Arylations palladium pivalate

A study of the palladium-catalysed reaction of benzene with iodoarenes has included a synthesis of a phosphine-ligated aryl palladium pivalate complex. However, this species fails to form the biaryl product and it is suggested that a ligandless arylpalladium(II) carboxylate complex is involved in the carbon-hydrogen cleavage step. In the palladium-catalysed reaction of cyanobenzene with iodoarenes in trifluoroacetic acid, biphenyl derivatives are formed by substitution of hydrogen ortho to the cyano group. The first step in the process is likely to involve co-ordination of... 

They were able to extend the scope of the direct arylation to simple, completely unactivated arenes, such as benzenes by development of a palladium-pivalic acid co-catalyst system (Scheme 28) [48]. 

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

Coupling Reactions. Palladium pivalate is an effective catalyst for mild and efficient direct arylation reactions. One account described the intramolecular arylation phenolic ethers (eq 1). Initial optimization with Pd(OAc)2 in conjunction with electron-deficient phosphines led to the desired biphenyl in low yield. Upon the addition of carboxylic acid additives, the yield improved markedly with the optimal additive being pivalic acid. Indeed it was determined that the additive was not needed when Pd(OPiv)2 was errqtloyed as a catalyse although improved yields were observed when the title compound was used in conjunction with the acid additive. The role of the pivalate is believed to be that of a proton shuttle in a concerted metallation-deprotonation (CMD) sequence. A further advantage of using Pd(OPiv)2 was the rate enhancement of the arylation with most reactions complete in less than 6 h (vs. 12 or more hours with Pd(OAc)2). The catalyst was applied to a range of electron-rich and -deficient arenes with good to excellent yields. 

Imidazole /V-oxide substrates may be used in a similar fashion. Initial investigations revealed that the use of palladium acetate in conjunction with an electron deficient 4-fluorophenylphosphine in acetonitrile at 70 °C provides C2 arylation in high yields. With the goal of achieving the same reactivity at or near room temperature it was determined that the use of palladium acetate in conjunction with a Buchwald ligand, catalytic copper bromide and 30 mol% pivalic acid in acetonitrile could also achieve high yields of C2 arylation at 25 °C. As was the case with thiazole V-oxides. if the C2 and C5 positions of the imidazole are blocked C4 arylation may also be achieved in synthetically useful yield (Scheme 15). 

O/t/20-arylation of benzoic acids is often preferable to ortho-arylation of benzamides if conversion of the amide moiety to other functional groups is desired. However, only a few reports have dealt with the orf/io-functionalization of free benzoic acids due to challenges that involve such transformations. The reactions can be complicated by decarboxylation of the product and the starting material. Despite those difficulties, several methods for direct o/t/io-arylation of benzoic acids have been developed. Yu has shown that arylboronates are effective in arylation of benzoic acids under palladium catalysis [59], The reactions require the presence of palladium acetate catalyst, silver carbonate oxidant, and benzoquinone. Even more interestingly, the procedure is applicable to the arylation of unactivated sp3 C-H bonds in tertiary carboxylic acids such as pivalic acid (Scheme 13) if aryl iodide coupling partner is used. Aryl trifluoroborates can also be used [60],... 

Scheme 14 Vinylic to aryl to allylic palladium migration followed by pivalate displacement...

Lafrance M, Fagnou K (2006) Palladium-catalyzed benzene arylation incorporation of catalytic pivalic acid as a proton shuttle and a key element in catalyst design. J Am Chem Soc 128 16496-16497... 

Further improvements in palladium catalysis were achieved with a larger excess of benzene as co-solvent, and also with DavePhos (95) as ligand and pivalic acid as additive (Scheme 9.31) [70]. This catalytic system tolerated various valuable functional groups, such as a nitro substituent. These reaction conditions allowed not only for the achievement of better yields of biaryls with aryl bromides as electrophiles, but also improved chemoselectivies of these transformations. Thus, in competition experiments between benzene (87) and fluorobenzene (96), the latter reacted preferentially in a ratio of >11 < 1 (Scheme 9.31) [70],... 

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

All C-H activation procedures for polymers reported thus far have been carried out under dry inert atmosphere using sealed vessels (Schlenk glassware). Similar to small-molecule procedures, polar (DMF, DMAc) and nonpolar (toluene, THE) aprotic solvents have been used and are degassed prior to use. Most thiophene-based monomers are not commercially available and must be synthesized according to literature procedures. It is very important that these monomers be extremely pure and free of all aryl impurities since other aryl bonds may undergo C-H activation and be incorporated into the polymer. All examples have employed palladium (II) acetate or the Herrmann-Beller catalyst. The latter can be prepared from Pd(OAc)2 and tris-(t)-tolyl)phosphine. All phosphine ligands, anhydrous bases and pivalic acid are commercially available and are stored under inert atmosphere. 

Fagnou and co-workers disclosed an effective palladium-catalyzed protocol for direct arylations of unactivated arenes using aryl bromides.A catalytic system comprising of [Pd(OAc)2] and DavePhos as ligand, along with substoichiometric amounts of pivalic acid 78, generated a highly active catalyst for the arylation of simple arenes like benzene 6 (Scheme 20). 

Using a similar protocol involving pivalic acid as an additive, the palladium-catalyzed regioselective C6-arylation of 3-aminoimidazo[ l,2-a]pyrazine was accomplished (eq 25). The use of di-teTt-butyl(methyl)phosphonium tetrafluoroborate as a ligand provided the products of C6 and C2 arylation in a ratio of 49 1. Furthermore, the competitive C2 -H activation pathway was avoided by replacing di-fert-butyl(methyl)phosphonium tetrafluoroborate by triphenylphosphine. ... 

Thiophenes could be directly arylated under phosphine-free, pivalate-mediated conditions with low catalyst loading using a bis(alkoxo)palladium(II) complex (eq 16). ... 

The Ar-H functionalization approach has also been used in the preparation of polymers. For instance, a diketopyrrolopyrrole-based polymer was prepared via a palladium-catalyzed direct C-H (hetero)arylation reaction between a di(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-l,4-dione and 4,7-dibromo-2,l,3-benzothiadiazole (eq31). The reaction was conducted using palladium acetate as the catalyst and pivalic acid as an additive. A survey of different phosphines demonstrated that molecular weights of the same order and similar polydispersity indexes (PDI) were obtained using tri-terf-butylphosphonium and tri-ferf-cyclohexyl tetrafluoroborate. ... 

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