TMSCl-mediated one-pot, three-component synthesis of 2H-indazolo[2,1-b] phthalazine-triones

Article abstract of DOI:10.1002/jhet.135

(Chemical Equation Presented) A simple, efficient, and cost-effective method for the synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives by a one-pot, three-component condensation reaction of phthalazide, dimedone, or 1,3-cyclohexane

Full text of DOI:10.1002/jhet.135

728
TMSCl-Mediated One-Pot, Three-Component Synthesis of
2H-Indazolo[2,1-b]phthalazine-triones
Vol 46
Lingaiah Nagarapu,* Rajashaker Bantu, and Hari Babu Mereyala
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500607, India
*E-mail: nagarapu@iict.res.in
Received October 21, 2008
DOI 10.1002/jhet.135
Published online 14 July 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple, efficient, and cost-effective method for the synthesis of 2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione derivatives by a one-pot, three-component condensation reaction of phthalazide,
dimedone, or 1,3-cyclohexanedione and aromatic aldehydes under CH3CN/DMF (8:2) media at 80ꢀC
for 30–60 min in the presence of trimethylsilyl chloride (TMSCl) is described.
J. Heterocyclic Chem., 46, 728 (2009).
INTRODUCTION
organometalic reagents and cuprates) and its non-aggre-
gation nature substantially simplify the analysis of the
reaction mechanism. Because of this, it has been exten-
sively used as a protecting group for various functional
groups such as hydroxy and amino group [20(a),22] and
as a promoter for cycloaddition and conjugate addition
reactions [21(a)] under mild and convenient conditions
to offer the products in excellent yield with high selec-
tivity and one-pot cyclocondensation of dimedone, alde-
hydes, with/without urea or thiourea to form octahydro-
quinazolones and 1,8-dioxo-octahydro xanthenes in
excellent yields [23]. However, to the best of our knowl-
edge, there is no report on the synthesis of 2H-inda-
zolo[2,1-b]phthalazine-1,6,11(13H)-triones using TMSCl
as a reagent. In this communication, we report a
TMSCl-mediated simple, efficient, and environmentally
benign three-component condensation reaction of
aromatic aldehydes 1a-p, 5,5-dimethyl-1,3-cyclohexane-
dione 2a or 1,3-cyclohexanedione 2b and phthalhydra-
zide 3 in the preparation of 13-aryl-2,3,4,13-tetrahy-
droindazolo[1,2-b]phthalazine-1,6,11(13H)-trione or 3,4-
dihydro-3,3-dimethyl-13-aryl-2H-indazolo[1,2-b]phthala-
zine-1,6,11(13H)-trione derivatives 4a-p (Scheme 1).
One-pot multicomponent reactions (MCRs) by virtue
of their convergence, productivity, facile execution, and
high yield have attracted considerable attention in recent
years [1]. There have been tremendous developments in
three- or four-component reaction specially the Biginelli
[2], Passerini [3], Ugi [4], and Mannich [5] reactions,
which have further led to renaissance of MCRs. Never-
theless, great efforts have been and still are being made
to find and develop new MCRs.
The development of new synthetic methods for the ef-
ficient preparation of heterocycles containing phthala-
zine ring fragment (antihypoxic and antipyretic agent I
and HAV 3C inhibitor II) is an interesting challenge
because they show some pharmacological and biological
activities [6–8]. Phthalazine derivatives were reported to
possess anticonvulsant [8], cardiotonic [9], and vasore-
laxant [10] activities. Therefore, a number of methods
have been reported for the synthesis of phthalazine
derivatives [11–19]. In recent years, the development of
more economical and environmental friendly conversion
processes is gaining interest in the chemical community
(Figure 1).
In continuation of our work on the use of silica-sup-
ported reagents [20], TMSCl has attracted our interest.
Among the various silicon-based acidic reagents,
TMSCl has received considerable attention as an inex-
pensive and readily available reagent for various organic
transformations [21]. Advantages such as its compatibil-
ity with many synthetically valuable nucleophiles (e.g.,
RESULTS AND DISCUSSION
During the course of our studies directed towards the
development of practical, and eco-friendly procedures
[24], we developed the applicability of TMSCl for effi-
cient, convenient, and facile synthesis of 13-aryl-
C
V
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TMSCl-Mediated One-Pot, Three-Component Synthesis of
2H-Indazolo[2,1-b]phthalazine-triones
729
nedione 2b. No observable substituent effect was noted
for the various aromatic aldehydes.
