A novel synthetic protocol for the heteroannulation of oxocarbazole and oxoazacarbazole derivatives through corresponding oxoketene dithioacetals

Article abstract of DOI:10.1002/jhet.1523

An efficient novel strategy for the heteroannulation of 6,7-dihydropyrazolo[3,4-b]carbazol-8(1H,5H,9H)-one 4 and 5-N-benzyl-6,7- dihydropyrazolo[3,4-b]carbazol-8(1H,9H)-one 5 has been developed to allow the incorporation of pyrazole, isoxazole, pyrimidine, benzodiazepine, and benzothiazepine rings through their corresponding oxoketene dithioacetal derivatives 6 and 7, respectively.

Full text of DOI:10.1002/jhet.1523

18
A Novel Synthetic Protocol for the Heteroannulation of Oxocarbazole and
Oxoazacarbazole Derivatives through Corresponding Oxoketene
Dithioacetals
Vol 51
*
Ruchi Tyagi, Navjeet Kaur, Bhawani Singh, and Dharma Kishore
Department of Chemistry, Banasthali University, Banasthali-304 022 (Rajasthan), India
*
E-mail: bsyadav2000@gmail.com
Received June 2, 2011
DOI 10.1002/jhet.1523
Published online 7 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient novel strategy for the heteroannulation of 6,7-dihydropyrazolo[3,4-b]carbazol-8(1H,5H,9H)-
one 4 and 5-N-benzyl-6,7-dihydropyrazolo[3,4-b]carbazol-8(1H,9H)-one 5 has been developed to allow the
incorporation of pyrazole, isoxazole, pyrimidine, benzodiazepine, and benzothiazepine rings through their
corresponding oxoketene dithioacetal derivatives 6 and 7, respectively.
J. Heterocyclic Chem., 51, 18 (2014).
INTRODUCTION
[13], oxazepines [14], thiazepines [15], and so forth have
attracted the attention of chemists on account of significant
medicinal properties associated with these nuclei. In view
of the prodigious range of activities of these molecules, it
was considered of interest to develop libraries of compounds
from carbazoles and azacarbazoles that contained the fused
pyrazole nucleus on one side and the bioactive pharmaco-
phores such as the isoxazole, pyrazole, pyrimidine, benzo-
diazepines, benzothiazepines, and so forth on the other
side. The presence of the aforementioned moieties on the
both sides in the same molecular framework could contrib-
ute significantly in enhancing the biopotency by providing
an additive effect to the overall efficacy in the resulting
molecules.
As a part of an ongoing endeavor to create novel het-
erocyclic scaffolds through simple and straightforward
expedient routes, we have explored the application of
oxoketene dithioacetals-based cyclization reactions to the
heteroannulation of oxocarbazole and oxoazacarbazole
nucleus. Herein, we describe in this article, the preliminary
results from studies of our synthetic efforts that have
allowed an efficient synthetic entry to the novel heterocy-
clic materials depicted in Scheme 1.
Development of compound libraries of medicinally
potent agents from “privileged heterocyclic scaffolds” is
a rapidly emerging subject in medicinal chemistry [1].
Benzodiazepines have been recognized to belong to this
class [2]. Recently, bio-efficacy of pyrimidines and their
derivatives has been widely explored on account of their
applications as privileged structures, a term introduced by
Evans et al. [3a], that are capable of providing ligands to a
number of functionally and structurally discrete biological
receptors [3b,c]. Ubiquity of carbazoles, azacarbazoles, and
pyridocarbazoles (such as ellipticine, olivacine, carbaquina-
cine, etc.) in the chemical literature [4] is undoubtedly a
consequence of multifarious biological response, which they
elicit in combating a variety of body ailments. Recent
demonstrations that some of their derivatives can be
used as anti-HIV [5] agents have stimulated further in-
terest in this nucleus from yet another perspective. This
has stimulated enormous research efforts to be directed
toward the synthesis of their structural analogs where
different constitution and biological activity in new
materials could allow them to be used as novel chemo-
therapeutic agents [6]. Condensed heterocyclic systems
containing indoles [7], carbazoles [8], azacarbazoles [9],
pyrazoles [10], isoxazoles [11], pyrimidines [12], diazepines
The oxocarbazole 4 and oxoazacarbazole 5 derivatives
required for this study, were readily obtained from commer-
cially available 5-nitroindazole. The conventional reduction
© 2013 HeteroCorporation

January 2014
A Novel Synthetic Protocol for the Heteroannulation
19
Scheme 1. Synthesis of heteroring fused pyrazolo-carbazoles and azacarbazoles from oxoketene dithioacetals.
