Highly Active, Regioselective, and Enantioselective Hydroformylation with Rh Catalysts Ligated by Bis-3,4-diazaphospholanes Thomas P. Clark, § Clark R. Landis,* ,§ Susan L. Freed, ² Jerzy Klosin,* ,² and Khalil A. Abboud ‡ Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue, Madison, Wisconsin 53706, Chemical Sciences, The Dow Chemical Company, 1776 Building, Midland, Michigan 48674, and Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611 Received January 10, 2005; E-mail: landis@chem.wisc.edu; jklosin@dow.com As with catalytic hydrogenation of alkenes by rhodium com- plexes, key attributes of rhodium-catalyzed alkene hydroformyla- tion 1 (perfect atom economy, inexpensive reactants, demonstrated performance on industrial scales, readily modified phosphorus ligands) make pursuit of the enantioselective transformation ir- resistible. Whereas hydrogenation effects net loss of the CdC functional group, hydroformylation results in its transformation to a more versatile functional group, the aldehyde. Although new ligand developments over the last fifteen years have yielded significant progress, the general application of enantioselective hydroformylation lags well behind that of enantioselective hydro- genation. Several factors are responsible: (1) enantioselective hydroformylation is relatively slow, with turnover frequencies commonly in the range of tens to hundreds per hour for terminal alkenes and much slower rates for internal alkenes; (2) effective enantioselective hydroformylation of terminal alkenes requires control of regioselectivity that favors branched isomers; and (3) few of the effective ligands exhibit good activity and selectivity for a range of different substrates, even when one considers only 1-alkenes. We report new chiral bis-3,4-diazaphospholane ligands that constitute unusually active and selective ligands for rhodium- catalyzed hydroformylation of styrene, allyl cyanide, and vinyl acetate. Recently, we reported the facile synthesis of a wide variety of chiral mono- and bis-3,4-diazaphospholanes 2 that are readily resolved, extended into small libraries, and applied to asymmetric allylic alkylation both in solution 3 and on bead. 4 This work demonstrated that mono-3,4-diazaphospholanes bearing carboxylic acid functionalized substituents in the 2 and 5 positions can be expanded to collections of new ligands using simple coupling chemistry. One-step synthesis of bis-3,4-diazaphospholanes 2 and 3 proceeds with ca. 30% yield upon reaction of the azine 1 with 1,2-diphosphinobenzene in the presence of either succinyl chloride or phthaloyl chloride (Scheme 1). Coupling the carboxylic acid groups of either 2 or 3 with resolved chiral amines followed by chromatographic separation of the resulting diastereomers yields enantiomerically pure bis-3,4-diazaphospholanes 4, 5, 6, and 7. The crystallographic structure of 7a is shown in Figure 1. Prominent ligands for enantioselective hydroformylation include BINAPHOS (10), 5 Kelliphite (11), 6,7 ESPHOS (12), 8 Chiraphite (13), 9 and the sugar-derived phosphite (14). 10 Literature data for these ligands suggest that 10 is generally the most useful. § The University of Wisconsin s Madison. ² The Dow Chemical Company. ‡ University of Florida. Scheme 1 Figure 1. Two views of the crystallographic structure of 7a. For clarity, only one of the nearly C2-related diazaphospholane rings is shown. Hydrogens are shown for the phospholane 2 and 5 positions, only. The succinyl group was eliminated from the lower view for ease of viewing. Published on Web 03/17/2005 5040 9 J. AM. CHEM. SOC. 2005, 127, 5040-5042 10.1021/ja050148o CCC: $30.25 © 2005 American Chemical Society