Aqua mediated indium(III) chloride catalyzed synthesis of fused pyrimidines and pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2012.04.001

The utilization of water as solvent and indium trichloride as promoter for the three-component combinatorial synthesis of a variety of bioactive pyrimidine and pyrazole derivatives (2-10) from aldehydes, 1,3-dicarbonyl compounds, and electron-rich amino h

Full text of DOI:10.1016/j.tetlet.2012.04.001

Tetrahedron Letters 53 (2012) 3018–3022
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aqua mediated indium(III) chloride catalyzed synthesis of fused
pyrimidines and pyrazoles
⇑
Jitender M. Khurana , Ankita Chaudhary, Bhaskara Nand, Anshika Lumb
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The utilization of water as solvent and indium trichloride as promoter for the three-component combi-
natorial synthesis of a variety of bioactive pyrimidine and pyrazole derivatives (2–10) from aldehydes,
1,3-dicarbonyl compounds, and electron-rich amino heterocycles like 6-amino-1,3-dimethyl uracil and
3-methyl-1-phenyl-1H-pyrazol-5-amine catalyzed by indium trichloride under reflux has been studied.
A new class of pyrimidine derivatives (2) has also been synthesized and the structure was confirmed
by single crystal X-ray analysis. The reactions are environmentally benign, reaction product could be iso-
lated easily and the catalyst could be recycled, which makes it an appealing synthetic protocol.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 January 2012
Revised 31 March 2012
Accepted 1 April 2012
Available online 12 April 2012
Keywords:
Pyrimidine and pyrazole derivatives
Water
Indium trichloride
One-pot synthesis
Multi-component reaction
Indium trichloride1 has invoked enormous interest as a green
and mild Lewis acid of high potential to construct carbon–carbon
or carbon–heteroatom bonds in various organic transformations
due to its low toxicity, air and water compatibility, ease of handling,
and high solubility in water and organic solvents. Performing organ-
ic reactions in water has become highly enviable in recent years to
meet environmental considerations.2,3 Multi-component reactions
(MCRs) leading to interesting heterocyclic scaffolds, which blends
the economic aspects with environmental ones are particularly use-
ful for the combinatorial chemistry4 as they provide the opportunity
to introduce several diversity elements in a single step.5 Many het-
erocyclic compounds containing the pyrazole ring display a broad
spectrum of pharmacological and biological activities, such as
anti-bacterial, anti-depressant, anti-hyperglycemic, anti-inflamma-
tory, and anti-tumor.6 Pyrazolopyridines possess biological activi-
ties such as potent cyclin dependent kinase 1 (CDK1) inhibitor,7
HIV reverse transcriptase inhibitors,8 CCR1 antagonists,9 protein ki-
nase inhibitors,10 and cGMP degradation inhibitors, besides several
herbicidal and fungicidal activities.11 Pyridopyrimidines also exhi-
bit promising biological and pharmacological activities such as
anti-folate,12 anti-bacterial,13 tyrosine kinase inhibitors,14 anti-
microbial,15 calcium channel antagonist,16 anti-inflammatory,17
analgesic,17 anti-leishmania,18 tuberculostatic,19 anti-convulsant,20
diuretic and potassium-sparing,21 and anti-aggressive activities.22
Literature search reveals that the synthesis of pyrimido pyrim-
idines can be achieved using [bmim]Br,23 pyrazolo quinolines
using ethylene glycol under MW irradiation,24a or diammonium
hydrogen phosphate,24b and indeno fused pyrazolopyridines using
L
-proline24c as a catalyst. Though, indium trichloride25 has been re-
ported for the synthesis of N-heterocycles there is no such report
on the generalized and combinatorial synthesis of all these deriva-
tives via MCR methodology using indium trichloride as a catalyst.
In view of our work aimed at developing environmentally benign
strategies for the synthesis of heterocyclic compounds with high
diversity,26 we decided to investigate the synthesis of target
compounds.
We report herein a new, convenient, diversity-oriented, and
highly efficient protocol for the synthesis of novel pyrimidine-2,
4-diones (2), pyrimido[4,5-b]quinolines (3–5), pyrimido[2,3-d]
pyrimidines (6), pyrazolo[3,4-b]quinolin-5-ones (7), pyrazolo[4,3-
e]pyridin-5-ones (8), pyrazolo[4,3-e]pyridine-5(1H)-ones (9), and
pyrazolo[3,4-b]quinoline-5,10-diones (10) via three component
condensation of aldehydes, 1,3-dicarbonyl compounds and elec-
tron-rich amino heterocycles like 6-amino-1,3-dimethyl uracil and
3-methyl-1-phenyl-1H-pyrazol-5-amine catalyzed by indium tri-
chloride in water under reflux (Fig. 1).
