Studies on uracils: A facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

Article abstract of DOI:10.1016/j.tetlet.2004.01.094

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5- formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.

Full text of DOI:10.1016/j.tetlet.2004.01.094

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2405–2408
Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-,
pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines
using microwave irradiation in the solid state
Ipsita Devi, Harsha N. Borah and Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Received 2 December 2003; revised 7 January 2004; accepted 16 January 2004
Abstract—N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under
microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent
yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine
derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Development of new solid phase reactions1 and trans-
ferring solution phase to solid phase reaction are sub-
jects of recent interest in the context of generating
libraries of molecules for the discovery of biologically
active leads and also for the optimization of drug can-
didates. The potential application of microwave tech-
nology in organic synthesis,2 particularly in solid phase
organic reactions is increasing rapidly because of reac-
tion simplicity, less pollution and minimum reaction
times providing rapid access to large libraries of diverse
small molecules.
there is no report of oxazine derivatives fused to uracil.
Pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines and
pyrimido[4,5-d]pyrimidines represent broad classes of
annelated uracils, which have received considerable
attention over the past years due to their wide range of
biological activities. Compounds with these ring systems
have bronchiodilator,8 vasodilator,8 antiallergic,9 car-
diotonic,10 antihypertensive10a and hepatoprotective10a
activity. Some of them exhibit antimalarial,11 analgesic12
and antifungal13 properties. As such, the synthesis of
these ring systems is well documented14 but the synthetic
methods rely mostly on cyclocondensation and usually
require drastic conditions, long reaction times and
complex synthetic pathways. Wamhoff reported a new
route for the synthesis of some annelated uracils based
on [4+2] cycloaddition,15 but these reactions have some
limitations and are confined to the preparation of pyr-
ido[2,3-d]pyrimidines and quinazolines only. In contin-
uation of our studies and the development of highly
expedient methods for the synthesis of annulated ura-
cils16 of biological importance, we report in this com-
The importance of oxazines and their annelated sub-
strates3 is well recognized by synthetic as well as bio-
logical chemists. One of the most important examples is
the 3,1-benzoxazine derivative Efavirenz,4 which has
recently been approved as an anti-HIV drug. Analogues
of this ring system such as quinazoline derivative DPC
961 have also been reported as anti-HIV agents.5 Thi-
eno[2,3-d]oxazinones are potent antiviral agents and
Herpes-protease inhibitors.6 Although a number of
compounds with this ring system have been synthesized
with diverse biological activities,7 to our knowledge
munication
a
novel microwave-assisted one-pot
synthesis of oxazino[4,5-d]-, pyrano-[2,3-d]-, pyrido[2,3-
d]- and pyrimido[4,5-d]pyrimidines, based on [4+2]
cycloaddition reactions in the solid state, which allows
access to a range of structural variations by modification
of the reacting components.
Keywords: Microwave-assisted reaction; Solid phase reaction; Oxaz-
ino[4,5-d]pyrimidine; Pyrido[2,3-d]pyrimidine; Pyrimido[4,5-d]pyrim-
idine; Pyrano[2,3-d]pyrimidine.
Our synthetic strategy, reacting N,N-dimethyl-5-formyl-
barbituric acid 1 with maleimide 2 under microwave
* Corresponding author.
pulak_jyoti@yahoo.com
Fax:
+91-376-2370011;
e-mail:
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.094

