Indium-Mediated Asymmetric Barbier-Type Propargylations: Additions to Aldehydes and Ketones and Mechanistic Investigation of the Organoindium Reagents

Abstract

We report a simple, efficient, and general method for the indium-mediated enantioselective propargylation of aromatic and aliphatic aldehydes under Barbier-type conditions in a one-pot synthesis affording the corresponding chiral alcohol products in very good yield (up to 90%) and enantiomeric excess (up to 95%). The extension of this methodology to ketones demonstrated the need for electrophilic ketones more reactive than acetophenone as the reaction would not proceed with just acetophenone. Using the Lewis acid indium triflate [In(OTf)(3)] induced regioselective formation of the corresponding homoallenic alcohol product from acetophenone. However, this methodology demonstrated excellent chemoselectivity in formation of only the corresponding secondary homopropargylic alcohol product in the presence of a ketone functionality. Investigation of the organoindium intermediates under our reaction conditions shows the formation of allenylindium species, and we suggest that these species contain an indium(III) center. In addition, we have observed the presence of a shiny, indium(0) nugget throughout the reaction, irrespective of the stoichiometry, indicating disproportionation of indium halide byproduct formed during the reaction.

An Approach to the Bicyclic C‐5–C‐17/C‐19–C‐20 (BC) Portion of Neoclerodane Diterpenes by Intramolecular Diels–Alder Reaction

“…A highly diastereoselective IMDA reaction of a sterically congested 1,3‐diene served as the key step. Since the preparation of 10 in enantiomerically pure form is known,6a,30 the transition to an enantioselective synthesis is easy. The total synthesis of neoclerodanes by further transformation of 4 is currently under investigation.…”

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

“…We found allenylindium along with chiral aminoalcohol ligand could afford the desired product with a d.r. of up to 10:1 . However, it requires stoichiometric amount of expensive indium metal under cryogenic condition.…”

Enantioselective Indium-Catalyzed Transformations

“…As a rare example, an asymmetric Barbier-type propargylation of aldehydes 34 with propargyl bromide 35 was developed by Singaram et al, in 2012. 22 The process was mediated by 2 equivalents of indium and the same quantity of chiral 1,2-aminoalcohol 36 as ligand in THF, leading to the corresponding chiral homopropargylic alcohols 37 in moderate to high yields (53-90%) and enantioselectivities (74-95% ee), as illustrated in Scheme 10. The catalyst system tolerated (hetero)aromatic as well as aliphatic aldehydes.…”