O
X
X
NaNO2
H
OEt
N
N
HCl
N
HO
EtONa
+
0-5oC
Cl
N
N
N
NH2
H
H
1a
1
O
2-3
O
2a - 3a
Japp-Klingemann reaction
X = CH2, N-CH2-C6H5
X
O
N
N
X
N
H
N
H
Fischer indolization
N
O
N
H
N
H
4-5
CS2 + MeI
Base
SMe
X
SMe
N
O
N
H
N
H
6-7
HZ
H2N-YH
X
H2N-C-NH2, C2H5ONa
Y
H2N
SMe
Z
OC2H5
X
SMe
N
X
NH
N
N
Y
N
N
N
H
N
N
N
N
N
N
H
H
H
H
H
Y
8-11
16-19
12-15
2 or 2a or 4 or 6 X=CH2
3 or 3a or 5 or 7 X=N-CH2-C6H5
16 X=CH2
Z=NH
12 X=CH2
13 X=N-CH2-C6H5 Y=O
14 X=CH2 Y=S
15 X=N-CH2-C6H5 Y=S
Y=O
8
X=CH2
Y=NH
17 X=N-CH2-C6H5 Z=NH
18 X=CH2 Z=S
19 X=N-CH2-C6H5 Z=S
9
X=N-CH2-C6H5 Y=NH
10 X=CH2 Y=O
11 X=N-CH2-C6H5 Y=O
of 5-nitroindazole gave its amine analog (i.e., 5-amniindazole 1)
which furnished corresponding diazonium chloride (1a)
after diazotization. Application of the Japp–Klingemann
reaction on aryldiazonium salts with 2-hydroxymethylene
cyclohexanone has been demonstrated in the literature [16]
to provide an easy access to the corresponding aryl
hydrazones, whose subsequent cyclocondensation in acid
under the conditions of Fischer indolization offers a very
convenient synthetic entry to the corresponding oxocarbazole
derivatives [17]. The use of 3-hydroxymethylene-4-
piperidone in this synthesis affords the corresponding
oxoazacarbazoles [16]. A protocol based on this technique
of oxocarbazole and oxoazacarbazole ring formation when
applied to 5-indazolyldiazonium chloride 1a with 2-
hydroxymethylene cyclohexanone 2a and further to 1-N-
benzyl-3-hydroxymethylene-4-piperidone 3a generated
pyrazolo-annulated oxocarbazole 4 and oxoazacarbazole
5, respectively (Scheme 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

20
R. Tyagi, N. Kaur, B. Singh, and D. Kishore
Vol 51
RESULTS AND DISCUSSION
The synthetic plan conceived for the preparation of the
CONCLUSION
In conclusion, two noteworthy features from the strat-
egy employed in synthesis of the reported compounds
are apparent from our study. Firstly, it established that
the Fischer indolization of 1-(5-indazolyl)-2-(1′-oxo-2′-
cyclohexyl) hydrazone and 1-(5-indazolyl)-2-(1′-N-
benzyl-4′-oxo-3′-piperidinyl) hydrazone provided a very
convenient synthetic entry to the corresponding difficultly
accessible pyrazolo-fused oxocarbazole and oxoazacarba-
zole derivatives 4 and 5, respectively. It established further
the versatility of the Japp–Klingemann reaction to pro-
vide a one-pot synthetic protocol to the preparation of
heteroaryl hydrazones (on to the adjacent methylene
carbon of a cyclic carbonyl species), which are not
accessible by the conventional procedures. Secondly,
it provided an easy access to the formation of corresponding
oxoketene dithioacetals derivatives and their reaction
with bidentate nucleophiles to give pyrazole, isoxazole,
pyrimidine, and azepine condensed carbazole and azacar-
bazole derivatives of biological interest in high purity
and yield.
