Trineopentylphosphine (TNpP) in combination with palladium provides a highly effective catalyst for the Buchwald-Hartwig coupling of sterically demanding aryl bromides and chlorides with sterically hindered aniline derivatives. Excellent yields are obtained even when both substrates include 2,6-diisopropyl substituents. Notably, the reaction rate is inversely related to the steric demand of the substrates. X-ray crystallographic structures of Pd(TNpP)2, [Pd(4-t-Bu-C6H4)(TNpP)(μ-Br)]2, and [Pd(2-Me-C6H4)(TNpP)(μ-Br)]2 are reported. These structures suggest that the conformational flexibility of the TNpP ligand plays a key role in allowing the catalyst to couple hindered substrates. The Pd/TNpP system also shows good activity for the Suzuki coupling of hindered aryl bromides.
A high-yielding stereospecific route to the synthesis of single geometric isomers of diaryl oxime ethers through Suzuki coupling of N-alkoxyimidoyl iodides is described. This reaction occurs with complete retention of the imidoyl halide geometry to give single E- or Z-isomers of diaryl oxime ethers. The Sonogashira coupling of N-alkoxyimidoyl iodides and bromides with a wide variety of terminal alkynes to afford single geometric isomers of aryl alkynyl oxime ethers has also been developed. Several of these reactions proceed through copper-free conditions. The Negishi coupling of N-alkoxyimidoyl halides is introduced. The E and Z configurations of nine Suzuki-coupling products and two Sonogashira-coupling products were confirmed by X-ray crystallography.
The engineering of
reaction mixtures that ensure the solubility
of inorganic salt byproducts without compromising the reactivity is
a grand challenge for continuous flow manufacturing in upstream pharmaceuticals
and fine chemicals process development. Aqueous cross-coupling reactions
are possible solutions. We report the study of an aqueous phase Pd-catalyzed
Cu-free direct arylation of an alkyne using a hydrophilic ligand towards
understanding the role of water on the cross-coupling kinetics. Kinetic
analyses of theoretically estimated molar flux rates and the measured
reaction kinetics reveal a transition from mass transfer to kinetically
controlled deprotonation and carbopalladation mechanisms. Interfacial
contact areas of immiscible aqueous–organic phases control
the crossover from the mass-transfer-limited to the reaction-rate-limited
regime. Highly agitated batch reactors and multiphase capillary flow
reactors are needed to overcome the mass transport limitations and,
thus, discover the transition from the apparent reaction kinetics
to the true reaction kinetics. Comparison of previously reported Density
Functional Theory calculations with experimentally measured activation
energies, ranging from 14.8 to 20.0 kcal/mol, elucidates the theoretical
possibility of designing the aqueous phase C–C cross-coupling
reaction with similar reactivity as purely organic reactions. Although
ambiguity remains concerning which reaction step is rate-determining
in either the deprotonation or the carbopalladation mechanism, our
discovery undergirds that one mechanism or the other could dominate
in aqueous designed direct arylations.
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