A wide array of forms of palladium has been utilized as precatalysts for Heck and Suzuki coupling reactions over the last 15 years. Historically, nearly every form of palladium used has been described as the active catalytic species. However, recent research has begun to shed light on the in situ transformations that many palladium precatalysts undergo during and before the catalytic reaction, and there are now many suggestions in the literature that narrow the scope of types of palladium that may be considered true “catalysts” in these coupling reactions. In this work, for each type of precatalyst, the recent literature is summarized and the type(s) of palladium that are proposed to be truly active are enumerated. All forms of palladium, including discrete soluble palladium complexes, solid-supported metal ligand complexes, supported palladium nano- and macroparticles, soluble palladium nanoparticles, soluble ligand-free palladium, and palladium-exchanged oxides are considered and reviewed here. A considerable focus is placed on solid precatalysts and on evidence for and against catalysis by solid surfaces vs. soluble species when starting with various precatalysts. The review closes with a critical overview of various control experiments or tests that have been used by authors to assess the homogeneity or heterogeneity of catalyst systems.

On the Nature of the Active Species in Palladium Catalyzed Mizoroki–Heck and Suzuki–Miyaura Couplings – Homogeneous or Heterogeneous Catalysis, A Critical Review

The palladium-catalyzed α-arylation of ketones has become a useful and general synthetic method. In this process, an enolate is generated from a ketone and base in the presence of an aryl halide, and a palladium catalyst couples this enolate with the aryl halide. With the advent of new catalysts composed of sterically hindered, electron-rich alkylphosphine and N-heterocyclic carbene ligands, this process now encompasses a broad range of enolates and related anions, including those derived from amides, esters, aldehydes, nitriles, malonates, cyanoesters, nitroalkanes, sulfones, and lactones. In the proposed mechanism for this reaction, the carbon−carbon bond of the product is formed by reductive elimination from an arylpalladium enolate intermediate. The structures and reactions of arylpalladium complexes of enolate, cyanoalkyl, and malonate ions have been studied to determine how the binding mode and electronic and steric parameters influence the rate and mechanism of reductive elimination.

Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles

Transition metal-catalyzed cross-coupling reactions of alkyl metals and aryl halides or pseudohalides have emerged as a powerful methodology for the formation of Csp3-Csp2 bonds over the past decades.1 However, significant attention has also been focused on Pdand Ni-catalyzed Csp3-Csp2 bond-forming reactions that involve aryl metals and haloalkyl compounds lacking -hydrogen atoms as cross-coupling partners.2 In contrast, until a few years ago, few examples were reported in the literature concerning transition metalcatalyzed reactions of aryl metals with functionalized alkyl halides including R-halocarbonyl compounds and R-bromosulfones bearing -hydrogen atoms,3 and a single example of Pd-catalyzed cross-coupling reaction of aryl metals and unfunctionalized alkyl halides bearing -hydrogen atoms had been described.4 Only in recent years, successful procedures for the Pd-,5 Ni-,6 Rh-,7 Fe-,8 V-,9 Co-,10 and Cu-catalyzed11 cross-coupling reactions of aryl metals and unfunctionalized alkyl halides bearing -hydrogen atoms have been developed.12 Nevertheless, new, effective, and more environmentallybenignmethodologiesfortheformationof(cyclo)alkyl-aryl bonds, which require a reduced number of synthetic operations, have emerged as valuable alternatives to the conventional cross-coupling reactions. These methodologies (Scheme 1) are based on transition metal-catalyzed simple or 2-fold C-H bond functionalization according to the following approaches: (a) highly regioselective Pd-catalyzed direct arylation reactions of unactivated sp3-hybridized C-H bonds with aryl halides (eq a, Scheme 1);13 (b) Pd-catalyzed direct alkylation reactions of aryl C-H bonds with alkyl metals (eq b, Scheme 1);14 Au-15 or Pdcatalyzed16 direct alkylation reactions of aryl C-H bonds with alkyl halides or pseudohalides (eq c, Scheme 1); (d) Pd-catalyzed arylations of unactivated sp3-hybridized C-H bonds with aryl metals (eq d, Scheme 1);14c (e) Pd-, Ru-, or Cu-catalyzed cross-coupling reactions of sp3-hybridized C-H bonds with arylboronic acids using air as oxidant (eq d, Scheme 1);17 and (f) cross-dehydrogenative coupling of alkyl and aryl C-H bonds (eq e, Scheme 1).18 Finally, great attention, particularly in the past decade, has also been focused on the design, development, and application of transition metal-catalyzed coupling reactions of aryl halides and pseudohalides with a wide variety of substrates containing activated sp3-hybridized C-H bonds (eq f, Scheme 1). A mini-review on this topic was published by Scolastico and Poli in 1999,19 and three excellent reviews that concern the results obtained in this rapidly growing area of extensive research by the groups of Miura, Natsume, Hartwig, and Buchwald up to the end of 2002 were published by Miura,20 Hartwig,21 and Lloyd-Jones22 a few years later. However, the reviews by Miura20 and Hartwig21 were limited in that they fundamentally emphasized the author’s own work and * To whom correspondence should be addressed. E-mail: rossi@dcci.unipi.it. Chem. Rev. 2010, 110, 1082–1146 1082

Transition metal-catalyzed direct arylation of substrates with activated sp3-hybridized C-H bonds and some of their synthetic equivalents with aryl halides and pseudohalides.

