Imidazo pyridine, synthesis from

The position of methylation of 2-methylimidazo[l,2-a]pyridine (2) has been established as N-1 by an ambiguous synthesis of l,2-dimethylimidazo[l,2-o]pyridine (3) from (4) (65JHC331). This work was extended by others to protonation and to methylation of other imidazo[l,2-o]pyridines <66JOCl29S), and it verified earlier conjectures concerning the position of quaternatization (55CB1093,26CB2048, 64JCS4226). 

If, on the other hand, an amino group can be introduced ortho to the nitro group, reduction of 202 or 203 makes available the starting materials for fused heterocycles. One example is the synthesis of imidazo[4,5-c]pyridines 205 from diamino pyridines such as 204. 

The synthesis of imidazo[l,2- ]pyridine derivatives from simple substituted pyridines is also developed recently. Fu et al. reported an efficient Cul-catalyzed aerobic oxidative C-H functionalization of substituted pyridines with N-(alkylidene)-4//-l,2,4-triazol-4-ammes leading to imidazo[l,2- ] pyridine derivatives in moderate to good yields using O2 (1 atm) as the oxidant (Scheme 8.63). The reaction proceeds by the cleavage of the N-N bond in the N-(alkylidene)-4//-l,2,4-triazol-4-amines and activation of an aryl C(sp )-H bond in the substituted pyridines [108]. 

Jiang and coworkers developed a highly efficient synthesis of imidazo[l,2-a]pyridine derivatives from pyridine with ketone oxime esters using Cul catalyst (Scheme 8.64). The C(sp )-H bond of ketone oxime esters and C(sp )-H bond pyridinium were activated in this transformation. Air is used as the sole oxidant and HOAc and H2O are the only green by-products [109]. 

Scheme 8.64 Synthesis of imidazo[l,2-a]pyridine derivatives from pyridine with ketone oxime esters.

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

Imidazo[4,5- ]pyridines can be synthesized by a large number of routes, from which condensation of the appropriate carboxylic acid or acid chloride with the corresponding diaminopyridine, sometimes requiring cyclization of the intermediate amide with strong acid, appears to be the most widely used method <1996CHEC-II(7)283>. A recent example has been reported for the synthesis of pyridoimidazole C-nucleosides, and although the yield in this particular case was low, no epimerization at the C-1 stereocenter was observed (Equation 29) <2003TL5807>. 

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... 

Rearrangement of alkoxycarbonyl imidazole acryl azides in diphenyl ether at high temperatures afforded imidazo[l,5-c]pyrimidinone or imidazo[4,5-c]pyridinone derivatives <02TL5879>. Efficient synthesis of imidazopyridodiazepines from peri annulation in imidazo[l,2-a]pyridine has been described <02TL9119>. A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[l, 2-a]pyridines has been published <02TL9051>. Novel 2,3-dihydroimidazo[2,l-h][l,3]oxazoles were prepared from intramolecular nucleophilic i/wo-substitution of 2-alkylsulfonylimidazoles <02S2691>. 4,4 -Bi-l//-imidazol-2-ones were efficiently synthesized from 5-amino-ot-imino-1 //-imidazole-4-acetonitriles and isocyanates <02JOC5546>. 

Solid-supported a-bromoketone 148 was condensed with various 2-aminopyridines or 2-aminopyrimidine derivatives to give imidazo[l,2-a]pyridines or imidazo[l,2-fl]pyriniidine derivatives 149 after cleavage with acid <03TL6265>. An abnormal aza-Wittig reaction on solid-phase parallel synthesis of 3-aryl-2,4-dioxo-l,3,5-triazino[l,2-a]benzimidazoles was observed <03TL3705>. New spiroimidazolidinone derivatives 151 were prepared Irom SynPhase lanterns from dipeptides anchored on the solid-supports 150 <03JCO356>. 

The 3-substituted-imidazo[l,5-a]pyridines (ix) were conveniently synthesized in a two step protocol from picolinic esters (vii) via the formation of picolinamides (viii) under microwave radiation by Aravapalli et al. [12]. Zhu et al. [13] used the ionic liquid 1,2,3-trimethyl-imidazole tetrafluroborate for the synthesis of ZnOHF nanabelts (NBs). 

In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1/-/-imidazo[4,5- i]pyridine (PHIP), a mutagenic compound isolated from cooked beef, and its 3-methyl isomer have been accomplished. The synthesis of PHIP began with the commercially available 3-phenylpyridine, which was aminated at the 6-position with sodium amide in toluene by the Chichibabin reaction in 58% yield. 

Other examples of scale-up involved a triphenylphosphine-free one-pot Wittig olefination, a one-step three-component synthesis of imidazo annulated pyridine and a metal-catalyzed Suzuki coupling. Kappe and co-workers also recently transferred conditions for reactions originally performed on a small scale with a mono-modal system, to scale-up by parallel synthesis in a multimodal batch reactor [13]. Typically, the scale-up was 100-fold, from 1 mmol examples included Biginelli condensations, Heck and Negishi couplings, and Diels-Alder cycloadditions with gaseous reactants. 

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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