Synthesis of novel derivatives of pyrano[2,3-d]pyrimidinevia intramolecular cyclocondensation reaction under acidic and basic conditions

Article abstract of DOI:10.2174/157017812801322516

In this study analogues of compounds based on pyrano[2,3-d]pyrimidine were synthesized. 1,3-dimethyl-5-(thiomethyl)-2,4,7-trioxo-1,3,4,7-tetrahydro-2H- pyrano[2,3-d]pyrimidine-6-carboxylic acid 3 and 1,3-dimethyl-5-(thiomethyl)-2H- pyrano[2,3-d]pyrimidine

Full text of DOI:10.2174/157017812801322516

386
Letters in Organic Chemistry, 2012, 9, 386-389
Synthesis of Novel Derivatives of pyrano[2,3-d]pyrimidinevia Intramolecu-
lar Cyclocondensation Reaction Under Acidic and Basic Conditions
Ahmed Al-Sheikh*,a, Kamal Sweidanb, Munjed Ibrahima, Mohammed Alarjaha and Norbert Kuhnc
aFaculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
bDepartment of Chemistry, University of Jordan, Amman, Jordan
c Institutfür Anorganische Chemie der Universität Tübingen, Auf der Morgenstelle 18, D-72076, Germany
Received December 11, 2011: Revised April 30, 2012: Accepted April 30, 2012
Abstract: In this study analogues of compounds based on pyrano[2,3-d]pyrimidine were synthesized. 1,3-dimethyl-5-
(thiomethyl)-2,4,7-trioxo-1,3,4,7-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carboxylic acid
3
and 1,3-dimethyl-5-
(thiomethyl)-2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-trione 4 were obtained by the treatment of Triethylammonium 5-
[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(thiomethyl)methyl]-1,3-dimethylpyrimidine-2,4,6-trionate 1 with methyl
sulfonic acid and pyridine, respectively. 5,5-dianilino-1,3-dimethyl-5,6-dihydro-2H-pyrano[2,3-d]pyrimidine-
2,4,7(1H,3H)-trione 6 was obtained after oxidizing compound 4 to produce 1,3-dimethyl-5-(methylsulfinyl)-2H-
pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-trione 5 , then the sulfoxide group on compound 5 was replaced by aniline group.
Keywords: 1,3-dimethylbarbituric acid, intramolecular cyclocondensation, meldrum's acid, pyrano[2,3-d]pyrimidine.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
Pyrimidine derivatives are known to exhibit diverse
pharmacological activities as nicotinic acid receptor agonists
for the treatment of dyslipidemia [1, 2], treatment of cancer
and rheumatic diseases [3], through their anti-bacterial [4, 5],
cardiotonic, antihypertensive [6, 7], antifungal [8], antialler-
gic [9], and analgesic activities [10].
2.1. Preparation of 1,3-dimethyl-5-(thiomethyl)-2,4,7-
trioxo-1,3,4,7-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
Carboxylic Acid 3
The triethylammonium 5-[(2,2-Dimethyl-4,6-dioxo-1,3-
dioxan-5-ylidene)(thiomethyl) methyl]-1,3-dimethyl pyri-
midine-2,4,6-trionate 1 have been conveniently prepared by
the reaction of 5-[bis(thiomethyl)methylene] meldrum's acid
2 with 1,3-dimethylbarbituric acid in the presence of triethy-
lamine [16].
The increasing interest in Pyrano[2,3-d]pyrimidine led to
find numerous synthetic methods for preparation of this class
of compounds in the literature. The methods differed intart-
ing materials, reaction conditions and techniques. Yu et al.
[11] reported the synthesis of pyrano[2,3-d]pyrimidine by
reacting arylmethylidenemalononitrite and barbituric acid
using ionic liquids as solvents. Bhuyan et al. [12] reacted 5-
formyl-6-hydroxy uracils with meldrum's acid at reflux.
Balalaie et al. [13] starting with aldehyde, malononitrile,
barbituric acid and L proline as a catalyst for preparing
Pyrano[2,3-d]pyrimidine via Domino Knoevenagel-cyclo-
condensation reaction. Naimi-Jamal et al. [14] reported a
solvent-free and catalyst-free synthesis method. Bhuyan et
al. [15] used microwave irradiation in the solid state to pre-
pare this class of compounds.
O
SCH3
O
O
H3C
H3C
O
N
O
O
O
O
O
SCH3
SCH3
HNEt3
H3C
H3C
O
CH3
O
N
1
H3C
2
Treating salt 1 with methylsulfonic acid at ambient con-
ditions afforded the corresponding Intramolecular cycliza-
tion to produce 3 in good yield. Analytical data was in
agreement with proposed structure. For example, unlike salt
In this study, we report the synthesis of analogue novel
derivatives of pyrano[2,3-d]pyrimidine by intramolecularcy-
clocondensation reaction for triethylammonium 5-[(2,
1
2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)
(thiomethyl)
1, H-NMR spectrum of 3 shows no peaks corresponding to
methyl]-1,3-dimethyl pyrimidine-2,4,6-trionate salt 1 under
acidic and basic conditions.
methyl protons in meldrum's acid ring and shows a broad
and short peak at 13.67 corresponding to carboxylic acid
(1H, COOH). The other peaks appeared at 2.46(s,3H,SCH3)
and 3.23, 3.38 (2s, 6H, NCH3) receptively.
The plausible reaction mechanism is an intramolecular
cyclization which involves the reaction of enolate anion on-
barbituric ring as nucleophile with carbonyl group onmel-
*Address correspondence to this author at the Faculty of Pharmacy, Umm
Al-Qura University, P.O. Box 13174 -Makkah, Saudi Arabia; Tel:
0096625270000 Ext. 4268; Fax:
E-mail: ahmedalsheikh@yahoo.com
+
966-2-5270000 Ext. 4225;
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of Novel Derivatives of pyrano[2,3-d]pyrimidine via
Letters in Organic Chemistry, 2012, Vol. 9, No. 6
387
O
SCH3
thiomethyl group and the other one was added in Michael
addition reaction to produce 5,5-dianilino-1,3-dimethyl-5,6-
dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-trione
compound 6. Analytical data were in agreement with our
proposal for this reaction. For example; DEPT-NMR
spectrum showed a CH2 peak at 40.253.1H-NMR spectrum
showed peak of CH2 protons at 4.07 (s, 2H, CH2) and aro-
H3C
O
COOH
O
N
N
O
3
CH3
O
SCH3
O
O
O
SCH3
H3C
H3C
O
H3C
O
COOH
O
O
C
CH3SO3H/ rt.
N
H3C
CH3
+
O
N
O
CH3
N
O
3
O
N
CH3
H3C
1
Scheme 1.
drum's acid ring to form new ꢀ bond which is followed by
the elimination of acetone (Scheme 1).
matic protons at 7.28 – 7.54 (m, 10H, Haromatic). The other
peaks appeared at 3.13, 3.24 (2s, 6H, NCH3) and 10.09, 14.1
(2s, 2H, NH) receptively.
2.2. Preparation of 1,3-dimethyl-5-(thiomethyl)-2H-
pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-trione 4 and its
Sulfoxide Derivative 5
3. FURTHER WORK
Pyrano[2,3-d]pyrimidine compound exhibited pharma-
cological activities. Our next steps will be to test compounds
3, 4, 5, and 6 for their activities. The synthesis of analogue
novel derivatives of pyrano[2,3-d]pyrimidine based on com-
pound 6 where more biologically active group will be used.
Compound 1 was heated to reflux in pyridine solvent
which produced 1,3-dimethyl-5-(thiomethyl)-2H-pyrano[2,3-
d]pyrimidine-2,4,7(1H,3H)-trione 4 in good yield.
Interestingly thiomethyl group (SCH3) could not be re-
placed with nucleophilic reagents such as amines [17]. In
order to replace the thiomethyl group with amine it was nec-
essary to activate the thiomethyl group. The treatment of
compound 4 with m-chloroperbenzoic acid (MCPBA) pro-
duced compound 5 in good yield. The sulfoxidederivatives
of compound 4 afforded more reactive form (compound 5) to
nucleophilic displacement reaction with amines. It is known
that the nucleophilic displacement of methylsulfoxide group
occurs more rapidly than the corresponding displacement of
thiomethyl [18, 19]. Compound 5 can be regarded as useful
intermediate for the preparation of next compound.
HN
O
H
N
H3C
N
O
N
O
O
CH3
6
O
O
SCH3
4. EXPERIMENTAL
O
S
CH3
H3C
O
4.1. Materials and Instruments
N
H3C
O
N
All experiments have been performed in purified solvents
under argon. 1,3-Dimethylbarbituric acid, Meldrum's acid,
Carbon disulfide, Iodomethane, Triethylamine, Pyridine,
Aniline,m-Chloroperbenzoic acid were purchased from Ald-
rich and used without further purification. Nuclear magnetic
resonance (NMR) spectra were acquired by a Brucker DRX
400 NMR spectrometer with tetramethylsilane (1H, 13C) as
external standards. Elemental analyses were determined by
Carlo Erba Company, model 1106.
N
O
O
N
O
O
CH3
CH3
4
5
2.3. Preparation of 5,5-dianilino-1,3-dimethyl-5,6-
dihydro-2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-
trione 6
Triethylammonium 5-[(2,2-dimethyl-4,6-dioxo-1,3-dio-
xan-5-ylidene)(thiomethyl) methyl]-1,3-dimethylpyrimidine-
2,4,6-trionate 1 was obtained according to a published pro-
cedure [16]. 5-[bis(thiomethyl)methylene]meldrum's acid2
was obtained according to a published procedure [20].
Compound 6 could be obtained by refluxing compound 5
with aniline. The best yield could be achieved when the ratio
of compound 5:aniline is 1:2. The proposed explanation for
this is that one equivalent of aniline substituted the

388 Letters in Organic Chemistry, 2012, Vol. 9, No. 6
Al-Sheikh et al.
4.2.
1,3-dimethyl-5-(thiomethyl)-2,4,7-trioxo-1,3,4,7-
Yield: 54%; 1H NMR (400.13 MHz, CD2Cl2):
2.78(s,3H,S(O)CH3); 3.13, 3.24 (2s, 6H, NCH3); 4.07 (s, 2H,
CH2); 7.28 – 7.54 (m, 10H, Haromatic); 10.09, 14.1 (2s, 2H,
NH) ppm. 13C NMR (100.62 MHz, DMSO-d6): 27.9, 28.0
(NCH3); 40.22(CH2); 91.0 (C5pyrimidine); 119.83 – 137.0 (Haro-
matic); 163.68, 164.98, 168. (CO); 168.3 (C4pyrimidine) ppm.
Anal. Calcd. for C21H20N4O4: C, 64.28; H, 5.14; N,14.28; S,
11.85. Found: C, 63.94; H, 5.63; N, 14.19%.
tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carboxylic
Acid( 3)
To a solution of 1 (4.58g, 10mmol) in 20 ml THF,
(0.65ml, 10mmol) of methanesulfonic acid was added drop-
wise. The mixture was stirred at r.t. for 1 h. The THF was
removed under vacuum. The residue was dissolved in 20 ml
CH2Cl2, the solution was extracted with 10ml of water. The
organic layer was dried over Na2SO4 and evaporated to dry-
ness. The residue was recrystallized from dichloromethane /
diethylether.
Yield: 53%; 1H NMR (400.13 MHz, DMSO-d6):
2.46(s,3H,SCH3); 3.23, 3.38 (2s, 6H, NCH3); 13.68 (s, 1H,
COOH) ppm. 13C NMR (100.62 MHz, DMSO-d6): 16.93
(SCH3); 28.13, 29.77 (NCH3);92.33 (C5pyrimidine); 108.99
(C3pyran); 148.60 (CSMe); 153.7 (COOH); 156.80, 158.44,
160.08 (CO); 166.09 (C4pyrimidine) ppm. Anal. Calcd. for
C11H10N2O6S: C, 44.29; H, 3.38; N, 9.39; S, 10.75. Found:
C, 44.35; H, 3.77; N, 9.45; S, 10.78%.
5. ACKNOWLEDGEMENTS
Financial support by the Deutsche Forschungsgemein-
schaft (DFG) and the Higher Council for Science and Tech-
nology of Jordan is gratefully acknowledged.
CONFLICT OF INTEREST
Declared none.
REFERENCES
[1]
Palani, A.; Su, J.; Xiao, D.; Huang, X.; Rao, A. U.; Chen, X.;
Tang,H.; Qin, J.; Huang, Y. R.; Aslanian, R. G.; Mckittrick, B. A.;
Degrado,S. J. Pyrano[2,3-d]pyrimidines as Nicotinic Acid Receptor
Agonists for the Treatment of Dyslipidemia and Their Preparation
and Pharmaceutical Compositions. U.S. Pat. Appl. Publ. US
2008019978, 2008.
4.3. 1,3-dimethyl-5-(thiomethyl)-2H-pyrano[2,3-d]pyri-
midine-2,4,7(1H,3H)-trione (4)
(4.58, 10mmol) of 1 was heated at reflux in pyridine for
5h. The precipitate was filtered off, washed with distilled
water and dried under vacuum. The residue was recrystal-
lized from dichloromethane / diethylether.
Yield: 67%; 1H NMR (400.13 MHz, CD2Cl2):
2.31(s,3H,SCH3); 3.26, 3.46 (2s, 6H, NCH3); 5.56 (s, 1H,
C=CH) ppm. 13C NMR (100.62 MHz, DMSO-d6): 15.95
(SCH3); 28.52, 29.83 (NCH3); 96.47 (C5pyrimidine); 150.0
(CSMe); 156.0, 159.0, 160.0 (CO); 164.0 (C4pyrimidine) ppm..
Anal. Calcd. for C10H10N2O4S: C, 47.24; H, 3.96; N,11.02; S,
12.61. Found: C, 46.73; H, 4.08; N, 11.11; S, 12.96%.
[2]
[3]
Boatman, P.D.; Richman, J.G.; Semple, G. Nicotinic Acid Receptor
Agonists. J. Med. Chem., 2008, 51(24), 7653-7662.
Toshiyuki, S.; Hisashi, K.; Hiroyuki, A.; Kazuhide, H.; Tetsuya, I.;
Shinichi, K.; Takayuki, Y.; Toyomichi, N.; Hironori, K.; Masahiro,
T.; Yoshikazu, H.; Mitsuru, T.; Takayuki, Y.5-amino-2,4,7-trioxo-
3,4,7,8-tetrahydro-2h-pyrido[2,3-d] pyrimidine derivatives and re-
lated compounds for the treatment of cancer. PCT Int. Appl. WO
2005/121142, 2005.
Ghorab, M. M.; Hassan, A.Y. Synthesis and antibacterial properti-
esof new dithienyl containing pyran, pyrano[2,3-b] pyridine,
pyrano[2,3-d]pyrimidine and pyridine derivatives. Phosphorus,
Sulfur, Silicon & Related Elem., 1998, 141(1), 251–261.
Eid, F.A.; Abd El-Wahab, A.H.; Ali, G.A.; Khafagy, M.M. Synthe-
sis and antimicrobial evaluation of naphtho[2,1-b]pyrano[2,3-
d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine de-
rivatives. Acta Pharm., 2004, 54(1), 13-26.
[4]
[5]
4.4.
1,3-dimethyl-5-(methylsulfinyl)-2H-pyrano[2,3-
d]pyrimidine-2,4,7(1H,3H)-trione (5)
To a solution of 4(2.6, 10 mmol) in 20 ml CH2Cl2, (1.73,
10mmol) of m-chloroperbenzoic acid was added at -60°C.
The mixture was stirred overnight. The CH2Cl2 was removed
under vaccum. The residue was stirred in 20 ml diehylether
for 5 minutes. The precipitate was filtered off and dried un-
der vacuum.The residue was recrystallized from dichloro-
methane / diethylether.
Yield: 58%; 1H NMR (400.13 MHz, CD2Cl2):
2.78(s,3H,S(O)CH3); 3.31, 3.53 (2s, 6H, NCH3); 6.66 (s, 1H,
C=CH) ppm. 13C NMR (100.62 MHz, DMSO-d6): 30.21,
31.64 (NCH3); 44.80(S(O)CH3); 104.0 (C5pyrimidine); 151.12
(CSCH3); 157.26, 160.18 (CO); 170.41 (C4pyrimidine) ppm.
Anal. Calcd. for C10H10N2O5S: C, 44.44; H, 3.72; N,10.37; S,
11.85. Found: C, 44.29; H, 3.72; N, 10.37; S, 11.65%.
[6]
[7]
Furuya, S.; Ohtaki, T. Pyridopyrimidine derivatives, their produc-
tion and use. Eur. Pat. Appl. EP 608565, 1994; Chem. Abstr.1994,
121, 205395.
