An efficient and regioselective one-pot multi-component synthesis of pyrimido[4,5-d]pyrimidine derivatives in water

Article abstract of DOI:10.1016/j.tetlet.2013.12.095

Pyrimido[4,5-d]pyrimidine derivatives 4 have been prepared in an efficient and regioselective manner in water via multi-component reaction of isothiocyanate 1, aromatic aldehyde 2, N,N-dimethyl-6-amino uracil 3 in the presence of p-toluenesulfonic acid (p-TSA) as a Lewis acid catalyst.

Full text of DOI:10.1016/j.tetlet.2013.12.095

Tetrahedron Letters 55 (2014) 1168–1170
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and regioselective one-pot multi-component synthesis
of pyrimido[4,5-d]pyrimidine derivatives in water
⇑
⇑
Swarup Majumder , Pallabi Borah, Pulak J. Bhuyan
Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrimido[4,5-d]pyrimidine derivatives 4 have been prepared in an efficient and regioselective manner in
water via multi-component reaction of isothiocyanate 1, aromatic aldehyde 2, N,N-dimethyl-6-amino
uracil 3 in the presence of p-toluenesulfonic acid (p-TSA) as a Lewis acid catalyst.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 22 August 2013
Revised 24 December 2013
Accepted 25 December 2013
Available online 4 January 2014
Keywords:
Pyrimido[4,5-d]pyrimidine
Multicomponent reaction
Isothiocyanate
N,N-Dimethyl 6-amino uracil
p-Toluenesulfonic acid (p-TSA)
The use of hazardous solvents, expensive and toxic reagents,
multistep synthesis and production of unwanted side-products
are some of the drawbacks in synthetic organic chemistry.1 Now
a days, water is becoming a solvent of choice in organic synthesis
because it is non-toxic, non-corrosive, non-flammable, cheap and
environment friendly.2 Furthermore, reaction in water has unique
reactivity and selectivity, and can be easily separated from organic
products by simple methods.3 Accordingly, the development of
synthetically useful reactions in water is gaining considerable
attention of the scientific community.4
In multi-component reaction (MCR), three or more components
combine in one pot process to afford a single product.5 These reac-
tions, by virtue of their convergence, low energy consumption,
minimum waste production, facile execution, high selectivity and
productivity, represent an important platform for the design and
discovery of various drugs and drug related molecules.6,7
Pyrimido[4,5-d]pyrimidine derivatives are well known as bron-
chodilators,8 vasodilators,9 antiallergic,10 antihypertensive,11 and
anticancer12 agents. Therefore, lot of efforts have been made to-
wards the synthetic manipulation of uracil for the preparation of
pyrimido[4,5-d]pyrimidine derivatives, which usually requires forc-
ing conditions, long reaction times and complex synthetic
pathways.13 Therefore, there is a need to develop more efficient
and sustainable chemical process for the synthesis of pyrimi-
do[4,5-d]pyrimidines.
In continuation of our interest in the design and discovery of
new reactions for the synthesis of heterocycles14 herein we report
p-TSA-catalysed efficient and regioselective multi-component syn-
thesis of pyrimido[4,5-d]pyrimidine derivatives using water as sol-
vent (Scheme 1).
Initially, a mixture containing isothiocyanate 1a (1 mmol), benz-
aldehyde 2a (1 mmol) and N,N-dimethyl 6-amino uracil 3a
(1 mmol) was reacted in the absence of any catalyst (Table 1, en-
try-1) under reflux condition in water, but the reaction did not oc-
cur. When the reaction was conducted in the presence of catalytic
amount of p-TSA, a satisfactory result was obtained.15 Use of
20 mol % of p-TSA (Table 1, entry-4), was found to be sufficient
for obtaining optimum yields of the desired pyrimido[4,5-d]pyrim-
idine 4a. Further decrease or increase in the amount of catalyst (Ta-
ble 1, entries-2–3 and 5) did not improve the yield of the product.
Encouraged by the yield of product, we extended the reaction
by using different Brønsted bases and Lewis acids (Table 1, entries
6–10) but no satisfactory results were obtained. Generalization of
O
NCS
Ph
O
N
p-TSA
N
N
N
PhCHO
+
+
Water,
Reflux
1-2h
H2N
N
O
S
N
H
O
4a
75%
1a
2a
3a
⇑
Scheme 1. Synthesis of pyrimido[4,5-d]pyrimidine derivatives 4a reflux condition
in water.
Corresponding authors. Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail address: majumderswar@yahoo.co.in (S. Majumder).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.095

