Synthesis of novel classes of Pyrido[2,3-d]-pyrimidines, pyrano[2,3-d]pyrimidines, and pteridines

Article abstract of DOI:10.1080/00397910600775622

6-Amino-5-formyluracils 1 and 5-formyl-6-hydroxyuracils 4 react with Meldrum's acid 2 in the presence of piperidine as catalyst under thermolytic conditions to afford 6-carboxy-2,4,7-trioxopyrido[2,3-d]pyrimidines 3 and 6-carboxy-2,4,7-trioxopyrano[2,3-d]pyrimidines 5 in good yield. Under identical conditions, 6-amino-5-nitrosouracils 6 react with 2 to afford pteridine-6-carboxylic acids 7 in good yields. Copyright Taylor & Francis Group, LLC.

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Synthesis of Novel Classes of
Pyrido[2,3‐d]‐pyrimidines,
Pyrano[2,3‐d]pyrimidines, and Pteridines
a
a
Mohit Lal Deb & Pulak J. Bhuyan
a
Medicinal Chemistry Division, Regional Research Laboratory (CSIR), Jorhat,
Assam, India
Version of record first published: 16 Feb 2007.
To cite this article: Mohit Lal Deb & Pulak J. Bhuyan (2006): Synthesis of Novel Classes of
Pyrido[2,3‐d]‐pyrimidines, Pyrano[2,3‐d]pyrimidines, and Pteridines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:20, 3085-3090
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Synthetic Communications , 36: 3085–3090, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600775622
Synthesis of Novel Classes of Pyrido[2,3-d]-
pyrimidines, Pyrano[2,3-d]pyrimidines,
and Pteridines
Mohit Lal Deb and Pulak J. Bhuyan
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat,
Assam, India
Abstract: 6-Amino-5-formyluracils 1 and 5-formyl-6-hydroxyuracils 4 react with
Meldrum’s acid 2 in the presence of piperidine as catalyst under thermolytic conditions
to afford 6-carboxy-2,4,7-trioxopyrido[2,3-d]pyrimidines 3 and 6-carboxy-2,4,7-
trioxopyrano[2,3-d]pyrimidines 5 in good yield. Under identical conditions, 6-amino-
5-nitrosouracils 6 react with 2 to afford pteridine-6-carboxylic acids 7 in good yields.
Keywords: Meldrum’s acid, pteridines, pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyri-
midines, uracil
The importance of uracil and its annelated substrates is well recognized by
[
1]
synthetic and biological chemists. Pyrido[2,3-d]pyrimidines, pyrano[2,3-d]
pyrimidines, and pteridines represent broad classes of annelated uracils and
have received considerable attention over the past years because of their
wide range of biological activities. A number of compounds with these ring
[
2]
systems have diverse pharmacological activity such as antibacterial,
[
3]
[4]
[4a]
[4a]
antitumor,
anti-bronchits.
cardiotonic,
[
hepatoprotective,
Some of them exhibit antialergic,
antihypertensive,
and
[7]
antimalerial,
5]
[6]
[
8]
[9]
analgesic, and antifungal properties. Therefore, large efforts have been
directed toward the synthetic manipulation of uracils for the preparation of
[
these molecules. In this regard, the synthetic exploitation of the nucleophi-
10]
[11]
lic double bond of uracil is an important reaction strategy.
Received in India March 9, 2006
Address correspondence to Pulak J. Bhuyan, Medicinal Chemistry Division,
Regional Research Laboratory (CSIR), Jorhat 785 006, Assam, India. E-mail:
pulak_jyoti@yahoo.com
3
085

3
086
M. L. Deb and P. J. Bhuyan
Meldrum’s acid appears to be an attractive reagent in organic
synthesis because of its high acidity, steric rigidity, and high
[
12]
reactivity.
As a part of our continued interest in the development of highly
expedient methods for the synthesis of annelated uracils of biological
[
13]
significance,
-hydroxyuracils as 1,4-dienes in a [4 þ 2] cycloaddition reaction.
the present article, we report the synthesis of novel classes of 6-carboxy-
,4,7-trioxopyrido[2,3-d]-pyrimidines, 6-carboxy-2,4,7-trioxopyrano[2,3-d]
we recently utilized 6-amino-5-formyluracils and 5-formyl-
[14]
6
In
2
pyrimidines, and pteridine-6-carboxylic acids (lumazines) from 6-amino-5-
formyluracils, 5-formyl-6-hydroxyuracils, and 6-amino-5-nitroso-uracils
based on the cyclocondensation reaction, which allows access to a range of
structural variation (Scheme 1).
Scheme 1.