In our initial endeavor to synthesize pyrimido[4,5-b]quino-
line derivatives, a reaction of 4-chlorobenzaldehyde (1.0 mmol),
6-amino-1,3-dimethyl uracil (1.0 mmol) and dimedone (1.0 mmol)
was carried out in water in the absence of any catalyst under reflux
conditions. The reaction did not proceed to completion even after
14 h and a number of spots were observed on TLC (Table 1, entry 1).
To explore the suitable reaction conditions, the above model
reaction was performed in the presence of various catalysts
(20 mol %) such as NaBr, LiBr, AlCl3, InCl3, CeCl3, and TMSCl in
water under reflux. The results are summarized in Table 1. The
⇑
Corresponding author.
E-mail address: jmkhurana@chemistry.du.ac.in (J.M. Khurana).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.001

J. M. Khurana et al. / Tetrahedron Letters 53 (2012) 3018–3022
3019
O
N
Ar
O
O
N
R
O
O
N
R
O
O
N
Ar
O
O
N
N
N
N
H
O
N
H
O
O
N
H
O
N
H
NH2 OH
(4a-b)
(3a-f)
Ar
(5a-c)
(2a-b, 2e-g)
O
O
Ar
O
Ar
Ar
O
N
N
N
N
N
N
H
O
N
N
N
N
N
N
(8a-c)
Ph
Ph
Ph
(7a-b)
(9a-b)
(6a-d)
Ar
O
O
N
N
N
Ph
(10a-f)
Figure 1. General structure of pyrimidine-2,4-diones (2), pyrimido[4,5-b]quinolines (3–5), pyrimido[2,3-d]pyrimidines (6), pyrazolo[3,4-b]quinolin-5-ones (7), pyrazolo[4,3-
e]pyridin-5-ones (8), pyrazolo[4,3-e]pyridine-5(1H)-ones (9), and pyrazolo[3,4-b]quinoline-5,10-diones (10).
Table 1
Optimization of reaction conditionsa
Entry
Catalyst (mol %)
Solvent
Temp
Time
Yield (%) (product)
b
1
2
3
4
5
6
7
8
None
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
14 h
6 h
6 h
6 h
15 min
1 h
3 h
3 h
30 min
15 min
1 h
–
–
–
–
b
LiBr (20)
AlCl3 (20)
NaBr (20)
InCl3 (20)
InCl3 (20)
CeCl3 (20)
TMSCl (20)
InCl3 (15)
InCl3 (25)
InCl3 (20)
InCl3 (20)
b
b
92 (2a)
91 (3a)
70d (2a)c
63d (2a)c
79 (2a)
92 (2a)
86 (2a)
87 (3a)
9
H2O
H2O
10
11
12
EtOH/H2O (1:1, v/v)
EtOH/H2O (1:1, v/v)
Reflux
1 h
a
b
c
Reactions were carried out using equimolar amounts of 6-amino-1,3-dimethyl uracil, 4-chlorobenzaldehyde, and dimedone.
Incomplete reaction with number of spots on TLC.
Mixture of 2a and 3a.
d
Yields after column chromatography.
reactions performed using 20 mol % of NaBr, LiBr, and AlCl3 as
catalysts, were found to be incomplete and gave a complex
reaction mixture (Table 1, entries 2–4). Then we conducted the
above reaction in the presence of InCl3 (20 mol %) in water under
reflux. The reaction was observed to be complete after 15 min as
analyzed by TLC using petroleum ether/ethyl acetate (60:40) as
eluent. The solid product was filtered, washed with ethanol, and
characterized by IR, NMR, and mass spectral analyses and found
to be 6-amino-5-[(4-chlorophenyl)-(2-hydroxy-4,4-dimethyl-6-o
xo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dio ne
(2a, 92%) (Table 1, entry 5) which was not the targeted pyrimi-
do[4,5-b]quinoline. The product 2 has been proposed as an inter-
mediate in the synthesis of pyrimido[4,5-b]quinolines (3). The
structure of 2a was also confirmed by single crystal X-ray analysis
(Fig. 2).27
In order to confirm if 2a could be cyclized to give reported pyrim-
idoquinolines, the above reaction was repeated and monitored by
TLC. It was observed that the product 2a was formed after 15 min
However if the reaction was continued further, complete disappear-
ance of 2a was observed after another 45 min and a new product
was formed which was identified to be 5-(4-chlorophenyl)-
1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]
quinoline-2,4,6-trione (3a, 91%) (Table 1, entry 6) by spectral anal-
Figure 2. X-ray crystallographic structure of 2a.