Aromatic aldehydes 1a-p, 1,3-cyclohexanedione 2a-b
with phthalhydrazide 3 in the presence of TMSCl
undergo a fast 1:1:1 addition reaction at 80ꢀC in
CH3CN/DMF for 30–60 min to produce 2H-inda-
zolo[2,1-b]phthalazine-1,6,11(13H)-trione
derivatives
Figure 1. Antihypoxic and antipyretic agent I & HAV 3C inhibitor II.
4a-p (Scheme 1). The results were excellent in terms of
yields and product purity in the presence of TMSCl
instead of p-TSA24, compounds 4a-p are stable solids
whose structures are fully supported by IR, H, and 13C
2,3,4,13-tetrahydroindazolo[1,2-b]phthalazine-1,6,11(13H)-
trione or 3,4-dihydro-3,3-dimethyl-13-aryl-2H-indazolo-
1
NMR spectroscopy’s, mass spectrometry and elemental
analysis.
[1,2-b]phthalazine-1,6,11(13H)-trione derivatives by
a
one-pot three-component condensation reaction of aro-
matic aldehydes 1a-p, 5,5-dimethyl-1,3-cyclohexanedione
2a or 1,3-cyclohexanedione 2b and phthalhydrazide 3 in
CH3CN/DMF (8:2) at 80ꢀC (Scheme 1).
A feasible pathway (Scheme 2) might involve the role
of TMSCl as a Lewis acid, which activated the aromatic
aldehydes 1 by coordinating to the carbonyl group fol-
lowed by the removal of TMSOH and HCl with enol
form of 1,3-cyclohexanedione 2 to form a heterodienes
5. Then, the subsequent Michael-type addition of the
phthalhydrazide 3 followed by cyclization affords the
corresponding products 4.
In conclusion, we have successfully demonstrated a
novel catalytic application of TMSCl for the efficient
synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-
trione derivatives. This simple procedure is efficient and
can be applied to a wide variety of aromatic aldehydes.
Shorter reaction times and excellent product yields
make this catalytic system an alternative method for the
synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-
trione derivatives. Further application to explore this
simple catalytic system is under progress.
Initially, a pilot reaction was attempted using benzal-
dehyde 1, 5,5-dimethyl-1,3-cyclohexanedione 2a and
phthalhydrazide 3 in the presence of TMSCl (0.5 equiv)
without any solvent. After 3 h, only 27% of 3,3-di-
methyl-13-phenyl-2,3,4,13-tetrahydroindazolo[2,1-b]phth-
alazine-1,6,11-trione product 4a was isolated. Increasing
the amount of TMSCl (1.0 equiv) did not improve the
product yield to a considerable amount. Subsequently,
we investigated the effect of different solvents on the
reaction rate as well as yield of the products. In protic
solvents such as MeOH or EtOH, the reaction was very
slow and resulted in lower product yield. Similar results
were obtained in coordinating solvents such as THF,
diethyl ether, and dimethyl ether. On the other hand,
conducting the reactions in chlorinated solvents such as
dichloromethane and chloroform improved both the reac-
tion rates as well as product yields. After screening for
different solvents, acetonitrile/DMF (8:2) came out as
the solvent of choice, which not only afforded the prod-
ucts in good yield, but also with higher reaction rates
(95% yield in 0.5 h). The formation of compound 4a
was evident from the appearance of [MþH]þ peak at
m/z 373 in mass spectrum (ESI), AC¼¼O stretching at
1667 cmꢁ1 in IR and the appearance of methine proton
EXPERIMENTAL
Melting points were measured with Fiescher-Johns melting
point apparatus. 1H NMR spectra were recorded with an
AVANCE 300 Bruker (at 300 MHz) and Gemini 200 MHz
spectrometers in CDCl3. Chemical shifts relative to TMS as in-
ternal standard are given as d values in ppm. 13C NMR was
Scheme 2
1
as singlet at d 6.34 in H NMR
To extend the scope of this catalytic transformation,
the general applicability of this method was verified by
reacting a number of substituted benzaldehydes with
5,5-dimethyl-1,3-cyclohexanedione 2a or 1,3-cyclohexa-
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

730
L. Nagarapu, R. Bantu, and H. B. Mereyala
Vol 46
recorded in CDCl3 on a Varian (75 Hz) spectrometer. IR spec-
tra were taken with a Perkin–Elmer 1725A FT-IR spectropho-
tometer. EI–MS mass spectra were measured at 70 eV (EI).