Synthesis of Novel Classes of Annelated Uracils
3087
6
15]
-Amino-5-formyluracil 1a was prepared from 6-amino-1,3-dimethylur-
[
[16]
acil
under the Vilsmeier–Haack formylation reaction condition.
In a
typical experimental procedure, equimolar amounts of 6-amino-5-formyl
uracil 1a and Meldrum’s acid 2 were refluxed in a mixture of methanol and
chloroform (1:1) to afford 6-carboxy-2,4,7-trioxopyrido[2,3-d]pyrimidines
3a in good yield. The structure of the compound 3a was determined from
1
the spectroscopic data and elemental analysis. The H NMR spectrum
showed the absence of the aldehyde proton and presence of a proton at d
7.40 as a singlet and another broad peak for one proton at d 8.95. The other
signals appeared at d 3.00 (s, 3H, N-CH ) and 3.15 (s, 3H, NCH ). The
3
3
þ
mass spectrum revealed a strong molecular ion peak at (M þ H) 252
employing the positive ionization technique). The compound, on treatment
with aqueous NaHCO solution, evolves CO with effervescence, which
(
3
2
evidences the presence of a carboxylic acid group. Similarly, compounds
b,c were synthesized from the reaction of 1b,c with 2 and characterized in
Table 1.
Under identical conditions, 1,3-dimethyl-5-formyl-6-hydroxyuracil
3
[
17]
4
acid 2 to afford 6-carboxy-2,4,7-trioxo-pyrano[2,3-d]pyrimidine 5a in good
a,
prepared from 1,3-dimethyl-6-hydroxyuracil, reacts with Meldrum’s
yields. The structure of the product was ascertained by spectroscopic and
1
elemental analysis. The H NMR spectrum showed the absence of the
aldehyde proton and the presence of a proton at d 7.95 as a singlet and a
broad peak for one proton at d 9.20. The other signals appeared at d 3.05
(
s, 3H, N-CH ) and 3.10 (s, 3H, NCH ). The mass spectrum exhibited a
3
3
þ
strong molecular ion peak at (M þ H) 253. Similarly, 6-carboxy-2,4,7-
trioxopyrano[2,3-d]pyrimidines 5b,c were synthesized from the reaction of
4
b,c with 2 and characterized in Table 1.
To explore the synthetic utility of the condensation process further, we
studied the reactivity pattern of comparatively less reactive 6-amino-5-nitroso
uracils 6 with Meldrum’s acid 2 and found them to react moderately to afford
Table 1. Pyrido[2,3-d]pyrimidines 3, pyrano[2,3-d]pyrimidines 5, and pteridines 7
Reaction
time (h)
Yield
(%)
1
2
R
Entry
Product
R
Mp (8C)
1
2
3
4
5
6
7
8
9
3a
3b
3c
5a
5b
5c
7a
7b
7c
CH3
H
CH3
H
18
18
18
20
20
20
21
22
21
61
63
57
63
60
56
70
73
69
345–347
.350
.350
278–280
337–339
.350
326
.330
.330
C
2
H
5
5
5
H
CH
CH3
3
CH
H
3
C
2
H
H
CH
H
3
CH
H
3
C
2
H
H

