A new protocol for the direct acylation of aryl bromides with aldehydes is established. It appears to involve palladium-amine cooperative catalysis, affording synthetically important alkyl aryl ketones in moderate to excellent yields in a straightforward manner, and broadening the scope of metal-catalyzed coupling reactions.

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The Pd-catalyzed Mizoroki-Heck reaction of olefins with aryl halides, more often simply called the Heck reaction, was recently recognized with the 2010 Nobel Prize in chemistry. Although highly selective with electron-deficient olefins, which generally yield the linear β-arylated product exclusively, the Heck reaction is less satisfactory with electron-rich olefins. This substrate typically generates a mixture of both α- and β-arylated regioisomeric products, hampering wider application of the reaction in chemical synthesis. Pioneering studies by a number of researchers revealed that high α-regioselectivity could be obtained under Pd-diphosphine catalysis either through (i) the substitution of aryl triflates for halides or (ii) the addition of stoichiometric silver or thallium salts when aryl halides are used. Under these conditions, the arylation is believed to proceed via an ionic pathway. However, silver introduces added cost, thallium salts are toxic, and triflates are generally commercially unavailable, base sensitive, and thermally labile. Believing that the ionic pathway would be promoted in an ionic medium, in the early 2000s, we attempted the Pd-catalyzed arylation of the benchmark electron-rich olefin butyl vinyl ether with aryl bromides in an imidazolium ionic liquid. We were delighted to observe that highly regioselective α-arylation could readily be accomplished, with no need for silver additives, thallium additives, or aryl triflates. A range of other electron-rich olefins has since been shown to be viable as well. The high α-selectivity probably results from the high ionic strength of the medium, which facilitates the dissociation of halide anions from the [L(2)Pd(Ar)X] intermediate, channeling the arylation into the ionic pathway. Hydrogen bonding interactions may also play a role, however. We subsequently discovered that the α-arylation can indeed be significantly accelerated by a hydrogen bond donor salt, in both ionic liquids and common solvents. Evidence shows that the concentration of the cationic Pd(II)-olefin species along the ionic pathway is increased as a result of hydrogen bonding between the hydrogen bond donor and the halide anion. More recently, we reported that cheaper and greener alcohols allow the Heck arylation of electron-rich olefins to proceed in a much faster, productive, and totally α-regioselective manner, circumventing the need for an ionic medium or hydrogen bond donor salt. In particular, aryl chlorides with diverse properties have been demonstrated to be viable substrates for the first time. Significantly, it appears that ethylene glycol facilitates both the oxidative addition of ArCl to Pd(0) and the subsequent dissociation of chloride from Pd(II). A closely related reaction, acylation of aryl halides with aldehydes, was also developed. Proceeding via the intermediacy of an electron-rich enamine, this Pd-pyrrolidine cooperative catalysis affords alkyl aryl ketones in a straightforward manner, extending the Heck reaction from olefins to aldehydes.

The first, general, and highly efficient catalytic system that allows a wide range of activated and unactivated aryl chlorides to couple regioselectively with olefins has been developed. The Heck arylation reaction is likely to be controlled by the oxidative addition of ArCl to Pd(0). Hence, an electron-rich diphosphine, 4-MeO-dppp, was introduced to facilitate the catalysis. Solvent choice is critical, however; only sluggish arylation is observed in DMF or DMSO, whereas the reaction proceeds well in ethylene glycol at 0.1-1 mol % catalyst loadings, displaying excellent regioselectivity. Mechanistic evidence supports that the arylation is turnover-limited by the oxidative addition step and, most importantly, that the oxidative addition is accelerated by ethylene glycol, most likely via hydrogen bonding to the chloride at the transition state as shown by DFT calculations. Ethylene glycol thus plays a double role in the arylation, facilitating oxidative addition and promoting the subsequent dissociation of chloride from Pd(II) to give a cationic Pd(II)-olefin species, which is key to the regioselectivity observed.