Nothing to sm(Ir)k at: Under appropriate reaction conditions, iridium hydride catalysts promote the isomerization of primary allylic alcohols. The best catalysts, like (R)-1 (P green, O red, N blue, Ir yellow), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.

Undoubtedly, the catalytic asymmetric isomerization of allylic amines into enamines stands out as one of the most accomplished and well-studied reaction in asymmetric catalysis as illustrated by its industrial application. [1,2] In contrast, the related asymmetric isomerization of primary allylic alcohols to the corresponding aldehydes still constitutes a significant challenge in organic synthesis. [2] Successful examples of highly active and selective catalysts for this transformation remain rare and rely almost solely on the use of chiral rhodium complexes. [3] Furthermore, high catalyst loadings, elevated temperatures, long reaction times, poor catalyst accessibility, and limited substrate scope have prevented widespread use of this method. We have recently shown that the hydrogenation catalyst [Ir(PCy 3 )(pyridine)(cod)]BAr F 4 1 (Cy = cyclohexyl, cod = 1,5-cyclooctadiene, BAr F 4 = tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate) promoted exclusively the isomerization of primary allylic alcohols under appropriate experimental conditions (Scheme 1). [4] Very low loadings of this analogue of Crabtrees catalyst were used to quantitatively isomerize a wide range of substrates at room temperature with appreciable reaction rates. On one hand, the mild reaction conditions appeared well-suited for studying the asymmetric version of the reaction. On the other hand, any variation of the electronic and steric requirements of 1 induced a complete loss of catalytic activity, suggesting this might impose severe constraints on the design of related chiral complexes. Herein, we report the identification of a highly active and selective iridium catalyst for the asymmetric isomerization of primary allylic alcohols into the corresponding chiral aldehydes.Initial investigations began with a survey of known chiral (P,N) iridium complexes which have been shown to be highly active and selective catalysts in the asymmetric hydrogenation of olefins (2-6 a, Figure 1). [5][6] Reactions were carried out on the model substrate 7 in THF at room temperature for 18 hours using 5 mol % of the precatalyst (Table 1, entries 1-5). The iridium complexes were activated by slowly bubbling hydrogen directly through the solution for 5 minutes. To favor isomerization and to avoid competing hydrogenation, the substrate was added only after complete extrusion of excess hydrogen by degassing the solution. Whereas complexes 2-4 did not display any catalytic activity, the pyridyl/phosphinite catalyst 5 afforded 19 % of the aldehyde 8, albeit in a nearly Scheme 1. Iridium-catalyzed isomerization of primary allylic alcohols. Figure 1. Scope of iridium catalysts investigated. Cy = cyclohexyl, Ad = adamantyl.

An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air-stable complexes relied on the preliminary mechanistic information available, and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation. Sterically unbiased chiral aldehydes that were not accessible previously have been obtained with high levels of enantioselectivity, thus validating the initial hypothesis regarding the selected ligand-design elements. A rationale for the high enantioselectivities achieved in most cases is also presented.

Abstract:The catalytic asymmetric isomerization of allylic amines to enamines stands out as one of the most accomplished and well-studied reactions in asymmetric catalysis as illustrated by its industrial application. In contrast, the related asymmetric isomerization of primary allylic alcohols to the corresponding aldehydes still constitutes a significant challenge in organic synthesis. Herein, we show that under appropriate reaction conditions, iridium-hydride catalysts promote the isomerization of primary allylic alcohols under very mild reaction conditions. The best catalysts deliver the desired chiral aldehydes with unprecedented levels of enantioselectivity and good yields. Mechanistic hypotheses have been drawn based on preliminary investigations.

Aldehydes Q 0320Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols. -Highly active and selective iridium catalysts for the asymmetric isomerization of primary allylic alcohols to chiral aldehydes are identified. Mechanistic hypotheses are developed on the basis of preliminary investigations. -(MANTILLI, L.; GERARD, D.; TORCHE, S.; BESNARD, C.; MAZET*, C.; Angew. Chem., Int. Ed. 48 (2009) 28, 5143-5147; Dep. Chim. Org., Univ. Geneve, CH-1211 Geneve 4, Switz.; Eng.) -Bartels 45-081