ysis after work-up. Reactions conducted using CeCl3 and TMSCl, as

3020
J. M. Khurana et al. / Tetrahedron Letters 53 (2012) 3018–3022
Table 2
Synthesis of 6-amino-5-[aryl-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-diones (2) and 5-aryl-1,3,8,8-tetramethyl-5,8,9,10-
tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-triones (3) (Scheme 1)a
R
Product (2)
Yield (%)
Product (3)
Entry
Time (min)
Mp (° C) (Obsd)
Entry
Time (min)
Yield (%)
Mp (° C) (Obsd)
Mp (° C) (Lit.)23
4-ClC6H4
4-BrC6H4
2a
2b
2c
2d
2e
2f
15
15
92
92
190–192
185–187
3a
3b
3c
3d
3e
3f
60
60
60
60
60
90
91
90
90
89
91
89
290–292
280–282
>300
>300
222–224
296–298
292–294
281–283
–
>300
–
4-HOC6H4
4-CH3OC6H4
4-O2NC6H4
2-Thiophenyl
(CH3)2CH
Not isolated
Not isolated
15
15
15
93
91
92
168–170
218–220
230–232
295–296
2g
a
Reactions were carried out using equimolar amounts of 6-amino-1,3-dimethyl uracil, aldehyde, and dimedone in water under reflux using 20 mol % of InCl3.
O
N
R
O
O
N
R
O
O
N
O
O
N
InCl3, H2O
Reflux
N
InCl3, H2O
Reflux
N
+
RCHO
+
O
O
N
H
(3a-f)
O
NH2
NH2 OH
(2a-b, 2e-g)
(1a)
Scheme 1. Synthesis of 6-amino-5-[aryl-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl) methyl]-1,3-dimethyl-1H-pyrimidine-2,4-diones and 5-aryl-1,3,8,8-tetramethyl-
5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-triones.
Table 3
InCl3 catalyzed three component synthesis of pyrimidoquinoline/pyridopyrimidine derivatives (Scheme 2)a
Entry
Ar
1,3-Dicarbonyl compound
Time (min)
Yield (%)
Mp (° C)
Obsd
Lit.23
4a
4b
5a
5b
5c
6a
6b
6c
6d
4-ClC6H4
4-O2NC6H4
4-ClC6H4
4-O2NC6H4
4-BrC6H4
4-ClC6H4
4-CH3C6H4
4-O2NC6H4
3-O2NC6H4
1b
1b
1c
1c
1c
1d
1d
1d
1d
45
60
50
60
60
60
60
60
60
92
93
91
92
91
88
87
90
89
222–224
>300
268–270
268–270
>300
>300
>300
252–254
>300
310–313
301–303
–
–
–
>300
>300
254–256
>300
a
Reactions were carried out using equimolar amount of 6-amino-1,3-dimethyl uracil, aldehyde, and 1,3-dicarbonyls in water under reflux using 20 mol % of InCl3.
O
N
Ar
O
(1b)
N
O
O
O
N
H
(4a-b)
H
O
Ar
O
O
N
(1c)
N
N
O
O
InCl3, H2O
Reflux
NH2
+
H
ArCHO
O
N
O
N
H
O
(5a-c)
O
O
Ar
O
(1d)
N
O
N
N
(6a-d)
Scheme 2. Synthesis of pyrimidoquinolines/pyridopyrimidines.
catalysts in water under reflux showed the formation of a new
product on TLC corresponding to 2a after 45 min, besides the start-
ing materials. The reactions were complete after 3 h, using CeCl3
and TMSCl but yielded a mixture of 2a and 3a (Table 1, entries 7
and 8).
Subsequently, to assess the effect of amount of the catalyst on
the reaction time and yield of the product 2a, we attempted the
above condensation reaction using 15 mol % and 25 mol % of InCl3.
The reaction when conducted using 15 mol % of the catalyst re-
quired longer time for completion (30 min) while on increasing
the amount of the catalyst to 25 mol %, no significant improvement

J. M. Khurana et al. / Tetrahedron Letters 53 (2012) 3018–3022
3021
Ar
O
(1b)
N
O
O
N
N
H
Ph
(7a-b)
O
O
Ar
N
O
(1d)
N
N
Ph
(8a-c)
InCl3, H2O
Reflux
ArCHO +
N
NH2
N
Ar
N
O
(1e)
O
O
N
N
O
O
Ph
(9a-b)
OH
(1f)
Ar
O
O
N
N
N
Ph
(10a-f)
Scheme 3. Synthesis of pyrazole derivatives.
