An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential

Article abstract of DOI:10.1016/j.tet.2008.05.009

Several novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their 6-alkyl and 8-alkyl derivatives have been synthesised in high overall yields starting from 5-nitro and 6-nitroindazoles in a three-step route involving the regioselective cyclisation of thioureidoindazoles and indazolyl dithiocarbamates as the key steps. Some assorted thiazoloindazoles have been screened for anticancer properties, which demonstrated the anticancer potential of at least one product, justifying its further follow-up.

Full text of DOI:10.1016/j.tet.2008.05.009

Tetrahedron 64 (2008) 6711–6723
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An expedient, regioselective synthesis of novel 2-alkylamino- and
2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential
,
a
b
b
Manas Chakrabarty a , Taraknath Kundu , Shiho Arima , Yoshihiro Harigaya
*
a Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700 009, India
b School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their 6-alkyl and
8-alkyl derivatives have been synthesised in high overall yields starting from 5-nitro and 6-nitro-
indazoles in a three-step route involving the regioselective cyclisation of thioureidoindazoles and in-
dazolyl dithiocarbamates as the key steps. Some assorted thiazoloindazoles have been screened for
anticancer properties, which demonstrated the anticancer potential of at least one product, justifying its
further follow-up.
Received 18 February 2008
Received in revised form 30 April 2008
Accepted 1 May 2008
Available online 3 May 2008
Keywords:
Thiazolo[5,4-e]- and -[4,5-g]indazoles
Anticancer
Ó 2008 Elsevier Ltd. All rights reserved.
Regioselective synthesis
Thioureidoindazoles
Indazolyl dithiocarbamates
Bromine in acetic acid
1. Introduction
resistant chronic myelogenous leukaemia,11 3-(indol-2-yl)indazoles
as potent inhibitors of Chek1 kinase12 and 3-substituted (indazol-
Heterocyclic compounds are extensively used as drugs, phar-
maceuticals, agrochemicals, fine chemicals, etc. as well as lead
molecules in these areas.1 During the last few years, we have been
actively engaged in developing novel syntheses of potentially bio-
active condensed nitrogen heterocycles. Because of the importance
of 1,3-azoles2 in general and thiazoles3 in particular, we have re-
cently developed new syntheses of condensed thiazoles, viz. thia-
zolocarbazoles4 and thiazoloindoles.5a In view of the reported
diverse bioactivities of condensed thiazoles,5b we were on the look
out for newer thiazoloheteroarenes with bioactive potential as our
synthetic targets. We chose the thiazoloindazole skeleton as our
target since indazoles too display diverse biological activities and
are common components of drugs and pharmaceuticals.6
In fact, substituted and condensed indazoles are recently being
increasingly reported as bioactive molecules. Some recent exam-
ples of substituted indazoles are granisetron used in CNS disorder,7a
7-substituted indazoles developed as neuronal-NOS inhibitors,7b
antiinflammatory bendazac and benzydamine,8 platelet aggrega-
tion inhibitor as well as anticancer YC-1,9 the antidepressant drug
candidate FS-32,10a a promising NSAID WAY-169916,10b c-ABL in-
hibitory 3-benzimidazol-2-yl-1H-indazoles for curing GleevecÔ-
5-yl)- and (indazol-7-yl)benzenesulfonamides as inhibitors of SAH/
MTA nucleosidase13a and L1210 murine leukaemia cell cycle,13b
respectively.
Recent examples of bioactive condensed indazoles are pyr-
imido[1,2-b]indazoles, showing promising anticancer activity
against human carcinoma A549 cell lines,14a and the PI3 kinase
modulatory thiazolo[4,5-g]dihydroindazoles with therapeutic po-
tential for inflammatory and allergic diseases.14b,c
This ambience motivated us to try to develop an efficient
synthesis of thiazoloindazoles because of their bioactive potential.
The recent reports on the synthesis of other bioactive condensed
thiazoles, viz. anticancer (against human carcinoma cell lines A549)
2-aminothiazolonapthalimides,15a HIV-integrase inhibitory thia-
zolo[5,4-b]pyridin-5(4H)-ones15b and GSK-3 inhibitory thiazolo[5,4-
f]quinazolin-9-ones15c prompt us to report herein our recent success
on the development of a short, expedient and regioselective syn-
thesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-
g]indazoles and their (indazolic) N-alkyl and N-benzenesulfonyl
derivatives. The results of cytotoxic (A549) evaluation of some of the
synthesised thiazoloindazoles are also presented herein.
2. Results and discussion
Our plan was to construct the thiazole nucleus on the indazole
framework starting from 5-nitro and 6-nitroindazoles. The thiazole
* Corresponding author. Tel.: þ91 33 23031150; fax: þ91 33 23506790.
E-mail address: chakmanas@yahoo.co.in (M. Chakrabarty).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.009

6712
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
ring can be built up from an arylamine either (i) by treatment with
thiocyanogen, usually generated in situ from thiocyanates and
bromine alone16a or bromine in acetic acid16b or 1,3-dichloro-
thiourea16c or (ii) by the oxidative cyclisation of derived thioureides
using bromine in acetic acid (Hugershoff reaction),17a–c para-
toluenesulfonic acid-on-clay,4b NBS-DBU5a or N-benzyl-DABCO
tribromide.17d Alternatively, the derived thioamides may be made
to undergo oxidative cyclisation by oxidants like potassium ferri-
cyanide (Jacobson reaction),18a,b manganese(III) acetate,18c Dess–
Martin periodinane18d or DDQ.18e A third option is by condensing
the arylamine with Appel’s salt,19a followed by cyclisation of the
resulting 5-arylamino-4-chloro-1,2,3-dithiazole by conventional
heating19b or by microwave irradiation.15c,19c
Of the aforesaid, we adopted the protocol involving thioureides
as intermediates. Like indoles, indazoles are also susceptible to
halogenation at C-3, especially under basic conditions.20 Therefore,
we decided to start with N-protected indazoles. Accordingly, 5-
nitroindazole (1) was successively protected as its 1-benzene-
sulfonyl derivative (2), reduced to the corresponding amine (3) and
condensed separately with methyl, ethyl and benzyl iso-
thiocyanates to furnish in excellent yields the corresponding thio-
ureidoindazoles (4a–c). The thiocarbonyl carbons of 4a–c
resorted to the Hugerschoff reaction since it does not involve any
extractive work-up. Each of 4a–c was, therefore, treated separately
with bromine in acetic acid at room temperature, which expedi-
tiously furnished the respective 2-alkylamino-6-benzenesulfo-
nylthiazolo[5,4-e]indazoles (5a–c) in high yields. The cleavage of
the protecting group by mild alkaline hydrolysis smoothly afforded
the unprotected thiazoloindazoles (6a–c) in excellent yields
(Scheme 1).
We initially anticipated, based on our previous experience,4a
that the use of bromine in acetic acid as the cyclising agent in the
unprotected indazole nucleus may additionally cause bromination
in the products. That is why we started with the N-benzensulfonyl
derivative (2). However, when the unprotected 5-aminoindazole
itself (7) was subjected to a similar sequence of reactions, the
parent thiazoloindazoles (6a–c) were formed efficiently via the
underivatised thioureidoindazoles (8a–c) (also shown in Scheme
1). Our initial concern thus turned out to be unfounded. The
structures of 8a–c received similar 13C NMR (dC]S 180–182.5) and
mass spectrometric [m/z 175: MꢀRNH2; m/z 133: MꢀRNCS] sup-
port. The individual 1H and 13C chemical shifts of 5a–c and 6a–c
(ascertained from HMQC and HMBC spectra for 5a and 6a and by
comparison for the rest) immediately revealed that the carbon
appearing at
d
181–182 and their mass spectral peaks at m/z 315
chemical shifts of CH-4 (ca. d 119), CH-5 (d 108) and CH-8 (d 131)
[MꢀRNH2] and m/z 273 [MꢀRNCS] lent support to the formation of
together can be considered as a marker for identifying this partic-
ular thiazoloindazole skeleton.
thioureide moieties.
For the cyclisation of 4a–c, we first tried tosic acid-on-clay and
NBS–DBU since we had earlier successfully used these reagents for
the regioselective synthesis of thiazolocarbazoles4b and thiazo-
loindoles,5a respectively. Since, in the thiazolocarbazole series, tosic
acid-on-clay proved to be more efficient for the N-benzylthiour-
eidocarbazole, the N-benzylthioureidoindazole (4c) was tried with
this cyclising agent. Thus, 4c was uniformly adsorbed on tosic acid
(1 equiv)-doped montmorillonite K10 clay and heated at 60–70 ꢁC.
But even after 8 h, no reaction took place at all. The reagent NBS–
DBU was next tried, this time on 4a. The reaction was quite fast, and
the sole product, isolated in a mere 25% yield, was identified as the
corresponding angularly cyclised product, i.e., the thiazolo[5,4-
e]indazole (5a) (Scheme 1). The conspicuous appearance of two
As planned, the methodology was extended to 6-nitroindazole
(9) and its 1-benzenesulfonyl derivative (10). Each of 9 and 10 was
subjected to the same sequence of reactions, leading to the isolation
of again only the angularly cyclised products, viz. 2-alkylamino-8-
benzenesulfonylthiazolo[4,5-g]indazoles (13a–c) and the related
deprotected thiazoloindazoles (14a–c) in excellent yields in each
step (Scheme 2). In this series too, the individual NMR assignments
of at least one member, viz. 13c and 14b, were determined from
their HMQC and HMBC spectra, and the same for the rest were
ascertained by comparison. Pertinently, initially we tried to cyclise
12a by NBS–DBU, but unlike its 5-thioureido isomer (4a), it did not
react at all, even at 50 ꢁC.
Two more extensions of the present methodology were then
aimed at. One was to try to synthesise 2-alkylthiothiazoloindazoles,
and the other was to check if the observations made for the
2-alkylamino derivatives of both [5,4-e]- and [4,5-g]-isomers also
hold good for their indazolic 1-alkyl derivatives. The first target was
achieved by the cyclisation (by bromine in acetic acid) of methyl
and ethyl 1H-indazol-5/6-yl dithiocarbamates (17a,b/19a,b). The
latter, were prepared by condensing 5/6-aminoindazoles (7/15)
one-proton doublets at
d 7.98 (H-4) and d 7.70 (H-5) with ortho-
coupling (J¼9 Hz) supported angular cyclisation, since in the al-
ternative linearly cyclised product, a thiazolo[4,5-f]indazole, each
of the two corresponding protons (H-4 and H-8) would have
appeared as a doublet with para-coupling.
We could trace the low yield of 5a to its poor solubility in
dichloromethane, which was used for extracting it. We, therefore,
O2N
O2N
H2N
(ii)
(i)
N
96%
92%
N
N
N
H
N
N
1
3
SO2Ph
SO2Ph
2
RHN
N
S
S
RHNCHN
(iv): 25% (R = Me)
or, (v): 92-96%
(iii)
90-94%
N
N
N
N
4a-c SO2Ph
5a-c
SO2Ph
RHN
N
2
4
S
S
R'
RHNCHN
(iii)
8
(vi)
90-95%
(v)
N
N
H
N
87-93%
82-92%
6
N
H
N
N
H
7: R' = NH2
1: R' = NO2
6a-c
8a-c
(ii) 90%
For 4-6, 8: R = Me (a), Et (b), Bn (c)
Scheme 1. Reagents and conditions: (i) NaOH (2.5 equiv), n-Bu4NþHSO4ꢀ (1.5 mol %), THF, 1 h; PhSO2Cl (1.2 equiv), 2–3 h; (ii) 10% Pd–C (10% w/w), NH2NH2$H2O, MeOH, reflux, 3 h;
(iii) RNCS (1.5 equiv), dry THF, reflux, 2–3 h; (iv) NBS (1.1 equiv), DBU (2 equiv), ꢀ10 ꢁC; CC, n$Al2O3; (v) Br2–AcOH (1:10), THF, rt, 30–45 min; (vi) K2CO3 (4 equiv), MeOH–H2O (3:1),
reflux, 1–1.5 h.

