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Synthesis of imidazo[1,5-a]pyridines

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Copper(I) catalysis enables a direct transannulation of N-heteroaryl aldehydes or ketones with alkylamines via Csp3-H amination in the presence of oxygen as the sole oxidant. This transformation provides a rapid and concise access to multifunctional imidazo[1,5-a]pyridines.
M. Li, Y. Xie, Y. Ye, Y. Zou, H. Jiang, W. Zeng, Org. Lett., 2014, 16, 6232-6235.


A copper/iodine cocatalyzed decarboxylative cyclization of α-amino acids with either 2-benzoylpyridines or 2-benzoylquinolines provides 1,3-disubstituted imidazo[1,5-a]pyridines and 1,3-disubstituted imidazo[1,5-a]quinolines in excellent yields.
H. Wang, W. Xu, L. Xin, W. Liu, Z. Wang, K. Xu, J. Org. Chem., 2016, 81, 3681-3687.


A copper(II)-catalyzed tandem reaction between pyridine ketone and benzylamine proceeded via an efficient condensation-amination-oxidative dehydrogenation process, affording 1,3-diarylated imidazo[1,5-a]pyridines in excellent yields using clean O2 as an oxidant.
H. Wang, W. Xu, Z. Wang, L. Yu, K. Xu, J. Org. Chem., 2015, 80, 1856-1865.


An efficient three-component coupling reaction of substituted picolinaldehydes, amines, and formaldehyde produces imidazo[1,5-a]pyridinium ions in high yields under mild conditions, allowing the incorporation of diverse functionality and chiral substituents. Higher order condensations are also described that provide access to multidentate NHC ligands useful for a variety of applications.
J. T. Hutt, Z. D. Aron, Org. Lett., 2011, 13, 5256-5259.


An iron-catalyzed efficient C-H amination for the construction of imidazole-fused-ring systems can be conducted in anisole as green solvent with water as the only byproduct. The reaction provides Imidazo[1,5-a]pyridines, imidazo[5,1-b]oxazoles, imidazo[5,1-b]thiazoles, imidazo[1,5-a]pyrazines, and imidazo[1,5-a]imidazoles.
J. Peng, S. Li, J. Huang, Q. Meng, L. Wang, W. Xin, W. Li, W. Zhou, L. Zhang, J. Org. Chem., 2023, 88, 16581-16588.


A denitrogenative transannulation of pyridotriazoles with nitriles using BF3·Et2O as catalyst provides imidazo[1,5-a]pyridines. The combination of solvents (dichlorobenzene-dichloroethane) plays a crucial role in achieving quantitative yields of desired products under metal-free conditions.
A. Joshi, D. C. Mohan, S. Adimurthy, J. Org. Chem., 2016, 81, 9461-9469.


A metal-free sequential dual oxidative amination of C(sp3)-H bonds under ambient conditions affords imidazo[1,5-a]pyridines in very good yields. The reaction involves two oxidative C-N couplings and one oxidative dehydrogenation process with six hydrogen atoms removed.
Y. Yan, Y. Zhang, Z. Zha, Z. Wang, Org. Lett., 2013, 15, 2274-2277.


Heterocyclic benzylamines can be reacted with TFAA as trifluoromethylating reagent to provide imidazo-fused N-heterocycles. Alternatively, a two-step synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzyl (pseudo)halides using trifluoroacetamide as trifluoromethylating reagent proceeds via alkylation followed by dehydrative cyclization.
G. Schäfer, M. Ahmetovic, S. Abele, Org. Lett., 2017, 19, 6578-6581.