General procedure. A solution of benzaldehyde 1a (10
mM), dimedone 2a (10 mM) and phthalhydrazide 3 (12 mM),
and CH3CN/DMF (8 mL/2 mL) containing TMSCl (10 mM)
was refluxed (80ꢀC) till the reaction was completed (monitored
by TLC). After completion, the reaction mass was poured into
ice cold water, stirred, and filtered. The solid product 4a
obtained was filtered through a Buckner funnel, washed with
hexane (2 ꢂ 5 mL) and dried. Spectral data for new
compounds:
1362, 1265, 701 cmꢁ1
.
1H NMR (200 MHz, DMSO-d6): d ¼
2.15–2.42 (m, 4H); 3.23–3.46 (m, 2H); 6.60 (s, 1H); 7.25–7.48
(m, 2H, Ar); 7.72–7.93 (m, 3H, Ar); 8.03–8.37 (m, 2H, Ar).
LC/MS: m/z ¼ 413 [MþH]þ. Anal. Calcd for C21H14Cl2N2O3:
C, 61.03; H, 3.41; N, 6.78%. Found: C, 61.01; H, 3.42; N,
6.77%.
13-(2-Chlorophenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4k). Pale yellow crystalline pow-
der, Yield: 91.1%; mp 250–252ꢀC. IR (KBr): Vmax 2925,
1660, 1366, 1270, 703 cmꢁ1. H NMR (200 MHz, DMSO-d6):
1
d ¼ 2.22–2.58 (m, 4H); 3.31–3.47 (m, 2H); 6.63 (s, 1H);
7.26–7.50 (m, 4H, Ar); 7.90–7.95 (m, 2H, Ar); 8.10–8.19 (m,
1H, Ar), 8.31–8.36 (m, 1H, Ar); LC/MS: m/z ¼ 379 [MþH]þ.
Anal. Calcd for C21H15ClN2O3: C, 66.58; H, 3.99; N, 7.40%.
Found: C, 66.58; H, 3.88; N, 7.42%.
13-(2,4-Dichlorophenyl)-3,3-dimethyl-2,3,4,13-tetrahydro-
indazolo[2,1-b]phthalazine-1,6,11-trione (4b). Pale yellow
crystalline powder; Yield: 94.8%; mp 208–209ꢀC. IR (KBr):
1
Vmax 2942, 1657, 1362, 1268, 711 cmꢁ1. H NMR (200 MHz,
13-(4-Chlorophenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4l). Pale yellow crystalline pow-
der, Yield: 92.0%; mp 272–273ꢀC. IR (KBr): Vmax 3290,
DMSO-d6): d ¼ 1.24 (s, 3H); 1.25 (s, 3H); 2.31 (s, 2H); 3.16–
3.41 (dd, J ¼ 2.2, 18.8 Hz, 2H); 6.57 (s, 1H); 7.28–7.36 (m,
2H, Ar); 7.46 (d, J ¼ 8.3 Hz, 1H, Ar); 7.80–7.89 (m, 2H, Ar);
8.23–8.38 (m, 2H). LC/MS: m/z ¼ 441 [MþH]þ. Anal. Calcd
for C23H18Cl2N2O3: C, 62.60; H, 4.11; N, 6.35%. Found: C,
62.53; H, 4.10, N, 6.35%.
13-(3-Hydroxyphenyl)-3,3-dimethyl-2,3,4,13-tetrahydro-
indazolo[2,1-b]phthalazine-1,6,11-trione (4f). Light yellow
crystalline powder, mp 257–258ꢀC. Yield: 89.2%. 1H NMR
(200 MHz, DMSO-d6): d ¼ 1.20 (s, 6H); 2.27 (s, 2H); 3.11–
3.41 (dd, J ¼ 1.4, 18.8, 2H); 6.23 (s, 1H); 6.63–6.82 (m, 3H,
Ar); 7.02–7.10 (t, J ¼ 8.0, 1H, Ar); 7.84–7.89 (m, 2H, Ar);
8.16–8.32 (m, 2H, Ar); 9.02 (brs, 1H, OH). LC/MS: m/z ¼
389 [MþH]þ. Anal. Calcd for C23H20N2O4: C, 71.12; H, 5.19;
N, 7.21%. Found: C, 71.11; H, 5.17; N, 7.21%.
