Palladium-catalyzed direct arylations

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. 

Protons at C2 of imidazole 1-oxides 228 are acidic and are exchanged with deuterium even in weakly acidic solution. The exchange rate increases with increasing pH (2004S2678). Although the mechanism is not fully understood, the palladium-catalyzed direct arylation of imidazole 1-oxides most likely involves deprotonation so that the observed regi-oselective arylation reflects the propensity to proton abstraction found to decrease in the order C2 > C5 > C4 (2009JA3291). 

Head-to-tail dimerisation of methyl acrylate to the dimethyl ester of 2-methylenepentane-dioic acid (126) occurred in 82-85% yield in the presence of catalytic amounts of P(RNCH2CH2)3N with R = PP, Bu or Bz but the less sterically hindered proazaphosphatrane with R = Me, gave oligomer or pol-ymer. The proazaphosphatrane, P(RNCH2CH2)3N with R = Bu also acts as an effective ligand for the palladium-catalyzed direct arylation of ethyl cyano-acetate (127) with aryl bromides (e.g. 128) to form (129) in high yield. ... 

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]. 

Mechanistic Considerations in the Development and Use of Azine, Diazine and Azole iV-Oxides in Palladium-Catalyzed Direct Arylation... 

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. 

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... 

Scheme 3 A plausible electrophilic aromatic substitution mechanism for palladium-catalyzed direct arylation...

Scheme 9 Effect of carboxylate additives on palladium-catalyzed direct arylation of benzene...

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

Campeau L-C, Fagnou K (2006) Palladium-catalyzed direct arylation of simple arenes in synthesis of biaryl molecules. Chem Commun 1253-1264... 

Gorelsky SI, Lapointe D, Fagnou K (2008) Analysis of the concerted metalation-deprotonation mechanism in palladium-catalyzed direct arylation across a broad range of aromatic substrates. J Am Chem Soc 130 10848-10849... 

Ackermann L, Althammer A, Fenner S (2008) Palladium-catalyzed direct arylations of heteroarenes with tosylates and mesylates. Angew Chem Int Ed 48 201-204... 

Campeau L-C, Schipper Dl, Fagnou K (2008) Site-selective sp2 and benzylic sp3 palladium-catalyzed direct arylation. 1 Am Chem Soc 130 3266-3267... 

An elegant application of regioselective palladium-catalyzed direct arylations of anilides in the presence of stoichiometric amounts of AgOAc in trifluoroacetic acid [65] permitted the preparation of chiral diamines with varying steric demands (Scheme 9.28) [66]. 

Scheme 9.29 Palladium-catalyzed direct arylation of azulene (85).

Scheme 9.31 Palladium-catalyzed direct arylations of arenes with the aryl bromide 94 and pivalic acid as additive.

Scheme 9.32 Proposed mechanism of palladium-catalyzed direct arylations with pivalic acid as additive.

Scheme9.33 Palladium-catalyzed direct arylation of pentafluorobenzene (102) with aryl halides 94 and 103.

C—H bond arylations of electron-deficient heteroarenes, such as azines, remain highly challenging. An elegant and versatile solution was recently elaborated, however, through a redistribution of electron density in the starting pyridine by chemical modification [77, 78]. It was found that pyridine N-oxides smoothly underwent regioselectively palladium-catalyzed direct arylations with a variety of aryl bromides (Scheme 9.36) [77a]. 

Scheme 9.36 Palladium-catalyzed direct arylation of pyridine N-oxide (115).

Scheme 9.38 Palladium-catalyzed direct arylation of tetrafluoropyridine (119).

Table 9.2 Representative examples of palladium-catalyzed direct arylations of furan (124), thiophene (125) and pyrrole (126).

Scheme 9.41 Palladium-catalyzed direct arylations of 3,4-disubstituted thiophenes 142 and 145.

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. 

An efficient method was developed for the regioselective preparation of 2-aryl- and 2,5-diarylselenophenes by the palladium-catalyzed direct arylation (14JOC5987). Examples are given below. 

In 1985, Ohta and coworkers reported on intermolecular direct arylations, and probed the palladium-catalyzed direct arylations of indole derivatives with electron-... 

During the following decades, palladium-catalyzed direct arylations proved to be valuable tools for organic synthesis, and a comprehensive review on these transformations is provided by Masahiro Miura and Tetsuya Satoh in Chapter 10. 

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