Synthesis of some novel functionalized dihydropyrido[2,3-d]pyrimidines via an one-pot three-component reaction catalysed by InCl3

Article abstract of DOI:10.1016/j.tetlet.2012.05.102

Some novel functionalized dihydropyrido[2,3-d]pyrimidine derivatives 4 were synthesized using a one-pot three-component reaction of 6-aminouracils 1, aryl aldehydes 2 and 3-cyanoacetyl indole 3 using InCl₃ as catalyst.

Full text of DOI:10.1016/j.tetlet.2012.05.102

Tetrahedron Letters 53 (2012) 4015–4017
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Synthesis of some novel functionalized dihydropyrido[2,3-d]pyrimidines via
an one-pot three-component reaction catalysed by InCl3
⇑
P. Seetham Naidu, 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:
Some novel functionalized dihydropyrido[2,3-d]pyrimidine derivatives 4 were synthesized using a one-
pot three-component reaction of 6-aminouracils 1, aryl aldehydes 2 and 3-cyanoacetyl indole 3 using
InCl3 as catalyst.
Received 12 April 2012
Revised 22 May 2012
Accepted 23 May 2012
Available online 30 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dihydropyridine
Pyrimidine
Indole
Multi-component reactions (MCRs)
Indium chloride
Hantzsch 1,4-dihydropyridines (1,4-DHP) are an important
class of compounds with vital medicinal value which are used for
the treatment of cardiovascular disease such as hypertension and
angina pectoris (I, Fig. 1).1 In human body, the DHP’s go through
a cytochrome P450 (CYP) catalysed biochemical process and oxi-
dized into the corresponding pyridine (II, Fig. 1).2 It is worth men-
tioning that the 1,4-DHP motif present in coenzymes NADH and
NADPH mediates hydrogen-transfer reactions in living system.3
Thus, there is a continuous quest to comprehend these biological
process and to develop suitable methods for the synthesis of func-
tionalized dihydropyridines and their annelated analogues.4
The importance of uracil (pyrimidine-2,4-dione) and its ann-
elated derivatives is well recognized by the synthetic as well as
biological chemists.5 Pyrido[2,3-d]pyrimidines represent a broad
class of annelated uracils which have received considerable
attention over the past years due to their wide range of biological
activities such as antibacterial,6 antitumour,7 cardiotonic,8 hepato-
protective,8a antihypertensive,8a and bronchodilator9 properties.
Additionally, some compounds of this class exhibit antialergic,10
antimalarial,11 analgesic12 and antifungal activities.13 Conse-
quently, efforts have been directed towards the synthetic manipu-
lation of uracil for the preparation of these complex molecules.14
Indole nucleus is a prominent structural subunit present in
many naturally occurring compounds that possess significant
pharmacological and biological properties.15 A number of indole
derivatives having heterocycles at the 3-position have been
obtained from nature with potential biological activity.16 For
example, five novel indole alkaloids, meridians A–E (III, Fig. 1) have
been isolated from tunicate Splidium meridium, which show cyto-
toxicity towards tumour cell lines and have potent inhibition
against several protein kinases.17 Tryotophandehydrobutyrine
diketo-piperazine (TDD, IV, Fig. 1) is an inhibitor of glutathione-
S-transferase (GST) enzymes18 due to which many tumour cells
become resistant to chemotherapeutic agents.
In recent years, indium chloride catalysed reactions have at-
tracted tremendous interest throughout scientific communities
imparting high regio- and chemo-selectivities in various chemical
transformations,19 due to its low toxicity, air and water compatibil-
ity, operational simplicity and remarkable ability to suppress side
reactions in acid sensitive substrates.
R1
R1
EtO2C
Me
CO2Et
Me
EtO2C
CO2Et
Me
N
Me
II.
N
H
I.
H2N
R
1 = CH3 or H
N
CH3
N
R4
N
O
3
R
2
R
N
H
O
CH3
N
N
R1
H
H
III; meridianians
IV; TDD
⇑
Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan).
Figure 1. Biologically active dihydropyridines, pyridines and indoles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.102