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I. Devi et al. / Tetrahedron Letters 45 (2004) 2405–2408
Table 1. Microwave-assisted solid state/thermal reactions
Entry
Product
MW
Reaction time
Thermal (h)
Yield (%)
Thermal
Mp (°C)
Power (%)
Temperature (°C) MW (min)
MW
1
2
3
4
5
6
3
80120
6060
6080
80120
6010
60
5
5
5
5
9070229
87
5a –65
5b –907
65
65
181–182
266
6
85
84
60228–230
85
57
7
–125
6
6
5
8a 0
8b
6
215–217
100–110
7
6
80
54
241–242
irradiation (Synthwave 402 Monomode Reactor From
Prolabo) in the solid state, afforded the pyrano[2,3-
d]pyrimidine derivative 3 in excellent yields. Compound
1, which was synthesized by treating N,N-dimethylbar-
bituric acid with the Vilsmeier reagent in refluxing
benzene17 gave, on treatment with an equimolar amount
of maleimide 2 under microwave irradiation at 120 °C
for 5 min followed by work-up, compound 319 in 90%
yield. The structure of this compound was confirmed on
the basis of spectroscopic data and elemental analysis.
The 1H NMR spectrum showed the absence of the
aldehyde proton and the presence of one proton at d
8.30and another at d 3.60. The mass spectrum revealed
a strong molecular ion peak at 339 Mþ. With suitable
conditions established, the microwave-assisted reaction
was extended by utilizing some other active dienophiles
like isocyanates and isothiocyanates with the compound
1. Thus the reaction of N,N-dimethyl-5-formylbarbituric
acid 1 with phenyl isocyanate 4a under microwave-
assisted conditions in the absence of solvent gave the
corresponding oxazino[4,5-d]pyrimidine 5a in very high
yield (Table 1). The structure of the compound was
ascertained from spectroscopic data and elemental
analysis. Under identical conditions, compound 1
reacted with phenyl isothiocyanate 4b to afford the
corresponding thiooxazino[4,5-d]pyrimidine analogue
5b. The reactions were then performed thermally using a
number of solvents, and chloroform was found to be the
most suitable solvent in terms of solubility of the reac-
tants, time required and overall yield of the products.
Our observations with the thermal reactions, using
chloroform as solvent are recorded in Table 1. It is very
interesting to note that elimination of the solvent and
shifting from conventional thermal to microwave heat-
ing reduced the reaction times from hours to minutes
with improved yields besides simplifying the work-up
procedure (Scheme 1).
In order to explore the synthetic utility of the process,
we have investigated the reactivity pattern of 6-amino-
1,3-dimethyl-5-formyluracil 618 with maleimide 2 under
microwave-assisted conditions in the solid state. This
reaction was found to proceed in a smooth manner
providing pyrido[2,3-d]pyrimidine 7 in excellent yield.
The structure of the compound was confirmed from
spectroscopic data and elemental analysis. The 1H
NMR spectrum showed the characteristic signal at d
8.25 for one proton and absence of an aldehydic proton.
The mass spectrum revealed a molecular ion peak at 336
Mþ. In a similar way, treatment of N,N-dimethyl-6-
amino-5-formyluracil 6 with phenyl isocyanate 4a and
phenyl isothiocyanate 4b under microwave-assisted
conditions afforded pyrimido[4,5-d]pyrimidines 8a and
8b in very good yields (Table 1).
The formation of the products can be explained by the
mechanism outlined in Scheme 2. Potentially, the N,N-
dimethyl-5-formylbarbituric acid 1 and N,N-dimethyl-6-
amino-5-formyluracil 6, which can also exist as 1,4-diene
following tautomeric shifts, first react with the dieno-
phile maleimide 2 to give the intermediates [A]. The
intermediates [A] then lose water or water followed by
oxidation to afford the products 3 and 7.
Further studies of the reaction are in progress. In con-
clusion, we have demonstrated a novel microwave-
O
N
O
O
O
O
Me
Me
O
N
MW
N
Ph
Ph
N
N
Ph
N
+
O
O
N
N
O
O
O
O
Me
Me
Me
CHO
N
2
7
3
X
O
N
OH
O
O
O
Ph
Me
O
Me
Ph
Me
N
C
Ph
MW
N
N
N
N
1, X=OH
6, X=NH2
+
N
X
O
N
N
X
X
Me
Me
8 a. X=O
b. X=S
4 a. X=O
b. X=S
5 a. X=O
b. X=S
Scheme 1.

