3-Substituted imidazo pyrimidines

The tautomeric equilibrium in variously substituted imidazo- 53 (93KGS1353) and triazolo-fused pyrimidines 54 (88KGS1489 91KGS1539 93KGS1353 93KGS1357) has been comprehensively studied by Desenko and colleagues, whose results were summarized in a special review (95KGS147). 

The mass spectrum of formycin (54a) showed M+ and MH+ ions due to the protonated base moiety of the molecule <78MI 712-01). The mass spectra of 5-substituted oxazolo[4,5-d]pyrimidines (78) proceeds via loss of the C-5 substituent <82KGS1255>. The main fragmentations of substituted imidazo[4,5-/>]pyrazines (79) <89KGS532> and oxazolo[5,4- have been determined. 

The microwave assisted hydrazinolysis of substituted imidazo[l,2-a]pyrimidine (x) gave way to mono (xi) and disubstituted (xii) 2-amino-IH-imidazoles [14]. 

The parent compound is a moderately weak base (pK 3.59), comparable with substituted aminopyrazines. The 2,3-dihydro compound 5, however, is very much stronger (pK 9.32). The base-weakening effect of the nitrogen in the 7-position is clearly demonstrated by comparison with the dihydroimidazopyridine (7). The latter compound has a pKa of 12.51 units. Similar effects are found in the imidazopyridazine and imidazo-pyrimidine series. No evidence has been found for covalent hydration in any of the triazaindenes studied. ... 

Substituted imidazo[l,5-a]pyrimidines 190 suffer a ring transformation to give the corresponding 4-hydroxy-5-methyl-IbPs 187-189 when heated in PPA. However, compounds 187-189 can also be obtained from the more accessible appropriately substituted pyrimidine-4-(3H)-ones 191 and PPA (82JOC167). 

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... 

Substituted imidazo[l,2-typical example of this versatile reaction, (40) reacted with 2-aminopyridine (39) to give the imidazopyridine (43) in 86% yield via intermediates (41) and (42) (Scheme 12). 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

The isomeric imidazo[l,5-a]pyrimidine (161) gave the 1,3-dibromo derivative when exposed to bromine or NBS (72BSF2481). Iodination of benzimidazo[2,l- >]quinazolin-12(5 or 6//)-ones was accomplished by boiling them with bromine in the presence of sodium or potassium iodide. Substitution took place at the 9-position in the benzimidazo moiety (91MI3). 

An efficient one-pot synthesis of some novel azolo[l,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[l,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of a-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal . 

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... 

A number of pyrimidines fused to five- or six-membered rings have been degraded to substituted pyrimidines and many of these reactions have been summarized elsewhere <1994HC(52)1>. A recent example used Raney nickel to remove a sulfur atom from the imidazo[4, 5 4,5]thieno[3,2-r/]pyrimidinone 966 <20010L3209, 2002JOC3365>. 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

Reactions with methylphenylcyclopropenone (154) provided an opportunity to compare the reactivities of the two different C—CO bonds. The reaction of 2-aminopyridines with methylphenylcyclopropenone (154) proceeded more slowly than with the diphenyl analog (153). In ether, formation of the ds-2-oxopyrido[l,2-a]pyrimidines (158 R1 = Me) and/or the imidazo[l,2-c<]pyridines (162) was observed, indicating that the cycloaddition proceeds via cleavage of the PhC—CO bond. The methyl-substituted trans-2-oxopyrido[l,2-a]pyrimidine (160 R1 = Me) was only detected in the reaction mixture of 2-amino-3-methylpyridine, where the H NMR spectrum exhibited signals assigned to 160 (R1 = Me, R = 9-Me). The compound was not isolated. The imidazo[l,2-a]pyridines (162) readily hydrolyzed to the acids (163), work-up therefore leading mainly to isolation of the acids. 

The reaction of 4,5-diphenylimidazole-1,2-diamine 152 with substituted chalcones 153 in dimethylformamide for 1 h proceeds with the elimination of the hydrazine amino group, oxidation and formation of the appropriate 2,3,5,7-tetraaryl-5,6-dihydroimidazo[l,2-a]pyrimidin-6-ol 154 in low or moderate yields [126] (Scheme 4.47). The treatment of the same diamine with dibromo derivatives 155 produced imidazo[l,2-a]pyrimidines 156 [126]. 

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