Academia / Industry Collaborations towards the Functionalization of Aryl Azoles.

Aryl azoles can be found in numerous active pharmaceutical ingredients (APIs). Milvexian is a Factor Xia inhibitor currently in phase III for the treatment of thrombotic events containing an ortho-substituted 1-aryl-1H-1,2,3-triazole moiety. During the process development of Milvexian, we assessed multiple approaches for the preparation of 4-chloro-1,2,3-triazole, intermediate 1.

Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets.

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases.

Iridium-imine and -amine complexes relevant to the (S)-metolachlor process: structures, exchange kinetics, and C-H activation by Iri causing racemization.

Iridium complexes of DMA-imine [2,6-dimethylphenyl-1'-methyl-2'-methoxyethylimine, 1 a) and (R)-DMA-amine [(1'R)-2,6-dimethylphenyl-1'-methyl-2'-methoxyethylamine, 2 a] that are relevant to the catalytic imine hydrogenation step of the Syngenta (S)-Metolachlor process were synthesized: metathetical exchange of [Ir2Cl2(cod)2] (cod=1,5-cyclooctadiene) with [Ag(1 a)2]BF4 and [Ag((R)-2 a)2]BF4 afforded [Ir(cod)(kappa2- -1 a)]BF4 (11) and [Ir(cod)(kappa2-(R)-2 a)]BF4 ((R)-19)), respectively. These complexes were then used in stopped-flow experiments to study the displacement of amine 2 a from complex 19 by imine 1 a to form the imine complex 11, thus modeling the product/substrate exchange step in the catalytic cycle. The data suggest a two-step associative mechanism characterized by k1=(2.

Chiral iridium [corrected] xyliphos complexes for the catalytic imine hydrogenation leading to the metolachlor herbicide: isolation of catalyst-substrate adducts.

Iridium complexes relevant to the catalytic enantioselective hydrogenation of 2-methyl-6-ethylphenyl-1'-methyl-2'-methoxyethylimine (MEA-imine, 1) in the Syngenta Metolachlor (3) process were prepared and characterized. Reaction of the diphosphane (S)-1-[(R)-2-(diphenylphosphanyl)ferrocenyl]ethyldi(3,5-xylyl)phosphane ((S)-(R)-Xyliphos, (S)-(R)-4) with [Ir(2)(micro-Cl)(2)(cod)(2)] (cod=1,5-cyclooctadiene) afforded [Ir(Cl)(cod)[(S)-(R)-4]] (7), which reacted with AgBF(4) to form [Ir(cod)[(S)-(R)-4]]BF(4) (8). Complexes 7 and 8 reacted with iodide to yield [Ir(I)(cod)[(S)-(R)-4]] (9).

Bridging fluorides and hard/soft mismatch in d6 and d8 complexes: the case of [Tl(mu-F)3Ru(PPh3)3].

[RuCl2(PPh3)3] reacts with thallium(I) fluoride to give either [Tl(mu-F)3Ru(PPh3)3] (1) or [Tl(mu3-F)(mu2-Cl)2Ru2(mu2-Cl)(mu2-F)(PPh3)4] (2) depending on the excess of TlF used. Both 1 and 2 were fully characterized, including X-ray structure determinations. Complex 1 reacts with dihydrogen to form the known ruthenium hydride complex [Ru(H)2(H2)(PPh3)3] upon hydrogenolysis of the Ru-F bond.

Titanium-catalyzed stereoselective geminal heterodihalogenation of beta-ketoesters.

[reaction: see text] beta-Ketoesters can be effectively monofluorinated with F-TEDA using CpTiCl(3) as a catalyst. With the use of this catalyst, the extent of the competing difluorination does not reach 10%. [TiCl(2)(TADDOLato)] complexes catalyze the one-pot enantioselective heterodihalogenation of beta-ketoesters with F-TEDA and NCS to afford alpha-chloro-alpha-fluoro-beta-ketoesters in moderate to good yields.