I. Devi et al. / Tetrahedron Letters 45 (2004) 2405–2408
2407
O
O
O
Y
O
OH
H
O
NPh
O
Me
O
Me
O
Me
O
CHO
N
N
-H2O
or
N
O
NPh
3 or 7
X
N
N
MW
N
Y
-(H
2O+H2)
O
Me
Me
[A]
Me
1, Y=O
6, Y=NH
1, X=OH
6, X=NH2
(Utilising 1) Y=O
or
(Utilising 6) Y=NH
Scheme 2.
A.; Kumar, R. Ind. J. Chem. 1990, 29(B), 1141–1142; (e)
Ahluwalia, V. K.; Sharma, H. R.; Tyagi, R. Tetrahedron
1986, 42, 4045–4048; (f) Ahluwalia, V. K.; Aggarwal, R.;
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L. J. Org. Chem. 1976, 411, 1095–1099; (h) Wamhoff, H.;
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Maki, Y. Heterocycles 1994, 37, 563–570; (j) Srivastava,
P.; Saxena, A. S.; Ram, V. J. Synthesis 2000, 541–544.
assisted solid state synthesis of a number of annelated
uracils of biological significance in excellent yields.
Furthermore, the results delineated above have dem-
onstrated that microwave-assisted reactions in the solid
state can replace classical methods, allowing easy and
rapid access to novel heterocycles of biological signifi-
cance and reducing the reaction times from hours to
minutes with improved yields.
15. Walsh, E. B.; Wamhoff, H. Chem. Ber. 1989, 122, 1673–1679.
16. (a) Bhuyan, P. J.; Borah, H. N.; Sandhu, J. S. Tetrahedron
Lett. 2002, 43, 895–897; (b) Bhuyan, P. J.; Borah, H. N.;
Boruah, R. C. Tetrahedron Lett. 2003, 44, 1847–1849; (c)
Devi, I.; Kumar, B. S. D.; Bhuyan, P. J. Tetrahedron Lett.
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References and notes
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19. In a typical experimental procedure, equimolar amounts
(0.184 g,
of N,N-dimethyl-5-formylbarbituric acid
1
4. Pederson, O. S.; Pederson, E. B. Synthesis 2000, 479–495,
and references cited therein.
5. Magnus, M. A.; Confalone, F. N.; Storace, L. Tetrahedron
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1 mmol), and N-phenylmaleimide 2 (0.173 g, 1 mmol),
were added to the reaction vessel of the microwave reactor
(Synthewave 402 Monomode Reactor from Prolabo) and
allowed to react under microwave irradiation at 80%
(480W) power and 120 °C for 5 min. The automatic mode
stirrer helps in mixing and the uniform heating of the
reactants. The reaction vessel was cooled to room
temperature and the solid compound obtained was crys-
tallized from ethanol to give a product 3 (0.306 g, 90%).
The structure was confirmed from spectroscopic data
and elemental analysis. Mp 229 °C 1H NMR (300 MHz
CDCl3) d 3.05 (s, 3H), 3.15 (s, 3H), 3.60 (s, 1H), 7.00–7.15
(m, 5H), 8.30 (s, 1H). IR 1720, 1710, 1695, 1610 cmꢀ1. MS
339 Mþ. CHN analysis (calcd %) C, 60.17; H, 3.83; N,
12.39; C17H13N3O5 (found %) C, 60.10; H, 3.90; N, 12.35.
Similarly, the other reactions have been carried out and