Table 4
InCl3 catalyzed synthesis of pyrazole derivatives (Scheme 3)a
Entry
Ar
1,3-Dicarbonyl compound
Time (min)
Yield (%)
Mp (° C)
Obsd
Lit.
24ab
7a
7b
8a
8b
8c
9a
9b
10a
10b
10c
10d
10e
10f
4-O2NC6H4
4-ClC6H4
4-CH3OC6H4
4-ClC6H4
4-O2NC6H4
4-ClC6H4
4- F3CC6H4
C6H5
4-CH3OC6H4
4-O2NC6H4
3-O2NC6H4
4-FC6H4
1b
1b
1d
1d
1d
1e
1e
1f
1f
1f
1f
1f
45
45
60
60
45
45
60
60
50
45
45
60
60
91
89
87
89
93
88
92
86
89
90
91
89
87
175–178
180–182
220–222
270–272
>300
181–183
240-242
264-266
272–274
>300
–
–
24ab
222–22424c
271–27224c
318-31924c
–
–
266–26724b
274–27524b
326–32824b
288–28924b
281–28324b
243–24524b
288–290
280–282
242–244
4-ClC6H4
1f
a
Reactions were carried out using equimolar amount of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aldehyde, and 1,3-dicarbonyls in water under reflux using 20 mol % of
InCl3.
b
Compounds are known but their melting points are reported for the first time.
in the time or yield of the product, 2a was observed (Table 1, en-
tries 9 and 10).
factorily to give the products 2 which on subsequent reactions
could be cyclized to give pyrimidoquinolines 3 and no undesirable
side reactions were observed. It is noteworthy that in case of elec-
tron-deficient aldehydes the uncyclized products were obtained
(Table 2, entries 2a, 2b, 2e), whereas electron-rich aldehydes like
4-hydroxybenzaldehyde, 4-methoxybenzaldehyde were more
likely to provide the pyrido[2,3-d]pyrimidines directly, without
isolation of the corresponding uncyclized intermediates. These re-
The condensation of 4-chlorobenzaldehyde (1.0 mmol), 6-ami-
no-1,3-dimethyl uracil (1.0 mmol), and dimedone (1.0 mmol)
could also be achieved in water/ethanol (1:1, v/v) at room temper-
ature using 20 mol % of InCl3 and gave 86% of uncyclized interme-
diate product 2a (Table 1, entry 11). However it could not be
cyclized to give the product 3a even after 24 h at room tempera-
ture. This could be due to the fact that cyclization by the loss of
water molecule from NH2 and OH groups of 2a to form the cyclized
product 3a, probably requires high temperature. This emerges
from the fact that the above reaction in water/ethanol (1:1, v/v)
does undergo cyclization at higher temperature under reflux
though in slightly inferior yields (87%) (Table 1, entry 12).
Thus refluxing all the components in the presence of 20 mol % of
InCl3 in water proved to be the optimum conditions for this reac-
tion (Table 1). Therefore, reactions of substituted aromatic, hetero-
aromatic, and aliphatic aldehydes were carried our under the
optimized reaction conditions. The condensations proceeded satis-
28
sults are listed in Table 2 (Scheme 1).
The optimized reaction conditions for three component conden-
sation were also evaluated by using other cyclic 1,3-dicarbonyl
compounds, such as cyclohexane-1,3-dione (1b), 5-methyl-cyclo-
hexane-1,3-dione (1c), and indane-1,3-dione (1d).
Condensations with cyclohexane-1,3-dione (1b) led to the for-
mation of stable dihydropyrimido[4,5-b]quinolines (Table 3, entries
4a–b) while condensations with 5-methyl-cyclohexane-1,3-dione
(1c) led to the formation of novel dihydropyrimido[4,5-b]quinolines
(Table 3, entries 5a–c). Condensations with indane-1,3-dione (1d)
yielded the aromatized pyrido[2,3-d]pyrimidines (Table 3, entries

3022
J. M. Khurana et al. / Tetrahedron Letters 53 (2012) 3018–3022
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347; (c) Terrett, N. K.; Bell, A.
S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6, 1819; (d) Elguero, J. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E.
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6a–d) in good yields. The formation of pyrido[2,3-d]pyrimidines is
compatible with the literature18 report which has stated that
the dihydro[2,3-d]pyrimidine-2,4-diones are unstable to air and
oxidized to corresponding aromatized product (Scheme 2).
Furthermore to explore the generality and diversity of the protocol,
we extended the present methodology for the condensation of 3-
methyl-1-phenyl-1H-pyrazol-5-amine, aromatic aldehydes, and
cyclic diketones like cyclohexane-1,3-dione (1b), indane-1,3-dione
(1d), cyclopentane-1,3-dione (1e), and 2-hydroxy-1,4-naphthoqui-
none (1f) using InCl3 as catalyst in water under reflux (Scheme 3).
