Imidazo pyridines, direct arylations

Direct C-H arylation of imidazo[l, 2-pyridines with aryl bromides is possible with a Pd—Fc304 catalyst, which can be recovered magnetically and reused (Scheme 32) (13T5660).The reaction proceeds regioselectively at C-3. 

An efficient and simple tandem protocol for the synthesis of 1,2,3-triazole-fused imidazo-[l,2-a]pyridines was reported in 2013. The reactions followed a copper-catalyzed tandem azide-allq ne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation sequence and showed high generality and functional group tolerance. Good yields (59-77%) of 1,2,3-triazole-fused imidazo[l,2-a]pyridines were produced in a single step (Scheme 3.7). 

Direct Arylation of Imidazo[l,5-a]pyridines. The title compound has demonstrated excellent catalytic activity for the arylation of various itnidazo[l,5-a]pyridines with aryl iodides at the C-3 or C-1 positions. Initially, 3-(pyridin-2-yl)imidazo[l,5-a]pyridine 1 was arylated at the C-1 position in the presence of catalytic Pd(phen)2(PFe)2 and 2 equiv CS2CO3 in DMA at 150 °C (eq 1). Then, similar reaction conditions were applied to the C-1 arylation of unsubstituted imidazo[l,5-a]pyridine 2 (eq 2). A variety of aryl iodides were tolerated in the latter transformation. A one-pot, sequential arylation with 4-iodoanisole and 4-iodobenzotrifluoride, respectively, was successful in 61% yield. ... 

Direct arylation of imidazo[l,2-a]pyridines with arylhalides using [RuCl2(p-cymene)]2/Cs2C03 catalyst was explored by Yi and co-workers [(Eq. 25)] [96]. Arylation took place only at the imidazole C-H bond and arylated products at C-3 position were isolated in higher yields with aryliodides (80-93%) than with arylbromides (70-86%). 

The palladium-catalysed reaction of the pyrazolo-pyrimidine derivative (141) with 3-bromotoluene may result in arylation at the 3-position in the pyrazole ring or at an sp hybridized site in the 7-methyl side-chain depending on the base and ligands used. After initial insertion of the palladium catalyst into the aryl halide bond, palladation of (141) occurs by a concerted metalation-deprotonation pathway and is followed by reductive elimination. Concerted metalation-deprotonation is also likely in the palladium-acetate-catalysed reaction of imidazo[l,2-a]pyridines with aryl bromides to give 3-substituted derivatives such as (142). A careful mechanistic study of the arylation of pyridine A-oxide by bromotoluene, catalysed by palladium acetate and t-butylphosphine, has shown that direct reactions of an aryl palladium complex with... 

Thiophenes and benzothiophenes were used by Ke, Liu, and coworkers to evaluate the efficacy of a group of a-hydroxyimine palladium complexes in direct cross-coupling reactions with aryl and heteroaryl bromides such as 4-bromobenzonitrile (47), 4-bromoanisole (48), and 5-bromopyrimidine (49) (33 examples 50—97% yield) (2015OM4881). In particular, complex 50 operated most efficiently under aerobic conditions and with low catalyst loading (0.55 mol%). This success prompted further exploration of cross-coupling reactions with other heteroaryls such as furans, thiazoles, imidazo[l,2-a]pyridine, and triazoles (19 examples 57—96% yield). 

Kim and Lee demonstrated the use of magnetically recoverable, bimetallic Pd-Fc304 nanocrystals at 1 mol% Pd loading in the direct C-3 regioselective arylation of imidazo[l,2-a]pyridine (Scheme 7). ° The catalyst could be recycled 10 times without loss of catalytic activity. 

Wang, Ji, and coworkers developed a CuI/BF3-Et20/02 system for the synthesis of heteroaromatic imidazo[l,2- ]pyridines from ketones with 2-aminopyridines (Scheme 8.61). The C(sp )-H bonds of ketones are activated under these oxidation conditions. A total of four hydrogen atoms are removed, and two new C-N bonds are formed in one step to construct the imidazo[l,2- ] pyridines [103]. Hajra et al. developed a Cu(0Ac)2-H20-catalyzed direct oxidative cyclization via C-H amination between 2-aminopyridines and methyl aryl/heteroaryl ketones... 

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