S. Majumder et al. / Tetrahedron Letters 55 (2014) 1168–1170
1169
Table 1
the reaction was done by employing substituted isothiocyanate 1,
different aromatic aldehydes 2 and 6-amino uracil 3 in the pres-
ence of p-TSA (20 mol %) in refluxing water. The results are sum-
marized in Table 2.
Catalyst screening for compound 4aa
O
NCS
Ph
O
N
Cat.
N
+
+
PhCHO
N
N
Next, the substrate scope of the reaction was investigated by
using various aromatic aldehydes in the reaction process. All the
reactions, consisting of those involving ortho- and para-substituted
benzaldehydes, proceed smoothly and afforded the novel pyrimi-
do[4,5-d]pyrimidine derivatives in moderate to good yields
(Table 2). Electronic effects could be observed in the reaction pro-
cess. The electron-donating group (EDG) at the para position of the
benzaldehydes required less reaction time to give comparatively
high yields of the product (Table 2, entries 2–3, 9–10 and 16–17)
while stronger EWG-substituted ones gave evidently poor yields
(Table 2, entries-1, 4–5, 8, 11–12 and 15). ortho-Substituted benz-
aldehydes, irrespective of EDG or EWG, afforded the corresponding
pyrimido[4,5-d]-pyrimidine derivatives in relatively lower yields,
indicating an obvious steric effect (Table 2, entries 6 and 13). We
also tried the reaction using lower aliphatic aldehydes viz.
acetaldehyde and propanal, but no satisfactory results were ob-
tained and we could not get the desired product.
Water,
O
Reflux
H2N
N
S
N
H
4a
O
1a
2a
3a
Entry
Catalyst (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
—
4
2
2
1
2
3
4
2
NRc
60
70
75
55
50
20
40
30
45
p-TSA (5)
p-TSA (10)
p-TSA (20)
p-TSA (30)
Et3N
DBU
InCl3
Yb(OTf)3
CH3COOH
2
1.5
10
a
Benzaldehyde (1 mmol), phenylisothiocyanate (1 mmol) and N,N-dimethyl-6-
aminouracil (1 mmol), p-TSA catalyst.
b
Isolated yield.
No reaction.
c
The structures of the compound pyrimido[4,5-d]pyrimidine
derivative 4a were fully characterized by 1H and 13C NMR, MS, IR
spectra and elemental analysis. In IR spectrum, stretching frequen-
cies at 1707 and 3214 cmÀ1 confirmed the presence of C@O
functional groups and characteristic NH proton of compound 4a
respectively. The 1H NMR spectrum showed a sharp singlet at d
5.59 for single proton and broad distinct singlet in the region of d
7.46 corresponds to NH proton along with the two methyl protons
resonate at 3.15 and 3.65 ppm. The mass spectrum compound 4a
shows a sharp distinguishable peak m/z at 379.6 [M+H]+. Further,
the structure was confirmed from the analysis of 2D NMR spectra
(HMQC). Similarly, compounds 4b–r were synthesized and
characterized.
A plausible mechanism for the regioselective formation of prod-
ucts 4a is shown in Scheme 2. Initially, the intermediate X is
formed in situ from the reaction of phenylisothiocyanate 1a with
N,N-dimethyl-6-amino uracil 3a. Then, nucleophilic attack of
intermediate X to aldehyde 2a in the presence of the catalyst gave
intermediate Y which upon cyclization and dehydration afforded
the desired product 4a.
Table 2
Synthesis of compound 4
X
O
Ar
O
NCS
p-TSA
N
N
N
+
+
H2N
ArCHO
Water,
Reflux
1-2h
N
R
O
S
N
H
N
R
O
2
1
3
4
X
R= H, CH3
X=H, CH3
Entry
Isothiocyanate
R
Aldehyde
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C6H5NCS
C7H8NCS
C7H8NCS
C7H8NCS
C7H8NCS
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
p-ClPh
p-CH3Ph
p-OCH3Ph
p-BrPh
p-NO2Ph
o-BrPh
Ph
p-ClPh
p-CH3Ph
p-OCH3Ph
p-NO2Ph
p-BrPh
o-BrPh
Ph
4b
4c
4d
4e
4f
4g
4h
4i
70
80
82
71
67
63
73
68
79
80
65
66
60
77
72
78
84
4j
4k
4l
In conclusion, we have developed an efficient method for the
regioselective synthesis of pyrimido[4,5-d]-pyrimidine derivatives
via one pot three-components reaction under reflux condition in
water. Environmentally benign, inexpensive, and economically
feasible catalyst (p-TSA) was used as catalyst in the reaction pro-
cess. The water can be reused for the next cycle, so the waste
can be reduced effectively.
4m
4n
4o
4p
4q
4r
ClPh
p-CH3Ph
p-OCH3Ph
a
Isolated yield.
H
O
O
O
2a
O
PhCHO
Ph
Ph
S
Ph
N
N
NH
2a
Ph
N
C
S
+
N
HN
H
H2N
N
O
N
N
O
1a
H
O
N
N
S
3a
H
+
X
O
O
Ph
Ph
OH2
Ph
Ph
-H2O
-H
HN
N
N
N
O
N
N
S
O
N
N
H
S
H
Y
4a
Scheme 2. Plausible mechanism of compound 4a.

1170
S. Majumder et al. / Tetrahedron Letters 55 (2014) 1168–1170
5. (a) Pirrung, M. C.; Sarma, K. D. J. Am. Chem. Soc. 2004, 126, 444; (b) Da Silva, E.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
095.
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15. General procedure for synthesis of pyrimido[4,5-d]pyrimidines:
A mixture of
phenylisothio-cyanate 1a (1 mmol, 0.135 g), benzaldehyde 2a (1 mmol,
0.106 g) and N,N-dimethyl-6-amino uracil 3a (1 mmol, 0.155 g) in water
(5 mL) was refluxed for 1 h in the presence of catalytic amount of p-TSA
(20 mol %). After completion of the reaction (monitored by TLC), the mixture
was cooled to room temperature, filtered and washed with water (25 mL). The
crude product was purified by recrystallization from EtOH to give 4a. Yield:
Yield: 75% (284 mg); mp. 269–270 °C; IR (KBr)
mmax: 3214, 2822, 1707.4,
1676.7 cmÀ1
;
1H NMR (300 MHz, DMSO-d6): d 3.15 (s, 3H), 3.65 (s, 3H), 5.59 (s,
1H), 7.02–7.34 (m, 10H), 7.46 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 28.36,
30.38, 35.61, 105.80, 125.22, 125.82 (2C), 126.50 (2C), 126.88, 128.04, 128.29
(2C), 128.45 (2C), 129.60, 138.09, 139.92, 145.86, 150.81; MS (EI): 379.68
(M+H)+; Anal. Calcd for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.80. Found: C,
63.29; H, 4.61; N, 14.29.