materials 8–19 (Scheme 1) required it to be executed in
three stages. The first stage of this strategy involved the
conversion of 5-indazolyldiazonium chloride 1a to the
pyrazolo-fused oxocarbazoles 4 and oxoazacarbazoles 5,
respectively. These were realized by the interaction of
indazolyldiazonium chloride 1a with 2-hydroxymethylene
cyclohexanone 2a and 1-N-benzyl-3-hydroxymethylene-
4-piperidone 3a, respectively, under the conditions of
Japp–Klingemann reaction followed by the Fischer
indolization [7] of the resulting hydrazones with Kent’s
acid (HCl : AcOH; 1 : 4 v/v). The compounds 4 and 5 were
intern-obtained following the reported procedure that
consisted of treating cyclohexanone 2 and 1-N-benzyl-4-
piperidone 3, respectively, with ethyl formate in presence
of sodium ethoxide. The second stage of the strategy
required the conversion of 4 and 5 to the corresponding
oxoketene dithioacetals derivatives 6 and 7 from their reac-
tion with CS2 and CH3I in presence of a base. Oxoketene
dithioacetals are useful 3-carbon 1,3-dipolarophiles that have
been extensively employed in the literature for the prepara-
tion of five-membered, six-membered, and seven-membered
heterocyclic rings from its reaction with bidentate nucleo-
philes such as hydrazine hydrate, hydroxylamine hydrochlo-
ride, urea, thiourea, o-phenylenediamine, o-aminophenol,
and o-aminothiophenol [18]. Application of this strategy
on oxoketene dithioacetal derivatives 6 and 7 with the
indicated bidentate nucleophiles gave the pyrazoles (8
and 9), isoxazoles (10 and 11), pyrimidines (12–15), and
azepines (16–19), respectively, in high yield and purity
(Scheme 1). The structure of compounds 6, 7 and 8–19
was established on the basis of their microanalysis results
EXPERIMENTAL
Melting points were determined on an open capillary and are
uncorrected. The IR spectra were recorded on Schimadzu FTIR-
8400S (Prague, Czech Republic). 1H NMR spectra were recorded
in DMSO-d6 and in CDCl3 on Bruker DRX-300 spectrometer
(Billerica, MA) using TMS as internal reference and values are
expressed in d ppm. Mass spectra were taken on a Jeol SX-102
mass spectrometer (Tokyo, Japan) at 70 eV. 5-aminoindazole
required in synthesis was prepared from the reduction [19] of
commercially available 5-nitroindazole.
1
General procedure for the preparation of oxocarbazoles
and oxoazacarbazoles (4–5).
as well as their IR, H NMR and MS spectral data. The
spectral data of these compounds unequivocally established
the structures of these molecules. The IR spectra of 4 and 5
showed the presence of the strong absorption band near
1700cmÀ1 for CO group. The formation of corresponding
oxoketene dithioacetals 6 and 7 was confirmed by the
appearance of the band near about 680 cmÀ1 for C–S
stretching. As pyrazole, isoxazole, pyrimidine, diazepine,
and thiazepine rings in 8–19 resulted from the condensa-
tion involving the carbonyl group of 6 and 7 with biden-
tate nucleophiles, the disappearance of the CO absorption
band in IR spectra in compounds 8–19 provided strong
evidence in favor of the formation of these compounds.
The most diagnostic evidence for the formation of com-
pounds 8–19 was provided by the appearance of a signal in
the region of d 10.1 for the indole NH in the 1H NMR spectra
in all compounds (NH proton of indazole nucleus appeared
at a much downfield region d 12.0 ppm). The appearance
of the M+ peak corresponding to their molecular weight in
MS spectra confirmed the formation of the compounds and
established their structures.
Part I. Preparation of 1-(5-indazolyl)-2-(1′-N-benzyl-4′-oxo-
3′-piperidinyl)hydrazone using Japp–Klingemann reaction.
