Pyrimidines annulated

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

Pyrimidine annulation of 2-chloro-3-cyanopyridine 373 with guanidine in dimethyl sulfoxide (DMSO) at 130 °C afforded the diaminopyrido[2,3-,7 pyrimidine 374 (Equation 31) <2001H(55)1679>. 

Pyrimidine-annulated methanooxepene 35a is formed via regioselective heterocyclization of 6-cyclopent-2-enyl-5-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3//)-dione in the presence of concentrated sulfuric acid. The above-mentioned pyrimidinedione and 5-cyclopent-2-enyl-6-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3/7)-dione give similar annulated bromomethanooxepenes 35b and 36, respectively, when cyclization is performed with pyridine hydrotribromide or hexamethylenetetramine hydrotribromide <2003M1137>. 

Azole approach. The substituted isothiazole (142) can be reacted with an ortho ester to form a methyleneamine which reacts with hydroxylamine to yield the 5-oxide (143). With amidines, (142) yields 4-amino derivatives (75JHC883). The reaction of 5-amino-4-ethoxycar-bonylisothiazole with iminoethers results in pyrimidine annulation, as in the formation of... 

Accordingly, uracil-/3-enamino ester, after treatment with dihalotriphe-nylphosphorane (via iminophosphorane), gives, with isocyanates in a normal kind of pyrimidine annullation (90LA901), pyrimido[4,5-pyrimidines containing a 2-alkoxy group capable of several subsequent reactions (88S919) (Scheme 56). 

Oxazoline functionalization of a singly bonded C o dimer was achieved via a one-pot reaction of CgoECBn with OH and aromatic nitriles (14JOC197). A simple metal-free heterocyclization of uracil amides 158 was efficiendy carried out with hypervalent iodine Phl(OAc)2 in the presence of BF3 OEt2 affording pyrimidine-annulated oxazolines 159 in high yields (14TL5625). 

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. Synthesis by Annulation of the 1,2,4-Triazole Ring ONTO A Pyrimidine Structure... 

Some annulated pyrimidines react with ynamines via [2 + 2] cycloadducts to give 1,5-diazocine systems. The reaction strongly depends on the substitution pattern of the starting material and may also lead to 1,4-diazocine systems (see Section 1.3.1.2.).46,47... 

A series of annulated purines 114-6 have been synthesised as potential inhibitors of xanthine oxidase but, in general, they showed poor activity and the simple pyrimidines 117 were more effective in vitro < 96MI06 96CA(125)86586 96JMC2529 >. 

The pyrrolo[2,3-c/]pyrimidine anticancer agent is prepared utilizing, as a key sequence, Michael condensation of 2,6-diamino-4(.37/)-pyrimidinone with nitroalkenes, followed by the Nef reaction that leads to the annulated pyrrole ring (Eq. 10.67).98... 

Synthesis of the annulated thicno[3, 2 5,6]pyndo[4,3-z/]pynmidinoncs 74 and 75 involves the formation of the outer six-membered (pyrimidine) ring via a carbodiimide (Scheme 23) <2006HCA1337>. 

As with other series involving the annulation of a pyrimidine ring onto a five-membered ring, the usual requirement is to have two adjacent functional groups, one of which is an amine. The use of a cyano group as the other functional group occupies the majority of examples in such syntheses. Therefore, it is not surprising that this situation holds in the syntheses of pyrrolo[2,3-,y pyrimidines from pyrroles. 

When an amino group is adjacent to a carboxamide group, annulation usually leads to a pyrrolo[2,3-r/ pyrimidin-4-one 164. Such is the case when 163 is allowed to react with aliphatic carboxylic esters (Equation 61) <1996H(42)691>. 

There is one example of annulation of a pyrimidine ring to a saturated thiophene ring. Ketone 477 is condensed with. J-ethylthiourea HBr at room temperature in water over 18 h. The product is the reduced thienopyrimidine 478 (Equation 179) <1994NN1 B5>. 

A vigorous reaction occurs when 1,2,5-thia- and selena-diazole A -oxides annulated onto pyrimidine rings are treated with 10-30% hydrogen peroxide resulting in the formation of 6-amino-5-nitrouracils (Scheme 25) <2000CHE1359>. 

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>. 

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