Palladium‐Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Heterocyclic Acceptors

Holder, Jeffrey C.; Marziale, Alexander N.; Gatti, Michele; Mao, Bin; Stoltz, Brian M.

doi:10.1002/chem.201203643

Cited by 89 publications

(61 citation statements)

References 26 publications

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“…2, 57 ). 15a We propose that the active catalyst is likely a palladium(II) hydroxide, which are known to undergo rapid transmetallation with arylboronic acids. 19 Though the precise role of NH 4 PF 6 has not been established, we postulate that the presence of the non-coordinating counterion may stabilize the cationic intermediates on the proposed catalytic cycle, or otherwise favor a resting state, that is, on the productive catalytic cycle.…”

Section: Plausible Catalytic Cyclementioning

confidence: 98%

“…15 Typically, reactions under these conditions occur between room temperature and 40 °C. Gratifyingly, we discovered that these milder conditions facilitate increased yields with substrates that had reacted with good ee, but poor yields under the initial reported conditions (in the absence of NH 4 PF 6 and water).…”

Section: Determination Of Substrate Scopementioning

confidence: 99%

“…This olefin insertion is the enantioselectivity- determining step. The lowest energy diastereomer of this insertion reaction has been calculated to be transition state 59-ts , 15a which leads to the observed ( R ) stereochemistry of the product ketones. Migratory insertion of the substrate olefin into the aryl-palladium bond affords carbon-bound palladium enolate 62 , which likely isomerizes to its oxygen-bound tautomer, enolate 61 .…”

Section: Plausible Catalytic Cyclementioning

confidence: 99%

“…Fortuitously, these additives also allowed reactions to be conducted at temperatures as low as ambient temperature. 15 …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones

et al. 2015

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The development and optimization of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and readily-available reagents in an operationally simple and robust transformation that yields β-quaternary ketones in high yields and enantioselectivities. Notably, the reaction itself is highly tolerant of atmospheric oxygen and moisture and therefore does not require the use of dry or deoxygenated solvents, specially purified reagents, or an inert atmosphere. The ring size and β-substituent of the enone are highly variable, and a wide variety of β-quaternary ketones can be synthesized. More recently, the use of NH4PF6 has further expanded the substrate scope to include heteroatom-containing arylboronic acids and β-acyl enone substrates.

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Section: Plausible Catalytic Cyclementioning

confidence: 98%

Section: Determination Of Substrate Scopementioning

confidence: 99%

Section: Plausible Catalytic Cyclementioning

confidence: 99%

“…Fortuitously, these additives also allowed reactions to be conducted at temperatures as low as ambient temperature. 15 …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones

et al. 2015

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“…16 After the initial disclosure, we observed that in addition to catalyzing conjugate additions to 5-, 6-, and 7-membered enones, the Pd/PyOx catalyst successfully reacted with chromones and 4-quinolones. 17 Intrigued by the broad substrate scope and operational simplicity of this highly asymmetric process, we conducted a thorough study to optimize the reaction conditions, including measures to reduce the catalyst loading, lower the reaction temperature, and further generalize the substrate scope. We also performed mechanistic and computational investigations toward elucidating the catalytic cycle, active catalyst species, and the stereoelectronic effects on enantioselectivity of this reaction.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted Cyclic Enones: Insights from Computation and Experiment

et al. 2013

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Enantioselective conjugate additions of arylboronic acids to β-substituted cyclic enones have been reported previously from our laboratories. Air and moisture tolerant conditions were achieved with a catalyst derived in situ from palladium(II) trifluoroacetate and the chiral ligand (S)-t-BuPyOx. We now report a combined experimental and computational investigation on the mechanism, the nature of the active catalyst, the origins of the enantioselectivity, and the stereoelectronic effects of the ligand and the substrates of this transformation. Enantioselectivity is controlled primarily by steric repulsions between the t-Bu group of the chiral ligand and the α-methylene hydrogens of the enone substrate in the enantiodetermining carbopalladation step. Computations indicate that the reaction occurs via formation of a cationic arylpalladium(II) species, and subsequent carbopalladation of the enone olefin forms the key carbon-carbon bond. Studies of non-linear effects and stoichiometric and catalytic reactions of isolated (PyOx)Pd(Ph)I complexes show that a monomeric arylpalladium-ligand complex is the active species in the selectivity-determining step. The addition of water and ammonium hexafluorophosphate synergistically increases the rate of the reaction, corroborating the hypothesis that a cationic palladium species is involved in the reaction pathway. These additives also allow the reaction to be performed at 40 °C and facilitate an expanded substrate scope.

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2‐[(4 S )‐4‐(1,1‐Dimethylethyl)‐4,5‐dihydro‐2‐oxazolyl]‐pyridine and 2‐[(4 R )‐4‐(1,1‐Dimethylethyl)‐4,5‐dihydro‐2‐oxazolyl]‐pyridine

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Austeri

Lauzon

et al. 2021

Encyclopedia of Reagents for Organic Synthesis

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Palladium‐Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Heterocyclic Acceptors

Cited by 89 publications

References 26 publications

Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones

Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones

Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted Cyclic Enones: Insights from Computation and Experiment

2‐[(4 S )‐4‐(1,1‐Dimethylethyl)‐4,5‐dihydro‐2‐oxazolyl]‐pyridine and 2‐[(4 R )‐4‐(1,1‐Dimethylethyl)‐4,5‐dihydro‐2‐oxazolyl]‐pyridine

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