the products have been characterized (Table 1).
6. Jarvest, R. L.; Fiuto, J. L.; Ashman, S. M.; Dabrowski,
C. E.; Fernandez, A. V.; Jennings, L. J.; Lavery, P.; Tew,
D. G. Bioorg. Med. Chem. Lett. 1999, 2, 443–448.
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1982, 257, 5085–5091; (b) Takita, T.; Uniezawa, H.; Kato,
K.; Niitsuma, S. Tetrahedron Lett. 1985, 36, 5785–5786;
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Song, S. Y.; Joo, W. H.; Falck, J. R.; Shiro, M.; Shin,
D. S.; Yoon, Y. J. J. Org. Chem. 2003, 68, 7918–7920.
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113, 40711.
9. Kitamura, N., Onishi, A. Eur. Pat. 163599, 1984; Chem.
Abstr. 1984, 104, 186439.
1
10. (a) Furuya, S.; Ohtaki, T. Eur. Pat. Appl. EP 608565,
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11. Davoll, J.; Clarke, J.; Elslager, E. F. J. Med. Chem. 1972,
15, 837–838.
12. (a) Kretzschmer, E. Pharmazie 1980, 35, 253–257; (b)
Senda, S.; Izumi, H. Yakugaku Zasshi 1969, 89, 266–271.
13. Ahluwalia, V. K.; Batla, R.; Khurana, A.; Kumar, R. Ind.
J. Chem. 1990, 29(B), 1141–1142.
14. (a) Cheng, T.; Wang, Y.; Cai, M. Youji Huaxue 1988, 8,
250–253; (b) Spada, M. R.; Klein, R. S.; Otter, B. A. J.
Heterocycl. Chem. 1989, 26, 1851–1857; (c) Ahluwalia, V.
K.; Kumar, R.; Khurana, K.; Batla, R. Tetrahedron 1990,
46, 3953–3962; (d) Ahluwalia, V. K.; Batla, R.; Khurana,
5a. Mp 181–82 °C H NMR (300 MHz, CDCl3) d 3.00 (s,
3H), 3.10 (s, 3H), 6.65 (s, 1Hþ), 7.00–7.20 (m, 5H). IR 3400,
1710, 1695 cmꢀ1. MS 30 3 M . CHN analysis (calcd %) C,
55.44; H, 4.29; N, 13.86; C14H13N3O5 (found %) C, 55.40;
H, 4.25; N, 13.80. 5b. Mp 228–230 °C 1H NMR (300 MHz,
CDCl3) d 3.00(s, 3H), 3.10(s, 3H), 6.50(s, 1H), 6.95–7.15
(m, 5H). IR 3435, 1710, 1695 cmꢀ1. MS 319 Mþ. CHN
analysis (calcd %) C, 52.66; H, 4.07; N, 13.16;
C14H13N3O4S (found %) C, 52.60; H, 4.00; N, 13.10.
1
7. Mp 266 °C H NMR (300 MHz, CDCl3) d 3.00 (s, 3H),
3.15 (s, 3H), 6.95–7.15 (m, 5H), 8.25 (s, 1H). IR 1715,
1700, 1695, 1610 cmꢀ1. MS 336 Mþ. CHN analysis (calcd
%) C, 60.71; H, 3.57; N, 16.66; C17H12N4O4 (found %) C,
60.65; H, 3.50; N, 16.65.

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I. Devi et al. / Tetrahedron Letters 45 (2004) 2405–2408
8a. Mp 215–217 °C 1H NMR (300 MHz, CDCl3) d 3.05 (s,
8b. Mp 241–242 °C 1H NMR (300 MHz, CDCl3) d 3.05 (s,
3H), 3.15 (s, 3H), 6.90–7.15 (m, 5H), 8.15 (s, 1H). IR 1710,
3H), 3.15 (s, 3H), 6.90–7.15 (m, 5H), 8.20 (s, 1H). IR 1710,
1695 cmꢀ1. MS 284 Mþ. CHN analysis (calcd %) C, 59.15;
H, 4.22; N, 19.71; C14H12N4O3 (found %) C, 59.10; H,
4.15; N, 19.66.
þ
1695 cmꢀ1. MS 30 0 M. CHN analysis (calcd %) C, 56.00;
H, 4.00; N, 18.66; C14H12N4O2S (found %) C, 55.95; H,
3.95; N, 18.61.