A
solution of 5-indazolyl amine 1 (1.08 g, 1.0 mmol) in aqueous
HCl (2 mL conc. HCl in 4 mL water) was treated with a cold
saturated solution of sodium nitrite (0.7 g in 2 mL water) while
the temperature was kept at 0–5ꢀC. The solution was kept
aside for 10 min. It was then added portion wise to an ice-
cooled mixture containing (E)-1-N-benzyl-3-hydroxymethylene-4-
piperidone 3a (2.17g, 1.0 mmol), sodium acetate trihydrate
(1.80 g), methanol (10 mL) and water (6mL) over a period of
0.5 h with stirring. The contents were allowed to stand for further
0.5 h and the resulting solid mass was filtered, washed with
water, dried, and recrystallized from ethanol. 1-(5-indazolyl)-2-
(1′-oxo-2′-cyclohexyl) hydrazone was prepared from 2-
hydroxymethylidene cyclohexanone 2a by adopting the same
methodology.
Part II. General procedure for the cyclization of hydrazones
by Fischer indolization.
A solution of crude hydrazone
(0.68 g, 0.01 mmol) suspended in a mixture of acetic acid and
HCl (4 : 1) was refluxed on a pre-heated oil bath at 125–130ꢀC
for 0.5–1 h. The contents were then cooled and poured into ice-
cold water with stirring and basified with ammonia till
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DOI 10.1002/jhet

January 2014
A Novel Synthetic Protocol for the Heteroannulation
21
neutralization. The separated brown solid was purified by passing
through a column of silica gel using 50% benzene in pet ether
as eluant.
and dried over anhydrous sodium sulfate and filtered. On
removal of solvent, the compound 8 (1.65 g, 71%) was obtainÀed1.
mp 204–206ꢀC. IR (KBr): n 3340, 2920, 1605, 1020, 680 cm
;
6,7-Dihydropyrazolo[2,3-b]carbazol-8(1H,5H,9H)-one
(4). The compound 4 (1.46 g, 65%) was obtained following the
procedure described in parts I and II. mp 238–40ꢀC. IR (KBr) : n
1H NMR (300MHz, CDCl3 and DMSO-d6): d 13.1 (1H, s, NH
of pyrazole ring), 12.2 (1H, s, NH of pyrazole ring), 10.08 (1H,
s, NH of indole ring), 8.44 (1H, s, CH of pyrazole ring), 7.78
(2H, s, ArH), 2.86 (2H, t, J = 6.5 Hz, CH2), 2.79 (2H, t, J = 6.5 Hz,
CH2), 2.13 (3H, s, CH3) ppm; MS: m/z 295 (17%) [M+]; anal.
calcd./found for C15H13N5S: C, 61.01/60.91; H, 4.44/4.32; N,
23.41/23.33, S, 10.86/10.74.
3290, 2920, 1720, 1510, 1020 cmÀ1 1H NMR (300 MHz,
;
CDCl3 and DMSO-d6): d 12.4 (1H, s, NH of pyrazole ring),
10.1 (1H, s, NH of indole ring), 8.20 (1H, s, CH of pyrazole
ring), 7.85 (2H, s, ArH), 2.43 (2H, t, J = 6.5 Hz, CH2), 2.10
(2H, m, CH2), 1.89 (2H, t, J = 6.5 Hz, CH2); MS: m/z 225
[M+]; anal. calcd./found for C13H11N3O: C, 69.32/69.22; H,
4.92/4.78; N, 18.52/18.46.
Preparation of 5-N-benzyl-3-methylthio-2,4,9,11-
tetrahydropyrazolo[3,4-a]pyrazolo[3,4-b]-5-azacarbazole
(9). Compound 9 (1.57 g, 76%) was prepared from compound 7
using same method adopted for preparation of the compound 8. mp
5-N-Benzyl-6,7-dihydropyrazolo[2,3-b]-5-azacarbazol-8
(1H,9H)-one (5). The compound 5 (2.21 g, 70%) was also
obtained as compound 4. mp 277–79ꢀC. IR (KBr): n 3220,
1
172–74ꢀC. IR (KBr): n 3300, 2990, 1530, 1040, 690cmÀ1; H
NMR (300MHz, CDCl3 and DMSO-d6): d 13.3 (1H, s, NH),
12.2 (1H, s, NH), 10.3 (1H, s, NH), 8.16 (1H, s, CH), 7.76 (2H,
s, ArH), 7.72–7.65 (5H, m, ArH), 4.29 (2H, s, CH2), 4.14 (2H, s,
CH2), 2.34 (3H, s, CH3) ppm; MS: m/z 386 (16%) [M+]; anal.
calcd./found for C21H18N6S: C, 68.55/68.46; H, 4.97/4.81; N,
21.75/21.64; S, 8.30/8.21.
