Palladium-Catalyzed Direct Arylation Reactions

Apparently, these direct reactions have a significant advantage (that is, the stoichiometric metallation or halogenation of aromatic substrates is not required), and have recently been undergone significant development [2-11]. The representative examples (as well as related examples) that lead to biaryl compounds by means of 

Modem Arylation Methods. Edited by Lutz Ackermann 

Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim 

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Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

In terms of palladium-catalyzed direct arylation reactions, there are three general mechanisms that are commonly applied (Scheme 7). 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Lipshutz and colleagues presented recently palladium-catalyzed direct coupling reactions of alkyl iodides and vinyl bromides or iodides catalyzed by 1 mol% Pd(amphos)Cl2 in the presence of zinc and TMEDA in a biphasic aqueous/poly-(ethylene glycol tocopheryl sebacate) reaction medium [198], Internal olefins were obtained in 51-95% yield. For aryl-substituted (Aj-vinyl bromides, retention of double bond geometry was observed, while different degrees of isomerization occurred for (Z)-isomers, which may indicate the intervention of a radical addition process in the course of the coupling process. Alkyl-substituted (Z)-vinyl halides were transformed in contrast with retention of alkene geometry. Aryl halides also reacted [199],... 

Palladium-catalyzed direct arylation of 2-phenyl-5-oxazolecarboxanilide (98) with bromobenzene in the presence of Pd(OAc)2 proceeded to give 2,4,5-triphenyloxazole (99) (33%) along with considerable amount of 2,4-diphenyloxazole (20%) [58]. In this reaction carbamoyl group acted as a directing group for the arylation at the 3-position, after which it cleaved and the C(2) and C(5) were arylated to give 2,3,5-triphenyloxazole [58]. 

Ongoing research in our group and by others [62-65] on the mechanism of palladium-catalyzed direct arylation has led to the advancement of a second mode of C-H bond cleavage where a Wheland-like intermediate is not involved in the reaction pathway (Scheme 4). This pathway, which we have termed a concerted metalation-deprotonation (CMD) mechanism, appears less dependent on arene... 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

Palladium-catalyzed direct arylation of heteroaromatic Af-oxides using aryl triflates was reported to afford the corresponding 2-aryl heteroaromatic Af-oxides (Scheme 5) [21]. The reaction was carried out with a range of both azine Af-oxides and aryl triflates. The arylation can also be carried out as a sequence of reactions to yield various diarylated products. The regioselectivity and scope for the direct arylation of 3-substimted azine A -oxides have been investigated. The method can be apphed for the synthesis of compounds that exhibit antimalarial [22] and antimicrobial [23] activities. 

Although the majority of direct arylations have been catalyzed by palladium, rhodium, and ruthenium, some additional studies have also focused on direct arylations catalyzed by first-row metals, such as iron and copper. For example, an iron-catalyzed direct arylation reaction between arylzinc reagents and 2-arylpyridine derivatives has been reported (Equation 19.146). Several direct couplings of heteroarenes with aryl halides (Equation 19.147) or hypervalent iodine reagents ° catalyzed by copper halides have also been reported. 

Campeau LC, Stuart DR, Leclerc JP, Bertrand-Laperle ME, Villemure HY, Sun S, Lasserre N, Guimond M, Lecavallier Fagnou K (2009) Palladium-catalyzed direct arylation of azine and azole N-oxides reaction development, scope, and applications in synthesis. J Am Chem Soc 131 3291-3306. doi 10.1021/ja808332k... 

More complex mechanisms may involve the deprotonation of a substrate that is bound to the transition metal. The bidentate nature of the acetate anion is critical in some palladium-catalyzed direct arylation/C-H activation reactions. In these reactions, the acetate moiety participates in a concerted metalation-deprotonation (CMD) step wherein a transition metal-bound acetate group removes a proton from an aryl C(sp2)-H bond as the metal-C(sp2) bond is being formed (eq 32). Many acetate bases have been used (e.g., KOAc, NaOAc, CsOAc, and CsPiv), and the optimal base used in these reactions is generally determined during the optimization process. 

Palladium-catalyzed Direct Arylation of Indoles and Thiophenes. Five-membered ring heterocycles possessing only one heteroatom and no Af-oxide function can also be arylated using palladium(II) complexes, a phosphine ligand, and an inorganic base. In one example, a tandem palladium-catalyzed Heck coupling reaction and direct intramolecular C2 arylation reaction on a )V-(2-chlorobenzyl)-5-bromoindole was reported (eq 30). The procedure, which is catalyzed by palladium acetate, uses tn-tert-butylphosphonium tetrafluoroborate as a ligand and ferf-butyl acrylate as the alkene for the Heck reaction (eq 30). ... 

Sultones are the internal esters of hydroxy sulfonic acids and are the sulfur analogs of lactones. Sultones are demanded scaffolds in medicinal chemistry research. Biological studies on sultones are mainly concerned with their toxicological, skin sensitization, and antiviral activities [20]. Sultones are synthetically useful heterocycles which can react with a variety of compounds to introduce the alkylsulfonic acid function and therefore used as sulfoalkylating agents [21]. There have been several new developments for the synthesis of sultones which have also been applied in the total synthesis of natural products. In recent years, the palladium-catalyzed direct arylation of several aromatics via a C-H bond activation using aryl halides has led to successes. An intramolecular version of this reaction has allowed the synthesis of several biaryls via the formation of five- to seven-membered rings. Thus, the sultones should be synthesized by C-H activation via two pathways (Scheme 4.14). 

Bromo- and iodoimidazoles are useful intermediates for further functionalization. 4(5)-Aryl- I //-imidazoles 57 can be efficiently and selectively prepared by palladium-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-l//-imidazole 56 with arylboronic acids under phase-transfer conditions, which then underwent highly selective palladium-catalyzed and copper(I) iodide mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-l//-imidazoles 58 in modest to good yields <07JOC8543>. A new procedure for the synthesis of a series of substituted 2-phenylhistamines 60 utilizing a microwave-promoted Suzuki... 

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