2- imidazo pyridines, preparation

Palmer AM, Nettekoven U. Preparation of tricyclic imidazo-pyridines by asymmetric ketone hydrogenation in the presence of ruthenium phosphino-oxazoline catalyst. Tetrahedron Asymm. 2007 18(20) 2381-2385. 

Theoretical calculations have predicted that imidazo[l,2-a]pyrimidine (160) should be attacked at C-3 by electrophiles, although reactivity will be lower than in the corresponding imidazo[l,2-a]pyridines (see D,l,e) (74JHC1013). The 3-bromo derivative of 160 was formed when the parent was treated with NBS in chloroform (66JOC809). The usual transformation of oxo to chloro was responsible for the preparation of 5-chloroimidazo[ 1,2-a]pyrimidine [66LA(699) 127]. 

Irnidazo[ 1,2-tf ]py ridines were covered in CHEC(1984) <1984CHEC(6)613> along with others imidazoles fused to six-membered rings and they were reviewed together with imidazo[l,5- ]pyridines in CHEC-II(1996) <1996CHEC-II(8)249>. The chemical literature on this heterocycle is very abundant, due to its easy synthesis (most of the preparations use readily available 2-aminopyridines) and to the very broad spectrum of bioactivities displayed by many derivatives. A simple Beilstein search on the fully conjugated heterocycle (free sites everywhere) disclosed ca. 3000 hits for the past decade. Therefore, this chapter cannot be exhaustive in view of space limitations, but will mainly focus on the original synthetic methods that have appeared in the last decade. 

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>. 

The chelate effect also favors oxidative addition of the C2—H bonds of imidazo-lium salts because it provides stabilized complexes. The reaction of a pyridine-imidazolium salt with [lrCl(cod)]2 yields the oxidative addition product, even in the absence of a base (Scheme 3.9), thus confirming that the oxidative addition of an imidazolium salt should be considered as a vahd process for the preparation of NHC—M—H complexes [24]. 

The imidazo[4,5-. ]pyridines 71 and 72 have been prepared and a significant difference in melting points was observed compound 71 decomposed at 214°C, the imine 72 at 122 °C, and the cyclized product 73 at 150 °G <2001S2393>. 

Imidazo[4,5- ]pyridines 117 <2003BML2485>, 118 <2004BML3165>, 119 <2005BML2129>, and 120 <2003BML289> have been prepared from the corresponding diaminopyridine and the appropriate trialkyl ortho-formate or, in the case of 120, triethyl orthopropionate. However, in each case, the authors fail to report product yields. 

Imidazo[4,5- ]pyridines have also been prepared through cyclization of the requisite diamine with ethyl acetimi-date hydrochloride (Equation 43) <1996JME487> or by cyclization with 4-methylsulfonylbenzoyl chloride (Equation 44) <2001JME350>. Further examples of this type can be found in <1996CHEC-II(7)283>. 

Antiviral 2,5-disubstituted imidazo[4,5-f]pyridines have been reported for the treatment of hepatitis C <2007BML390, 2007BML5111>. A method for the preparation of substituted l//-imidazo[4,5-f]pyridines as immune response modifiers has been reported <2007W0092641>. 6-Phenyl-l//-imidazo[4,5-f]pyridine-4-carbo-nitrile derivatives have been reported to act as cathepsin K and S inhibitors <2007USP179138>. Imidazo[4,5-4pyridine derivatives have also been prepared as C3A receptor antagonists <2007W0034277>. 

Bohme and Weisel obtained 4-oxo-4//-pyrid o [ 1,2-a] pyrimidine (59) from 2-aminopyridine and ethyl 2-chloroacetoacetate. The yield was 10% in toluene in the presence of p-toluenesulfonic acid, 30% in acetic acid, and 59% in polyphosphoric acid. The triethylamine-catalyzed reaction in benzene led to the imidazo[l,2-a]pyridine 58.64 4-Oxo-4//-pyrido[ 1,2-a]-pyrimidine (59) was also prepared from 2-aminopyridine and 2-chloro-3-oxobutyronitrile.67... 

A number of other five-membered ring nitrogen heterocycles have been prepared by cyclative cleavage. The illustrative examples (Fig. 4) depict the synthesis of pyrazolones,12 succinimides and phthalimides,13 pyrrolo[3,4-h] pyridines,14 2-aminoimidazolones,15 imidazo[4,5-fr]pyridin-2-ones,16 and l,2,4-triazoline-3,5-diones.17... 

Imidazolium ligands, in Rh complexes, 7, 126 Imidazolium salts iridium binding, 7, 349 in silver(I) carbene synthesis, 2, 206 Imidazol-2-ylidene carbenes, with tungsten carbonyls, 5, 678 (Imidazol-2-ylidene)gold(I) complexes, preparation, 2, 289 Imidazopyridine, in trinuclear Ru and Os clusters, 6, 727 Imidazo[l,2-a]-pyridines, iodo-substituted, in Grignard reagent preparation, 9, 37—38 Imido alkyl complexes, with tantalum, 5, 118—120 Imido-amido half-sandwich compounds, with tantalum, 5,183 /13-Imido clusters, with trinuclear Ru clusters, 6, 733 Imido complexes with bis-Gp Ti, 4, 579 with monoalkyl Ti(IV), 4, 336 with mono-Gp Ti(IV), 4, 419 with Ru half-sandwiches, 6, 519—520 with tantalum, 5, 110 with titanium(IV) dialkyls, 4, 352 with titanocenes, 4, 566 with tungsten... 

Aminopyridines are useful substrates for the preparation of fused heterocycles. Imidazo[ 1,2- ]pyridines may be prepared in moderate to good yield by three-component coupling of 2-aminopyridine, aldehydes and isocyanides <1998S661>. The reaction proceeds by nucleophilic attack of the isocyanide onto an iminium species formed by condensation of 2-aminopyridine with the aldehyde component followed by 1,3-FI shift. For example, 2-aminopyridine reacts with benzylisocyanide and 2-hydroxyacetaldehyde in the presence of 2equiv of glacial acetic acid in methanol to give iiuidazo[2- ]pyridine 84 in 44% yield (Equation 57). 

Imidazo[2- ]pyridines bound to solid supports via acid or base labile linkers can be prepared by reaction of resin-bound a-bromoketones with 2-aminopyridines <2003TL6265>. 5-Azaindoles may be prepared by cyclization of ortho-alkynyl aminopyridines in moderate to high yield in the presence of catalytic amounts of Cul <1998TL5159> (Equation 58). 

A study on the preparation of a relatively large number of imidazo[4,5-fr]pyridine-2-thiones and imidazo[4,5-c]pyridine-2-thiones demonstrates that the solubility of these compounds is poor in most solvents <88CHE653>. 

Imidazo[4,5-6]pyridine 4-oxides (122) have been reported to be easily prepared in excellent yield from imidazo[4,5-/)]pyridines (121) by oxidation with either hydrogen peroxide in acetic acid or MCPBA (Equation (2)) <65JOC4066,82JHC513). 

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