1685, 1512, 1479, 1181, 1125 cmꢁ1 1H NMR (200 MHz,
.
DMSO-d6): d ¼ 2.23–2.43 (m, 4H); 3.21–3.52 (m, 2H); 6.33
(s, 1H); 7.23–7.43 (m, 4H, Ar); 7.92–7.77 (m, 2H, Ar); 8.17–
8.35 (m, 2H, Ar). LC/MS: m/z ¼ 379 [MþH]þ. d ¼ (75 MHz,
CDCl3 þ DMSO-d6) 21.6, 23.8, 30.4, 60.5, 63.7, 117.7, 126.6,
127.8, 129.0, 132.6, 133.4, 134.2, 135.9, 152.7, 153.5, 155.1,
161.8, 167.3, 191.8. Anal. Calcd for C21H15ClN2O3: C, 66.58;
H, 3.99; N, 7.40%. Found: C, 66.55; H, 3.99; N, 7.38%.
13-(3-Hydroxyphenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4m). Pale yellow crystalline pow-
der, Yield: 89.4%; mp 267–268ꢀC. 1H NMR (200 MHz,
DMSO-d6): d ¼ 2.21–2.43 (m, 4H); 3.20–3.61 (m, 2H); 6.24
(s, 1H); 6.66–6.82 (m, 3H, Ar); 7.10 (t, J ¼ 8.8 Hz, 1H, Ar);
7.86–7.89 (m, 2H, Ar); 8.21–8.32 (m, 2H, Ar); 9.04 (brs, 1H).
LC/MS: m/z ¼ 361 [MþH]þ. Anal. Calcd for C21H16N2O4: C,
69.99; H, 4.48; N, 7.77%. Found: C, 69.98; H, 4.49; N,
7.77%.
13-Naphthalen-1-yl-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4n). Pale yellow crystalline pow-
der, Yield: 88.9%; mp 260–262ꢀC; 1H NMR (200 MHz,
DMSO-d6): d ¼ 2.19–2.38 (m, 4H); 3.22–3.62 (m, 2H); 7.10
(s, 1H); 7.34–7.64 (m, 4H, Ar); 7.75–7.89 (m, 4H, Ar); 8.09–
8.11 (m, 1H, Ar); 8.29–8.34 (m, 1H, Ar); 8.47 (d, J ¼ 8.0 Hz,
1H, Ar). LC/MS: m/z ¼ 395 [MþH]þ. Anal. Calcd for
C25H18N2O3: C, 76.13; H, 4.60; N, 7.10%. Found: C, 76.11;
H, 4.61; N, 7.11%.
3,3-Dimethyl-13-naphthalen-1-yl-2,3,4,13-tetrahydroinda-
zolo[2,1-b]phthalazine-1,6,11-trione (4g). Pale yellow crys-
talline powder, Yield: 88.4%. mp 264–265ꢀC. 1H NMR (200
MHz, DMSO-d6): d ¼ 1.19 (s, 3H); 1.23 (s, 3H); 2.25 (s, 2H);
3.20–3.47 (dd, J ¼ 2.2, 18.8 Hz, 2H); 7.12 (s, 1H); 7.36–
7.59(m, 4H, Ar); 7.75–7.84 (m, 5H, Ar); 8.15–8.36 (m, 2H,
Ar). LC/MS: m/z
¼
423 [MþH]þ. Anal. Calcd for
C27H22N2O3; C, 76.76; H, 5.25; N, 6.63%. Found: C, 76.76;
H, 5.24; N, 6.63%.
3,3-Dimethyl-13-(3,4,5-trimethoxyphenyl)-2,3,4,13-tetra-
hydroindazolo[2,1-b]phthalazine-1,6,11-trione
(4h). Pale
yellow crystalline powder, mp 202–203ꢀC; Yield: 86.2%. 1H
NMR (200 MHz, DMSO-d6): d ¼ 1.24 (s, 3H); 1.25 (s, 3H);
2.32 (s, 2H); 3.12–3.44 (dd, J ¼ 2.2, 18.8, 2H); 3.77 (s, 3H);
3.82 (s, 6H); 6.34 (s, 1H); 6.57 (s, 2H, Ar); 7.82–7.86 (m, 2H,
Ar); 8.26–8.34 (m, 2H, Ar).LC/MS: m/z ¼ 463 [MþH]þ.