2910, 1735, 1520, 1040 cmÀ1 1H NMR (300 MHz, CDCl3
;
and DMSO-d6): d 11.9 (1H, s, NH of pyrazole ring), 10.8
(1H, s, NH of indole ring), 8.15 (1H, s, CH of pyrazole ring),
7.79 (2H, s, ArH), 7.72–7.66 (5H, m, ArH), 4.32 (2H, s, CH2
of benzyl hydrogen), 3.39 (2H, t, J = 6.4 Hz, CH2), 2.63
(2H, t, J = 6.4 Hz, CH2) ppm; MS: m/z 316 [M+]; anal. calcd./
found for C19H16N4O: C, 72.13/72.02; H, 5.10/4.03; N,
17.71/17.62.
Preparation of 3-methylthio-2,4,5,9,11-pentahydroisoxazolo
[3,4-a]pyrazolo[3,4-b]carbazole
(10).
Hydroxylamine
hydrochloride (2.78 g, 4.0 mmol) was added to sodium
methoxide (3.24 g, 6.0 mmol) in absolute methanol (30 mL) and
stirred for 10 min. The compound 6 (1.77 g, 4.0 mmol) was added
and the mixture was refluxed for 5 h. Most of the methanol was
evaporated under reduced pressure and the mixture was poured
into ice-cold water. The solid separated was filtered, washed
with diethyl ether, and dried. Recrystallization from ethanol
gave 10 (1.18 g, 72%). mp 169–70ꢀC. IR (KBr): n 3450, 2995,
Preparation of 7-(bis(methylthio)methylene)-6,7-dihydropyrazolo
[4,3-b]carbazol-8(1H,5H,9H)-one (6).
A mixture of 6,7-
dihydropyrazolo[2,3-b]carbazol-8(1H,5H,9H)-one 4 (2.04 g,
6.0 mmol) and CS2 (1.14 mL, 6.0 mmol) was added to a well
stirred and cold suspension of t-BuOK (1.34 g, 1.0 mmol) in dry
benzene (4.0 mL) and DMF (3.0 mL), and the reaction mixture
was allowed to stand at room temperature for 4 h. Methyl iodide
(2.0mL, 1.0mmol) was gradually added with stirring and external
cooling (exothermic reaction), and the reaction mixture was
allowed to stand for 4 h at room temperature with occasional
shaking and then refluxed on a water bath for 3 h. The aqueous
portion was extracted with benzene, combined the extracts and
washed with water, dried over anhydrous sodium sulfate and the
solvent was removed by distillation. The compound 6 (1.545g,
58%) obtained was recrystallized from ethanol. mp 310–12ꢀC. IR
1600, 1532, 900, 700 cmÀ1 1H NMR (300 MHz, CDCl3 and
;
DMSO-d6): d 12.2 (1H, s, NH), 10.2 (1H, s, NH), 8.4 (1H,
s, CH), 7.79 (2H, s, ArH), 2.76 (2H, t, J = 6.5 Hz, CH2), 2.59 (2H,
t, J = 6.5 Hz, CH2), 2.33 (3H, s, CH3) ppm; MS: m/z 296 (12%)
[M+]; anal. calcd./found for C21H18N6S: C, 60.79/60.68; H, 4.08/
3.99; N, 18.91/18.83; S, 10.82/10.74.
Preparation of 5-N-benzyl-3-methylthio-2,4,9,11-
tetrahydroisoxazolo[3,4-a]pyrazolo[3,4-b]-5-azacarbazole
(KBr): n 3230, 2925, 1680, 1540, 1050, 680 cmÀ1
;
1H NMR
(11).
compound 7 instead of 6. IR (KBr): n 3420, 3000, 1600, 1520,
890, 680 cmÀ1 1H NMR (300 MHz, CDCl3 and DMSO-d6):
The compound 11 (1.47g, 70%) was prepared by using
(300MHz, CDCl3 and DMSO-d6): d 11.7 (1H, s, NH of pyrazole
ring), 10.06 (1H, s, NH of indole ring), 8.10 (1H, s, CH of
pyrazole ring), 7.80 (2H, s, ArH), 2.46 (2H, t, J = 6.5 Hz, CH2),
2.30 (2H, t, J = 6.5 Hz, CH2), 2.13 (6H, s, CH3) ppm; MS: m/z
329 (15%) [M+]; anal. calcd./found for C16H15N3OS2: C, 58.33/
58.24; H, 4.59/4.51; N, 12.87/12.79, S, 10.60/10.53.