M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
6713
(ii) : 93%
(v)
N
(iii) R'NCS : 92-94%
N
N
94-96%
N
O2N
N
R
N
N
R'HNCHN
S
SO2Ph
13a-c
S
SO2Ph
10: R = SO2Ph
9: R = H
12a-c
R'HN
95% (i)
(vi) 92-97%
6
90% (ii)
(v)
4
(iii) : R'NCS
92-95%
N
90-94%
8
N
H
N
N
N
H
16a-c
R'HNCHN
S
H2N
N
H
N
S
15
14a-c
2
R'HN
For 12,13,14,16: R' = Me (a), Et (b), Bn (c)
Scheme 2. Reagents and conditions: as in Scheme 1.
with carbon disulfide in the presence of pyridine and triethylamine,
followed by treatment with methyl/ethyl iodides. Pertinently, this
protocol had earlier been used for the preparation of indolyl
dithiocarbamates21a for their subsequent cyclisation by NBS–
DBU21b or NBS–Et3N21c to indolic phytoalexins. Our experiments
led to the formation of both 2-alkylthiothiazolo[5,4-e]indazoles
(18a,b from 7) and 2-alkylthiothiazolo[4,5-g]indazoles (20a,b from
15) in quite good yields (Scheme 3). The occurrence of angular
cyclisation in both the isomeric classes was, as before, evident from
the appearance of two ortho-coupled protons in their 1H NMR
spectra (see Section 4).
indicative of the 1-alkyl derivatives, whereas the CH-3 signal at ca.
127 and, more importantly, the C-7a signal at ca. 150 were
suggestive of the 2-alkyl isomers (22a–c). In the case of the 6-nitro
series, the chemical shifts of H-3 and CH-3 could differentiate be-
tween the two alkyl isomeric classes. Thus, the related signals
d
d
appeared at ca.
isomers (23a,b), whereas the respective values were ca.
1 Hz) and ca. 124 for the 2-alkyl derivatives (24a,b).
d
8.1 (s) and ca.
d
133, respectively, for the 1-alkyl
d
8.7 (d,
d
Once properly identified, each of the 1-alkyl-5-nitroindazoles
(21a–c) and 1-alkyl-6-nitroindazoles (23a,b) was separately and
successively reduced to the corresponding amines (25a–c; 28a,b),
condensed with methyl isothiocynate, and the resulting 1-alkyl-5/
6-(N0-methylthioureido)indazoles (26a–c; 29a,b) were cyclised by
bromine in acetic acid to furnish the respective 2-methylamino
derivatives of 6-alkylthiazolo[5,4-e]indazoles (27a–c from 26a–c)
and 8-alkylthiazolo[4,5-g]indazoles (30a,b from 29a,b) in around
90% yield in each step (Scheme 5).
For diversification, 5-amino-1-methylindazole (25a) was addi-
tionally converted, following the same protocol, to 2-ethylamino-
and 2-benzylamino-6-methylthiazolo[5,4-e]indazoles (32a,b) via
the intermediacy of the respective thioureidoindazoles (31a,b)
(Scheme 5). On scrutiny, it transpired that the 1H and 13C NMR
spectroscopic data of the 6/8-alkylthiazoloindazoles of both [5,4-
e]-type (27a,b) and [4,5-g]-type (30a,b) were quite similar to those
of the parent 6/8-desmethylthiazoloindazoles (6a,b and 14a,b,
respectively).
RS
S
S
N
RSCHN
(ii)
93/87%
75/70%
N
N
N
N
5
6
(i)
N
H
N
H
R
N
17a,b
18a,b
N
H
(ii)
90/84%
78/82%
RSCHN
7: R = 5-NH2
N
H
15: R = 6-NH2
N
H
N
S
19a,b
S
20a,b
RS
For 17-20: R = Me (a), Et (b)
Scheme 3. Reagents and conditions: (i) CS2 (2–3 equiv), Py–Et3N (3:1), RI (1.5 equiv);
(ii) Br2–AcOH (1:10), THF, rt, 30–45 min.
Thus, the cyclisations of both thioureidoindazoles and indazolyl
dithiocarbamates, with or without alkyl substitution at the inda-
zolic N(1), were regioselective, leading to the formation of only the
angular thiazoloindazoles. Also, the use of bromine in acetic acid
did not cause nuclear bromination, contrary to our concern, at any
of the cyclisation steps. Most of the steps do not require any
chromatographic separation, and the yields were excellent
throughout. The method is thus well poised for scale-up.
In order to make a comparative evaluation of the present method
withthreeextantsynthesesof thethiazoloindazoleskeleton (assuch
or modified) that we could trace in the literature, a comparison was
necessitated. In the earliest reports,22a–c the synthesis of 2-methyl-
thiazolo[5,4-e]- and -[4,5-g]indazoles was achieved starting from
5-amino- and 6-aminoindazoles, respectively, via the successive
intermediacies of ortho-thiocyanato-aminoindazoles, followed by
cyclisation of the derived thiophenoxides by acetic anhydride. The
overall yields were merely ca.19% and 26% in the three-step route. In
contrast, ours was a two-step route, furnishing, for example, the 2-
alkylaminothiazolo[5,4-e]- (6a–c) and -[4,5-g]indazoles (16a–c) in
ca. 77–86% and 83–89% overall yields starting from the same ami-
noindazoles. Besides, in the previous route, the ready isomerisation
of thiocyanates to isothiocyanates was cited as a major problem,22a–c
and thiocyanation was reported not to be always ortho-oriented.23
Later, the linear 2-aminothiazolo[5,4-f]indazole itself was prepared
The NMR spectroscopic data of both 18 and 20 further revealed
that these two isomeric classes can be distinguished from each
other by the appearance of the 13C chemical shift of CH-5, which
was ca.
d 110 for 18a,b and ca. d 116 for 20a,b.
In order to materialise the second target, each of 5-nitroindazole
(1) and 6-nitroindazole (9) was separately N-alkylated to furnish
both N(1)-alkyl (21a–c from 1; and 23a,b from 9) and N(2)-alkyl
(22a–c from 1; 24a,b from 9) derivatives in around 90% overall
yields in both the isomeric classes (Scheme 4).
The 1-alkyl and 2-alkyl isomers could be differentiated from
each other by some of their 1H and/or 13C chemical shifts. For the
5-nitro series, only the 13C chemical shifts were critical. Thus, the
chemical shifts for CH-3 (ca.
d
136) and for CH-7 (ca.
d
110) were
5
5
6
5
(i)
87-90%
O2N
+
O2N
O2N
N
N
6
N
6
N
R
N
R
N
H
1: 5-NO2
From 1: 21a-c (45-49%)
From 9: 23a,b (52/48%)
From 1: 22a-c (35-42%)
From 9: 24a,b (36/39%)
9: 6-NO2
For 21-24: R = Me (a), Et (b),n-Pr (c)
Scheme 4. Reagents and conditions: (i) (a) NaOH (2.5 equiv), n-Bu4NþHSO4
ꢀ
(1.5 mol %), THF, rt, 1 h; RI (1.2 equiv), 3 h; (b) CC, silica gel.

6714
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
MeHN
2
4
S
S
N
MeHNCHN
R'
8
(v)
MeNCS
6
87-92%
N
N
N
(iii): 88-94%
N
N
R
N
R
5
R
27a-c
25a-c: R' = NH2
21a-c: R' = NO2
(ii)
90-94%
26a-c
5
6
MeNCS
(v)
4
(iii): 91/88%
N
8
95/93%
N
N
R'
N
R
N
N
R
MeHNCHN
S
N
R
30a,b
S
28a,b: R' = NH2
2
(ii)
92/90%
29a,b
MeHN
23a,b: R' = NO2
For 25-30: R = Me (a), Et (b), n-Pr (c)
RHN
S
S
N
RHNCHN
H2N
(v)
(iii)
90/92%
N
N
89/91%
N
N
N
N
Me
Me
Me
25a
31a,b
For 31,32: R = Et (a), Bn (b)
Scheme 5. Reagents and conditions: as in Scheme 1.
32a,b
directly from 6-aminoindazole by treatment with thiocyanogen,
generated in situ from copper(II) thiocyanate and acetic acid.24a,b
-[4,5-g]indazoles as well as their (indazolic) N-benzenesulfonyl and
N-alkyl derivatives. Since the cyclisations were regioselective in all
the cases, furnishing only the angular products, our route is quite
suitable for scale-up. Additionally, since some of the synthesised
thiazoloindazoles, particularly 14c, have shown worthwhile anti-
cancer potential, the present work of ours becomes even more
important.
A
comparison of our method with this route is inconsequential since it
dealt with only one product, which was a linear thiazoloindazole. In
the third and most recent report,14b,c a library of 2-alkylamino-8-
arylthiazolo[4,5-g]-4,5-dihydroindazoles were prepared by the
condensation–cyclisation of 2-alkylamino-thiazolocyclohexenone
carboxylates with aryl hydrazines by heating in acetic acid. Since
patented, the yields of the products, i.e., 4,5-dihydroindazoles could
not be gathered. Moreover, the thiazolocyclohexenone carboxylates
had to be preformed in a multi-step way. Our method is thus a better
method on all counts.
4. Experimental section
4.1. General
Seven thiazoloindazoles, viz. 5a,14a–c,18a and 30a,bweretested
at 25, 50 and 100 mmol solutions in DMSO for anticancer activity
Solvents were purified and dried using standard techniques. Pet.
ether refers to petroleum ether, bp 60–80 ꢁC. Silica gel G (Merck,
India) was used for analytical TLC, and silica gel (60–120 mesh;
Qualigens, India) and neutral alumina (Brockmann standard; BDH,
India) were used for column chromatography (CC). Melting points
(in celsius) were recorded on a Toshniwal apparatus and are un-
corrected. IR spectra were recorded in Nujol mull (unless stated
otherwise) and also in neat or as KBr pellets on a Nicolet Impact
410, Nicolet Magnus 750 series II, Shimadzu FTIR-8300 or Perkin–
Elmer 782 spectrophotometers. The 1H (200 MHz) and 13C
(50 MHz) NMR spectra of 4c, 8b, 12b,c, 22c, 24a and 31a were
recorded on a Bruker AC-200 spectrometer. For all other com-
pounds, the 1H (500 MHz) and 13C (125 MHz) NMR (PND and DEPT
135) spectra, and 2D NMR (viz. HMQC and HMBC) spectra of 5a, 6a,
13c, 14b and 27a were recorded in a Bruker DRX-500 spectrometer.
LR EIMS as well as HR EIMS, FABMS (m-nitrobenzyl alcohol as liquid
matrix) and ESI-MS (þve; TOF) were recorded on JEOL JMS-
AX505HA, JEOL JMS Mstaion 700 or Micromass Q-Tofmicro mass
spectrometers. Elemental analyses were performed on a Dr. Hans
Hoesli analyser. 5-Nitroindazole and 6-nitroindazole were pro-
cured commercially from Lancaster.
against human lung carcinoma A549 cell line at using the methyl
thiazolyl tetrazolium bromide assay (MTT).25 The experiments were
done in triplicate. The results (Table 1) revealed that at 25 mmol
concentrations, the screened products showed weak to moderate
(ca. 29–72%) inhibition with respect to control, i.e., DMSO. Of these,
14c appeared to be more effective, warranting its further follow-up.
Further investigation with few other cell lines is also underway, and
the results will be published elsewhere in due course.
3. Conclusion
We have developed a short, expedient and highly efficient
synthesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and
Table 1
Growth inhibitory effectsa of thiazoloindazoles on human lung carcinoma A549 cell
line
Concentrationsb
(
mmol)
Thiazoloindazoles
5a
14a
14b
14c
18a
30a
30b
25
50
100
52.7
56.2
70.4
29.5
56.3
71.4
47.1
75.9
72.0
72.1
N.D.c
76.8
67.6
73.2
58.7
62.2
68.1
63.5
55.7
70.2
77.2
4.1.1. 1-Benzenesulfonyl-5-nitro-1H-indazole (2)
To a solution of 5-nitro-1H-indazole (1, 1.63 g, 10 mmol) in THF
at room temperature were added powdered NaOH (1.0 g, 25 mmol)
and n-Bu4NHSO4 (51 mg, 0.15 mmol, 1.5 mol %). The resulting
mixture was stirred for 1 h and then cooled in an ice-bath. PhSO2Cl
(1.4 mL, 11 mmol) was added dropwise to it and stirred at room
temperature for another 2 h, when the reaction was complete
a
The growth inhibitions (%) of the treated carcinoma cells were calculated rela-
tive to growth of untreated (control) cells.
b
Exponentially growing cells were treated with different micromolar concentra-
tions of investigated thiazoloindazoles during a period of 72 h, and cytotoxicity was
measured using MTT survival assay. All experiments were performed in triplicates.
c
N. D.: not determined.

