A novel three-component one-pot synthesis of pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines using microwave heating in the solid state

Article abstract of DOI:10.1016/j.tetlet.2003.09.063

Microwave-assisted three-component cyclocondensation of barbituric acids 1, benzaldehyde 2 and alkyl nitriles 3 proceeds in the absence or presence of triethylamine to afford pyrano[2,3-d]pyrimidines 4 and 6-aminouracils 5 or 6-hydroxyaminouracils 6 react with 2 and 3 under identical conditions to yield pyrido[2,3-d]pyrimidines 7, all in high yields.

Full text of DOI:10.1016/j.tetlet.2003.09.063

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8307–8310
A novel three-component one-pot synthesis of
pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines using
microwave heating in the solid state
a
b
a,
Ipsita Devi, B. S. D. Kumar and Pulak J. Bhuyan *
a
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785 006, Assam, India
Soil Microbiology Division, Regional Research Laboratory, Jorhat 785 006, Assam, India
b
Received 17 June 2003; revised 27 August 2003; accepted 5 September 2003
Abstract—Microwave-assisted three-component cyclocondensation of barbituric acids 1, benzaldehyde 2 and alkyl nitriles 3
proceeds in the absence or presence of triethylamine to afford pyrano[2,3-d]pyrimidines 4 and 6-aminouracils 5 or 6-hydroxy-
aminouracils 6 react with 2 and 3 under identical conditions to yield pyrido[2,3-d]pyrimidines 7, all in high yields.
©
2003 Elsevier Ltd. All rights reserved.
1
0
Multicomponent reactions (MCRs) by virtue of their
convergence, productivity, ease of execution and gener-
ally high yields of products have attracted considerable
attention from the point of view of combinatorial
of reports have appeared in literature which usually
require forcing conditions, long reaction times and
complex synthetic pathways. Thus new routes for the
synthesis of these molecules have attracted considerable
attention in search for a rapid entry to these
heterocycles.
1
chemistry. The first MCR was described by Strecker in
2
1
850 for the synthesis of amino acids. However, in the
past decade there have been tremendous development
in three- and four-component reactions and grea3t
efforts continue to be made to develop new MCRs.
Solid-phase organic synthesis is a subject of recent
1
1
In our continued interest in the development of highly
expedient methods for the synthesis of annelated uracil
libraries, we report in this paper a novel three-compo-
nent one-pot synthesis of well functionalised
pyrano[2,3-d]- and pyrido[2,3-d]pyrimidines under
microwave irradiation in the solid state (Scheme 1).
4
interest in the context of generating libraries of
molecules for the discovery of biologically active leads
and also for the optimisation of potent drug candidates.
The potential application of microwave technology in
5
organic synthesis, particularly in the solid state, is
The experimental procedure is simple: equimolar
amounts of N,N-dimethylbarbituric acid 1a (0.156 g, 1
mmol), benzaldehyde 2 (0.106 g, 1 mmol) and mal-
ononitrile 3a (0.066 g, 1 mmol) were added in the
reaction vessel of the microwave reactor (Synthewave
increasing rapidly because of its reaction simplicity, less
pollution, and minimum reaction time providing rapid
access to large libraries of diverse molecules.
Pyrano[2,3-d]- and pyrido[2,3-d]pyrimidines are
annelated uracils which have received considerable
attention over the past years due to their wide range of
biological activity. Compounds with these ring systems
have diverse pharmacological activity such as antitu-
4
02 Monomode Reactor from Prolabo) and allowed to
react under microwave irradiation at 60% power and
0°C for 4 min. The automatic mode stirrer helps in
8
mixing and uniform heating of the reactants. The reac-
tion vessel was cooled to room temperature and the
solid compound obtained was recrystallised from aceto-
nitrile to give 4a (0.248 g 80%) mp 210°C. The structure
was confirmed as 4a from the spectroscopic data and
elemental analysis. The IR spectra exhibited sharp
6
7
7a
mour, cardiotonic, hepatoprotactive, antihyperten9-
7
a
8
sive,
antibronchitic
and antifungal activity.
Therefore, for the preparation of these complex
molecules large efforts have been directed towards the
synthetic manipulation of uracils. As a result, a number
−1
−1
bands at 3250 cm (NH ) and 2218 cm (CN). The
2
NMR spectra showed the absence of the methylene
proton of the barbituric acid and the presence of a
proton at 5.10 (s, 1H). The other signals appeared at l
*
0
Corresponding author. E-mail: pulak jyoti@yahoo.com
–
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.063

