Enantioselective Pd(II)-Catalyzed Aerobic Oxidative Amidation of Alkenes and Insights into the Role of Electronic Asymmetry in Pyridine-Oxazoline Ligands

McDonald, Richard I.; White, Paul B.; Weinstein, Adam B.; Tam, Chun Pong; Stahl, Shannon S.

doi:10.1021/ol200784y

Cited by 112 publications

(41 citation statements)

References 38 publications

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“…7,10 Our initial efforts using a simple cyclohexenyl triflate 1a with ( Z )-alkenol 2a , in the presence of a chiral pyrox ligand, resulted in the formation of the desired product 3a in 15% yield albeit a good enantiomeric ratio of 95:5 (Figure 1e). 14 Attempts to improve the yield of this reaction were met with similar outcomes. Analyzing the reaction mixture with ESI-MS provided evidence of a species with a composition to that of the proposed π-allyl intermediate shown in Figure 1e.…”

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confidence: 92%

Palladium-Catalyzed Enantioselective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

2015

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We report a highly enantioselective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions β, γ or δ to a carbonyl group in high enantioselectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective β-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products.

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confidence: 92%

Palladium-Catalyzed Enantioselective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

2015

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“…40 The primary hypothesis is that the ligand has a well-defined coordination sphere, leading to uniquely effective catalysis due to its electronic asymmetry as has also been implicated by Stahl and coworkers in enantioselective aza-Wacker reactions. 41 Specifically, it is believed that the “electronically rich” oxazoline module promotes coordination of the electron rich TBHP in a trans fashion. As such, the relatively electron poor quinoline module supports trans coordination of the alkene.…”

Section: Introductionmentioning

confidence: 99%

Imparting Catalyst Control upon Classical Palladium-Catalyzed Alkenyl C–H Bond Functionalization Reactions

2011

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Conspectus The functional group transformations carried out by the palladium-catalyzed Wacker and Heck reactions are radically different, but they are both alkenyl C-H bond functionalization reactions that have found extensive use in organic synthesis. The synthetic community depends heavily on these important reactions, but selectivity issues arising from control by the substrate, rather than control by the catalyst, have prevented the realization of their full potential. Because of important similarities in the respective selectivity-determining nucleopalladation and β-hydride elimination steps of these processes, we posit that the mechanistic insight garnered through the development of one of these catalytic reactions may be applied to the other. In this Account, we detail our efforts to develop catalyst-controlled variants of both the Wacker oxidation and the Heck reaction to address synthetic limitations and provide mechanistic insight into the underlying organometallic processes of these reactions. In contrast to previous reports, we discovered that electrophilic palladium catalysts with non-coordinating counterions allowed for the use of a Lewis basic ligand to efficiently promote TBHP-mediated Wacker oxidation reactions of styrenes. This discovery led to the mechanistically guided development of a Wacker reaction catalyzed by a palladium complex with a bidentate ligand. This ligation may prohibit coordination of allylic heteroatoms, thereby allowing for the application of the Wacker oxidation to substrates that were poorly behaved under classical conditions. Likewise, we unexpectedly discovered that electrophilic Pd-σ-alkyl intermediates are capable of distinguishing between electronically inequivalent C–H bonds during β-hydride elimination. As a result, we have developed E-styrenyl selective oxidative Heck reactions of previously unsuccessful electronically non-biased alkene substrates using arylboronic acid derivatives. The mechanistic insight gained from the development of this chemistry allowed for the rational design of a similarly E-styrenyl selective classical Heck reaction using aryldiazonium salts and a broad range of alkene substrates. The key mechanistic findings from the development of these reactions provide new insight into how to predictably impart catalyst control in organometallic processes that would otherwise afford complex product mixtures. Given our new understanding, we are optimistic that reactions that introduce increased complexity relative to simple classical processes may now be developed based on our ability to predict the selectivity-determining nucleopalladation and β-hydride elimination steps through catalyst design.

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“…The relative energies of these eight intermediates can be rationalized by the modest trans effect of the hydroxyl group compared to the allylic carbanion and the enhanced trans effect of the oxazoline N compared to the pyridine N. 27 As a result, C4_up is more stable than trans_C4_up . In addition, C4_down is less stable than trans_C4_down due to the steric repulsion between the t -Bu group of the ligand and the adjacent allylic group.…”

Section: Resultsmentioning

confidence: 99%

Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene

Zhang

McCammant

et al. 2016

J. Org. Chem.

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The three-component coupling of isoprene, an alkenyl triflate and styrenylboronic acid catalyzed by a palladium pyrox complex access to skipped dienes from simple chemical feedstocks. Unfortunately, the transformation proceeds with only moderate selectivity and yields. The reaction mechanism and factors responsible for the resulting regioselectivity were elucidated using M06/SDD/6–311++G(d,p) + SMD calculations. Distortion of the palladium coordination sphere in the transition structure of the migratory insertion step is found to control the 4,1- vs. 1,x-selectivity. The calculated Δ ΔG‡ of 1.0 kcal/mol for this step is in excellent agreement with the experimentally observed selectivity of 1:9.9 disfavoring the 4,1-product. The transmetallation was found to be the regioselectivity determining step for the formation of the 1,2- vs. 1,4-addition products. Systematic conformational searches for the transmetallation transition structure revealed a series of steric interactions between the t-Bu on the ligand and the substrates in the model system that are balanced by additional repulsive interactions between the substrates and the pyridyl portion of the ligand. The combination of these effects leads to the low to moderate 1,2- vs. 1,4- selectivity in the experimentally studied system.

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Enantioselective Pd(II)-Catalyzed Aerobic Oxidative Amidation of Alkenes and Insights into the Role of Electronic Asymmetry in Pyridine-Oxazoline Ligands

Cited by 112 publications

References 38 publications

Palladium-Catalyzed Enantioselective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

Palladium-Catalyzed Enantioselective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

Imparting Catalyst Control upon Classical Palladium-Catalyzed Alkenyl C–H Bond Functionalization Reactions

Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene

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