Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

Abstract

A small family of new chiral hybrid, diphosphorus ligands, consisting of phosphine-phosphoramidites <b>L1</b> and <b>L2</b> and phosphine-phosphonites <b>L3a–c</b>, was synthesized for the application in Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins. High-pressure (HP)-NMR and HP-IR spectroscopy under 5–10 bar of syngas has been employed to characterize the corresponding catalyst resting state with each ligand. Indole-based ligands <b>L1</b> and <b>L2</b> led to selective <i>ea</i> coordination, while the xanthene derived system <b>L3c</b> gave predominant <i>ee</i> coordination. Application of the small bite-angle ligands <b>L1</b> and <b>L2</b> in the highly selective asymmetric hydroformylation (AHF) of the challenging substrate 2,3-dihydrofuran (<b>1</b>) yielded the 2-carbaldehyde (<b>3</b>) as the major regioisomer in up to 68% yield (with ligand <b>L2</b>) along with good ee’s of up to 62%. This is the first example in which the asymmetric hydroformylation of <b>1</b> is both regio- and enantioselective for isomer <b>3</b>. Interestingly, use of ligand <b>L3c</b> in the same reaction completely changed the regioselectivity to 3-carbaldehyde (<b>4</b>) with a remarkably high enantioselectivity of 91%. Ligand <b>L3c</b> also performs very well in the Rh-catalyzed asymmetric hydroformylation of other heterocyclic olefins. Highly enantioselective conversion of the notoriously difficult substrate 2,5-dihydrofuran (<b>2</b>) is achieved using the same catalyst, with up to 91% ee, concomitant with complete regioselectivity to the 3-carbaldehyde product (<b>4</b>) under mild reaction conditions. Interestingly, the Rh-catalyst derived from <b>L3c</b> is thus able to produce both enantiomers of 3-carbaldehyde <b>4</b>, simply by changing the substrate from <b>1</b> to <b>2</b>. Furthermore, 85% ee was obtained in the hydroformylation of <i>N-</i>acetyl-3-pyrroline (<b>5</b>) with exceptionally high regioselectivities for 3-carbaldehyde <b>8Ac</b> (>99%). Similarly, an ee of 86% for derivative <b>8Boc</b> was accomplished using the same catalyst system in the AHF of <i>N-</i>(<i>tert</i>-butoxycarbonyl)-3-pyrroline (<b>6</b>). These results represent the highest ee’s reported to date in the AHF of dihydrofurans (<b>1</b>, <b>2</b>) and 3-pyrrolines (<b>5</b>, <b>6</b>)