From α-Arylation of Olefins to Acylation with Aldehydes: A Journey in Regiocontrol of the Heck Reaction

Abstract

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.

Palladium complexes of heterobidentate ligands: Active catalysts for direct acylation of aryl halides with aldehydes via C(sp 2 )-H activation

“…have been deployed for the C H activation reactions. The aldehyde C H activation by direct acylation of aryl halides with aliphatic aldehydes is an interesting prospect to get alkyl-aryl ketones; which are potential intermediates in different pharmaceutical, fragrance, dye and agrochemical industries [14][15][16][17][18][19][20][21][22]. Friedel-Crafts acylation has been a traditional way of acylating arenes, which has the strict limitation of reacting with activated benzene derivatives only [23].…”

“…Synthesis of alkyl-aryl ketones by direct acylation of aryl halides with aliphatic aldehydes have been reported by using palladium complexes of phosphine ligands as well as palladium nanopaticles [16][17][18][19][20][21]. Selection of ligands plays an important role in determining the efficiency of the catalysts for generating the Pd(0) species for the reaction cycle to start.…”

Iron-containing mesoporous aluminosilicate catalyzed direct alkenylation of phenols: Facile synthesis of 1,1-diarylalkenes

“…However, the major drawback of the Mizoroki–Heck-type reaction in the synthesis of 1,1-disubstituted olefins rests on its poor selectivity toward the formation of α-products [20–23]. In general, the reaction shows β-selectivity, and there are only a few reports available concerned with α-substituted products [24–26]. Sabarre and Love reported a one-pot rhodium-catalyzed alkyne hydrothiolation followed by a nickel-catalyzed Kumada-type cross coupling with Grignard reagents to afford 1,1-disubstituted olefins [27].…”

Palladium‐Catalyzed Asymmetric Reductive Heck Reaction of Aryl Halides

“…[16] We found that both R 3 NH + salts and glycol were needed in our study of the asymmetric Heck reaction of aryl halides. [17] In our DFT studies, hydrogen bonding of trialkylammonium NH and alcoholic ROH with a halide ion not only lowered the barrier, but also stabilized the ionized products.…”