Heterocyclics imidazo pyrimidines

The formal derivation of the analogs, described in the foregoing, represents, from the point of view of systematic organic chemistry, a shift to the derivatives of other heterocyclic systems. In the case of pyrimidine aza analogs we arc dealing with derivatives of symmetrical or asymmetrical triazine in the case of purine aza analogs, the derivatives produced are those of imidazo[4,5]-i -triazine and z -triazolo [4,5-d] pyrimidine. 

Paudler and Helmick515 have measured half-lives for deuteration of some heterocycles by deuterated sulphuric acid at 100 °C. The equivalent first-order rate coefficients (lO ) are as follows imidazo[l, 2-a]pyridine, 427(3-H) imidazo[l,2-a]pyridine-N-methiodide, 62(3-H) imidazo[l,2-a]pyrimidine, 123-(3-H) imidazo[l,2-a]pyrimidine-N-methiodide, < 6.4 (3-H, 5-H) 1,2,4-tri-azolo [1,5-a]pyridimidine, 128(5-H) 1,2,4-triazolo [1,5-a]pyrimidine-N-methiodide, 11.7 (5-H). The lower reactivity in each case of the corresponding methiodides shows that the bases react as such and not as the conjugate acids. 

Kinetic studies of base-catalysed hydrogen exchange of heterocyclic compounds have been carried out. Paudler and Helmick515 measured second-order rate coefficients for deuteration of derivatives of imidazo[l,2-a]pyridine(XXXIII), imidazo[l,2-a]pyrimidine(XXXIV), and 1,2,4-triazolo[1,5-a]pyrimidine(XXXV)... 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

Reaction of pyrido[ 1,2- pyrazin-4-one 304 with methyl cyanoacetate, cyanamide, and JI-oxo nitriles in AcOH at 70 °C gave imidazo[ l,2- ] pyridine 331, imidazo[l,2- ]-pyrimidine 332, and tetracyclic heterocycles 333, respectively <1996JHC639>. 

A general scheme, which constructs the thiazolo variety of various bridgehead heterocycles, is basically an extension of HTIB-mediated modification of Hantzsch thiazole synthesis (Scheme 51). Thus, synthesis of 3-substituted-5,6-dihydro-4//-imidazo[2,l-b]thiazoles 202 has been achieved by the treatment of a-tosyloxyacetophenones (generated by the oxidation of 51 with HTIB) with ethylenethiourea [92JCS(P1)707], The method is successfully extended to synthesize 4,5,6,7-tetrahydrothiazolo[3,2-a]pyrimidines 203... 

Purines (purine = 7//-imidazo [4,5-rf]pyrimidine, C5H4N4) and pteridines (pteridine = pyrazino [2,3-d]pyrimidine, C6FI4N4) are compounds consisting of two fused A-heterocyclic rings. Adenine and guanine are important purines. They are used, for example, as building blocks for nucleotides (see discussion below). Folic acid (a vitamin), methopterin, and methotrexate are typical pteridines. 

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 pKa value for 2,3,6,7,8,9-hexahydro-4//-pyrimido[l,2-a]pyrimidine has been determined to be 11.22 using potentiometric titration methods. This value is nearly identical for the pKa values reported for the corresponding imidazo[l,2-a]pyrimidine and imidazo-[ 1,2-a ][ 1,3]diazepine heterocycles (62CJC1160). 

Heterocyclic chemistry was facilitated by microwave-expedited solvent-free chemistry utilizing mineral supported reagents [65]. The scope now includes parallel synthesis [66]. A representative multi-component condensation to create a library of imidazo[l,2-a]pyridines, imidazo[l,2-a]pyrazines and imidazo[ 1,2-a]pyrimidines is depicted in Scheme 12 [67]. 

Reaction of pyrido[l,2-a]pyrazin-4-one 145 with methyl cyanoacetate, cyanamide, and /3-oxo nitriles in AcOH at 70°C gave imidazo[l,2-a]pyridine 147, imidazo[l,2-u]pyrimidine 148, and tetracyclic heterocycles 149, respectively (96JHC639). 

Wang S-L, Hao W-J, Tu S-J et al (2009) Poly(ethyleneglycol) a versatile and recyclable reaction medium in gaining access to Benzo[4, 5]imidazo[l, 2-a]pyrimidines under micro-wave heating. J Heterocycl Chem 46 664—668... 

Ohler, E., El-Badawi, M., and Zbiral, E., Dialkyl (l,2-epoxy-3-oxoalkyl)phosphonates as synthons for heterocyclic carbonyl compounds. Synthesis of acyl-substituted thiazoles, indolizines, imidazo[ 1,2-fii]pyridines and imidazo[l,2-fii]pyrimidines, Chem. Ber., 118, 4099, 1985. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Cumulative Index of Heterocyclic Systems Imidazo[l,2-a]pyrimidine (978)... 

Various flve-membered heterocycles can be prepared by inter- or intramolecular addition/cyclizations of appropriate nucleophiles with alkynyliodonium salts via alkylidene carbene intermediates [856, 978, 979]. The intermolecular variant of this cyclization has been employed in the synthesis of 3-substituted-5,6-dihydroimidazo[2,l-( ]thiazoles [997], 2-substituted imidazo[l,2-a]pyrimidines [998] and 2-substituted-imidazo[l,2-fl]pyridines [999]. In a representative example, 2-substituted imidazo[l,2-fl]pyridines 744 were synthesized in good yield by cyclocondensation of 2-aminopyridine (742) with alkynyl(phenyl)iodonium tosylates 743 under mild conditions (Scheme 3.293) [999]. The mechanism of this cyclization involves... 

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