Anal. Calcd for C26H26N2O6C, 67.52; H, 5.67; N, 6.06%.
Found: C, 67.49; H, 5.62; N, 6.00%.
13-(4-Bromo-phenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4o). Pale yellow crystalline pow-
der, Yield: 93.0%; mp 280–281ꢀC. IR (KBr): Vmax 2942,
1658, 1363, 1265, 703 cmꢁ1. H NMR (200 MHz, DMSO-d6):
1
d ¼ 2.21–2.26 (m, 2H); 2.38–2.42 (m, 2H); 3.25–3.31 (dt, J ¼
5.7 Hz, 1H); 3.48–3.54 (dt, J ¼ 5.7 Hz, 1H); 6.30 (s, 1H);
7.34 (d, J ¼ 8.5 Hz, 2H), 7.43 (d, J ¼ 8.5 Hz, 2H, Ar); 7.88
(t, J ¼ 4.7 Hz, 2H, Ar); 8.19 (t, J ¼ 4.7 Hz, 1H, Ar), 8.31 (t,
J ¼ 4.7 Hz, 1H, Ar). dC (75 MHz, DMSO-d6) 21.7, 23.9, 36.2,
63.7, 69.2, 117.7, 121.0, 126.6, 127.4, 128.4, 129.0, 129.7,
130.9, 133.7, 134.4, 136.8, 153.1, 155.3, 160.7, 165.7, 192.2.
LC/MS: m/z ¼ 423 [MþH]þ. Anal. Calcd for C21H15BrN2O3:
C, 59.59; H, 3.57; N, 6.62%. Found: C, 59.59; H, 3.54; N,
6.61%.
13-Phenyl-2,3,4,13-tetrahydroindazolo[2,1-b]phthalazine-1,
6,11-trione (4i). Pale yellow crystalline powder, Yield:
93.8%. mp 224–225ꢀC. IR (KBr): Vmax 3290, 1685, 1512,
1
1479, 1181, 1125 cmꢁ1. H NMR (200 MHz, DMSO-d6): d ¼
2.18–2.45 (m, 4H); 3.19–3.61 (m, 2H); 6.34 (s, 1H); 7.23–
7.41 (m, 5H, Ar); 7.83–7.88 (m, 2H, Ar); 8.09–8.32 (m, 2H,
Ar). LC/MS: m/z
C21H16N2O3: C, 73.24; H, 4.68; N, 8.13%. Found: C, 73.20;
H, 4.64; N, 8.13%.
¼
345 [MþH]þ. Anal. Calcd for
13-(2,4-Dichlorophenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4j). Pale yellow crystalline powder,
Yield: 94.0%; mp 274–275ꢀC. IR (KBr): Vmax 2943, 1659,
13-(3-Methoxyphenyl)-2,3,4,13-tetrahydroindazolo[2,1-b]-
phthalazine-1,6,11-trione (4p). Pale yellow crystalline pow-
der, Yield: 88.2%; mp 210–211ꢀC. IR (KBr): Vmax 2942,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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TMSCl-Mediated One-Pot, Three-Component Synthesis of
2H-Indazolo[2,1-b]phthalazine-triones
731
1
1658, 1366, 1427, 701 cmꢁ1. H NMR (200 MHz, DMSO-d6):
d ¼ 2.21–2.46 (m, 4H); 3.19–3.65 (m, 2H); 3.79 (s, 3H,
OMe); 6.30 (s, 1H); 6.81 (dd, J ¼ 8.0 Hz, 1H, Ar); 6.94–6.96
(m, 2H, Ar); 7.24 (t, J ¼ 8.08 Hz, 1H, Ar); 7.89–7.91 (m, 2H,
Ar); 8.17–8.33 (m, 2H, Ar). LC/MS: m/z ¼ 375 [MþH]þ.
Anal. Calcd for C22H18N2O4: C, 70.58; H, 4.85; N, 7.48%.
Found: C, 70.55; H, 4.83; N, 7.48%.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet