Pyrano pyrimidines, synthesis

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

Scheme27 Synthesis of pyrano- and pyrido[2,3-d]pyrimidin-2,4-diones...

The synthesis of 4//-pyrano[2,3-d]pyrimidines, a class of compounds important in crop protection, is presented in Scheme 91. Dichlorotriphenyl-phosphorane affords iminophosphorane 247 with ethyl 2-amino-4//-pyran-3-carboxylate (246). Phenyl isocyanate cyclizes under alkoxide migration to afford pyrano[2,3-d]pyrimidines (248) (90LA995). 

Prajapati D, Gohain M (2006) An efficient synthesis of novel pyrano 2,3-d - and furopyrano 2,3-d pyrimidines via indium-catalyzed multi-component domino reaction. Beilstein J Org Chem 2. Doi 10.1186/1860-5397-2-11... 

Dave and Shah have reported a Gould-Jacod type reaction for the microwave-assisted synthesis of thieno[3,2-e]pyrimido[ 1,2-c]pyrimidines via intermediate thieno[2,3-d ] pyrimidines (Scheme 3.46)73. A one-pot synthesis of pyrano [2,3-d]pyrimidines was also described by Kidwai and co-workers starting from thiobarbituric acids. The thio-barbituric acid intermediates were also prepared by microwave heating, using basic alumina as the solid support (Scheme 3.46)74. 

A new, simple, synthesis of 2,4-diaryl-l, 3,5-triazines is shown in Scheme 1. It arose from an attempt to obtain the pyrano[4,3-rf]pyrimidine system by reacting aryl amidines with the 3-methoxymethylenedihydropyran-2,4-dione (1 X= CH2). As well as the desired products, diaryl-I,2,3-triazines were obtained in 30-40% yield. The use of 5-methoxymethylene-2,2-dimethyl-l,3-dioxan-4,6-dione (1 X= 0)(derived from Meldrum s acid) gives the triazines in better yield (> 50%). It was also observed that 3-methoxymethylenefuran-2,4-dione reacted with 5-methylisothiouronium bromide to yield 2,4-bismethylthio-l,3,5-triazine [95M99]. 

This synthesis involves Michael cycloaddition reaction of the readily available 4-hydroxycoumarine 1 with a cyanocrotonitrile 2 in ethanolic piperidine to afforded 2-amino-3-cyano-4-methyl-4H, 5H-pyrano-benzopyran-5-one (3). Treatment of 3 with acetic anhydride for 0.5 h and/or 3 h under reflux afforded N-acetyl and [l]benzopyrano[3/,4/ 5,6]pyrano(2,3-d) pyrimidine-6,8-dione derivatives (4) and (5a), respectively. Also, interaction of 3 with benzoyl chloride or formic acid gave the corresponding pyrimidine derivatives (5b,c) while its treatment with formamide afforded the aminopyrimi-dine derivative (6). 

Another multicomponent procedure used to construct oxygen containing heterocycles under MW conditions is the synthesis of pyrano[2,3-d]pyrimidine 56 [55]. 

Less common are literature examples in which mechanochemical reaction was carried out at elevated temperature. Naimi-Jamal reported the heating of double-walled ball-mill beaker equipped with fittings for circulating water at 96°C (boiling water as circulant) [45]. One-pot solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(lFf,3F0-diones 154 was achieved by simply ball milling a stioichiometric mixture of an aromatic aldehyde, malononitrile, and barbituric acid, without addition of solvent and catalyst (Scheme 2.53). Quantitative yields were obtained (Table 2.47) and products generally did not require purification, the solid products were just dried at 80°C in vacuum and recrystaUized, if necessary. Reaction presumably takes place by initial Knoevenagel condensation of aromatic aldehyde with malononitrile to afford the intermediate Michael acceptor, which subsequently reacts with barbituric acid. Tautomerization of Michael adduct is followed by intramolecular cyclocondensation and another tautomerization to afford pyrano[2,3-d]pyrimidine-2,4(177,37f)-diones 154. 

Reproduced from Mashkouri S, Naimi-Jamal MR. Mechanochemical solvent-free and catalyst-free one-pot synthesis of pyrano[2,3-d]pyrimidine-2,4 1H.3H)-diones with quantitative yields. Molecules 2009 14 474-9. With permission from MDPi. 

A one pot synthesis of pyrano [2,3-d] pyrimidines from thiobarbituric acids under microwave irradiation using basic alumina has been reported. A significant... 

A. Palasz, Monatsh. Chem. 2012,143,1175—1185. Synthesis of fused uracils pyrano[2,3-<3f]pyrimidines and l,4-his(pyrano[2,3-(7]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder... 

Cerric ammonium nitrate (CAN) catalysed synthesis of pyrano[2,3-three-component reaction. 

SCHEME 14 Synthesis of spiro[indoline-3,5 -pyrano[2,3-d]pyrimidine]-6 -carbonitriles 27 [111,112], p-TSA, p-toluenesulfonic acid. 

P.K. Paliwal, S.R. Jetti, S. Jain, Green approach towards the facile synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine derivatives and their biological evaluation, Med. Chem. Res. 22 (2013) 2984—2990. 

An efficient synthesis of pyrrlo[2,3-d]pyrimidine annulated pyrano[5,6-c]cou-marin/[6,5-c]chromone derivatives was achieved by intramolecular hetero-Diels-Alder reaction by microwave irradiation under solvent-free and solid supported conditions (Ramesh and Raghunathan, 2008). 

A novel one pot synthesis of pyrano[2,3-d]pyrimidines via the cyclocondensation of barbituric acids, benzaldehyde, and aliphatic nitriles under microwave irradiation in the solid state has been reported (Devi et al, 2003). The synthesis of pyrido[2,3-d]pyrimidines has also been performed under identical conditions via condensation of 6-aminouracils or 6-hydroxyaminouracils, benzaldehyde, and aliphatic nitriles. 

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