4016
P. Seetham Naidu et al. / Tetrahedron Letters 53 (2012) 4015–4017
Table 1
As part of our continued interest on the synthesis of diverse het-
erocyclic compounds of biological significance,20 we reported the
synthesis of various annelated uracils from the reaction of 6-amino
uracils with cyano olefins.21 In the present Letter, we report the
synthesis of some novel dihydropyrido[2,3-d]pyrimidines 4 from
an one-pot three-component reaction of 6-amino uracils 1, aryl
aldehyde 2 and 3-cyanoacetyl indole 3 using InCl3 as catalyst
(Scheme 1).
InCl3 catalysed one-pot synthesis of dihydropyrido[2,3-d]pyrimidines 4
Entry
R1
R2
X
Prod.
Reac. time
Yd. (%)
R3
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
O
O
O
O
O
O
O
O
O
O
O
S
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
6
4
8
7
5
5
7
4
8
8
5
7
6
8
8
6
6
82
87
78
75
83
85
80
85
71
69
83
74
79
68
67
77
75
p-NO2Ph
p-CH3Ph
p-OCH3Ph
p-ClPh
p-BrPh
Ph
p-NO2Ph
p-CH3Ph
p-OCH3Ph
p-ClPh
Ph
p-NO2Ph
p-CH3Ph
p-OCH3Ph
p-ClPh
p-BrPh
In a typical experimental procedure,22 equimolar amounts of
N,N-dimethyl-6-amino uracil 1a, aryl aldehyde 2a and 3-cyanoace-
tyl indole 3 were refluxed in ethanol using InCl3 as catalyst for 6 h.
After completion (monitored by TLC) of the reaction, the mixture
was cooled, filtered and washed with water and ethanol. The solid
product 4a obtained was purified by recrystallization from ethanol.
The structure of the compound was ascertained from the spectro-
scopic data and elemental analysis. The 1H NMR spectra of the
compound show the presence of two typical >NH protons at d
9.69 and d 11.88 respectively and the presence of one isolated pro-
ton at d 4.70 as a singlet. The IR spectra show the presence of the
nitrile group at 2200 cmÀ1. The generality of the reaction was
established by synthesizing a series of compounds 4b–q and char-
acterizing them (Table 1). In contrast to our earlier studies,21 the
nitrile group was not involved in the cyclization process to give
the pyrido[2,3-d]pyrimidine 5 (Scheme 1). It might be due to the
preferred activation of the carbonyl group by the catalyst, and
steric hindrance of the two bulky groups (aryl and 3-subtituted
indole) as shown in Scheme 2.
It was observed that aldehyde substrates bearing a variety of
either electron donating or electron withdrawing functional
groups were efficient for the three-component reaction, giving
the corresponding dihydropyrido[2,3-d]pyrimidine derivatives 4
in high yields. The aromatic aldehydes with electron-withdrawing
groups as substrates reacted very well at faster rate and the reac-
tion time is shorter compared with aromatic aldehydes with elec-
tron-donating groups. However, the use of heterocyclic aldehyde,
such as pyrole-2-carbaldehyde and thiophene-2-carbaldehyde
afforded simply the Knoevenagel condensed compounds without
any desired cyclized products.
9
10
11
12
13
14
15
16
17
H
H
H
H
S
S
S
S
H
S
Prod. = product, Reac. = Reaction, Yd. = Yield.
3
R
[In]
O
O
CHO
CN
CN
N
H
3
N
R
H
[A]
3
2
3
R
3
R
O
O
2
R
CN
2
N
R
CN
NH
-H2O
N
O
X
N
N
H
X
N
R
N
1
H
NH
[B]
R
H
1
[In]
4
[A]
1
[A]
3
R
O
3
The reaction was also studied simply in refluxing ethanol in the
absence of the catalyst, and we observed the formation of only
small amount of Knoevenagel condensed product of 2 and 3 with-
out any cyclized compound 4.
A reasonable mechanism of the reaction is given in the Scheme
2. First, the Knoevenagel condensed product [A] forms from the
reaction of compounds 2 and 3, which undergoes Michael addition
to compound 1 to give the intermediate [B]. The amine group of
the compound [B] then reacts with the intramolecular carbonyl
group to give the dihydropyrido[2,3-d]pyrimidines 4. The catalyst
might have activated the condensation and cyclization steps by
R
O
O
O
2
R
2
R
N
N
NH
C
X
N
R
N
NH
2
NH
[C]
X
N
R
N
N
H
1
1
H
5
Scheme 2. Reasonable mechanism of the reaction.
binding with the carbonyl group. Thus, in contrary to our earlier
studies pyrido[2,3-d]pyrimidine derivatives 5 were not formed
through an attack of the amine group at the nitrile group.
In summary, we have synthesized some novel dihydropyri-
do[2,3-d]pyrimidine derivatives via an one pot three component
reaction catalysed by InCl3. The work-up procedure of the reaction
is simple and the products were isolated simply by filtration and
purified by crystallization. Further study of the reaction is in
progress.
R3
O
R2
X
CN
N
N
R1
N
H
O
CHO
O
NH
R2
X
4
CN
N
Acknowledgments
InCl3
R3
O
N
R3
N
NH2
H
R1
The authors thank DST, New Delhi, for financial support and
PSN thank UGC, New Delhi for Junior Research Fellowship.
O
2: R3= H, NO2,
R2
N
1: X = O, S;
R1 = CH3, H;
3
CH3, OCH3, Cl, Br.
NH
NH2
R2 = CH3, H.
X
N
R1
N
References and notes
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Scheme 1. Synthesis of dihydropyrido[2,3-d]pyrimidines 4.

P. Seetham Naidu et al. / Tetrahedron Letters 53 (2012) 4015–4017
4017
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Compound 4a: Off white solid: mp >300 °C. IR (KBr)
mmax = 3584, 3284, 2915,
2200, 1697, 1646, 1611 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 3.14 (s, 3H),
.
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3.54 (s, 3H), 4.70 (s, 1H), 7.24 (m, 3H), 7.37 (m, 4H), 7.5 (d, 1H), 7.92 (d, 1H),
9.69 (s, 1H), 11.88 (s, 1H) 13C NMR (75 MHz, DMSO-d6) d 28.23, 30.45, 84.93,
89.03, 107.66, 112.79, 112.97, 120.19, 121.82, 122.69, 127.47, 127.64, 128.83,
129.06, 129.30, 129.59, 129.70, 132.89, 136.62, 144.05, 144.67, 145.47, 151.21,
161.19. MS (EI) 410.5 (M+H)+. Anal. Calcd for C24H19N5O2: C, 70.41; H, 4.64; N,
17.11. Found: C, 70.62; H, 4.55; N, 17.19. Similarly compounds 4b–q were
synthesized and characterized.