Pyrimidines, fused, syntheses using

Huge success of benzodiazepenes as pharmaceutical scaffolds has prompted preparation and evaluation of het-erocyde-annulated benzodiazepine derivatives. A tandem Michael addition-condensation sequence xmder MW irradiation was also proved to be useful for the synthesis of amino-substituted pyrimidine-fused diazepine derivatives of the type 96 from 4,5,6-triaminopyrimidine and chalcones [57]. Similarly, the pyridine-fused derivatives (97) were prepared xmder MW-assisted solvent and catalyst-free condition [58], Condensation of thiadiazole-annulated phen-ylene diamines with appropriate carbonyl compounds using sulfamic acid as organocatalyst led to the formation of corresponding diazepine derivatives 98 in excellent yields [59] (Figure 4). 

Pyrimidine-fused Systems.—o-Aminothiophencarboxylic acid derivatives have been extensively used for the synthesis of thienopyrimidine derivatives. Thus the mercapto-derivatives (464) have been synthesized by... 

When the synthesis of a heterocyclic system containing a diazole fused onto l,2,3-triazin-4-one (e.g., imidazo[4,5-i [l,2,3]tnazin-4-one (Section 10.13.9.1.l(i)) and pyrazolo[3,4-rf [l,2,3]triazin-4-one (Section 10.13.9.1.1(ii))) or 1,2,3-triazole fused onto pyrimidin-4(7)-(di)one (e.g., [l,2,3]triazolo[4,5-rf pyrimidin-4(7)-(di)one (Section 10.13.9.1.l(iv))) is required, the synthesis of the six-membered ring is the most reliable method. There are several recent accounts of six-membered annulations onto 1,2,3-triazoles to give [l,2,3]triazolo[4,5-r/ pyrimidines (Section 10.13.9.1.l(iv)), which are valuable alternatives to 1,2,3-triazole annulation using nitrosation techniques <1996CHEC-II(7)489>. 

The dual alkylation/S Ar cyclization of A 1,A z-bis(2,4-dimethoxybenzyl)ethane-l,2-diamine (bis-DMB-ethylene-diamine) with the chloromethyl pyrimidine 102 provided the fused ring diazepine 103, a transformation that could not be accomplished by simply using unprotected ethylenediamine (Scheme 56). The product is an intermediate toward the synthesis of potential folate-related antitumor agents that act as glycinamide ribonucleotide formyltrans-ferase inhibitors <2004HC0405>. 

We conclude this chapter with the synthesis of Novartis PKI 166 121, a new anti-cancer drug of great promise.16 It has fused pyrrole and pyrimidine rings and the reaction we have just discussed allows disconnection of the amine from the pyrimidine ring 121. Now we can use standard C-N disconnections on the two rings in turn 122 and 123 to reveal a much simpler starting material 124. 

Acetylenic pyrimidines undergo hetero-Diels-Alder reactions yielding pyrido-fused lactams with recent reports of improved yields using microwave-assisted conditions <2005TL3423>. The use of alkynes as dieneophiles has also been reported in an intramolecular reaction with chloropyrimidine (Scheme 55) <2000SL625>, in this case toward the total synthesis of cerpegin via demethylation. 

A lot of information about the structure, reactivity, and the best synthetic approaches for pyrimidopyrimidines has been described in CHEC-I. Additionally, some new methods of preparation of pyrimidopyrimidines have been reported in reviews on the synthesis of fused pyrimidines by Delia and Warner starting material in heterocyclic synthesis by Wamhoff, Dzenis, and Hirota <92AHC(55)129>. Pyrimidopyrimidines are especially interesting as structural analogues of natural compounds. 

The sulfur can be reductively removed by one of the many methods utilized for sulfur heterocycles. For the fused pyrimidine (703) zinc in acetic acid can be used (64JOC2135). In the 7-formylamino analogue (704), however, Raney nickel in aqueous ethanol was the best reagent for the reductive cyclization to form adenines (705) (78JOC960). It has been pointed out that nucleophilic substitution at C-7 in the [l,2,5]thiadiazolo[3,4-d]pyrimidine system easily takes place. This makes the compounds (704) readily available as key substances in this convenient approach to the synthesis of 9-substituted adenine derivatives. 

Aza-Wittig reactions in fused pyrimidine synthesis, 55, 159 synthetic uses, 57, 37 2-Azaanthraquinone, synthesis, 56, 275... 

Fused pyrimidines, formed by a tandem aza-Wittig/electrocycUzation reaction, are used in the synthesis of pyrazolo[3,4-d]pyrimidines, l,2,3-triazolo[4,5-d]pyrimidines and thiazolo[4,5-d]pyrimidine derivatives. ... 

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