M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
6715
(TLC). The reaction mixture was then poured into water (50 mL),
extracted with CH2Cl2 (3ꢂ50 mL). The organic layer was dried
(Na2SO4) and solvent evaporated to furnish the crude product,
which was crystallised from CH2Cl2 to furnish pure 2 (2.9 g; 96%) as
white needles, mp 208–210 ꢁC.
4.2.3. 1-Benzenesulfonyl-5-(N-benzylthioureido)-1H-indazole (4c)
White needles; yield: 0.396 g (94%); mp 180–182 ꢁC; IR: 3342,
3287, 1515, 1448, 1242, 1182, 1089, 1058, 726 cmꢀ1 1H NMR
(200 MHz; DMSO-d6):
;
d
4.72 (2H, d, J¼6 Hz), 7.15–7.41 (5H, m), 7.58
(2H, t, J¼7 Hz), 7.60 (1H, d, J¼8 Hz), 7.71 (1H, t, J¼7 Hz), 7.92 (2H, d,
J¼7 Hz), 7.95 (1H, s), 8.07 (1H, d, J¼8 Hz), 8.26 (1H, t, J¼6 Hz), 8.53
IR: 3119, 3070, 1523, 1375, 1348,1296, 1173, 1089, 1069, 904, 783,
730 cmꢀ1; 1H NMR (DMSO-d6):
d
7.43 (2H, t, J¼7.5 Hz), 7.56 (1H, t,
(1H, s) and 9.77 (1H, s); 13C NMR (50 MHz):
d 47.2 (NHCH2), 112.6,
J¼7.5 Hz), 7.80 (2H, d, J¼8 Hz), 8.14 (1H, d, J¼9 Hz), 8.28 (1H, dd,
116.2, 126.8, 127.0 (ꢂ2), 127.3 (ꢂ2), 128.2 (ꢂ2), 129.8 (ꢂ2), 134.9,
142.6 (all Ar–CH), 126.0, 136.0, 136.3, 136.9, 138.9 (all Ar–C), 181.2
(NHCSNH); LR EIMS: m/z (%) 422 (Mþ; 11), 388 (20), 316 (25), 315
(100), 273 (54), 251 (38), 174 (40), 141 (35), 132 (68), 107 (65), 106
(47), 104 (21), 91 (84), 77 (85). Anal. Calcd for C21H18N4O2S2: C,
59.71; H, 4.26; N, 13.27. Found: C, 59.68; H, 4.24; N, 13.29%.
J1¼9 Hz, J2¼2 Hz), 8.56 (1H, s) and 8.61 (1H, d, J¼1.5 Hz); 13C NMR:
d
114.3, 120.3, 125.4, 128.2 (ꢂ2), 130.9 (ꢂ2), 136.4, 144.3 (all Ar–CH),
126.3, 136.8, 142.6, 145.2 (all Ar–C); LR EIMS: m/z (%) 303 (Mþ; 53),
239 (26), 141 (56), 77 (100); HR EIMS: Calcd for C13H9N3O4S
303.0314, found 303.0312.
4.1.2. 5-Amino-1-benzenesulfonyl-1H-indazole (3)
4.3. Cyclisation of 4a using NBS–DBU
To a solution of 2 (0.91 g, 3 mmol) in MeOH (30 mL) was added
10% Pd–C (ca. 90 mg, 10% w/w), followed by NH2NH2$H2O (0.2 mL,
3.5 mmol). The resulting solution was refluxed until (3 h) the re-
action was complete (TLC), filtered through a Celite bed, the solvent
distilled off from the filtrate and the resulting residue crystallised
from pet. ether.–CH2Cl2 to furnish pure 3 as white crystals, mp 208–
210 ꢁC (0.755 g, 92%).
To a solution of 4a (0.344 g, 1 mmol) in dry THF (20 mL) at ꢀ5 to
ꢀ10 ꢁC was gradually added NBS (0.198 g, 1.1 mmol). After 5 min
DBU (0.1 mL, 2 mmol) was added to it and the resulting solution
stirred for 45 min. The solution was poured into 10% aq Na2S2O3
(30 mL), extracted with CH2Cl2 (4ꢂ25 mL), the pooled extracts
washed with water and dried (Na2SO4). The solvent was removed in
vacuo to furnish a residue, which was purified by CC over neutral
Al2O3 and elution with pet. ether–EtOAc (1:1), followed by crys-
tallisation from MeOH–CH2Cl2 to furnish pure 5a as white needles
(0.086 g, 25%; mp 226–228 ꢁC).
IR: 3428, 3342, 1613, 1512, 1259, 1185, 1062, 824, 726 cmꢀ1
NMR (DMSO-d6):
;
1H
d
5.09 (2H, s), 6.59 (1H, d, J¼1.5 Hz), 6.78 (1H, dd,
J1¼9 Hz, J2¼2 Hz), 7.34 (2H, t, J¼7.5 Hz), 7.46 (1H, t, J¼7.5 Hz), 7.61
(1H, d, J¼9 Hz), 7.62 (2H, d, J¼9 Hz) and 8.07 (1H, s); 13C NMR:
d
102.8, 114.0, 120.2, 127.7 (ꢂ2), 130.4 (ꢂ2), 135.3, 143.4 (all Ar–CH),
128.4, 133.7, 137.2, 147.3 (all Ar–C); LR EIMS: m/z (%) 273 (Mþ; 73),
132 (100), 105 (17), 77 (15), 51 (10); HR EIMS: Calcd for C13H11N3O2S
273.0572, found 273.0561.
4.4. Cyclisation using Br2–AcOH. General procedure
A solution of bromine (0.1 mL, 2 mmol) in acetic acid (1 mL) was
added dropwise with stirring to
a solution of the thiour-
4.2. Synthesis of thioureidoindazoles. General procedure
eidoindazoles (4a/b/c) in THF (15–20 mL) at room temperature,
stirred for 30–45 min, when the reaction became complete (TLC).
The solution was poured into 10% aq Na2S2O3 solution (50 mL) and
neutralised with aq K2CO3 when a white precipitate appeared. It
was filtered, washed with water and dried. The crude products was
crystallised from MeOH–CH2Cl2 to furnish pure thiazoloindazoles
(5a–c).
In a typical experiment, to a solution of the amine (3, 0.273 g,
1 mmol) in dry THF (20 mL) was added methyl, ethyl or benzyl
isothiocyanate (1.5 mmol). The resulting solution was refluxed until
the amine was fully consumed (TLC). The solvent was distilled off
and the residue crystallised from MeOH–CH2Cl2 to furnish pure
thioureidoindazoles (4a–c).
4.4.1. 6-Benzenesulfonyl-2-methylaminothiazolo[5,4-e]-1H-
indazole (5a)
4.2.1. 1-Benzenesulfonyl-5-(N-methylthioureido)-1H-indazole (4a)
White needles; yield: 0.32 g (92%); mp 206–208 ꢁC; IR: 3383,
Yield: 0.316 g (92%); mp 226–228 ꢁC; IR: 3204, 1599, 1566, 1275,
3151, 1533, 1500, 1248, 1195, 1169, 1142, 1069, 824, 724 cmꢀ1
;
1H
1170, 1124, 923, 726 cmꢀ1 1H NMR (DMSO-d6):
; d 2.93 (3H, d,
NMR (DMSO-d6):
d
2.90 (3H, d, J¼3.5 Hz), 7.56 (1H, br), 7.59 (2H, t,
J¼4.5 Hz, NHCH3), 7.56 (2H, t, J¼7.5 Hz, H-30), 7.67 (1H, t, J¼7.5 Hz,
H-40), 7.70 (1H, d, J¼9 Hz, H-4), 7.89 (2H, d, J¼7.5 Hz, H-20), 7.98 (1H,
d, J¼9 Hz, H-5), 8.06 (1H, q, J¼4.5 Hz, NHCH3) and 8.63 (1H, s, H-8);
J¼7.5 Hz), 7.70 (1H, d, J¼8.5 Hz), 7.71 (1H, t, J¼7.5 Hz), 7.88 (1H, br
s), 8.05 (1H, dd, J1¼8.5 Hz, J2¼1.5 Hz), 8.51 (1H, s) and 9.68 (1H, s);
13C NMR:
d
25.9 (NHCH3), 113.4, 115.4, 126.9, 127.9 (ꢂ2), 130.7 (ꢂ2),
13C NMR:
d
31.5 (NHCH3), 110.8 (CH-5), 121.5 (CH-4), 127.8 (ꢂ2, CH-
135.8, 143.5 (all Ar–CH), 116.2, 136.8, 137.2, 137.7 (all Ar–C), 182.6
(NHCSNH); LR EIMS: m/z (%) 346 (Mþ; 39), 315 (82), 312 (83), 290
(19), 174 (17), 171 (100), 141 (20), 132 (66), 105 (12), 77 (65), 74 (16),
20), 130.6 (ꢂ2, CH-30), 135.7 (CH-40), 141.7 (CH-3), 120.7 (C-8a), 121.3
(C-8b), 137.0 (C-5a), 137.1 (C-10), 151.0 (C-3a), 167.9 (C-2); LR EIMS:
m/z (%) 344 (Mþ; 82%), 313 (5), 203 (100), 176 (96), 126 (34), 98 (18),
51 (16); HR EIMS: Calcd for
346.0556.
C
15H14N4O2S2 346.0558, found
77 (11); HR EIMS: Calcd for
344.0397.
C15H12N4O2S2 344.0401, found
4.2.2. 1-Benzenesulfonyl-5-(N-ethylthioureido)-1H-indazole (4b)
4.4.2. 6-Benzenesulfonyl-2-ethylaminothiazolo[5,4-e]-1H-
indazole (5b)
White needles; yield: 0.324 g (90%); mp 150–152 ꢁC; IR: 3317,
3142, 3077, 1535, 1508, 1280, 1245, 1186, 1091, 837, 726 cmꢀ1
;
1H
White crystals; yield: 0.333 g (93%); mp 227–229 ꢁC; IR (KBr):
3206, 3117, 1589, 1557, 1374, 1276, 1172, 1095, 914, 825, 814,
NMR (CDCl3):
d
1.18 (3H, t, J¼7 Hz), 3.65 (1H, br s), 6.07 (1H, br s),
7.43 (1H, dd, J1¼9 Hz, J2¼2 Hz), 7.48 (2H, t, J¼7.5 Hz), 7.59 (1H, s),
7.59 (1H, tt, J1¼7.5 Hz, J2¼1 Hz), 7.97 (2H, dd, J1¼8.5 Hz, J2 1 Hz), 8.15
726 cmꢀ1; 1H NMR (DMSO-d6):
d
1.19 (3H, t, J¼7 Hz), 3.38 (2H, dq,
J1¼7 Hz, J2¼5 Hz), 7.56 (2H, t, J¼7.5 Hz), 7.68 (1H, t, J¼7.5 Hz), 7.70
(1H, s), 8.19 (1H, d, J¼9 Hz) and 8.31 (1H, br); 13C NMR:
d 14.6 (CH3),
(1H, d, J¼9 Hz), 7.89 (2H, d, J¼7.5 Hz), 7.98 (1H, d, J¼9 Hz), 8.12 (1H,
40.7 (NCH2), 115.0, 118.6, 120.2, 127.9 (ꢂ2), 129.8 (ꢂ2), 134.9, 141.3
(all Ar–CH), 126.9, 133.2, 137.6, 139.0 (all Ar–C) and 181.2
(NHCSNH); LR EIMS: m/z (%) 360 (Mþ; 2), 273 (87), 315 (11), 132
(100), 105 (23), 77 (23), 51 (13). Anal. Calcd for C16H16N4O2S2: C,
53.33; H, 4.44; N, 15.55. Found: C, 53.37; H, 4.46; N, 15.57%.
t J¼5 Hz) and 8.64 (1H, s); 13C NMR:
d 15.2 (CH3), 39.8 (NHCH2),
110.8, 121.5, 127.8 (ꢂ2), 130.6 (ꢂ2), 135.7, 141.7 (all Ar–CH), 120.7,
121.2, 137.0, 137.1, 151.1, 167.0 (all Ar–C); LR EIMS: m/z (%) 358 (Mþ;
88%), 217 (100), 189 (21). HR EIMS: Calcd for C16H14N4O2S2
358.0558, found 358.0563.

6716
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
4.4.3. 6-Benzenesulfonyl-2-benzylaminothiazolo[5,4-e]-1H-
indazole (5c)
4.7. Preparation of thioureidoindazoles 8a–c
White crystals; yield: 0.403 g (96%); mp 210–212 ꢁC; IR: 3217,
Following the general procedure described for the conversion of
3 to 4a–c, except that refluxing was carried out in dry methanol, the
thioureidoindazoles 8a–c were synthesised by the condensation of
the amine 7 (1 mmol) with the respective alkyl isothiocyanates. The
crude products were crystallised from CH2Cl2 to furnish pure 8a–c.
1619, 1560, 1278, 1169, 1095, 912, 726 cmꢀ1 1H NMR (DMSO-d6):
;
d
4.06 (2H, d, J¼5.5 Hz), 7.25 (1H, t, J¼7.5 Hz), 7.33 (2H, t, J¼7.5 Hz),
7.37 (2H, d, J¼7.5 Hz), 7.56 (2H, t, J¼7.5 Hz), 7.68 (1H, tt, J1¼7.5 Hz,
J2¼1 Hz), 7.71 (1H, d, J¼9 Hz), 7.79 (2H, dd, J1¼7.5 Hz, J2¼1 Hz), 7.98
(1H, d, J¼9 Hz), 8.64 (1H, t, J¼5.5 Hz) and 8.66 (1H, s); 13C NMR:
d
48.3 (NHCH2), 110.9, 121.6, 127.8 (ꢂ2), 127.9, 128.3 (ꢂ2), 129.2
4.7.1. 5-(N-Methyl)thioureido-1H-indazole (8a)
(ꢂ2), 130.6 (ꢂ2), 135.7, 141.7 (all Ar–CH), 120.7, 121.5, 137.1, 139.5,
140.9, 150.8, 167.3 (all Ar–C); LR EIMS: m/z (%) 420 (Mþ; 65), 316
(15), 315 (20), 279 (52), 106 (20), 91 (100); HR EIMS: Calcd for
Off-white crystals; yield: 0.18 g (87%); mp 233–235 ꢁC; IR: 3222,
1629, 1548, 1301, 1161, 1070 and 839 cmꢀ1 1H NMR (DMSO-d6):
;
d
2.83 (3H, d, J¼4.5 Hz), 7.15 (1H, d, J¼8.5 Hz), 7.39 (1H, br), 7.43 (1H,
d, J¼8.5 Hz), 7.58 (1H, d, J¼1 Hz), 7.98 (1H, s), 9.39 (1H, br s) and
12.98 (1H, s); 13C NMR:
32.2 (NHCH3), 111.2, 116.9, 125.8, 134.4 (all
C
21H16N4O2S2 420.0716, found 420.0714.
d
Ar–CH),123.7,132.2,138.8 (all Ar–C),182.5 (NHCSNH); LR EIMS: m/z
(%) 206 (Mþ; 90),175 (34),172 (100),157 (31),145 (27),133 (80),105
(17), 74 (16); HR EIMS: Calcd for C9H10N4S 206.0626, found
206.0626.
4.5. Deprotection of benzenesulfonyl group. General
procedure
To a solution of 5a–c (1 mmol) in MeOH (30 mL) was added an
aq solution (10 mL) of K2CO3 (0.55 g, 4 mmol), and the solution was
refluxed for 6–8 h until the reaction became complete (TLC). Water
(40 mL) was added to this solution and MeOH distilled off. On
cooling, crystals appeared, which were filtered, washed with water,
dried and recrysatllised from CH2Cl2 to furnish pure 6a–c.
4.7.2. 5-(N-Ethyl)thioureido-1H-indazole (8b)
White crystals; yield: 0.2 g (91%); mp 204–206 ꢁC; IR: 3235,
1549, 1333, 1299, 704 cmꢀ1 1H NMR (200 MHz; DMSO-d6):
; d 1.09
(3H, t, J¼6 Hz), 3.48 (2H, q, J¼6 Hz), 7.22 (1H, dd, J1¼9 Hz,
J2¼1.5 Hz), 7.49 (1H, d, J¼9 Hz), 7.54 (1H, t, J¼6 Hz), 7.65, 8.03 and
9.36 (1H, s each) and 13.04 (1H, br s); 13C NMR (50 MHz):
d 14.3
4.5.1. 2-Methylaminothiazolo[5,4-e]-1H-indazole (6a)
(CH3), 38.2 (NHCH2), 110.2, 115.8, 125.0 and 133.4 (all Ar–CH), 122.8,
131.5 and 137.9 (all Ar–CH) and 180.6 (NHCSNH); LR EIMS: m/z (%)
220 (Mþ; 73), 187 (22), 186 (50), 175 (45), 158 (40), 133 (100), 105
(15). Anal. Calcd for C10H12N4S C, 54.54; H, 5.45; N, 25.45. Found: C,
54.59; H, 5.43; N, 25.48%.
White flakes; yield: 0.184 g (90%) from 5a; 0.179 g (88%) from
8a; mp 284–286 ꢁC; IR: 3204, 1599, 1147, 1082, 935, 827 cmꢀ1 1H
;
NMR (DMSO-d6):
J¼9 Hz, H-5), 7.48 (1H, d, J¼9 Hz, H-4), 7.41 (1H, q, J¼4.5 Hz, NH–
CH3), 8.04 (1H, s, H-8) and 13.13 (1H, s, H-6); 13C NMR:
31.5
d
2.93 (3H, d, J¼4.5 Hz, NHCH3), 7.40 (1H, d,
d
(NHCH3), 108.7 (CH-5), 119.3 (CH-4), 131.8 (CH-8), 117.5 (C-8a),
119.1 (C-8b), 137.8 (C-5a), 147.6 (C-3a), 166.4 (C-2); LR FABMS: m/z
204 (Mþ); HR FABMS: Calcd for C9H8N4S 204.0470, found:
204.0486.
4.7.3. 5-(N-Benzyl)thioureido-1H-indazole (8c)
White needles; yield: 0.26 g (93%); mp 224–226 ꢁC; IR: 3367,
1544, 1337, 1315, 1160, 961, 740 cmꢀ1 1H NMR (DMSO-d6):
; d 4.68
(2H, d, J¼5.5 Hz), 7.16–7.19 (1H, m), 7.20 (1H, d, J¼8.5 Hz), 7.23–7.30
(4H, m), 7.49 (1H, d, J¼8.5 Hz), 7.65 (1H, s), 7.94 (1H, br s), 7.99, 9.50
4.5.2. 2-Ethylaminothiazolo[5,4-e]-1H-indazole (6b)
and 12.99 (1H, s each); 13C NMR:
d 48.1 (NHCH2), 111.1, 117.0, 125.9,
White needles; yield: 0.2 g (92%) from both 5b and 8b; mp
127.6, 128.1 (ꢂ2), 129.0 (ꢂ2) and 134.4 (all Ar–CH), 123.7, 132.3,
138.8 and 140.1 (all Ar–C), 182.3 (NHCSNH); LR EIMS: m/z (%) 282
(Mþ; 22), 248 (23), 175 (64), 133 (33), 107 (16), 91 (100); HR EIMS:
Calcd for C15H14N4S 282.0939, found 282.0932.
238–240 ꢁC; IR: 3208, 1605, 1569, 1149, 1082, 930, 833 cmꢀ1 1H
;
NMR (DMSO-d6):
d
1.22 (3H, t, J¼7.5 Hz), 3.39 (2H, dq, J1¼7.5 Hz,
J2¼5 Hz), 7.41 (1H, d, J¼9 Hz), 7.48 (1H, d, J¼9 Hz), 7.78 (1H, t,
J¼5 Hz), 8.05 (1H, s) and 13.12 (1H, s); 13C NMR:
d 15.3 (CH3),
39.7 (NHCH2), 108.6, 119.3, 131.8 (all Ar–CH), 117.5, 119.0, 137.8,
4.8. Preparation of 1-benzenesulfonyl-6-nitro-1H-
indazole (10)
147.6, 165.4 (all Ar–C); LR EIMS: m/z (%) 218 (Mþ; 100), 203 (63),
190 (43). HR EIMS: Calcd for
218.0618.
C10H10N4S 218.0627, found
Following the procedure described for the preparation of 2 from
1, 1.63 g (10 mmol) of 6-nitro-1H-indazole (9) was treated with
benzenesulfonyl chloride to furnish the crude product, which was
crystallised from CH2Cl2 to furnish pure 10.
4.5.3. 2-Benzylaminothiazolo[5,4-e]-1H-indazole (6c)
White needles; yield: 0.266 g (95%) from 5c; 0.257 g (92%) from
8c; mp 226–228 ꢁC; IR: 3178, 3124, 1597, 1570, 1473, 1449, 1354,
1183, 926 cmꢀ1
;
1H NMR (DMSO-d6):
d
4.59 (2H, d, J¼5.5 Hz), 7.25
4.8.1. 1-Benzenesulfonyl-6-nitro-1H-indazole (10)
Pale yellow needles; yield: 2.88 g (95%); mp 176–178 ꢁC; IR:
3106, 1532, 1379, 1351, 1314, 1263, 1172, 1092, 1062, 898, 844,
(1H, t, J¼7.5 Hz), 7.34 (2H, t, J¼7.5 Hz), 7.34 (2H, d, J¼7.5 Hz), 7.41
(1H, d, J¼8.5 Hz), 7.47 (1H, d, J¼8.5 Hz), 8.05 (1H, s), 8.33 (1H, t, J
5.5 Hz) and 13.14 (1H, s); 13C NMR:
d 48.3 (NHCH2), 108.7, 119.4,
742 cmꢀ1
;
1H NMR (DMSO-d6):
d
7.55 (2H, t, J¼7.5 Hz), 7.71 (1H, t,
127.8, 128.3 (ꢂ2), 129.2 (ꢂ2), 131.8 (all Ar–CH), 117.5, 119.3, 137.9,
139.9, 147.3, 165.6 (all Ar–C); LR EIMS: m/z (%) 280 (Mþ; 100), 279
(18), 189 (35), 176 (14), 106 (12), 91 (71); HR EIMS: Calcd for
J¼7.5 Hz), 7.97 (2H, d, J¼7.5 Hz), 8.09 (1H, d, J¼8.5 Hz), 8.18 (1H, dd,
J1¼8.5 Hz, J2¼2 Hz), 8.77 (1H, s) and 8.84 (1H, s); 13C NMR:
d 109.3,
120.2, 124.6, 128.2 (ꢂ2), 130.9 (ꢂ2), 136.3, 143.3 (all Ar–CH), 129.9,
136.8, 139.5, 148.9 (all Ar–C); LR EIMS: m/z (%) 303 (Mþ; 46), 239
(24), 141 (59), 77 (100), 51 (15); HR EIMS: Calcd for C13H9N3O4S
303.0313, found 303.0305.
C
15H12N4S 280.0782, found 280.0774.
4.6. Preparation of 5-amino-1H-indazole (7)
Following the procedure described for the reduction of 2 to 3,
5-nitro-1H-indazole (1, 0.49 g, 3 mmol) was reduced to 5-Amino-
1H-indazole as colourless cubes; yield: 0.36 g (90%); lit. mp 175–
178 ꢁC; CAS No. 19335-11-6; Sigma-Aldrich Catalogue item no.
A59557.
4.9. Reduction of 10 to 6-amino-1-benzenesulfonyl-1H-
indazole (11)
Following the same procedure described for reduction of 2 to
3, 1-benzenesulfonyl-6-nitro-1H-indazole (10, 0.91 g, 3 mmol)

