of acetic anhydride in the
PPA medium at 110–120°C. The reaction proceeded
non-selectively and was accompanied by the formation
of a by-product, the amount of which increases with
increasing temperature, and therefore methyl ketone 8
was obtained in a yield not exceeding 29%. According
4
the thiazole ring to indazole, but as doublets of the H
5
and H protons at 7.82 and 8.01 ppm with characte-
ristic spin-spin coupling constant of 9.3 Hz. The
assignment of the signals was made on the basis of the
5
proton H deshielding by the pyridine nitrogen of the
thiazole ring. In addition, in the NMR spectrum of
compound 6, the singlet signal of the N-methyl group
was observed at 4.14 ppm. Obviously, the upfield shift
of the latter is due to the fact that it is more influenced
by the thiazole ring.
1
to H NMR data, the by-product separated by column
chromatography was diketone 9 formed as a result of
the acetylation of the COCH group in monoketone 8.
3
This result indicates the 6,7-annelation of the 2-(fur-
The prochirality of the methylene protons (H and H )
α
β
2-yl)thiazole fragment to 1-methyl-1H-indazole, which
in the acetoacetyl substituent of compound 9 led to a
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018

4
28
EL’CHANINOV et al.
diastereotopic cleavage of their signals in the form of
two doublets at 6.22 and 6.80 ppm. In the IR spectrum
of compound 9, strong double absorption bands of the
carbonyl groups of the acetoacetyl fragment were
registered in the 1639–1675 cm region, confirming
the structure of this compound (Table 2).
conc. hydrochloric acid was carefully added in
portions 8.85 g (0.05 mol) of a mixture of compounds
1 and 2. The addition of each portion was accompanied
by a violent reaction with a strong exothermic effect.
At the end of the addition, the clear hot solution was
decanted from the tin residues. Upon cooling, forma-
tion of a tin amine salt was observed, which was
separated, suspended in 200 mL of 2-propanol and
subjected to decomposition with solid potassium
hydroxide until a slightly alkaline reaction. The
–
1
Acylation of compound 6 with benzoic acid was
carried out under the conditions described above, but
at a higher temperature (150–160°C). Unlike acetyla-
tion, the benzoylation of 6 proceeded smoothly and
selectively due to the absence of the activated methyl
group in the product obtained. The yield of phenyl-
ketone 10 was 68%.
Sn(OH) precipitate was separated, the filtrate was
2
evaporated to dryness and violet crystals of amine 3
were obtained, which were used without further
purification. Yield 3.60 g.
In summary, for the first time 6,7-annelation of
N-(1-Methyl-1H-indazol-6-yl)furan-2-carboxamide
2
-(fur-2-yl)thiazole fragment to 1-methyl-1H-indazole
was successfully carried out. Relative reactivity of the
resulting 7-(fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g]-
1,3]benzothiazole in reactions with medium-strength
(
4). Furoyl chloride (3.20 g, 24.5 mmol) was added to
a solution of 3.53 g (24 mmol) of amine 3 in 30 mL of
-propanol. The mixture was heated at reflux for 2 h,
and then poured into 50 mL of water, neutralized with
ammonia solution to a slightly alkaline reaction and
kept in a refrigerator for 24 h. The precipitate was
filtered off and crystallized from 2-propanol. Yield
2
[
electrophilic reagents was studied.
EXPERIMENTAL
4
.51 g, colorless crystals.
Physico-chemical studies were performed using the
equipment of the Center for Collective Use of the
Platov South Russian State Polytechnic University.
N-(1-Methyl-1H-benzimidazol-6-yl)furan-2-carbo-
thioamide (5). Phosphorus pentasulfide (2.66 g,
mmol) was added to a solution of 4.34 g (18 mmol)
6
The IR spectra were recorded on a Specord 75IR
1
of compound 4 in 15 mL of anhydrous pyridine. The
mixture was refluxed for 3 h, then cooled and poured
into 100 mL of water. The yellow precipitate was
separated and crystallized from aqueous 2-propanol.
Yield 3.33 g.
spectrometer in mineral oil. The H NMR spectra were
registered on a Varian Unity 300 instrument
(
300 MHz, DMSO-d ) relative to internal TMS. The
6
reaction progress was monitored by TLC on plates
coated with Al O II Brokman activity, evidenced with
2
3
iodine vapor (eluents – CH Cl , CHCl ). Elemental
7-(Fur-2-yl)-1-methyl-1H-pyrazolo[4,3-g][1,3]-
benzothiazole (6). To a solution of 3.33 g (12.96 mmol)
of compound 5 in 20 mL of 2-propanol were added
10 mL of 1% potassium hydroxide and then 40 mL of
a warm aqueous solution of 12.8 g (38.9 mmol)
K [Fe(CN) ]. The mixture was kept at room tempera-
ture overnight, the precipitate was separated and
crystallized from aqueous 2-propanol. Yield 1.06 g,
colorless crystals.