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I. De6i et al. / Tetrahedron Letters 44 (2003) 8307–8310
Scheme 1.
.00 (s, 3H, NCH ), 3.15 (s, 3H, NCH ). The mass
3
In order to explore the synthetic utility of the reaction
3
3
spectrum revealed a strong molecular ion peak at m/z
10. Similarly compound 4b–d were synthesized by
N,N-dimethyl-6-hydroxyamino uracils 6a was reacted
with 2 and 3a in a similar way under microwave-
assisted conditions. The reaction was found to proceed
smoothly providing the same product 7a obtained from
the reaction of 6-amino uracils. This can be explained
by the mechanism given in Scheme 2.
3
utilizing 1a–c, 2 and 3a–b and the structures were
confirmed from the spectroscopic data and elemental
1
2
analysis. The study of the three-component reaction
was then extended by performing the reactions seper-
ately in presence of triethylamine as catalyst and by
using dimethylformamide as solvent. In the presence of
catalyst the reactions occurred at a comparatively lower
power (40%). However the use of solvent afforded a
poor yield of the products and took more time (Table
A reasonable mechanism for the formation of the
product 7 is outlined in Scheme 2. The reaction occurs
via an initial formation of the cyano-olefin, from
the condensation of benzaldehyde and alkyl nitriles as
shown in Scheme 2, which suffers nucleophilic attack to
give the Michael adduct [A]. The intermediate [A] then
cyclizes and subsequently loses a hydrogen molecule to
afford the fully aromatized compound. This type of
1).
Under identical conditions, when N,N-dimethyl-6-
aminouracil 5a (0.155 g, 1 mmol) was treated with 2
(
0.106 g, 1 mmol) and 3a (0.066 g, 1 mmol) under
14
hydrogen loss is well precedented. In the case of the
-hydroxyaminouracils 6 the cyclic intermediate aroma-
microwave irradiation at 60% power and 80°C in a
reactor for 5 min, it gave pyrido[2,3-d]pyrimidine 7a
6
tizes by eliminating water. The initial formation of the
cyano-olefins was confirmed by synthesizing the
compounds from the reaction of benzaldehyde 2 and
alkyl nitriles 3 under identical conditions in the
microwave reactor, which on direct irradiation with 5
afforded the same compounds 7. Although we could
not isolate any intermediate, it is well established fact
that the electrophiles like cyano-olefins attack at the
C-5 position of the compounds 1, 5 or 6 to give the
(
0.276 g, 90%). The structure of the compound was
ascertained by spectroscopic data and elemental analy-
sis.
1
3
Similarly other pyrido[2,3-d]pyrimidines 7b–d
were synthesised from the reactions of 5a–b, 2 and 3a–b
and the structures were confirmed from their spectro-
1
3
scopic data and elemental analysis. The reactions were
then performed in the presence of the catalyst as well as
by using DMF as solvent and our observations are
recorded in Table 1.
Table 1. Microwave-assisted three-component reactions (in the absence or presence of catalyst/in solvent and solvent free)
Entry
Product
Time/power
With Et N
Yield (%)
Without Et N
In solvent (DMF)
Without Et N
With Et N
In solvent (DMF)+Et N
3
3
3
3
3
1
2
3
4
5
6
7
8
4a
4b
4c
4d
7a
7b
7c
7d
4 min
4 min
4 min
4 min
5 min
5 min
8 min
8 min
4 min
4 min
4 min
4 min
5 min
5 min
8 min
8 min
10 min
10 min
10 min
10 min
12 min
12 min
10 min
10 min
80
80
75
95
90
85
85
70
80
76
78
90
90
85
80
70
65
60
60
70
70
65
65
65