;
d 11.9 (1H, s, NH), 10.2 (1H, s, NH), 8.36 (1H, s, CH of pyrazole
ring), 7.82 (2H, s, ArH), 7.76–7.72 (5H, m, ArH), 4.39 (2H, s,
CH2), 4.19 (2H, s, CH2), 2.24 (3H, s, CH3) ppm; MS: m/z 387
(12%) [M+]; anal. calcd./found for C21H17N5OS: C, 68.37/68.26;
H, 4.69/4.60; N, 18.08/17.98; S, 8.28/8.21.
Preparation of 7-(bis(methylthio)methylene)-5-N-benzyl-6,7-
dihydropyrazolo[2,3-b]-5-azacarbazol-8(1H,9H)-one (7).
The
Preparation of 4-ethoxy-2-hydroxy-5,6,10,12-tetrahydropyrimido
compound 7 (1.936 g, 60%) was prepared by using stratgey
[4,5-a]pyazolo[3,4-b]carbazole (12).
To a mixture of urea
followed for preparation of compound 6. mp 288–90ꢀC. IR
(0.12 g, 2.0 mmol), sodium ethoxide (0.14g, 2.0 mmol), and
ethanol (25–30 mL) was added compound 6 (0.68 g, 2.0 mmol)
and the reaction mixture was refluxed for 10–14h. The solvent
was removed by distillation and residue was treated with glacial
acetic acid (4–5 mL just enough to dissolve the sodium salt of the
pyrimidine) and refluxed for 15min. The reaction mixture was
poured on crushed ice and precipitate obtained was purified
by crystallization with chloroform to give 12 (0.65 g, 76%). mp
(KBr): n 3370, 2960, 1800, 1500, 1025, 690 cmÀ1 1H NMR
;
(300 MHz, CDCl3 and DMSO-d6): d 12.01 (1H, s, NH of
pyrazole ring), 9.9 (1H, s, NH of indole ring), 8.20 (1H, s, CH
of pyrazole ring), 7.81 (2H, s, ArH), 7.78–7.74 (5H, m, ArH),
3.68 (2H, s, CH2), 2.26 (2H, s, CH2), 2.14 (6H, s, CH3) ppm;
MS: m/z 420 (15%) [M+]; anal. calcd./found for C22H20N4OS2:
C, 62.83/62.75; H, 4.79/4.71; N, 13.43/13.34, S, 15.45/15.35.
Preparation of 3-methylthio-2,4,5,9,11-pentahydropyrazolo[3,4-
185–86ꢀC. IR (KBr):
n 3610, 3330, 2990, 1530, 1550,
1
a]pyrazolo[3,4-b]carbazole (8).
Hydrazine hydrate (5.0mL,
1040 cmÀ1; H NMR (300 MHz, CDCl3 and DMSO-d6): d 12.1
(1H, s, NH), 10.02 (1H, s, NH), 8.28 (1H, s, CH), 7.78 (2H,
s, ArH), 4.02 (1H, s, OH), 3.73 (2H, q, J = 7.5 Hz, CH2), 2.52
(2H, t, J = 6.5 Hz, CH2), 2.32 (2H, t, J = 6.5 Hz, CH2), 1.25
2.0 mmol) and compound 6 (1.77 g, 2.0 mmol) were taken in
25–30 mL of ethanol and refluxed for 3 h. The solvent was
removed and the residue was dissolved in 10 mL of chloroform
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R. Tyagi, N. Kaur, B. Singh, and D. Kishore
Vol 51
(3H, t, J = 7.5 Hz, CH3) ppm; MS: m/z 321 (18%) [M+]; anal.
calcd./found for C17H15N5O2: C, 63.54/63.41; H, 4.71/4.63; N,
21.66/21.56.