3
088
M. L. Deb and P. J. Bhuyan
the ptridiene-6-carboxylic acid (lumazine) derivatives 7 in good yields. The
structures of the compounds were confirmed from the spectroscopic data and
1
elemental analysis (Table 1). The H NMR of compound 7a showed the
presence of one proton at d 9.10 as a singlet. The mass spectrum showed a
þ
strong molecular ion peak at (M þ H) 253. The IR spectrum showed the
absence of the -NH group and N 55 O group of the uracil derivative.
2
In conclusion, we have reported the synthesis of some novel classes of
-carboxy-2,4,7-trioxo pyrido[2,3-d]pyrimidines, 6-carboxy-2,4,7-trioxo
6
pyrano[2,3-d]pyrimidines, and lumazine derivatives by utilizing easily
available organic synthones such as Meldrum’s acid with suitably functiona-
lized uracil derivatives.
EXPERIMENTAL SECTION
1,3-Dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]
pyrimidine-6-carboxylic Acid 3
In a typical experimental procedure, equimolar amounts of 1,3-dimethyl-6-
amino-5-formyl uracil 1a (2 mmol, 366 mg) and Meldrum’s acid 2 (2 mmol,
288 mg) in the presence of piperidine (2 drops) were refluxed in a mixture
of methanol and chloroform (1:1, 15 ml) for 18 h. The solvent was evaporated
under reduced pressure, and the obtained solid compound was purified by pre-
parative thin-layer chromatography (TLC) using chloroform–ethyl acetate
(
1:5) as eluent. The product 3a was obtained in 61% yield (305.5 mg). Mp
1
3
45–3478C. H NMR (300 MHz, CDCl þ CH OD) d 3.00 (s, 3H), 3.15
3
3
1
3
s, 3H), 7.40 (s, 1H), 8.95 (s, br, 1H). C NMR (75 MHz) d 28.5 (N-Me),
(
3
1
6.8 (N-Me), 107.20 (C-10), 142.15 (C-6), 143.00 (C-7), 144.50 (C-5),
50.20 (C-2), 154.00 (C-9), 157.25 (C-4), 168.00 (-COOH). IR KBr v
max
2
1
þ
cm 3400 (br), 1705, 1690, 1655. MS: (M þ H) 252. Anal. calcd. for
C H N O C, 47.80; H, 3.58; N, 16.73. Found C, 47.75; H, 3.45; N, 16.70.
10 9 3 5
1,3-Dimethyl-2,4,7-trioxo-1,2,3,4-tetrahydro-2H-pyrano[2,3-d]
pyrimidine-6-carboxylic Acid 5
In a simple experimental procedure, equimolar amounts of 1,3-dimethyl-5-
formyl-6-hydroxyuracil 4 (2 mmol, 368 mg) and Meldrum’s acid 2
(
2 mmol, 288 mg) in the presence of piperidine (2 drops) were refluxed in
5 ml of ethanol for 20 h. The solvent was evaporated under reduced
pressure, and the solid compound obtained was purified by preparative TLC
1
using chloroform–ethyl acetate (1:3) as eluent. The product 5a was
1
obtained in 63% yield (317 mg). Mp 278–2808C. H NMR (300 MHz,
CDCl þ CH OD) d 3.05 (s, 3H), 3.10 (s, 3H), 7.95 (s, 1H), 9.20 (s, br,
3
3
3
1
H). C NMR (75 MHz) d 29.18 (N-Me), 36.53 (N-Me), 107.00 (C-10),
1

Synthesis of Novel Classes of Annelated Uracils
3089
1
44.23 (C-6), 145.00 (C-5), 151.10 (C-2), 153.80 (C-9), 156.75 (C-4), 169.17
21
(
-COOH), 171.00 (C-7). IR KBr v
þ
cm 3450 (br), 1750, 1705, 1690, 1660.
max
MS: (M þ H) 253. Anal. calcd. for C H N O C, 47.61; H, 3.17; N, 11.11.
1
0 8 2 6
Found C, 47.58; H, 3.14; N, 11.05.
1,3-Dimethyl-2,4,7-trioxo-1,2,3,4,7,8 hexahydropteridine-6-
carboxylic Acid 7
In a typical experimental procedure, equimolar amounts of 1,3-dimethyl-6-
amino-5-nitroso uracil 6a (2 mmol, 368 mg) and Meldrum’s acid 2
(2 mmol, 288 mg) and 0.25 mmol of NaOH were refluxed in water for 21 h.
The solvent was evaporated under reduced pressure, and the solid
compound obtained was purified by column chromatography using chloro-
form–ethyl acetate (1:3) as eluent. The product 7a was obtained in 70%
1
yield (401 mg). Mp 3268C. H NMR (300 MHz, CDCl þ CH OD) d 3.00
3
3
13
(
s, 3H), 3.10 (s, 3H), 8.10 (s, 1H). C NMR (75 MHz) d 29.00 (N-Me),
3
1
1
6
6.50 (N-Me), 108.50 (C-10), 142.50 (C-6), 143.00 (C-7), 149.50 (C-2),
2
1
55.00 (C-9), 157.50 (C-4), 168.00 (-COOH). IR KBr vmax cm
þ
3430,
735, 1695, 1660. MS: (M þ H) 253. Anal. calcd. for C H N O C,
1
5 17 3 3
2.71; H, 5.92; N, 14.63. Found: C, 62.68; H, 5.87; N, 14.70.
ACKNOWLEDGMENTS
The authors thank the director, Regional Research Laboratory (RRL),
Jorhat, for providing the facilities to perform the work. M. L. Deb thanks
Council of Scientific & Industrial Research (CSIR), New Delhi, for the
award of a junior research fellowship.
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