2
2
3
analysis was carried out on a Perkin Elmer 2400
analyzer. The melting points were determined by the
capillary method on a PTP apparatus.
The physico-chemical and spectral characteristics
of the compounds obtained are shown in Tables 1, 2.
3
6
1
-Methyl-1H-5(6)-nitroindazole (1, 2). To a
solution of 9.78 g (60 mmol) of 1-methyl-1H-indazole
in 20 mL of dimethylsulfoxide were successively
added 3.53 g (63 mmol) of powdered KOH and 8.52 g
5
-(1-Methyl-1H-pyrazolo[4,3-g][1,3]benzothiazol-
-yl)furan-2-carbaldehyde (7). A mixture of 0.255 g
1 mmol) of compound 6 and 0.42 g (3 mmol) of
urotropine in 5 g of polyphosphoric acid was stirred at
10–120°C for 6 h, then diluted with 10 mL of water
7
(
(
60 mmol) of methyl iodide. The mixture was stirred at
room temperature for 3 h, after which it was diluted
with 200 mL of water. The precipitate was separated
and crystallized from 2-propanol. Yield 9.45 g
1
and carefully neutralized with an ammonia solution.
The separated reaction product was extracted with
(
mixture of isomers), yellowish crystals.
-Methyl-1H-indazole-6-amine (3). To a mixture
of 16 g (0.135 mol) of granular tin and 100 mL of
1
1
0 mL of chloroform and chromatographed on a
column (l 10 cm, d 2.5 cm) filled with alumina, eluting
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018

SYNTHESIS AND SOME TRANSFORMATIONS
429
with chloroform. Compound 7 was crystallized from
ethanol. Yield 0.19 g, yellow crystals.
10 h at 150–160°C. Further isolation of the reaction
product was carried out in a manner analogous to
compound 7. Compound 10 was crystallized from
methanol. Yield 0.24 g, yellow-orange crystals.
1
-[5-(1-Methyl-1H-pyrazolo[4,3-g][1,3]benzothia-
zol-7-yl)fur-2-yl]ethanone (8). A mixture of 0.255 g
1 mmol) of compound 6 and 0.31 g (3 mmol) of acetic
anhydride in 5 g of polyphosphoric acid was stirred at
10–120°C for 28 h, then diluted with 10 mL of water
(
REFERENCES
1
1. Simonov, A.M., El’chaninov, M.M., Oleinikova, L.Ya.,
and Kolbacheva, N.G., Invention Certificate
no. 599510, 1977; Bull. Izobret., 1983, no. 23.
2. Grebennikov, V.A., El’chaninov, M.M., Nakhratskii, I.I.,
Simonov, A.M., and Bokaneva, S.A., Invention Certificate
no. 1203861, 1985; Bull. Izobret., 1986, no. 28.
and neutralized with an ammonia solution. Further
isolation of the reaction product was carried out similar
to compound 7. Compound 8 was crystallized from
methanol. Yield 0.086 g, colorless crystals.
1
-[5-(1-Methyl-1H-pyrazolo[4,3-g][1,3]benzothia-
3. El’chaninov, M.M and Aleksandrov, A.A., Russ. J. Gen.
Chem., 2016, vol. 86, no. 5, p. 1204. doi 10.1134/
S107036321605039X
zol-7-yl)fur-2-yl]butane-1,3-dione (9). Compound 9
was isolated by chromatography of the reaction mix-
ture obtained by acetylation of compound 6. Yield
4. Jacobson, P., Ber., 1886, vol. 19, pp. 1067, 1811.
0
.032 g, orange crystals.
5. Aleksandrov, A.A., El’chaninov, M.M., and Dedene-
va, A.S., Russ. J. Gen. Chem., 2012, vol. 82, no. 7,
p. 1263. doi 10.1134/S1070363212070134
[
5-(1-Methyl-1H-pyrazolo[4,3-g][1,3]benzothia-
zol-7-yl)fur-2-yl]phenylmethanone (10). A mixture
of 0.255 g (1 mmol) of compound 6 and 0.37 g
6. El’chaninov, M.M., Simonov, A.M., and Oleinikova, L.Ya.,
Chem. Heterocycl. Compd., 1983, vol. 19, no. 10,
p. 1041. doi 10.1007/BF 00505746
(
3 mmol) of benzoic acid in 5 g of PPA was stirred for
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018