Lactones pyrimidine ring

Shao reported the microwave-assisted hetero-Diels-Alder cycloaddition reaction of a series of acetylenic pyrimidines to introduce a fused lactone/lactam ring, with no degradation of either reactants or products typical for the harsh thermal conditions (150-190°C, 15-144h) [131]. In contrast to the results reported when conventional heating was applied, the Diels-Alder cycloaddition under microwave irradiation gave a high yield of the desired fused lactones or lactams [132]. This reaction provided a practical and general method for the preparation of fused bicyclic pyridines 205 (Scheme 74). 

More recently, to find more effective methods to construct bis(heterocycle)s containing a pyrimidine ring from MBH derivatives, the solid-phase parallel synthesis of new annulated pyrimidinone derivatives was disclosed (Scheme 4.219). " The resin-bound allyl amine derivatives 742 were treated with cyanogen bromide to yield the pyrazole derivatives 743 in good yields under standard conditions. The subsequent lactonization with cleavage of the resin afforded the pyrimidinone derivative 744 in good yields in the presence of 20% triethylamine in chloroform under reflux. 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

Lactones with oligoheteryl units in the macrocyclic ring skeleton can also be prepared in good yields from the reaction of cearan carboxylates with dihalides. Potts [53] obtained the triheteryl lactones 51 with a pyridine (X=CH) and a pyrimidine unit (X=N) in 60% (X=CH) and 55% yield (X=N) by cychzing the cesium salt 49 with the dibromo ojmpound 50 using DMF as solvent. 

The annulation of pyrimidine onto the triazole ring can be accomplished by the use of heterocyclic precursors that can be regarded as masked 1,3-bifunctional reagents. This way, triacetic acid lactone (41, Scheme 12) reacts as a masked 1,3-diketone and transforms AT to TP 42 together with ring isomer 43 and decarboxylation product 44 (02CRC517). 

The electrophiles or electrophilic intermediates that are or are postulated to be responsible for the carcinogenic action of chemicals include (i) positively charged carbonium, nitrenium, oxonium and episulfonium ions, (ii) free radicals, (iii) polarized double bonds, (iv) aldehydes, (v) strained rings such as epoxide, aziridine, lactones and sultones, and (vi) quinone/ quinoid/quinoneimine structures. Based on their reactivity (Table I), electrophiles may be graded from "soft" to "hard" similar to the concept of "soft" and "hard" acids and bases (18). In general, soft electrophiles react preferentially with soft nucleophiles whereas hard electrophiles react preferentially with hard nucleophiles. Thus, since the nucleophilic sites in the purine and pyrimidine bases in DNA are moderately hard nucleophiles, moderately hard electrophiles tend to have the greatest likelihood of covalent binding to DNA. Soft electrophiles often deplete the cellular pool of noncritical soft nucleophiles (such as GSH) before they can react with DNA. 

The methods most frequently used to synthesize these compounds are [6 + 0(a)] cyclizations. Ring closures may take place via intramolecular alkylation, condensation, or nucleophilic substitution. The starting materials for the cyclizations in the case of pyrazino-oxazines are always pyrazine derivatives. Only a few representatives of these systems have been prepared. Pyrimido-oxazines are the most explored group of compounds. In the bicyclic series, cyclizations have been carried out in most cases from pyrimidine intermediates and only rarely from morpholino intermediates. For the preparation of benzo-fused derivatives, both benzoxazine and quinazoline intermediates have been used. Pyrazino-oxazines represent a small group of compounds. For cyclizations, both pyrazino and oxazino intermediates have been used. There are many lactone structures among these compounds. For their preparation, the usual methods of lactone formation have been applied. 

---