Larry Yet

Palladium‐catalyzed Suzuki‐Miyaura and Buchwald‐Hartwig cross‐coupling reactions have become indispensable tools in the synthesis of otherwise inaccessible compounds because of the efficient, catalytic nature of these styles of reactions. The development of novel monophosphine ligands to achieve the cross‐coupling of substrates that are generally unreactive under standard conditions has developed into an extremely important area of research in the field of organometallic chemistry. Herein, we show the use of an imidazopyridine monophosphine ligand JagPhos I in the Suzuki‐Miyaura palladium‐catalyzed cross‐coupling reaction to deliver sterically‐hindered biaryls and unsymmetrical biheterocycles. We also report the scope and limitations of imidazopyridine monophosphine ligand JagPhos II in the Buchwald‐Hartwig amination reactions of (hetero)aryl halides with anilines, secondary amines, and primary amines.

Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes and were evaluated in the Suzuki–Miyaura cross-coupling reactions.

3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald–Hartwig amination compounds are presented with these ligands.

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