M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
6717
was reduced by NH2NH2$H2O/Pd–C to 6-amino-1-benzene-
4.11. Cyclisation of 12a–c to 2-alkylamino-8-
sulfonyl-1H-indazole (11), which was crystallised from pet. ether–
benzenesulfonylthiazolo[4,5-g]indazoles (13a–c)
CH2Cl2.
Following the general procedure described for the cyclisation of
4a–c to 5a–c, each of the thioureidoindazoles 12a–c (1 mmol) was
cyclised by Br2–AcOH to furnish the thiazolo[4,5-g]indazoles (13a–
c). All the crude products were purified by crystallisation from
MeOH–CH2Cl2.
4.9.1. 6-Amino-1-benzenesulfonyl-1H-indazole (11)
Colourless cubes; yield: 0.76 g (93%); mp 132–134 ꢁC; IR: 3437,
3348, 1617, 1486, 1331, 1225, 1192, 1139, 1089, 824, 764, 725 cmꢀ1
;
1H NMR (CDCl3):
d
4.16 (2H, s), 6.66 (1H, dd, J1¼8.5 Hz, J2¼2 Hz),
7.39 (1H, d, J¼8.5 Hz), 7.39 (1H, s), 7.43 (2H, t, J¼7.5 Hz), 7.54 (1H, t,
J¼7.5 Hz), 7.95 (1H, d, J¼2 Hz) and 7.94–7.98 (2H, m); 13C NMR:
4.11.1. 8-Benzenesulfonyl-2-methylaminothiazolo[4,5-g]-1H-
indazole (13a)
d
96.8, 114.9, 122.5, 127.8 (ꢂ2), 134.3, 142.1 (all Ar–CH), 119.0, 138.1,
142.9,148.9 (all Ar–C); LR EIMS: m/z (%) 273 (Mþ; 80),132 (100),104
(37), 77 (24), 51 (12); HR EIMS: Calcd for C13H11N3O2S 273.0572,
found 273.0571.
White crystals; yield: 0.33 g (95%); mp 262–264 ꢁC; IR (KBr):
3209, 1592, 1410, 1378, 1307, 1221, 1175, 1051, 726 cmꢀ1 1H NMR
;
(DMSO-d6):
d
2.99 (3H, d, J¼4.5 Hz), 7.48 (1H, d, J¼8.5 Hz), 7.57 (2H,
t, J¼7.5 Hz), 7.65 (1H, d, J¼8.5 Hz), 7.67 (1H, t, J¼7.5 Hz), 7.81 (2H, d,
4.10. Preparation of thioureidoindazoles 12a–c
J¼7.5 Hz), 8.26 (1H, d, J¼4.5 Hz) and 8.50 (1H, s); 13C NMR:
d 31.3
(NHCH3), 118.1, 120.0, 128.0 (ꢂ2), 130.7 (ꢂ2), 135.6, 144.9 (all Ar–
CH), 113.3, 122.5, 136.1, 137.0, 156.0, 170.3 (all Ar–C); LR EIMS: m/z
(%) 344 (Mþ; 90), 203 (100), 175 (25), 134 (18), 77 (11); HR EIMS:
Calcd for C15H12N4O2S2 344.0402, found 344.0403.
Each of the thioureidoindazoles 12a–c was prepared by con-
densation of the amine 11 (273 mg, 1 mmol) with the respective
alkyl isothiocyanates, following the general procedure described
for the syntheses of 4a–c. The crude products were crystallised
from MeOH–CH2Cl2 to furnish pure 12a–c.
4.11.2. 8-Benzenesulfonyl-2-ethylaminothiazolo[4,5-g]-1H-
indazole (13b)
4.10.1. 1-Benzenesulfonyl-6-(N-methylthioureido)-1H-
indazole (12a)
White flakes; yield: 0.336 g (94%); mp 214–216 ꢁC; IR: 3212,
1614, 1599, 1375, 1172, 1020, 725 cmꢀ1; 1H NMR (DMSO-d6):
d 1.24
White needles; yield 0.32 g (92%); mp 210–212 ꢁC; IR: 3311,
(3H, t, J¼7 Hz), 3.45 (2H, dq, J1¼7 Hz, J2¼5.5 Hz), 7.48 (1H, d,
J¼8.5 Hz), 7.59 (2H, t, J¼8 Hz), 7.66 (1H, d, J¼8.5 Hz), 7.68 (1H, t,
J¼8 Hz), 7.87 (2H, dd, J1¼8 Hz, J2¼1 Hz), 8.32 (1H, t, J¼5.5 Hz) and
3143, 1619, 1553, 1520, 1343, 1293, 1248, 1171, 725 cmꢀ1 1H NMR
;
(DMSO-d6):
d
2.97 (3H, d, J¼4.5 Hz), 7.39 (1H, d, J¼8.5 Hz), 7.58 (2H,
t, J¼7.5 Hz), 7.69 (1H, tt, J1¼8 Hz, J2¼1 Hz), 7.73 (1H, d, J¼8.5 Hz),
8.51 (1H, s); 13C NMR:
d 15.2 (CH3), 39.6 (NHCH2), 118.1, 120.0, 128.0
7.93 (2H, dd, J1¼8.5 Hz, J2¼1 Hz), 7.98 (1H, br), 8.43 (1H, s), 8.49 (1H,
(ꢂ2), 130.7 (ꢂ2), 135.6, 144.9 (all Ar–CH), 113.1, 122.5, 136.1, 137.0,
156.1, 169.7 (all Ar–C); LR EIMS: m/z (%) 358 (Mþ; 78), 217 (100), 189
(30). HR EIMS: Calcd for C16H14N4O2S2 358.0558, found 358.0554.
br s) and 9.98 (1H, br s); 13C NMR:
d
32.0 (NHCH3), 122.6, 127.9 (ꢂ2),
130.6 (ꢂ2), 135.7, 143.4 (all Ar–CH), 137.2, 141.1 (all Ar–C), 180.2
(NHCSNH); LR EIMS: m/z (%) 346 (Mþ; 38), 315 (95), 312 (90), 273
(36), 205 (10), 174 (33), 171 (100), 146 (22), 143 (44), 141 (24), 132
(60), 104 (19), 77 (87), 74 (13); HR EIMS: Calcd for C15H14N4O2S2
346.0559, found 346.0554.
4.11.3. 8-Benzenesulfonyl-2-benzylaminothiazolo[4,5-g]-1H-
indazole (13c)
White needles; yield: 0.405 g (96%); mp 211–213 ꢁC; IR (KBr):
3222, 1614, 1586, 1564, 1373, 1173, 804, 727 cmꢀ1; 1H NMR (DMSO-
4.10.2. 1-Benzenesulfonyl-6-(N-ethylthioureido)-1H-indazole (12b)
d6):
d
4.66 (2H, d, J¼5.5 Hz, NHCH2), 7.27 (1H, t, J¼7.5 Hz, H-40), 7.36
White crystals; yield: 0.33 g (92%); mp 208–210 ꢁC; IR: 3349,
(2H, t, J¼7.5 Hz, H-30), 7.41 (2H, d, J¼7.5 Hz, H-20), 7.48 (1H, d,
J¼8.5 Hz, H-4), 7.57 (2H, t, J¼7.5 Hz, H-300), 7.65 (1H, d, J¼8.5 Hz, H-
5), 7.67 (1H, t, J¼7.5 Hz, H-400), 7.81 (2H, d, J¼8 Hz, H-200), 8.51 (1H, s,
1619, 1541, 1348, 1304, 1187, 1089, 1069, 725 cmꢀ1 1H NMR
;
(200 MHz; DMSO-d6):
d
1.16 (3H, t, J¼7 Hz), 3.49 (2H, quintet,
J¼7 Hz), 7.37 (1H, d, J¼8.5 Hz), 7.57 (2H, t, J¼7 Hz), 7.70 (1H, t,
J¼7.5 Hz), 7.72 (1H, d, J¼8.5 Hz), 7.93 (2H, d, J¼7.5 Hz), 8.07 (1H,
H-6) and 8.82 (1H, t, J¼5.5 Hz, NHCH2); 13C NMR:
d 48.0 (NHCH2),
118.2 (CH-4),120.0 (CH-5),128.02 (CH-40),128.07 (ꢂ2, CH-200),128.3
(ꢂ2, CH-20), 129.3 (ꢂ2, CH-30), 130.7 (ꢂ2, CH-300), 135.6 (CH-400),
144.9 (CH-6), 113.4 (C-5a), 122.6 (C-8b), 136.1 (C-8a), 137.0 (C-10þ0),
139.4 (C-10), 155.8 (C-3a), 169.7 (C-2); LR EIMS: m/z (%) 420 (M ;
67), 419 (7), 315 (19), 280 (35), 273 (17), 132 (23), 106 (20), 91 (100);
HR EIMS: Calcd for C21H16N4O2S2 420.0714, found 420.0718.
br s), 8.43 (1H, s) and 9.87 (1H, s); 13C NMR (50 MHz):
d 14.0
(CH3), 40.7 (NHCH2), 104.7, 120.3, 121.9, 127.1 (ꢂ2), 129.8 (ꢂ2),
134.9 and 142.5 (all Ar–CH), 121.7, 136.4, 140.3, 141.3 (all Ar–C),
180.2 (NHCSNH); LR EIMS: m/z (%) 360 (Mþ; 52), 327 (32),
326 (92), 315 (45), 273 (41), 251 (11), 219 (16), 186 (14), 185
(100), 174 (18), 157 (32), 141 (15), 132 (80), 104 (18), 88 (15), 77
(66), 51 (18); HR EIMS: Calcd for C16H15N4O2S2 360.0714, found
360.0704.
4.12. Deprotection of benzenesulfonyl group of 13a–c
to 14a–c
4.10.3. 1-Benzenesulfonyl-6-(N-benzylthioureido)-1H-
indazole (12c)
Following the same procedure described for the deprotection of
5a–c to 6a–c, each of the 8-benzenesulfonylthiazoloindazoles
(13a–c, 1 mmol) was deprotected using aq methanolic potassium
carbonate under reflux to furnish 2-alkyl/benzylaminothiazolo[4,5-
g]indazoles (14a–c). The products were crystallised from CH2Cl2.
White needles; yield: 0.395 g (94%); mp 202–204 ꢁC; IR: 3363,
3151, 1619, 1540, 1301, 1222, 1169, 1096, 724 cmꢀ1
;
1H NMR
(200 MHz; DMSO-d6):
d
4.78 (2H, d, J¼4 Hz), 7.12–7.55 (6H, m), 7.57
(2H, t, J¼8 Hz), 7.70 (1H, m), 7.72 (1H, t, J¼8 Hz), 7.93 (2H, d,
J¼8 Hz), 8.44 (1H, s), 8.48 (1H, t, J¼4 Hz), 8.59 (1H, s) and 10.06 (1H,
4.12.1. 2-Methylaminothiazolo[4,5-g]-1H-indazole (14a)
s); 13C NMR (50 MHz):
d
47.2 (CH2), 105.1, 120.1, 121.8, 127.09 (ꢂ3),
White needles; yield 0.19 g (92%); mp 310–312 ꢁC; IR (KBr):
127.5 (ꢂ2), 128.3 (ꢂ2), 129.7 (ꢂ2), 134.8, 142.5 (all Ar–CH), 127.03,
136.3, 138.6, 140.2, 141.1 (all Ar–C), 180.8 (NHCSNH); LR EIMS: m/z
(%) 422 (Mþ; 9), 388 (17), 316 (27), 315 (100), 273 (52), 251 (38), 174
(45), 146 (24), 141 (31), 132 (65),107 (65), 106 (49), 104 (20), 91 (86),
79 (17), 77 (88); HR EIMS: Calcd for C21H18N4O2S2 422.0871, found
422.0871.
3216, 3023, 1586, 1556, 1371, 1239, 1045, 848, 748 cmꢀ1 1H NMR
;
(DMSO-d6):
d
2.95 (3H, d, J¼5 Hz), 7.25 (1H, d, J¼9 Hz), 7.56 (1H, d,
J¼9 Hz), 7.94 (1H, q, J¼4 Hz) and 8.02 (1H, s); 13C NMR:
d 31.5
(NHCH3), 114.5, 118.5, 135.4 (all Ar–CH), 108.1, 119.5, 135.6, 152.6,
168.0 (all Ar–C); LR EIMS: m/z (%) 204 (Mþ; 100), 175 (38). HR EIMS:
Calcd for C9H8N4S 204.0470, found 204.0473.