Palladium-mediated cross-coupling reactions are attractive organometallic transformations for the generation of C--C, C--N, C--O, and C--S bonds. Despite being widely employed in small-scale syntheses, cross-coupling reactions have not found important industrial applications because until recently, only reactive aryl bromides and iodides could be used as substrates. These substrates are generally more expensive and less widely available than their chloride counterparts. Over the past few years, new catalytic systems with the ability to activate unreactive and sterically hindered aryl chlorides have been developed. The new catalysts are based on palladium complexes that contain electron-rich and bulky phosphine or carbene ligands. The enhanced reactivity observed with these new systems has been attributed to the formation of unsaturated and reactive [PdL] species which can readily undergo oxidative addition reactions with ArX to yield [Pd(Ar)X(L)].

Monoligated palladium species as catalysts in cross-coupling reactions.

Pentaphenylferrocenyl di-tert-butylphosphine has been prepared in high yield from a two-step synthetic procedure, and the scope of various cross-coupling processes catalyzed by complexes bearing this ligand has been investigated. This ligand creates a remarkably general palladium catalyst for aryl halide amination and for Suzuki coupling. Turnovers of roughly 1000 were observed for aminations with unactivated aryl bromides or chlorides. In addition, complexes of this ligand catalyzed the formation of selected aryl ethers under mild conditions. The reactions encompassed electron-rich and electron-poor aryl bromides and chlorides. In the presence of catalysts containing this ligand, these aryl halides coupled with acyclic or cyclic secondary alkyl- and arylamines, with primary alkyl- and arylamines, and with aryl- and primary alkylboronic acids. These last couplings provide the first general procedure for reaction of terminal alkylboronic acids with aryl halides without toxic or expensive bases. The ligand ...

Air Stable, Sterically Hindered Ferrocenyl Dialkylphosphines for Palladium-Catalyzed C−C, C−N, and C−O Bond-Forming Cross-Couplings

Palladium-catalyzed reactions of aryl bromides and chlorides with two common stabilized carbanions-enolates of dialkyl malonates and alkyl cyanoesters-are reported. An exploration of the scope of these reactions was conducted, and the processes were shown to occur in a general fashion. Using P(t-Bu)(3) (1), the pentaphenylferrocenyl ligand (Ph(5)C(5))Fe(C(5)H(4))P(t-Bu)(2) (2), or the adamantyl ligand (1-Ad)P(t-Bu)(2) (3), reactions of electron-poor and electron-rich, sterically hindered and unhindered aryl bromides and chlorides were shown to react with diethyl malonate, di-tert-butyl malonate, diethyl fluoromalonate, ethyl cyanoacetate, and ethyl phenylcyanoacetate. Although alkyl malonates and ethyl alkylcyanoacetates did not react with aryl halides using these catalysts, the same products were formed conveniently in one pot from diethylmalonate by cross-coupling of an aryl halide in the presence of excess base and subsequent alkylation.

Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands.

Palladium-catalyzed arylation of ethyl cyanoacetate. Fluorescence resonance energy transfer as a tool for reaction discovery.

Palladium‐Catalyzed α‐Arylation of Esters and Protected Amino Acids.

Palladium‐Catalyzed Arylation of Malonates and Cyanoesters Using Sterically Hindered Trialkyl‐ and Ferrocenyldialkylphosphine Ligands.

The molecular and crystal structure is reported for the major diastereoisomer formed in a sterically hindered reaction of a substituted dinaphthodithiepine. The structure lends support to a reaction mechanism and transition state postulated to explain the experimentally determined preferential formation of this diastereoisomer over the minor component.

Neil A. Beare

Papers

Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands.

Palladium-catalyzed arylation of ethyl cyanoacetate. Fluorescence resonance energy transfer as a tool for reaction discovery.

Palladium‐Catalyzed α‐Arylation of Esters and Protected Amino Acids.

Palladium‐Catalyzed Arylation of Malonates and Cyanoesters Using Sterically Hindered Trialkyl‐ and Ferrocenyldialkylphosphine Ligands.

Syntheses and crystal structure of a (2,6-diisopropyldinaphtho[2,1-d:1′,2′-f][1,3]dithiepin-4-yl)(phenyl)methanol atropisomer