I. De6i et al. / Tetrahedron Letters 44 (2003) 8307–8310
8309
Scheme 2.
Michael adducts (C-alkylation) instead of O-alkylated
Siyal, C. W.; Duch, D. S.; Nichol, C. A. J. Med. Chem.
1980, 23, 327–329.
7. (a) Furuya, S.; Ohtaki, T. Eur. Pat. Appl. EP. 608565,
1
5
or N-alkylated compounds. The formation of the
Michael adduct is the key to explain the right orienta-
tion of the reaction.
1994; Chem. Abstr. 1994, 121, 205395; (b) Heber, D.;
Heers, C.; Ravens, U. Pharmazie 1993, 48, 537–541.
. Sakuma, Y.; Hasegawa, M.; Kataoka, K.; Hoshina, K.;
Yamazaki, N.; Kadota, T.; Yamaguchi, H. PCT Int.
Appl. WO 9105785, 1989; Chem. Abstr. 1991, 115, 71646.
. Ahluwalia, V. K.; Batla, R.; Khurana, A.; Kumar, R.
Ind. J. Chem. 1990, 29, 1141–1142.
8
In conclusion, we have demonstrated a novel multicom-
ponent reaction in the solid state that offers a simple
and efficient route for the synthesis of highly function-
alized pyrano[2,3-d]pyrimidines and pyrido[2,3-d]-
pyrimidines of potential biological importance in excel-
lent yields. Furthermore, the results delinated above
have demonstrated that microwave assisted multi-
component reactions in the solid state can replace
classical methods allowing easy and rapid access to
novel heterocycles of biological significance with
improved yields.
9
1
0. (a) Cheng, T.; Wang, Y.; Cai, M. Youji. Huaxue. 1988, 8,
250–253; (b) Spada, M. R.; Klein, R. S.; Otter, B. A. J.
Heterocyclic Chem. 1989, 26, 1851–1857; (c) Ahluwalia,
V. K.; Kumar, R.; Khurana, K.; Bhatla, R. Tetrahedron
1
990, 46, 3953–3962; (d) Ahluwalia, V. K.; Bhatla, R.;
Khurana, A.; Kumar, R. Ind. J. Chem. 1990, 29, 1141–
142; (e) Ahluwalia, V. K.; Sharma, H. R.; Tyagi, R.
1
Tetrahedron 1986, 42, 4045–4048; (f) Ahluwalia, V. K.;
Aggarwal, R.; Alauddin, M.; Gill, G.; Khanduri, C. H.
Heterocycles 1990, 31, 129–137; (g) Broom, A. D.; Shim,
J. L.; Anderson, C. L. J. Org. Chem. 1976, 411, 1095–
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H. N.; Sandhu, J. S. Tetrahedron Lett. 2002, 43, 895–897.
1
1
2. Compound 4a: mp 210°C; H NMR (300 MHz, CDCl ):
3
l 3.00 (s, 3H), 3.15 (s, 3H), 5.10 (s, 1H), 6.85–7.10 (m,
−
1
+
5
H); IR: 3300, 2195, 1710 cm ; MS: 310 M . CHN
analyses (calcd %): C, 61.93; H, 4.51; N, 18.06
C H N O ) (found %): C, 61.90; H, 4.45; N, 18.00.
2
002, 1682–1683; (e) Cheng, J. F.; Chen, M.; Arthenius,
T.; Nadzen, A. Tetrahedron Lett. 2002, 43, 6293–6296; (f)
Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal,
J. Tetrahedron Lett. 2002, 43, 6485–6488; (g) Bertozzi, F.;
Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147–
(
16
14
4
3
1
Compound 4b: mp 217°C; H NMR (300 MHz, CDCl ):
3
l 3.05 (s, 3H), 4.95 (s, 1H), 6.90–7.10 (m, 5H); IR: 3310,
−
1
+
2
205, 1715 cm ; MS: 296 M . CHN analyses (calcd %):
3
3
150; (h) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4,
309–3311; (i) Bora, U.; Saikia, A.; Boruah, R. C. Org.
C, 60.81, H, 4.05; N, 18.91 (C H N O ) (found %): C,
1
5
12
4
3
1
6
0.75; H, 4.10; N, 18.95. Compound 4c: mp 225°C; H
Lett. 2003, 5, 435–438; (j) Dallinger, D.; Gorobets, N. Y.;
Kappe, C. O. Org. Lett. 2003, 5, 1205–1208.
. Takaya, H.; Murahashi, S. Synlett 2001, 991–994 and
references cited therein.
NMR (300 MHz, CDCl +TFA): l 4.95 (s, 1H), 6.90–7.15
3
−1
+
(
m, 5H); IR: 3325, 2200, 1705 cm ; MS: 282 M . CHN
analyses (calcd %): C, 59.57, H, 3.54; N, 19.85
C H N O ) (found %): C, 59.50; H, 3.55; N, 19.90.
4
5
(
14
10
4
3
. (a) Pourashraf, M.; Delair, P.; Rasmaissen, M. O.;
Greene, A. E. J. Org. Chem. 2000, 65, 6966–6972; (b)
Cossy, J.; Willis, C.; Bellosta, V.; Jalmes, L. S. Synthesis
1
Compound 4d: mp 231°C; H NMR (300 MHz, CDCl ):
3
l 1.25 (t, 3H, J=7.3 Hz), 3.05 (s, 3H), 3.10 (s, 3H), 4.20
(q, 2H, J=7.3 Hz), 4.95 (s, 1H), 6.90–7.20 (m, 5H); IR:
−
1
+
2
002, 951–957.
3345, 1730, 1695 cm ; MS: 357 M . CHN analyses
(calcd %): C, 60.50, H, 5.32; N, 11.76 (C H N O )
6
. (a) Anderson, G. L.; Shim, J. L.; Broom, A. D. J. Org.
Chem. 1976, 41, 1095–1099; (b) Grivaky, E. M.; Lee, S.;
18
19
3
5
(found %): C, 60.50; H, 5.25; N, 11.80.