7.78–7.72 (4H, m, ArH), 7.69–7.61 (5H, m, ArH), 4.00 (1H,
s, NH), 4.25 (2H, s, CH2), 3.73 (2H, s, CH2), 1.98 (3H, s,
CH3) ppm; MS: m/z 462 (21%) [M+]; anal. calcd./found for
C21H22N6S: C, 70.11/70.01; H, 4.79/4.72; N, 18.09/17.98; S,
6.93/6.87.
Preparation of 6-N-benzyl-4-ethoxy-2-hydroxy-5,10,12
trihydropyrimido[4,5-a]pyazolo[3,4-b]-6-azacarbazole (13).
The compound 13 (1.45 g, 61%) was prepared using 7 and
adopting same method that was used for the preparation of 12.
mp 167–70ꢀC. IR (KBr) : n 3390, 1605, 1547, 1045, 1700,
Preparation of 7-methylthio-1,5,6,8,14-pentahydropyrazolo
[3,4-b]carbazolo[7,8-b]thiazepine (18).
Instead of o-
phenylenediamine, o-aminothiophenol (1.25g, 1.0 mmol) reacted
1
1155 cmÀ1; H NMR (300 MHz, CDCl3 and DMSO-d6): d 11.8
with the compound 6 to give 18 (0.72 g, 74%). mp 185–87ꢀC. IR
(1H, s, NH), 10.2 (1H, s, NH), 7.97 (1H, s, CH), 7.68 (2H, s,
ArH), 7.06–7.14 (5H, m, ArH), 4.97 (1H, s, OH), 4.24 (2H, s,
CH2), 3.62 (2H, s, CH2), 3.24 (2H, q, J = 7.5 Hz, CH2), 1.22
(3H, t, J = 7.5 Hz, CH3) ppm; MS: m/z 412 (16%) [M+]; anal.
calcd./found for C23H20N6O2: C, 66.98/66.87; H, 4.89/4.79; N,
20.38/20.31.
(KBr): n 3370, 3030, 1620, 1500, 1325, 1150, 650 cmÀ1 1H
;
NMR (300MHz, CDCl3 and DMSO-d6): d 12.3 (1H, s, NH),
10.3 (1H, s, NH), 8.36 (1H, s, CH), 7.81 (2H, s, ArH), 7.72–7.69
(4H, m, ArH), 2.25 (2H, t, J = 6.5 Hz, CH2), 2.43 (2H, t,
J = 6.5Hz, CH2), 1.88 (3H, s, CH3) ppm; MS: m/z 388 (27%)
[M+]; anal. calcd./found for C21H16N4S2: C, 64.92/64.82; H, 4.15/
4.08; N, 14.16/14.04; S, 16.41/16.35.
Preparation of 4-ethoxy-2-mercapto-5,6,10,12-tetrahydropyrimido
[4,5-a]pyazolo[3,4-b]carbazole (14). In place of urea, thiourea
(0.152 g, 2.0 mmol) was taken with the compound 6 to
give the compound 14 (0.687 g, 76%). mp 210–12ꢀC. IR
Preparation of 5-N-benzyl-7-methylthio-1,6,8,14-
tetrahydropyrazolo[3,4-b]5-azacarbazolo[7,8-b]thiazepine (19).
Similarly the compound 19 (0.96g, 68%) was prepared from
o-aminothiophenol and the compound 7. mp 83–84ꢀC. IR (KBr):
(KBr): n 3400, 1600, 1550, 1050, 1150 cmÀ1 1H NMR
;
(300 MHz, CDCl3 and DMSO-d6): d 12.2 (1H, s, NH), 10.06
(1H, s, NH), 8.44 (1H, s, CH), 7.79 (2H, s, ArH), 3.89
(2H, q, J = 7.5 Hz, CH2), 3.00 (1H, s, SH), 2.83 (2H, t, J = 6.5 Hz,
CH2), 2.22 (2H, t, J = 6.5 Hz, CH2), 1.68 (3H, t, J = 7.5 Hz, CH3)
ppm; MS: m/z 337 (12%) [M+]; anal. calcd./found for
C17H15N5SO: C, 60.52/60.44; H, 4.48/4.36; N, 20.63/20.53; S,
9.45/9.41.
n 3380, 3010, 1560, 1680, 1210cmÀ1 1H NMR (300MHz,
;
CDCl3 and DMSO-d6): d 12.08 (1H, s, NH), 10.2 (1H, s, NH),
8.16 (1H, s, CH), 7.82 (2H, s, ArH), 7.78–7.72 (4H, m, ArH),
7.69–7.65 (5H, m, ArH), 4.25 (2H, s, CH2), 3.77 (2H, s, CH2),
2.15 (3H, s, CH3) ppm; MS: m/z 479 (19%) [M+]; anal. calcd./
found for C27H21N5S2: C, 67.61/67.54; H, 4.41/4.36; N, 14.51/
14.44, S, 13.32/13.25.
