Copper- and Palladium-Catalyzed Amidation Reactions for the Synthesis of Substituted Imidazo[4,5-c]pyridines

Abstract

Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…Hindered di- tert -butylphosphino biaryl ligands, such as L20 and L21 , in combination with Pd 2 (dba) 3 ·CHCl 3 and K 2 CO 3 were optimal, providing the fused heterocycles in 60–99% yield. 282 Jui and Buchwald disclosed the regio- and chemocontrolled synthesis of N -arylbenzimidazoles, which involved two consecutive C–N bond-formation reactions with readily available starting materials ( Scheme 80 b). 281 Initial Pd-catalyzed aniline N-arylation enabled in situ preparation of halo- or sulfonoxyaniline precursors 358a and 358b .…”

Metal‐Catalyzed Cross‐Coupling Reactions of Aminopyridines

“…Clark and co‐workers successfully arylated N ‐Boc‐protected 3‐amino‐4‐chloropyridine 170 with various aryl halides 171 to obtain products 172 in good to high yields 116. The group used CuI and the ligand (±)‐ trans ‐1,2‐diaminocyclohexane, which was shown to give the best results (Scheme ).…”

“… Ullmann condensation of N ‐Boc‐3‐amino‐4‐chloropyridines ( 170 ) with aryl halides 171 . [a] (±)‐ trans ‐1,2‐diaminocyclohexane; [b] yield over two steps (arylation and deprotection) for coupling with 4‐bromoanisole and 3,5‐dimethylbromobenzene 116…”

An Improved Synthesis of Imidazo[4,5‐b]pyridines and Imidazo[4,5‐b]pyrazines by Palladium Catalyzed Amidation using Xantphos in a 1,4‐Dioxane:tert‐Amyl Alcohol Solvent System

“…[12] This method of preparing imidazoA C H T U N G T R E N N U N G [4,5-b]pyridines (IP b ) and their derivatives represents a useful protocol for obtaining these sought-after compounds. Due to our ongoing interest in this class of heterocycles, [12][13] further improvements were desired for IP b synthesis.…”

“…While excellent conversion was obtained in a 10:1 mixture, pyridine 3 was the primary product (entries 10 and 11). Switching to 1,4-dioxane, which demonstrated promise as the sole solvent, gave positive results (entries [12][13][14]. In a 1:1 1,4-dioxane:tAmOH mixture using XantPhos, little change was observed from solely 1,4-dioxane.…”