Imidazo pyrimidines formation

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. 

A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles 101 via the sequential formation of imidazo[l,2-a]pyrimidinium salts from readily available 2-aminopyrimidines 99 and a-bromocarbonyl compounds 100, followed by opening of the pyrimidine ring with hydrazine <06OL5781>. A... 

Later Parchinsky et al. [131] showed that Groebke reaction promoted by ammonium chloride as mild catalyst, often employing the Ugi-reaction, in the non-nucleophilic aprotic solvent (e.g., toluene) led to the formation of exclusively one product of the reaction - 3-aIkylamino-substimted imidazo[l,2-a]pyrimidines, while the formation of unwanted side-products was excepted in this method. 

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 with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

The formation of imidazo[l,2-c]pyrimidines (171) via a ring closure of 2-(2-sulfon-ylimino-1,2-dihydro-l-pyrimidinyl)acetamides (170) has been studied using DFT methods, which revealed the requirement for Brpnsted acid catalysis.220... 

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]. 

The imino-amine (51.6) reacts at room temperature with aldehydes or ketones with the formation of purines. The products obtained from aldehydes are slowly oxidized (by loss of two hydrogen atoms from the pyrimidine ring) at room temperature, but the ketone-derived purines are stable and are accompanied by smaller amounts of an imidazo[l,S-c]imidazoIe. During cyclization, the nitrile group is converted into a carboxamide. Pentane-2,4-dione, 2-furfuraldehyde and but-2-enal give the fully aromatized purine as the main or only product isolated (in 38-49% yield). Stirring an imino-nitrile for several hours or heating it for a few minutes with an anhydride converts it into a fused pyrimidine. 

A rapid one-pot synthesis of imidazo[l,2-a]pyridines, pyrazines and pyrimidines was described in 1999 by Varma and Kumar, who used recyclable montmorillonite clay Kio under solvent-free conditions with microwave irradiation (Scheme 10.114) [223]. The whole process, formation of the iminium ion by condensation of the aldehyde with an amine (1 min at 900 W in a domestic oven) then nucleophilic attack of the isocyanide (1 min at 450 W and 1 min cooling) took 3 min and gave the pure products in yields ranging from 56 to 88%. 

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