All the reactions proceeded smoothly and gave 4-aryl-3-methyl-1-
phenyl-1,4,6,7,8,9-hexahydropyrazolo[3,4-b]quinolin-5-ones (Table
4, entries 7a–b) as the sole product with cyclohexane-1,3-dione
(1b) and the fully aromatized product that is 4-aryl-3-methyl-1-
phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-ones (Table 4,
entries 8a–c), novel 4-aryl-3-methyl-1-phenyl-6,7-dihydro cyclo-
penta[b]pyrazolo[4,3-e]pyridine-5(1H)-ones (Table 4, entries 9a-b),
and 4-aryl-3-methyl-1-phenyl-1H-benzo[h] pyrazolo[3,4-b]quino-
line-5,10-di-ones (Table 4, entries 10a–f) with indane-1,3-dione (1d),
cyclopentane-1,3-dione (1e), and 2-hydroxy-1,4-naphthoquinone
(1f) respectively in good yields.
Apart from the greener reaction conditions, the products could
be isolated by simple filtration in excellent yields. The possibility
to recover and recycle InCl3 also offers another significant advan-
tage. Because InCl3 is soluble in reaction medium (water) and the
products are insoluble in water, the recovered filtrate containing
the catalyst could be recycled. Studies using 6-amino-1,3-dimeth-
yluracil, 4-chlorobenzaldehyde, and dimedone (1a) as model sub-
strates showed that the recovered filtrate could be successively
recycled in subsequent reactions without any significant decrease
of yield of 3a. A marginal loss of the yield was observed in first
two runs (91% and 89%), while in third and fourth run the yield
dropped to 75% and 65%, respectively.
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In conclusion, we have described a facile, environmentally benign
one-pot and three-component method for the synthesis of pyrimi-
dine/pyrazole annulated heterocyclic systems using 20 mol % InCl3
as catalyst in water. The advantages of this method include operational
simplicity, high yields, and the reusability of the reaction media
Acknowledgments
27. Crystallographic data for compound 2a in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication No.
CCDC-855405. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or
email: deposit@ccdc.cam.ac.uk).
A.C. and B.N. thank the C.S.I.R., New Delhi, India for the grant of
Senior Research Fellowship and A.L. is thankful to the University of
Delhi, India for the grant of UTA (University Teacher assistantship).
28. General procedure for the synthesis of 6-amino-5-[aryl-(2-hydroxy-4,4-dimethyl-
6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (2): In
a
typical experiment, a mixture of 4-chlorobenzaldehyde (0.14 g, 1.0 mmol), 6-
amino-1,3-dimethyluracil (0.15 g, 1.0 mmol), dimedone (0.14 g, 1.0 mmol),
InCl3 (20 mol % or 0.2 mmol), and 10 mL of water was placed in a 50 mL round-
bottomed flask and the mixture was stirred under reflux. The reaction was
complete within 15 min as analyzed by TLC using petroleum ether/ethyl
acetate (60:40) as eluent. The reaction mixture was allowed to cool to room
temperature. The precipitate formed was collected by filtration at pump,
washed with water and ethanol to yield 0.49 g (92%) of pure 6-amino-5-[(4-
chlorophenyl)-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-
dimethyl-1H-pyrimidine-2,4-dione (2a) as identified by spectral data.
General procedure for the synthesis of pyrimidine/pyrazole derivatives (3–10):
A mixture of aldehyde (1.0 mmol), 6-amino-1,3-dimethyl uracil/3-methyl-1-
phenyl-1H-pyrazol-5-amine (1.0 mmol), dimedone/cyclohexane-1,3-dione/
indane-1,3-dione/cyclopentane-1,3-dione/5-methyl-cyclohexane-1,3-dione/2-
hydroxy-1,4-naphthoquinone (1.0 mmol), InCl3 (20 mol % or 0.2 mmol), and
10 mL of water was placed in a 50 mL round-bottomed flask and stirred under
reflux for an appropriate time as mentioned in Tables 2 or 3 or 4. The progress
of the reaction was monitored by TLC (eluent/methanol/chloroform). After
completion of the reaction, the reaction mixture was allowed to cool at room
temperature. The precipitate formed was collected by filtration at pump,
washed with water and ethanol to obtain pure pyrimidine/pyrazole derivatives
(3–10). The products were identified by spectral data. The aqueous filtrate
containing InCl3 was used as such for investigating the recyclability of the
catalyst.
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.001.
References and notes
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