Heber, D.; Heers, C.; Ravens, U. Positive inotropic activity of 5-
amino-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
midine-2,4-dione in cardiac muscle from guinea-pig and man. Part
6: Compounds with positive inotropic activity. Pharmazie, 1993,
48, 537.
Hanafy, F.I. Synthesis and antifungal activity of some new
pyrido[2,3-d] pyrimidinesn. Eur. J. Chem., 2011, 2(1), 65-69.
Kitamura, N.; Onishi, A. Eur. Pat., 163599, 1984; Chem. Abstr.,
1984, 104, 186439.
Kretzschmar, E. On derivatives of 4-oxo-3,4-dihydropyrido[2,3-
d]pyrimidine. Pharmazie, 1980, 35, 253–256.
Yu, J.; Wang, H. Green Synthesis of Pyrano[2,2-d]pyrimidine
Derivatives in Ionic Liquids. Synth. Commun., 2005, 35(24), 3133-
3140.
Deb, M. L.; Bhuyan, P. J. Synthesis of Novel Classes of
Pyrido[2,3-d]pyrimidines, Pyrano[2,3-d]pyrimidines, and Pteridi-
nes. Synth. Commun., 2006, 36(20), 3085-3090.
Bararjanian, M.; Balalaie, S.; Movassagh, B.; Amani, A.M. One-
Pot Synthesis of Pyrano[2,3-d]pyrimidinone Derivatives Catalyzed
by L-Proline in Aqueous. Media J. Iran. Chem. Soc., 2009, 6(2),
436-442.
Mashkouri, S.; Naimi-Jamal, M.R. Mechanochemical Solvent-Free
and Catalyst-Free One-Pot Synthesis of Pyrano[2,3-d]Pyrimidine-
[8]
[9]
[10]
[11]
[12]
[13]
4.5. 5,5-dianilino-1,3-dimethyl-5,6-dihydro-2H-pyrano[2,
3-d]pyrimidine-2,4,7(1H,3H)-trione(6)
(2.55g,10 mmol) of 1 and (2.3m, 25mmol) of aniline
were heated at reflux in 20 ml ethanol for 8h. The ethanol
was removed under vacuum. The residue was recrystallized
from dichloromethane / diethylether.
[14]

Synthesis of Novel Derivatives of pyrano[2,3-d]pyrimidine via
Letters in Organic Chemistry, 2012, Vol. 9, No. 6
389
2,4(1H,3H)-Diones with Quantitative Yields. Molecules, 2009,
14(1), 474-479.
Methylthio-and 4-Amino-2-aryl-6H-1,3-oxazin-6-ones. Synth.
Commun., 1991, 21, 1213-1221.
[15]
[16]
Devi, I.; Kumar, B.S.D.; Bhuyan, P.J. 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. Tetrahe-
dron Lett., 2003, 44, 8307-8310.
Al-Sheikh, A.; Sweidan, K.; Sweileh, B.; Steimannd, M.; Schubert,
H.; Kuhn, B. Synthesis and Crystal Structure of Triethylammonium
5-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(methylthio)me-
thyl]-1,3-dimethylpyrimidine-2,4,6-trionateZ. Naturforsch. 2008,
63b, 1020-1022.
[18]
[19]
Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. Synthesis and reaction
of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one
derivatives. J. Heterocycl. Chem., 1987, 24(6), 1557–1567.
Barbeau, O. R.; Cano-Soumillac, C.; Griffin, R. J.; Hardcastle, I.R.;
Smith, G.C.M.; Richardson, C.; Clegg, W.; Harrington, R.W.;
Golding, B.T. Quinolinone and pyridopyrimidinone inhibitors of
DNA-dependent protein kinase. Org. Biomol. Chem., 2007, 5,
2670-2677.
[20]
Kuhn, N.; Al-Sheikh, A.; Maichle- Moessmer, C.; Steimann, M.;
Sweidan, K. The Crystal Structure of 5-Bis(thiomethyl)methylene
Meldrum's Acid. Z. Naturforsch. 2007, 62b, 1221-1223.
[17]
Huang, X.; Chen, B.C.; Wu, G.Y.; Chen, H.B. Novel Synthesis of
Acylaminomethylene Meldrum's Acids and their Thermolysis to 4-