Preparation of 6-N-benzyl-4-ethoxy-2-mercapto-5,8,12-
trihydropyrimido[4,5-a]pyrazolo[3,4-b]-6-azacarbazole (15).
Compound 15 (1.41 g, 64%) was prepared from 7 by using
same methodology that was used for preparation of 14. IR
Acknowledgments. Authors are grateful to the Director, CDRI,
Lucknow (India) for providing the spectral data of the
compounds and are also thankful to Department of Science and
Technology (DST), New Delhi (India) for providing the
financial assistance to “Banasthali Center for Education and
Research in Basic Sciences” under their CURIE (Consolidation
of University Research for Innovation and Excellence in
women Universities) program.
(KBr): n 3390, 1605, 1547, 1045, 1455, 1155 cmÀ1 1H
;
NMR (300 MHz, CDCl3 and DMSO-d6) d: 12.1 (1H, s, NH),
9.98 (1H, s, NH), 8.12 (1H, s, CH), 7.70 (2H, s, ArH), 7.09–
7.16 (5H, m, ArH), 4.18 (2H, s, CH2), 3.91 (1H, s, SH),
3.64 (2H, s, CH2), 3.29 (2H, q, J = 7.5 Hz, CH2), 1.25 (3H, t,
J = 7.5 Hz, CH3) ppm; MS: m/z 428 (25%) [M+]; anal. calcd./
found for C23H20N6OS: C, 64.47/64.38; H, 4.70/4.65; N,
19.61/19.55; S, 7.48/7.41.
Preparation of 7-methylthio-1,5,6,8,14-pentahydropyrazolo
REFERENCES AND NOTES
[3,4-b]carbazolo[7,8-b]diazepine (16).
A mixture of o-
phenylenediamine (1.08 g, 1.0 mmol), compound 6 (0.68 g,
2.0 mmol) and ethanol (20–25 mL) was refluxed for 4–5 h.
The solvent was distilled under reduced pressure and the
residue was quenched in crushed ice. It was extracted with
chloroform, washed with water, and dried over anhydrous
sodium sulfate to give 16 (0.6 g, 66%). mp 173–74ꢀC. IR
[1] Katritzky, A. R.; Abonia, R.; Yang, B. Synthesis 1998, 10, 1487.
[2] Chimirri, A.; Gitto, R.; Grasso, S.; Manforte, A. M.; Romeo,
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(KBr): n 3380, 2950, 1580, 1470, 1050, 680 cmÀ1 1H NMR
;
(300 MHz, CDCl3 and DMSO-d6): d 12.2 (1H, s, NH), 10.6
(1H, s, NH), 8.30 (1H, s, CH), 7.76 (2H, s, ArH), 7.62-7.58
(4H, m, ArH), 4.14 (1H, s, NH), 2.37 (2H, t, J = 6.5 Hz,
CH2), 2.19 (2H, t, J = 6.5 Hz, CH2), 1.66 (3H, s, CH3)
ppm, MS: m/z 371 (30%) [M+]; anal. calcd./found for
C21H17N5S: C, 67.90/67.81; H, 4.61/4.54; N, 18.75/18.68, S,
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[3,4-b]5-azacarbazolo[7,8-b]diazepine (17).
The compound
17 (0.65 g, 72%) was prepared from the o-phenylenediamine
and compound 7 using the aforementioned procedure. mp
176–77ꢀC. IR (KBr): 3300, 2990, 1530, 1405, 1040,
1
695 cmÀ1; H NMR (300 MHz, CDCl3 and DMSO-d6): d 12.1
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(1H, s, NH), 10.1 (1H, s, NH), 8.16 (1H, s, CH), 7.84 (2H, s, ArH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
A Novel Synthetic Protocol for the Heteroannulation
23
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet