Recent Developments in the Scope, Practicality, and Mechanistic Understanding of Enantioselective Hydroformylation

Abstract

In the nearly 80 years since catalytic hydroformylation was first reported, hundreds of billions of pounds of aldehyde have been produced by this atom efficient one-carbon homologation of alkenes in the presence of H and CO. Despite the economy and demonstrated scalability of hydroformylation, the enantioselective process (asymmetric hydroformylation, AHF) currently does not contribute significantly to the production of chiral aldehydes and their derivatives. Current impediments to practical application of AHF include low diversity of chiral ligands that provide effective rates and selectivities, limited exploration of substrate scope, few demonstrations of efficient flow reactor processes, and incomplete mechanistic understanding of the factors that control reaction selectivity and rate. This Account summarizes developments in ligand design, substrate scope, reactor technology, and mechanistic understanding that advance AHF toward practical and atom-efficient production of chiral α-stereogenic aldehydes. Initial applications of AHF were limited to activated terminal alkenes such as styrene, but recent developments enable high selectivity for unactivated olefins and more complex substrates such as 1,1'- and 1,2-disubstituted alkenes. Expanded substrate scope primarily results from new chiral phosphine ligands, especially phospholanes and bisdiazaphospholanes (BDPs). These ligands are now more accessible due to improved synthesis and resolution procedures. One of the virtues of diazaphospholanes is the relative ease of derivatization, including attachment to heterogeneous supports. Hydroformylation involves toxic and flammable reactants, a serious concern in pharmaceutical production facilities. Flow reactors offer many process benefits for handling dangerous reagents and for systematically moving from research to production scales. New approaches to achieving good gas-liquid mixing in flow reactors have been demonstrated with BDP-derived catalyst systems and lend assurance that AHF can be practically implemented by the pharmaceutical and fine chemical industries. To date, progress in AHF has been empirically driven, because hydroformylation is a complex, multistep process for which the origins of chemo-, regio-, and enantioselectivity are difficult to elucidate. Mechanistic complexity arises from three concurrent catalytic cycles (linear and two diastereomeric branched paths), significant pooling of catalyst as off-cycle species, and multiple elementary steps that are kinetically competitive. Addressing such complexity requires new approaches to collecting kinetic and extra-kinetic information and analyzing these data. In this Account, we describe our group's progress toward understanding the complex kinetics and mechanism of AHF as catalyzed by rhodium bis(diazaphospholane) catalysts. Our strategy features both "outside-in" (i.e., monitoring catalytic rates and selectivities as a function of reactant concentration and temperature) and "inside-out" (i.e., building kinetic models based on the rates of component st...

Mechanochemie gasförmiger Reaktanten

“…[48] Alternativ wurde gezeigt, dass der Gebrauch von supramolekularen Liganden die Regioselektivitätm etallkatalysierter Hydroformylierungen beeinflusst. Übergangsmetalle wie Rhodium erwiesen sich als hoch katalytisch, um die Hydroformylierung bei milden Reaktionsbedingungen (d. h. Te mperatur und Druck) zu ermçglichen.…”

Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds

“…leged structures in organometallic chemistry and homogeneous catalysis with applications ranging from alkene hydrogenation, [1] hydroformylation [2] and hydroacylation [3] to avariety of CÀCb ond-forming reactions. [4] Schrock and Osborns pioneering synthesis and study of these complexes over four decades ago, [5] coupled with advances in chiral phosphine ligands [6] and high-throughput experimentation, [7] established the transformative nature of asymmetric catalysis in organic synthesis (Scheme 1A).…”

“…Addition of one equivalent of NaBAr F 4 to ad iethyl ether solution of (1-Cl) 2 in excess benzene followed by filtration resulted in isolation of [(R,R)-( iPr DuPhos)Co(h 6 -C 6 H 6 )]-[BAr F 4 ]( 1-C 6 H 6 + )a sa no range solid in 90 %y ield (Scheme 3, top) that was also characterized by X-ray diffraction (Figure 2, left). [32] Ar elated compound, (Me 3 P) 2 Co-(h 6 -C 6 H 5 )BPh 3 was reported by Beauchamp and obtained as am ixture with (Me 3 P) 4 Co from addition of NaBPh 4 to (Me 3 P) 3 CoBr. [25] Use of NaBPh 4 as the chloride abstraction reagent produced the [BPh 4 ]-coordinated zwitterionic complex, (R,R)-( iPr DuPhos)Co(BPh 4 )( 1-BPh 4 )a sad ark orange solid in 95 %y ield (Scheme 3, bottom).…”

Asymmetric Hydrocyanation of Alkenes without HCN

“…[11] Owing to the various transformation of the aldehyde group,h ydroformylation-initiated tandem reactions towards more complex molecules have been achieved, including hydroaminomethylation, [12] hydroformylation/Fischer indole synthesis, [13] hydroformylation/Wittig reaction, [14] and other tandem processes. [16] Them ain reason might be the racemization of chiral branched aldehydes in the cascade process which usually led to the target products with very low enantioselectivity.I n2 013, Landis reported one-pot AHF-Wittig olefination (AHF-WO) sequences with their bis-diazophos as the chiral ligand for the AHF step. [16] Them ain reason might be the racemization of chiral branched aldehydes in the cascade process which usually led to the target products with very low enantioselectivity.I n2 013, Landis reported one-pot AHF-Wittig olefination (AHF-WO) sequences with their bis-diazophos as the chiral ligand for the AHF step.…”

“…[15] By contrast, asymmetric hydroformyla-tion-triggered cascade reactions have been rarely reported, although intensive research efforts and much progress have been made in asymmetric hydroformylation during the past decades. [16] Them ain reason might be the racemization of chiral branched aldehydes in the cascade process which usually led to the target products with very low enantioselectivity.I n2 013, Landis reported one-pot AHF-Wittig olefination (AHF-WO) sequences with their bis-diazophos as the chiral ligand for the AHF step. [17] Recently,o ur group have developed the rhodium-YanPhos-catalyzed asymmetric interrupted intramolecular hydroaminomethylation of trans-1,2-disubstituted alkenes.…”