6718
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
4.12.2. 2-Ethylaminothiazolo[4,5-g]-1H-indazole (14b)
NMR:
d
48.0 (NHCH2), 104.3, 118.5, 121.4, 127.7, 128.3 (ꢂ2), 129.1
White flakes; yield 0.203 g (93%); mp 276–278 ꢁC; IR (KBr):
(ꢂ2), 134.2 (all Ar–CH), 120.8, 138.0, 139.8, 140.9 (all Ar–C), 181.6
(NHCSNH); LR EIMS: m/z (%) 282 (Mþ; 22), 248 (18), 175 (38), 133
(28), 106 (22), 91 (100); HR EIMS: Calcd for C15H14N4S 282.0939,
found 282.0935.
3222, 3009, 1625, 1577, 1556, 1349, 1209, 915, 852, 787 cmꢀ1 1H
;
NMR:
d
1.22 (3H, t, J¼7 Hz, CH3), 3.41 (2H, q, J¼7 Hz, NHCH2), 7.25
(1H, d, J¼8.5 Hz, H-5), 7.57 (1H, d, J¼8.5 Hz, H-4), 7.99 (1H, t,
J¼5.5 Hz, NHCH2), 8.08 (1H, s, H-6) and 13.05 (1H, s, H-8); 13C NMR:
d
15.3 (CH3), 39.8 (NHCH2), 114.5 (CH-5), 118.5 (CH-4), 135.4 (CH-6),
4.15. Preparation of indazolyl dithiocarbamates. General
procedure
109.0 (C-5a), 119.5 (C-8b), 135.6 (C-8a), 152.6 (C-3a), 167.0 (C-2); LR
EIMS: m/z (%) 218 (Mþ; 100), 203 (58), 190 (43). HR EIMS: Calcd for
C
10H10N4S 218.0627, found 218.0619.
To a mixture of the amine 7 (0.133 g, 1 mmol), dry triethylamine
(0.5 mL) and dry pyridine (1.5 mL) was added carbon disulfide
(0.1 mL, 1.2 mmol) at 0 ꢁC and the solution kept at room tempera-
ture for 1 h. The reaction mixture was then treated with methyl or
ethyl iodide (1.2 mmol) at 0 ꢁC, stirred for another 2–3 h and then
the mixture was poured into 2 N H2SO4 (30 mL) and extracted with
CH2Cl2 (3ꢂ30 mL). The combined extracts were washed succes-
sively with water (50 mL), saturated aq Na2CO3 and water, dried
(Na2SO4) and the solvent evaporated to furnish the crude products
(17a,b), which were purified by crystallisation from pet. ether–
CH2Cl2.
4.12.3. 2-Benzylaminothiazolo[4,5-g]-1H-indazole (14c)
White needles; yield 0.27 g (97%); mp 246–248 ꢁC; IR: 3209,
1629, 1599, 1070, 979, 918, 839, 797 cmꢀ1 1H NMR (DMSO-d6):
;
d
4.63 (2H, d, J¼5.5 Hz), 7.26 (1H, d, J¼8.5 Hz), 7.28 (1H, t, J¼7.5 Hz),
7.36 (2H, t, J¼7.5 Hz), 7.42 (2H, d, J¼7.5 Hz), 7.59 (1H, d, J¼8.5 Hz),
8.05 (1H, s), 8.52 (1H, t, J¼5.5 Hz) and 13.07 (1H, s); 13C NMR:
d 48.4
(NHCH2), 114.6, 118.6, 128.3 (ꢂ2), 129.2 (ꢂ2), 135.4 (all Ar–CH),
109.3, 119.6, 135.6, 139.7, 152.3, 167.3 (all Ar–C); LR EIMS: m/z (%)
280 (Mþ; 100), 279 (19), 189 (42), 176 (14), 106 (12), 91 (79). Anal.
Calcd for C15H12N4S: C, 64.28; H, 4.28; N, 20.00. Found: C, 64.20; H,
4.29; N, 19.98%.
4.15.1. Methyl 1H-indazol-5-yl dithiocarbamate (17a)
White flakes; yield: 0.174 g (78%); mp 186–188 ꢁC (dec); IR:
4.13. Preparation of 6-amino-1H-indazole (15)
3223, 1597, 1522, 1147, 1028, 935, 806 cmꢀ1 1H NMR (DMSO-d6):
;
d
2.51 (3H, s), 7.32 (1H, br d, J¼8.5 Hz), 7.41 (1H, br), 7.49 (1H, d,
Following the procedure described for reduction of 2 to 3,
6-nitro-1H-indazole (9, 0.49 g, 3 mmol) was reduced to 6-amino-
1H-indazole (15); colourless needles; yield: 0.36 g (95%); mp
204–206 ꢁC (dec); lit. mp 204–206 ꢁC (dec); CAS No. 6967-12-0;
Sigma–Aldrich Catalogue no. A59565.
J¼8.5 Hz), 8.03,11.58 and 13.08 (1H, s each); 13C NMR:
d 18.7 (SCH3),
110.9, 116.1, 124.8 and 134.7 (all Ar–CH), 119.0, 123.3, 138.9 (all Ar–
C), 198.1 (NHCSSEt); LR EIMS: m/z (%) 223 (Mþ; 12%), 176 (18), 175
(100), 143 (11), 117 (9), 90 (10); HR EIMS: Calcd for C9H9N3S2
223.0328, found 223.0326.
4.14. Preparation of thioureidoindazoles 16a–c
4.15.2. Ethyl 1H-indazol-5-yl dithiocarbamate (17b)
Pale yellowcrystals; yield: 0.17 g (72%); mp 250–252 ꢁC (dec); IR:
The thioureidoindazoles 16a–c were synthesised by the con-
densation of the amine 15 (1 mmol) with the respective alkyl iso-
thiocyanates, following the general procedure described earlier for
the preparation of 8a–c. The crude products were purified by
crystallisation from CH2Cl2.
3230, 1593, 1507, 1149, 1036, 930, 804 cmꢀ1 1H NMR (DMSO-d6):
;
d
1.24 (3H, t, J¼7 Hz), 3.25 (2H, q, J¼7 Hz), 7.46 (1H, br), 7.53 (1H, d, J¼
8.5 Hz), 7.60 (1H, d, J¼8.5 Hz), 8.08 (1H, s)and 13.12 (1H, s); 13C NMR:
d
15.2 (CH3), 29.8 (SCH2), 108.3, 117.3, 123.1, 134.5 (all Ar–CH), 120.0,
122.5, 138.6 (all Ar–C), 197.9 (NHCSSEt). Anal. Calcd for C10H11N3S2:
C, 50.63; H, 4.64; N, 17.72. Found: C, 50.57; H, 4.62; N, 17.69%.
4.14.1. 6-(N-Methyl)thioureido-1H-indazole (16a)
Off-white prisms; yield 0.19 g (92%); mp 204–206 ꢁC; IR: 3234,
4.16. Cyclisation of 17a,b to 2-alkylthiothiazolo[5,4-e]-
indazoles (18a,b)
1629, 1569, 1240, 1052, 948, 860, 777 cmꢀ1
;
1H NMR (DMSO-d6):
d
2.93 (3H, d, J¼4.5 Hz), 6.97 (1H, d, J¼7.5 Hz), 7.67 (1H, d, J¼8.5 Hz),
7.73 (1H, s), 7.99, 9.67 and 12.94 (1H, s each); 13C NMR:
d
32.1
Following the general procedure described earlier for the cyc-
lisation of 4a–c to 5a–c, the indazolyl dithiocarbamates (17a,b)
were cyclised by Br2–AcOH to furnish regioselectively the 2-
alkylthiothiazolo[5,4-e]indazoles (18a,b), which were purified by
crystallisation from CH2Cl2.
(NHCH3), 104.1, 118.5, 121.5 and 134.2 (all Ar–CH), 120.8, 138.0 and
141.8 (all Ar–C), 181.9 (NHCSNH); LR EIMS: m/z (%) 206 (Mþ; 100),
175 (34), 172 (78), 133 (95), 105 (15); HR EIMS: Calcd for C9H10N4S
206.0626, found 206.0627.
4.14.2. 6-(N-Ethyl)thioureido-1H-indazole (16b)
4.16.1. 2-Methylthiothiazolo[5,4-e]-1H-indazole (18a)
White flakes; yield 0.204 g (93%); mp 182–184 ꢁC; IR: 3171,1626,
White flakes; yield: 0.19 g (90%); mp 211–213 ꢁC (dec); IR: 3204,
1546, 1507, 1341, 1241, 1049, 943, 777 cmꢀ1 1H NMR (DMSO-d6):
;
1601, 1580, 1442, 1376, 1045, 965, 919, 858 cmꢀ1; 1H NMR (DMSO-
d
1.13 (3H, t, J¼7 Hz), 3.51 (2H, quintet, J¼7 Hz), 6.98 (1H, d,
J¼8.5 Hz), 7.67 (1H, d, J¼8.5 Hz), 7.80 (2H, s), 7.99, 9.56 and 12.97
(1H, s each); 13C NMR:
15.0 (CH3), 39.5 (NHCH2), 103.9, 118.4,
d6):
d
2.79 (3H, s), 7.62 (1H, d, J¼9 Hz), 7.82 (1H, d, J¼9 Hz), 8.28 (1H,
16.7 (S–CH3), 110.4, 120.9, 133.1 (all
s) and 13.46 (1H, s); 13C NMR:
d
d
Ar–CH), 116.8, 125.8, 138.6, 149.0, 164.2 (all Ar–C); LR EIMS: m/z (%)
221 (Mþ; 100), 206 (11), 189 (11), 188 (92), 162 (17), 148 (10); HR
EIMS: Calcd for C9H7N3S2 221.0081, found 221.0072.
121.3, 134.1 (all Ar–CH), 120.7, 138.1, 141.0 (all Ar–C), 180.9
(NHCSNH); LR EIMS: m/z (%) 220 (Mþ; 76), 187 (19), 186 (50), 175
(42), 159 (12), 158 (42), 150 (13), 133 (100), 117 (13), 105 (16), 90
(17); HR EIMS: Calcd for C10H12N4S 220.0783, found 220.0781.
4.16.2. 2-Ethylthiothiazolo[5,4-e]-1H-indazole (18b)
Pale yellow crystals; yield: 0.2 g (84%); mp 188–190 ꢁC (dec); IR
(KBr): 3179, 3125, 1608, 1479, 1440, 1422, 1073, 1046, 1007,
4.14.3. 6-(N-Benzyl)thioureido-1H-indazole (16c)
Off-white plates; yield 0.27 g (95%); mp 193–195 ꢁC; IR: 3170,
921 cmꢀ1; 1H NMR (DMSO-d6):
d
1.41 (3H, t, J¼7.5 Hz), 3.34 (2H, q,
J¼7.5 Hz), 7.62 (1H, d, J¼9 Hz), 7.84 (1H, d, J¼9 Hz), 8.29 (1H, s) and
13.46 (1H, s); 13C NMR:
15.5 (CH3), 28.7 (SCH2), 110.4, 121.0, 133.2
1525, 1458, 1376, 1202, 1069, 943, 744 cmꢀ1 1H NMR (DMSO-d6):
;
d
4.74 (2H, d, J¼5.5 Hz), 6.98 (1H, dd, J1¼8.5 Hz, J2¼1.5 Hz), 7.22–
d
7.26 (1H, m), 7.31–7.34 (4H, m), 7.67 (1H, d, J¼8.5 Hz), 7.85 (1H, s),
(all Ar–CH), 116.7, 125.9, 138.6, 148.9, 162.7 (all Ar–C); HR ESI-MS:
7.98 (1H, s), 8.22 (1H, t, J¼5.5 Hz), 9.78 (1H, s) and 12.94 (1H, s); 13
C
Calcd for C10H9N3S2 (MþHþ) 236.0311, found 236.0318.