8
310
I. De6i et al. / Tetrahedron Letters 44 (2003) 8307–8310
C, 61.00, H, 5.12; N, 15.81 (C H N O ) (found %): C,
1
1
3. Compound 7a: mp 308°C; H NMR (300 MHz, CDCl ):
3
18 18
4
4
1
l 3.00 (s, 3H), 3.15 (s, 3H), 6.78–7.25 (m, 5H); IR: 3350,
60.95; H, 5.20; N, 15.70. Compound 7d: mp 215°C; H
−
1
+
2
195, 1710 cm ; MS: 307 M . CHN analyses (calcd %):
NMR (300 MHz, CDCl ): l 1.20 (t, 3H, J=7.3 Hz), 3.10
3
C, 62.53; H, 4.26; N, 22.79 (C H N O ) (found %): C,
(s, 3H), 4.30 (q, 2H, J=7.3 Hz), 6.90–7.20 (m, 5H); IR:
3350, 1730, 1700 cm ; MS: 340 M . CHN analyses
16
13
5
2
1
−1
+
6
2.45; H, 4.20; N, 22.70. Compound 7b: mp 320°C; H
NMR (300 MHz, CDCl ): l 3.20 (s, 3H), 7.10–7.30 (m,
(calcd %): C, 60.00; H, 4.74; N, 16.46 (C17
(found %): C, 60.12; H, 4.65; N, 16.41.
14. Yoneda, F.; Yano, T.; Higuchi, M.; Koshiro, A. Chem.
Lett. 1979, 155–158.
15. (a) Broom, A. D.; Shim, J. L.; Anderson, C. L. J. Org.
Chem. 1976, 411, 1095–1099; (b) Sivaprasad, A.; Sandhu,
J. S.; Baruah, J. N. J. Heterocyclic Chem. 1984, 21,
1657–1659.
H N O )
16 4 4
3
+
−1
5
H); MS: 293 M ; IR: 3345, 2210, 1710 cm . CHN
analyses (calcd %): C, 61.43, H, 3.78; N, 23.88
C H N O ) (found %): C, 61.55; H, 3.70; N, 23.63.
(
15
11
5
2
1
Compound 7c: mp 151°C; H NMR (300 MHz, CDCl +
3
TFA): l 1.25 (t, 3H, J=7.2 Hz), 3.25 (s, 3H), 3.30 (s,
3
H), 4.25 (q, 2H, J=7.2 Hz), 6.90–7.95 (m, 5H); MS: 354
+
−1
M ; IR: 3340, 1730, 1705 cm . CHN analyses (calcd %):