M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
6719
4.17. Alkyl 1H-indazol-6-yl dithiocarbamates (19a,b)
(3ꢂ30 mL). The organic layer was dried (Na2SO4) and the solvent
evaporated to furnish a mixture of N(1)-alkyl and N(2)-alkylni-
troindazoles, which were separated by CC over silica gel and pu-
rified by crystallisation from pet. ether–CH2Cl2.
Following the general method described before for the prepa-
ration of 17a,b from 7, the alkyl (1H-indazol-6-yl)dithiocarbamates
19a,b were prepared from 15 and purified by crystallisation from
pet. ether–CH2Cl2.
4.19.1. 1-Methyl-5-nitro-1H-indazole (21a)
Eluted with pet. ether–EtOAc (4:1); yellow needles; yield: 0.98 g
4.17.1. Methyl 1H-indazol-6-yl dithiocarbamate (19a)
(55%); mp 162–164 ꢁC (lit.26a mp 158–162 ꢁC); IR: 1613, 1513, 1493,
White flakes; yield: 0.167 g (75%); mp 134–136 ꢁC; IR: 3151,
1332,1202,1066, 791, 747 cmꢀ1; 1H NMR (CDCl3):
d 4.15 (3H, s), 7.46
1633, 1533, 1334, 1029, 950, 864, 731 cmꢀ1
;
1H NMR (DMSO-d6):
(1H, d, J¼9 Hz), 8.19 (1H, s), 8.28 (1H, dd, J1¼9 Hz, J2¼2 Hz) and 8.73
d
2.57 (3H, s), 7.21 (1H, ill-split d), 7.72 (1H, d, J¼8.5 Hz), 8.03 (1H, s),
(1H, d, J¼2 Hz); 13C NMR:
d 36.4 (NCH3), 109.6,119.3, 121.7, 135.9 (all
Ar–CH), 123.4, 141.9, 142.7 (all Ar–C). Anal. Calcd for C8H7N3O2: C,
54.24; H, 3.95; N, 23.73. Found: C, 54.29; H, 3.97; N, 23.70%.
8.11 (1H, br) and 13.06 (1H, s); 13C NMR:
d
18.8 (SCH3), 105.0, 118.5,
121.5, 134.3 (all Ar–CH), 121.5, 138.6, 140.4 (all Ar–C), 197.9
(NHCSSCH3); LR EIMS: m/z (%) 223 (Mþ; 15), 176 (25), 175 (100), 143
(9), 117 (15), 90 (12). Anal. Calcd for C9H9N3S2: C, 48.43; H, 4.04; N,
18.83. Found: C, 48.47; H, 4.05; N, 18.86%.
4.19.2. 1-Ethyl-5-nitro-1H-indazole (21b)
Eluted with pet. ether–EtOAc (7:1); yellow needles; yield: 0.94 g
(49%); mp 155–157 ꢁC; IR: 1613, 1586, 1513, 1334, 1195, 1069,
4.17.2. Ethyl 1H-indazol-6-yl dithiocarbamate (19b)
738 cmꢀ1
;
1H NMR (CDCl3):
d
1.56 (3H, t, J¼7 Hz), 4.49 (2H, q,
Pale yellow crystals; yield: 0.165 g (70%); mp 98–100 ꢁC; IR:
J¼7 Hz), 7.48 (1H, d, J¼9 Hz), 8.20 (1H, d, J¼0.5 Hz), 8.26 (1H, dd,
3124, 1633, 1527, 1334, 1023, 950, 837, 771, 724 cmꢀ1
;
1H NMR
J1¼9 Hz, J2¼2 Hz) and 8.72 (1H, d, J¼2 Hz); 13C NMR:
d 15.2 (CH3),
(DMSO-d6):
ill-split d), 7.73 (1H, d, J¼8.5 Hz), 8.04 (1H, s), 8.12 (1H, br), 11.72
(1H, s) and 13.07 (1H, s); 13C NMR:
14.9 (CH3), 29.7 (SCH2), 105.7,
d
1.26 (3H, t, J¼7.5 Hz), 3.22 (2H, q, J¼7.5 Hz), 7.21 (1H,
44.7 (NCH2), 109.5, 119.4, 121.6, 136.0 (all Ar–CH), 123.5, 141.0, 142.6
(all Ar–C); LR EIMS: m/z (%) 191 (Mþ; 100),176 (67),161 (11),145 (10),
130 (42),105 (15), 90 (24), 76 (19), 63 (21). Anal. Calcd for C9H9N3O2:
C, 56.54; H, 4.71; N, 21.99. Found: C, 56.58; H, 4.69; N, 21.96%.
d
118.6, 121.4, 134.3 (all Ar–CH), 121.7, 138.3, 140.4 (all Ar–C), 197.8
(NHCSSEt). Anal. Calcd for C10H11N3S2: C, 50.63; H, 4.64; N, 17.72.
Found: C, 50.60; H, 4.66; N, 17.75%.
4.19.3. 5-Nitro-1-n-propyl-1H-indazole (21c)
Eluted with pet. ether–EtOAc (9:1); yellow needles; yield: 0.92 g
(45%); mp 61–63 ꢁC; IR: 1610, 1586, 1511, 1186, 1151, 1067, 913, 787,
4.18. Cyclisation of 19a,b to 2-alkylthiothiazolo[4,5-g]-
indazoles (20a,b)
758 cmꢀ1; 1H NMR (CDCl3):
d
0.99 (3H, t, J¼7 Hz), 1.99 (2H, sextet,
J¼7 Hz), 4.41 (2H, t, J¼7 Hz), 7.47 (1H, d, J¼9 Hz), 8.21 (1H, d,
J¼0.5 Hz), 8.26 (1H, dd, J1¼9 Hz, J2¼2 Hz) and 8.72 (1H, d, J¼2 Hz);
The indazolyl dithiocarbamates (19a,b) were cyclised by Br2–
AcOH to furnish regioselectively the 2-alkylthiothiazolo[4,5-
g]indazoles (20a,b), following the general procedure described
earlier for the cyclisation of 17a,b to 18a,b. The products were
crystallised from CH2Cl2.
13C NMR:
d 11.7 (CH3), 23.5 (CH2), 51.4 (NCH2), 109.6, 119.4, 121.6,
136.0 (all Ar–CH), 123.4, 141.6, 142.6 (all Ar–C). Anal. Calcd for
10H11N3O2: C, 58.54; H, 5.36; N, 20.49. Found: C, 58.58; H, 5.38; N,
C
20.46%.
4.18.1. 2-Methylthiothiazolo[4,5-g]-1H-indazole (20a)
4.19.4. 2-Methyl-5-nitro-2H-indazole (22a)
White flakes; yield: 0.205 g (93%); mp 227–229 ꢁC; IR (KBr):
3153, 3078, 1628, 1484, 1377, 1238, 1052, 1004, 930, 838, 797,
Eluted with pet. ether–EtOAc (7:3); ochre yellow flakes; yield:
0.62 g (35%); mp 128–130 ꢁC (lit.26b mp 129–131 ꢁC); IR: 1613, 1513,
752 cmꢀ1; 1H NMR (DMSO-d6):
d
2.82 (3H, s), 7.60 (1H, d, J¼9 Hz),
1493, 1456,1332,1202,1066, 791, 744 cmꢀ1; 1H NMR (CDCl3):
d 4.29
7.79 (1H, d, J¼9 Hz), 8.19 (1H, s) and 13.56 (1H, s); 13C NMR:
d
16.7
(3H, s), 7.74 (1H, d, J¼9.5 Hz), 8.09 (1H, dd, J1¼9.5 Hz, J2¼2 Hz), 8.20
(SCH3), 115.9, 119.9, 135.7 (all Ar–CH), 120.6, 134.8, 153.4, 167.3 (all
Ar–C); LR EIMS: m/z (%) 221 (Mþ; 100), 220 (7), 206 (13), 189 (10),
188 (76), 179 (7), 175 (7), 142 (9). Anal. Calcd for C9H7N3S2: C, 48.87;
H, 3.17; N, 19.0. Found: C, 48.84; H, 3.16; N, 18.98%.
(1H, s) and 8.72 (1H, d, J¼2 Hz); 13C NMR:
d 41.3 (NCH3), 118.5,119.6,
120.6, 128.1 (all Ar–CH), 120.7, 143.4, 150.4 (all Ar–C). Anal. Calcd for
C8H7N3O2: C, 54.24; H, 3.95; N, 23.73. Found: C, 54.29; H, 3.94; N,
23.76%.
4.18.2. 2-Ethylthiothiazolo[4,5-g]-1H-indazole (20b)
4.19.5. 2-Ethyl-5-nitro-2H-indazole (22b)
Eluted with pet. ether–EtOAc (4:1); ochre yellow flakes; yield:
0.725 g (38%); mp 73–75 ꢁC; IR: 1619, 1566, 1334, 1149, 1062, 1003,
Pale yellow crystals; yield: 0.204 g (87%); mp 207–209 ꢁC; IR:
3150, 1628, 1445, 1242, 1048, 930, 804, 746 cmꢀ1; 1H NMR (DMSO-
d6):
d
1.45 (3H, t, J¼7.5 Hz), 3.40 (2H, q, J¼7.5 Hz), 7.63 (1H, d,
910, 758 cmꢀ1; 1H NMR (CDCl3):
d
1.72 (3H, t, J¼7.5 Hz), 4.58 (2H, q,
J¼9 Hz), 7.82 (1H, d, J¼9 Hz), 8.23 (1H, s) and 13.56 (1H, s); 13C
J¼7.5 Hz), 7.76 (1H, d, J¼9.5 Hz), 8.10 (1H, dd, J1¼9.5 Hz, J2¼2 Hz),
NMR:
d
15.4 (CH3), 28.6 (SCH2), 116.0, 119.9, 135.7 (all Ar–CH), 120.6,
8.28 (1H, s) and 8.74 (1H, d, J¼2 Hz); 13C NMR:
d 15.9 (CH3), 49.6
134.9, 153.2, 167.6 (all Ar–C); HR ESI-MS: Calcd for C10H10N3S2
(NCH2), 118.6, 119.7, 120.4, 126.6 (all Ar–CH), 120.5, 143.3, 150.1 (all
Ar–C). Anal. Calcd for C9H9N3O2: C, 56.54; H, 4.71; N, 21.99. Found:
C, 56.57; H, 4.70; N, 22.02%.
(MþHþ) 236.0311, found 236.0317.
4.19. Alkylations of 5/6-nitro-1H-indazole (1/9). General
procedure
4.19.6. 5-Nitro-2-n-propyl-2H-indazole (22c)
Eluted with pet. ether–EtOAc (6:1); ochre yellow flakes; yield:
0.86 g (42%); mp 116–118 ꢁC; IR: 1610, 1586, 1511, 1186, 1151, 1067,
To a solution of 5-nitro-1H-indazole (1) or 6-nitroindazole (9)
(1.63 g, 10 mmol) in THF (50 mL) were added the PTC (n-
Bu4NHþSOꢀ4 , 51 mg, 0.15 mmol) and powdered NaOH (1.0 g,
25 mmol). The solution was stirred for 1 h and then cooled in an
ice-bath, and the alkyl iodide (1.2 mmol) was added dropwise to
this solution, which was stirred at room temperature for another
3 h until the reaction was complete (TLC). The reaction mixture was
then poured into water (50 mL) and extracted with CH2Cl2
913, 787, 758 cmꢀ1 1H NMR (200 MHz; CDCl3):
; d 0.97 (3H, t,
J¼7 Hz), 2.08 (2H, sextet, J¼7 Hz), 4.43 (2H, t, J¼7 Hz), 7.74 (1H, d,
J¼9.5 Hz), 8.09 (1H, dd, J1¼9.5 Hz, J2¼2 Hz), 8.20 (1H, s) and 8.73
(1H, s); 13C NMR (50 MHz):
d 11.0 (CH3), 23.7 (CH2), 55.9 (NCH2),
118.2, 119.2, 120, 126.8 (all Ar–CH), 119.9, 142.9, 149.7 (all Ar–C).
Anal. Calcd for C10H11N3O2: C, 58.54; H, 5.36; N, 20.49. Found: C,
58.50; H, 5.34; N, 20.53%.

6720
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
4.19.7. 1-Methyl-6-nitro-1H-indazole (23a)
Calcd for C9H11N3: C, 67.08; H, 6.83; N, 26.09. Found: C, 67.05; H,
6.82; N, 26.12%.
Eluted with pet. ether–EtOAc (6:1); yellow needles; yield: 0.92 g
(52%); mp 125–126 ꢁC (lit.26c mp 125 ꢁC); IR: 1580,1527,1348,1222,
943, 844, 731, 731 cmꢀ1; 1H NMR (CDCl3):
d
4.13 (3H, s), 7.82 (1H, d,
J¼8.5 Hz), 7.99 (1H, dd, J1¼8.5 Hz, J2¼2 Hz), 8.09 (1H, s) and 8.36
(1H, s); 13C NMR:
36.5 (NCH3),106.1,115.7,122.2, and 133.5 (all Ar–
4.20.3. 5-Amino-1-n-propyl-1H-indazole (25c)
Colourless needles; yield: 0.47 g (90%); mp 167–169 ꢁC; IR:
d
3315, 3204, 1684, 1571, 1508, 1322, 1234, 1187, 857, 804 cmꢀ1 1H
;
CH), 127.4, 139.0, 146.8 (all Ar–C). Anal. Calcd for C8H7N3O2: C,
54.24; H, 3.95; N, 23.73. Found: C, 54.20; H, 3.96; N, 23.70%.
NMR (CDCl3):
d
0.90 (3H, t, J¼7 Hz), 1.92 (2H, sextet, J¼7 Hz), 3.30
(2H, br s), 4.26 (2H, t, J¼7 Hz), 6.84 (1H, dd, J1¼9 Hz, J2¼2 Hz), 6.91
(1H, d, J¼1.5 Hz), 7.20 (1H, d, J¼9 Hz) and 7.77 (1H, d, J¼1 Hz); 13
C
4.19.8. 1-Ethyl-6-nitro-1H-indazole (23b)
NMR: d 11.8 (CH3), 23.6 (CH2), 50.9 (NCH2), 103.9, 110.1, 118.7, 131.4
Eluted with pet. ether–EtOAc (9:1); yellow needles; yield 0.92 g
(all Ar–CH), 125.2, 135.6, 140.4 (all Ar–C); LR EIMS: m/z (%) 175 (Mþ;
80), 147 (12), 146 (100), 133 (16), 119 (20), 105 (8), 92 (10); HR EIMS:
Calcd for C10H13N3 175.1110, found 175.1108.
(48%); mp 99–100 ꢁC (lit.26d mp 98–99 ꢁC); IR: 1507, 1348, 1314,
1202, 1062, 970, 837, 738 cmꢀ1 1H NMR (CDCl3):
; d 1.58 (3H, t,
J¼7 Hz), 4.54 (2H, q, J¼7 Hz), 7.84 (1H, d, J¼9 Hz), 8.01 (1H, dd,
J1¼9 Hz, J2¼2 Hz), 8.12 (1H, d, J¼1 Hz) and 8.40 (1H, d, J¼1 Hz); 13
C
NMR:
d
15.4 (CH3), 44.7 (NCH2), 106.1,115.6, 122.2,133.1 (all Ar–CH),
4.21. Preparation of 1(N)-alkyl-5-(N-methylthioureido)-
indazoles (26a–c) from 25a–c
127.5, 138.1, 146.7 (all Ar–C); LR EIMS: m/z (%) 191 (Mþ; 81), 176
(100), 130 (45). HR EIMS: Calcd for C9H9N3O2 191.0695, found
191.0695.
Following the general procedure described earlier for the
preparation of 8a–c, the thioureidoindazoles 26a–c were syn-
thesised by the condensation of the amines 25a–c (1 mmol) with
methyl isothiocyanate and purified by crystallisation from CH2Cl2.
4.19.9. 2-Methyl-6-nitro-2H-indazole (24a)
Eluted with pet. ether–EtOAc (3:1); ochre yellow plates; yield
0.64 g (36%); mp 160–162 ꢁC (lit.26c,e mp 159–160 ꢁC); IR: 1619,
1560, 1527, 1341, 1301, 1162, 1062, 824, 731 cmꢀ1
;
1H NMR
4.21.1. 1-Methyl-5-(N-methylthioureido)-1H-indazole (26a)
(200 MHz; CDCl3):
J2¼3.5 Hz), 7.91 (1H, d, J¼9 Hz), 8.03 (1H, d, J¼3.5 Hz) and 8.68 (1H,
s); 13C NMR:
41.0 (NCH3), 115.2, 115.6, 121.2, 124.5 (all Ar–CH),
d
4.31 (3H, d, J¼3.5 Hz), 7.75 (1H, dd, J1¼9 Hz,
Colourless prisms; yield: 0.207 g (94%); mp 198–200 ꢁC; IR:
3217, 3164, 1546, 1500, 1255, 1056, 990, 771, 711 cmꢀ1 1H NMR
;
d
(DMSO-d6):
J¼8.5 Hz), 7.45 (1H, br), 7.56 (1H, d, J¼8.5 Hz), 7.62 (1H, d, J¼1 Hz),
7.99 (1H, s) and 9.46 (1H, s); 13C NMR:
32.1 (NHCH3), 36.2 (NCH3),
d
2.88 (3H, d, J¼4.5 Hz), 4.0 (3H, s), 7.25 (1H, d,
124.5, 146.4, 146.8 (all Ar–C). Anal. Calcd for C9H9N3O2: C, 54.24; H,
3.95; N, 23.73. Found: C, 54.29; H, 3.97; N, 23.70%.
d
110.7, 117.1, 125.9, 133.2 (all Ar–CH), 124.3, 132.4, 138.5 (all Ar–C),
182.5 (NHCSNH); LR EIMS: m/z (%) 220 (Mþ; 79),187 (30),186 (100),
171 (40), 164 (32), 147 (60), 146 (27), 132 (16); HR EIMS: Calcd for
4.19.10. 2-Ethyl-6-nitro-2H-indazole (24b)
Eluted with pet. ether–EtOAc (4:1); ochre yellow plates; yield
0.745 g (39%); mp 88–90 ꢁC (lit.26d mp 89–90 ꢁC); IR: 1619, 1560,
C10H12N4S 220.0783, found 220.0779.
1527, 1334, 1308, 1142, 1016, 744 cmꢀ1; 1H NMR (CDCl3):
d 1.68 (3H,
t, J¼7 Hz), 4.56 (2H, q, J¼7 Hz), 7.75 (1H, d, J¼9 Hz), 7.88 (1H, dd,
4.21.2. 1-Ethyl-5-(N-methylthioureido)-1H-indazole (26b)
J1¼9 Hz, J2¼2 Hz), 8.07 (1H, s) and 8.68 (1H, d, J¼1 Hz); 13C NMR:
White needles; yield: 0.2 g (90%); mp 177–179 ꢁC; IR: 3270,
d
16.0 (CH3), 49.8 (NCH2), 115.8, 116.0, 121.7, 123.3 (all Ar–CH), 124.7,
3161, 1541, 1522, 1506, 1244, 1193, 1051, 958, 887, 765 cmꢀ1 1H
;
146.8,147.1 (all Ar–C). Anal. Calcd for C9H9N3O2: C, 56.54; H, 4.71; N,
21.99. Found: C, 56.51; H, 4.69; N, 22.01%.
NMR (DMSO-d6):
d
1.38 (3H, t, J¼7 Hz), 2.89 (3H, d, J¼4.5 Hz), 4.41
(2H, q, J¼7 Hz), 7.25 (1H, d, J¼8.5 Hz), 7.47 (1H, br s), 7.61 (1H, d,
J¼9 Hz), 7.63 (1H, d, J¼1.5 Hz), 8.01 (1H, d, J¼0.5 Hz) and 9.47 (1H,
br s); 13C NMR:
d 15.8 (CH3), 32.2 (NHCH3), 44.0 (NCH2), 110.6, 117.1,
4.20. Reduction of 21a–c to 1-alkyl-5-aminoindazoles (25a–c)
125.7, 133.2 (all Ar–CH), 124.4, 132.4, 137.6 (all Ar–C), 182.5
(NHCSNH); LR EIMS: m/z (%) 234 (Mþ; 100), 201 (38), 200 (90), 185
(54), 178 (35), 161 (42), 146 (53), 133 (10), 105 (11); HR EIMS: Calcd
for C11H14N4S 234.0939, found 234.0932.
Following the procedure described for the preparation of 3 from
2,1-alkyl-5-nitro-1H-indazoles (21a–c, 3 mmol each) were reduced
by NH2NH2$H2O/Pd–C to the corresponding amines (25a–c), which
were purified by crystallisation from pet. ether–CH2Cl2.
4.21.3. 5-(N-Methylthioureido)-1-n-propyl-1H-indazole (26c)
White prisms; yield: 0.22 g (88%); mp 167–169 ꢁC; IR: 3250,
4.20.1. 5-Amino-1-methyl-1H-indazole (25a)
3177, 1540, 1507, 1248, 1056, 1023, 897, 824, 744 cmꢀ1 1H NMR
;
Colourless needles; yield: 0.415 g (94%); mp 156–158 ꢁC; IR:
(DMSO-d6):
d
0.81 (3H, t, J¼7 Hz), 1.82 (2H, sextet, J¼7 Hz), 2.89
3373, 3204, 3098, 1646, 1301, 1222, 1149, 870, 804, 744 cmꢀ1
;
1H
(3H, d, J¼4.5 Hz), 4.38 (2H, t, J¼7 Hz), 7.28 (1H, d, J¼8 Hz), 7.47 (1H,
NMR (CDCl3):
d
3.60 (2H, s), 3.99 (3H, s), 6.86 (1H, dd, J1¼8.5 Hz,
br s), 7.61 (1H, d, J¼8 Hz), 7.62 (1H, s), 8.0 (1H, d, J¼0.5 Hz) and 9.46
J2¼2 Hz), 6.91 (1H, d, J¼1 Hz), 7.19 (1H, d, J¼8.5 Hz) and 7.76 (1H, s);
(1H, s); 13C NMR:
d 12.0 (CH3), 23.7 (CH2), 32.2 (NHCH3), 50.5
13C NMR:
d
35.9 (NCH3), 103.8, 110.0, 118.8, 131.4 (all Ar–CH), 125.3,
(NCH2), 110.6, 117.0, 125.7, 133.2 (all Ar–CH), 124.3, 132.4, 138.2 (all
Ar–C), 182.5 (NHCSNH); LR EIMS: m/z (%) 248 (Mþ; 100), 217 (19),
215 (47), 214 (64), 192 (48), 188 (24), 185 (68), 175 (45), 172 (11), 170
(16), 163 (15), 147 (11), 146 (88), 133 (13), 105 (10); HR EIMS: Calcd
for C12H16N4S 248.1095, found 248.1098.
136.0, 140.5 (all Ar–C); LR EIMS: m/z (%) 147 (Mþ; 100), 146 (40), 119
(25). Anal. Calcd for C8H9N3: C, 65.31; H, 6.12; N, 28.57. Found: C,
65.28; H, 6.10; N, 28.60%.
4.20.2. 5-Amino-1-ethyl-1H-indazole (25b)
Colurless needles; yield: 0.44 g (91%); mp 100–102 ꢁC; IR: 3378,
3319, 3214, 1647, 1624, 1508, 1321, 1232, 1202, 1023, 847, 811 cmꢀ1
;
4.22. Cyclisation of 26a–c to 2-methylamino-6-
alkylthiazolo[5,4-e]indazoles (27a–c)
1H NMR (CDCl3):
d
1.47 (3H, t, J¼7 Hz), 3.60 (2H, br s), 4.35 (2H, q,
J¼7 Hz), 6.84 (1H, dd, J1¼9 Hz, J2¼2 Hz), 6.90 (1H, s), 7.21 (1H, d,
J¼8.5 Hz) and 7.77 (1H, s); 13C NMR:
d
15.3 (CH3), 44.1 (NCH2),103.9,
The thioureidoindazoles (26a–c) were cyclised by Br2–AcOH, as
described earlier, to furnish regioselectively the thiazolo[5,4-
e]indazoles, 27a–c, which were crystallised from pet. ether–CH2Cl2.
110.0, 118.7, 131.4 (all Ar–CH), 125.4, 135.1, 140.5 (all Ar–C); LR EIMS:
m/z (%) 161 (Mþ; 100), 146 (76), 133 (16), 119 (15), 105 (7). Anal.

M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
6721
4.22.1. 6-Methyl-2-methylaminothiazolo[5,4-e]-1H-indazole (27a)
Colourless needles; yield: 0.2 g (92%); mp 214–216 ꢁC; IR (KBr):
3230, 3134, 3103, 1625, 1557, 1476, 1305, 1230, 1149, 1059, 928, 813,
synthesised by the condensation of the amines 28a,b (1 mmol
each) with methyl isothiocyanate and purified by crystallisation
from CH2Cl2.
783 cmꢀ1
;
1H NMR (DMSO-d6):
d
2.93 (3H, d, J¼4.5 Hz, NHCH3),
4.03 (3H, s, NCH3), 7.48 (1H, d, J¼9 Hz, H-5), 7.51 (1H, d, J¼9 Hz, H-
4.24.1. 1-Methyl-6-(N-methylthioureido)-1H-indazole (29a)
4), 7.78 (1H, q, J¼4.5 Hz, NH–CH3) and 8.0 (1H, s, H-3); 13C NMR:
White prisms; yield: 0.2 g (91%); mp 211–213 ꢁC; IR: 3228, 3163,
d
31.5 (NHCH3), 36.5 (NCH3), 108.3 (CH-5), 119.2 (CH-4), 130.4 (CH-
1619, 1553, 1248, 1054, 992, 844, 771, 712 cmꢀ1 1H NMR (DMSO-
;
8), 118.1 (ꢂ2, C-8a, C-8b), 137.5 (C-5a), 147.7 (C-3a), 166.5 (C-2); LR
EIMS: m/z (%) 218 (Mþ; 100), 203 (14), 190 (19), 189 (21); HR EIMS:
Calcd for C10H10N4S 218.0627, found 218.0621.
d6):
(1H, d, J¼9 Hz), 7.68 (1H, s), 7.74 (1H, br s), 7.96 (1H, s) and 9.69 (1H,
s); 13C NMR:
32.2 (NHCH3), 36.1 (NCH3), 104.3, 118.9, 121.8, 133.1
d
2.92 (3H, d, J¼4.5 Hz), 3.97 (3H, s), 6.99 (1H, d, J¼7 Hz), 7.66
d
(all Ar–CH), 121.5, 137.9, 140.7 (all Ar–C), 182.0 (NHCSNH); LR EIMS:
m/z (%) 220 (Mþ; 78), 189 (20), 288 (13), 187 (29), 186 (100), 185
(18), 172 (10), 171 (17), 147 (73), 146 (26), 119 (20); HR EIMS: Calcd
for C10H12N4S 220.0783, found 220.0780.
4.22.2. 6-Ethyl-2-methylaminothiazolo[5,4-e]-1H-indazole (27b)
Colourless needles; yield 0.21 g (90%); mp 191–193 ꢁC; IR (KBr):
3204, 1606, 1555, 1407, 1207, 1188, 1142, 1062, 930, 824, 797 cmꢀ1
;
1H NMR (DMSO-d6):
d
1.44 (3H, t, J¼7 Hz), 3.0 (3H, d, J¼4.5 Hz), 4.49
(2H, q, J¼7 Hz), 7.56 (1H, d, J¼9 Hz), 7.58 (1H, d, J¼9 Hz), 7.84 (1H, q,
4.24.2. 1-Ethyl-6-(N-methylthioureido)-1H-indazole (29b)
J¼4.5 Hz) and 8.08 (1H, s); 13C NMR:
d
15.7 (CH3), 31.5 (NHCH3),
White crystals; yield: 0.205 g (88%); mp 188–190 ꢁC; IR: 3255,
44.2 (NHCH2), 108.2, 119.2 and 130.5 (all Ar–CH), 118.2, 119.4, 136.6,
147.8, 166.4 (all Ar–C); LR EIMS: m/z (%) 232 (Mþ; 100), 217 (60),
204 (33), 203 (30), 176 (35), 175 (21), 162 (16), 149 (16), 120 (14), 69
(17); HR EIMS: Calcd for C11H12N4S 232.0782, found 232.0779.
3156, 1623, 1544, 1312, 1242, 1055, 1015, 963, 850, 711 cmꢀ1 1H
;
NMR (DMSO-d6):
d
1.37 (3H, t, J¼7 Hz), 2.97 (3H, d, J¼4.5 Hz), 4.35
(2H, q, J¼7 Hz), 6.99 (1H, d, J¼8.5 Hz), 7.66 (1H, d, J¼8.5 Hz), 7.72
(1H, s), 7.77 (1H, br s), 7.97 (1H, d, J¼0.5 Hz) and 9.68 (1H, s); 13C
NMR:
d 15.7 (CH3), 32.2 (NHCH3), 43.9 (NCH2), 104.2, 118.9, 121.8,
4.22.3. 2-Methylamino-6-n-propylthiazolo[5,4-e]-1H-
indazole (27c)
133.1 (all Ar–CH), 121.7, 137.9, 139.8 (all Ar–C), 182.0 (NHCSNH); LR
EIMS: m/z (%) 234 (Mþ; 100), 203 (10), 201 (32), 200 (47), 185 (34),
178 (34), 161 (43), 146 (50), 133 (24), 74 (13); HR EIMS: Calcd for
White crystals; yield: 0.214 g (87%); mp 157–159 ꢁC; IR (KBr):
3253,1581, 1550,1471,1438,1409,1187, 794 cmꢀ1; 1H NMR (CDCl3):
C11H14N4S 234.0939, found 234.0943.
d
0.93 (3H, t, J¼7 Hz),1.97 (2H, sextet, J¼7 Hz), 3.13 (3H, s), 4.36 (2H,
t, J¼7 Hz), 5.89 (1H, br s), 7.33 (1H, d, J¼9 Hz), 7.61 (1H, d, J¼9 Hz)
and 7.93 (1H, s); 13C NMR:
11.8 (CH3), 23.6 (CH2), 32.2 (NHCH3),
d
4.25. Cyclisation of 29a,b to 2-methylamino-8-alkylthiazolo-
51.3 (NCH2), 107.7, 119.3, 130.3 (all Ar–CH), 118.1, 119.9, 137.1, 147.3,
167.6 (all Ar–C); LR EIMS: m/z (%) 246 (Mþ; 100), 218 (15), 217 (74),
204 (10), 189 (22), 175 (7), 149 (7); HR EIMS: Calcd for C12H14N4S
246.0940, found 246.0939.
[4,5-g]indazoles (30a,b)
The thioureidoindazoles (29a,b; 1 mmol each) were regiose-
lectively cyclised by Br2–AcOH, as described earlier for 5a–c, to
furnish the thiazolo[4,5-g]indazoles, 30a,b. The crude products
were purified by crystallisation from CH2Cl2.
4.23. Reduction of 23a,b to 1-alkyl-6-aminoindazoles (28a,b)
Following the procedure described earlier for the reduction of 2
to 3, 1-alkyl-6-nitro-1H-indazoles (23a,b 2 mmol each) were re-
duced by NH2NH2$H2O/Pd–C to the corresponding amines (28a,b),
which were crystallised from pet. ether–CH2Cl2.
4.25.1. 8-Methyl-2-methylaminothiazolo[4,5-g]-1H-indazole (30a)
White needles; yield: 0.207 g (95%); mp 238–240 ꢁC; IR (KBr):
3159, 3122, 1606, 1556, 1408, 1276, 1057, 846, 799, 722 cmꢀ1 1H
;
NMR (DMSO-d6):
d
2.97 (3H, d, J¼4.5 Hz), 4.09 (3H, s), 7.26 (1H, d,
J¼9 Hz), 7.56 (1H, d, J¼9 Hz), 7.98 (1H, s) and 8.04 (1H, q, J¼4.5 Hz);
4.23.1. 6-Amino-1-methyl-1H-indazole (28a)
13C NMR:
d 31.6 (NHCH3), 37.4 (NCH3), 114.7, 119.1, 134.1 (all Ar–CH),
Colurless needles; yield: 0.27 g (92%); mp 174–176 ꢁC (lit.26f mp
108.9,120.3,136.0,152.8,168.1 (all Ar–C); LR EIMS: m/z (%) 218 (Mþ;
100), 217 (14), 190 (18), 189 (30), 188 (16), 176 (13); HR EIMS: Calcd
for C10H10N4S 218.0627, found 218.0625.
173–174 ꢁC); IR: 3434, 3333, 3223, 1627, 1573, 1281, 864, 817 cmꢀ1
;
1H NMR (CDCl3):
d
3.88 (2H, br s), 3.91 (3H, s), 6.49 (1H, d, J¼1 Hz),
6.55 (1H, dd, J1¼8.5 Hz, J2¼2 Hz), 7.46 (1H, d, J¼8.5 Hz) and 7.79
(1H, d, J¼0.5 Hz); 13C NMR:
d
35.5 (NCH3), 91.9, 112.8, 122.2, 133.1
4.25.2. 8-Ethyl-2-methylaminothiazolo[4,5-g]-1H-indazole (30b)
White needles; yield: 0.215 g (93%); mp 183–185 ꢁC; IR: 3226,
3097, 1606, 1556, 1410, 1274, 1037, 836, 788 cmꢀ1; 1H NMR (DMSO-
(all Ar–CH), 118.3, 141.9, 146.1 (all Ar–C); LR EIMS: m/z (%) 147 (Mþ;
100), 146 (34), 119 (18); HR EIMS: Calcd for C8H9N3 147.0796, found
147.0792.
d6):
d
1.39 (3H, t, J¼7 Hz), 2.97 (3H, d, J¼4.5 Hz), 4.41 (2H, q, J¼7 Hz),
7.28 (1H, d, J¼8.5 Hz), 7.57 (1H, d, J¼8.5 Hz), 8.01 (1H, s) and 8.04
4.23.2. 6-Amino-1-ethyl-1H-indazole (28b)
(1H, q, J¼4.5 Hz); 13C NMR:
d 16.8 (CH3), 31.6 (NHCH3), 45.2 (NCH2),
Colourless needles; yield: 0.29 g (90%); mp 120–122 ꢁC; IR:
114.8,119.1,134.4 (all Ar–CH),108.5,120.4,135.1,152.7,168.0 (all Ar–
C); LR EIMS: m/z (%) 232 (Mþ; 100), 217 (33), 204 (15), 203 (7), 176
(26), 175 (10). Anal. Calcd for C11H12N4S: C, 56.90; H, 5.17; N, 24.14.
Found: C, 56.85; H, 5.15; N, 24.16%.
3375, 3323, 3191, 1626, 1314, 1281, 1241, 1182, 1109, 817 cmꢀ1 1H
;
NMR (CDCl3):
d
1.47 (3H, t, J¼7 Hz), 3.88 (2H, br s), 4.29 (2H, q,
J¼7 Hz), 6.54 (1H, s), 6.56 (1H, dd, J1¼8.5 Hz, J2¼2 Hz), 7.48 (1H, d,
J¼8.5 Hz) and 7.82 (1H, s); 13C NMR:
d 15.1 (CH3), 43.7 (NCH2), 92.0,
112.8, 122.3, 133.2 (all Ar–CH), 118.5, 140.9, 145.9 (all Ar–C); LR
EIMS: m/z (%) 161 (Mþ; 100), 146 (71), 133 (28), 119 (14), 92 (10); HR
EIMS: Calcd for C9H11N3 161.0953, found 161.0952.
4.26. Preparation of 1-methyl-5-(N-ethyl/benzylthioureido)-
indazoles (31a,b) from 25a
4.24. Preparation of 1-alkyl-6-(N-methylthioureido)indazoles
(29a,b) from 28a,b
Following the general procedure described previously for the
preparation of 8a–c, the thioureidoindazoles 31a,b were syn-
thesised by the condensation of the amine 25a (1 mmol) with ethyl
or benzyl isothiocyanates and purified by crystallisation from
CH2Cl2.
Following the general procedure described earlier for the
preparation of 8a–c, the thioureidoindazoles 29a,b were

6722
M. Chakrabarty et al. / Tetrahedron 64 (2008) 6711–6723
4.26.1. 5-(N-Ethylthioureido)-1-methyl-1H-indazole (31a)
100 mL of SDS solution (10% SDS in 0.01 M HCl) was added and kept
White needles; yield: 0.21 g (89%); mp 184–186 ꢁC; IR: 3244,
at 37 ꢁC for another 12 h. Then the absorbance at 560 nm was
recorded with a spectrophotometric plate reader (Bio-Tek, USA).
For results, see Table 1.
3149, 1542, 1508, 1241, 1051, 765, 706 cmꢀ1 1H NMR (200 MHz;
;
CDCl3):
(1H, d, J¼9 Hz), 7.40 (1H, d, J¼9 Hz), 7.62 (1H, s), 8.01 (1H, s) and
8.03 (1H, br s); 13C NMR (50 MHz):
14.2 (CH3), 35.7 (NCH3), 40.2
d
1.18 (3H, t, J¼8 Hz), 3.63 (2H, q, J¼8 Hz), 4.07 (3H, s), 7.28
d
Acknowledgements
(NHCH2), 110.6, 118.8, 125.4, 132.8 (all Ar–CH), 124.1, 128.8, 138.6 (all
Ar–C), 180.7 (NHCSNH); LR EIMS: m/z (%) 234 (Mþ; 92), 221 (15),
201 (31), 200 (100), 189 (21), 188 (22), 185 (14), 173 (15), 172 (73),
171 (45), 164 (30), 159 (14), 147 (93), 146 (32), 132 (16), 119 (13); HR
EIMS: Calcd for C11H14N4S 234.0939, found 234.0943.
The authors express their sincere thanks to the Director, Bose
Institute for providing laboratory facilities, the C.S.I.R., Govt. of India
for a fellowship (T.K.), Mr. B. Majumder and Mr. P. Dey, both of B.I.,
for recording the NMR and IR spectra, respectively. The authors are
immensely thankful to Prof. S. Chattopadhyay, Head, Bioorganic
Division, B.A.R.C., Mumbai, India for recording the NMR spectra of
some of the compounds and mainly for the biological screening of
the thiazoloindazoles.
4.26.2. 5-(N-Benzylthioureido)-1-methyl-1H-indazole (31b)
White prisms; yield: 0.27 g (91%); mp 182–184 ꢁC; IR: 3237,
3184, 1540, 1520, 1222, 1188, 1069, 963, 738, 704 cmꢀ1 1H NMR
;
(DMSO-d6):
d
4.01 (3H, s), 4.72 (2H, d, J¼5.5 Hz), 7.23 (1H, t, further-
split, J¼9 Hz), 7.30 (1H, dd, J1¼9 Hz, J2¼2 Hz), 7.31–7.32 (4H, m),
7.58 (1H, d, J¼9 Hz), 7.70 (1H, br s), 8.0 (1H, d, J¼1 Hz), 8.01 (1H, br
References and notes
s) and 9.56 (1H, s); 13C NMR:
d 36.3 (NCH3), 48.1 (NCH2), 110.6, 117.1,
1. (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and
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tritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3,
125.9, 127.6, 128.2 (ꢂ2), 129.0 (ꢂ2), 133.2 (all Ar–CH), 124.3, 132.5,
138.5, 140.1 (all Ar–C), 182.4 (NHCSNH); LR EIMS: m/z (%) 296 (Mþ;
29), 263 (10), 262 (33), 221 (18), 189 (23), 188 (8), 147 (38), 146 (13),
106 (10), 91 (100); HR EIMS: Calcd for C16H16N4S 296.1096, found
296.1089.
p
261; (c) Dondoni, A.; Meerino, P. Thiazoles. Comprehensive Heterocyclic
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4.27. Cyclisation of 31a,b to 2-ethylamino/benzylamino-6-
methylthiazolo[5,4-e]indazoles (32a,b)
3. (a) Wu, Y.-J.; Yang, B. V. Progress in Heterocyclic Chemistry; Gribble, G. W., Joule,
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The thioureidoindazoles (31a,b) were cyclised by Br2–AcOH, as
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4.27.1. 2-Ethylamino-6-methylthiazolo[5,4-e]-1H-indazole (32a)
White needles; yield: 0.21 g (90%); mp 217–219 ꢁC; IR (KBr):
3207, 1600, 1553, 1453, 1228, 1157, 929, 796 cmꢀ1; 1H NMR (DMSO-
d6):
J¼8.5 Hz), 7.51 (1H, d, J¼8.5 Hz), 7.82 (1H, t, J¼5.5 Hz) and 8.0 (1H,
s); 13C NMR:
15.3 (CH3), 36.5 (NCH3), 39.7 (NCH2), 108.2, 119.27,
d
1.20 (3H, t, J¼7 Hz), 3.32–3.41 (2H, m), 4.03 (3H, s), 7.47 (1H, d,
d
130.4 (all Ar–CH), 118.1, 119.20, 137.5, 147.8, 165.5 (all Ar–C); LR
EIMS: m/z (%) 232 (Mþ; 100), 231 (8), 217 (63), 204 (32), 203 (18),
190 (17), 189 (21), 176 (8); HR EIMS: Calcd for C11H12N4S 232.0782,
found 232.0775.
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4.27.2. 2-Benzylamino-6-methylthiazolo[5,4-e]-1H-indazole (32b)
White flakes; yield: 0.27 g (92%); mp 194–196 ꢁC; IR (KBr): 3201,
3085, 1590, 1553, 1448, 1345, 1224, 930, 793, 759, 702 cmꢀ1 1H
;
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d
4.05 (3H, s), 4.61 (2H, d, J¼5.5 Hz), 7.27 (1H, t,
J¼7.5 Hz), 7.33 (2H, t, J¼7.5 Hz), 7.41 (2H, d, J¼7.5 Hz), 7.49 (1H, d,
J¼9 Hz), 7.53 (1H, d, J¼9 Hz), 8.03 (1H, s) and 8.37 (1H, t, J¼5.5 Hz);
12. Fraley, M. E.; Steen, J. T.; Brnardic, E. J.; Arrington, K. L.; Spencer, K. L.; Hanney,
B. A.; Kim, Y.; Hartman, G. D.; Stirdivant, S. M.; Drakas, B. A.; Rickert, K.; Walsh,
E. S.; Hamilton, K.; Buser, C. A.; Hardwick, J.; Tao, W.; Beck, S. C.; Mao, X.; Lobell,
R. B.; Sepp-Lorenzino, L.; Yan, Y.; Ikuta, M.; Munshi, S. K.; Kuo, L. C.; Kreatsoulas,
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13C NMR:
d 36.5 (NCH3), 48.3 (NHCH2), 108.3, 119.3, 127.8, 128.3
(ꢂ2), 129.2 (ꢂ2), 130.5 (all Ar–CH), 118.1, 119.5, 137.6, 139.9, 147.5,
165.7 (all Ar–C); LR EIMS: m/z (%) 294 (Mþ; 100), 293 (12), 205 (10),
204 (11), 203 (76), 190 (15), 189 (7), 176 (6), 159 (5), 106 (9), 91 (43).
Anal. Calcd for C16H14N4S: C, 65.31; H, 4.76; N, 19.05. Found: C,
65.26; H, 4.77; N, 19.07%.
13. (a) Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.;
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4.28. Cytotoxicity assay
The human lung carcinoma cell line (A549) was cultured in
RPMI medium supplemented with 10% FCS at 37 ꢁC in a 5% CO2
atmosphere. Cells were plated overnight prior to the treatment
with 5a, 14a–c, 18a and 30a,b. Unsynchronised cells were treated
with different micromole concentrations of the investigated com-
pounds in DMSO for 72 h. The medium was then removed by as-
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containing MTT (0.5 mg/mL) was added to each well. After 4 h,
mL of PBS
´
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