Arylations pivalic acid

M Fe over the rate in the absence of Fe" ". The reaction was hindered by complexation of Fe " by CN , and produced pivalic acid as a by-product. Reduction was promoted more effectively by Cu than by Fe, and N-aryl-hydroxylamines added to the reaction mixture were oxidized to nitroso... 

The intermolecular direct arylation of simple benzenes was also evaluated [12]. Under conditions established for the fluorinated substrates, none of the desired cross-coupled product was formed. With the goal of increasing the amount of soluble base in the reaction mixture, varying amounts of different carboxylic acids were added. Both the amount and the type of acid was found to influence significantly the reaction outcome, with larger acids used in substoichiometric amounts providing superior outcomes. For example, as the steric bulk is increased from acetic acid to pivalic acid, an increase in conversion is noted. Under optimal conditions, addition of 30 mol% pivalic acid results in 100% conversion of the aryl bromide and an 82% isolated yield of benzene direct arylation is obtained. To rationalize the reactivity, it was proposed that the potassium pivalate may behave as... 

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],... 

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]. 

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.

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

In the Pd-catalyzed arylation of unactivated aienes such as benzene with ArBr, pivalic acid is a key cocatalyst. ... 

Atyl carbo lates and alkenyl acetates were also catalytically coupled with arylboroxines using NiCl2(PCy3)2 (Scheme 14.22). It was found that water can promote this transformation. The optimal amount of water is 0.88 equivalents (based on the acetate) for the atyl carbojgrlates and 1.0 equivalents for the alkenyl acetates.However, NiCl2(PCy3)2-catalysed coupling of aryl pivalates with aryl boronic acids does not require a water additive. ... 

Arylation reactions with the bidentate phosphines most likely proceed by the intermoiecuiar proton-abstraction mechanism, which is supported by DFT calculations as shown in the transformation of 41 into 42 (Scheme 11.12) [39]. Although the addition of pivalic acid has a beneficial effect in many cases, the fact that the... 

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). 

Chelation-assisted alkenylation of the ortho-C-H bond of aryl carbamates Ar-OCONEt2 with alkynes R C=CR, catalysed by [(p-cymene)RuCl2]2 in the presence of AgSbFg and pivalic acid at 100 °C over <24 h, has been shown to proceed... 

Aryl- and alkyl-carboxylic dihalophosphoric anhydrides acylate activated arenes without the need for a conventional Friedel-Crafts catalyst. The anhydrides are prepared in situ, and the low temperatures required (20 C) allow reasonable yields of ketones to be obtained from mixed anhydrides of low stability, for example those derived from acetic and pivalic acids [equation (8)]. 

The modified procedure involving pivalic acid has also been used to regioselectively arylate a pyridine iV-oxide at the a-position in the presence of an indolyl fragment (eq 8). ... 

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. ... 

A broadly applicable system for the arylation of various heterocycles with aryl bromides involves the employment of pivalic acid, along with Pd(OAc)2 and PCys (eq 160). It is h)q)othesized that the reaction involves a concerted metalation-deprotonation pathway. Other five-membered heterocycles react at the highlighted C-H position (eq 160). The same group also introduced electron-deficient fluoroarylphosphines for the direct functionalization of heteroarenes with aryl iodides. In the former report, low yields were obtained with 2-bromDpyridine or aryl halides bearing substituents such as nitro or cyano. A microwave-assisted protocol was instead developed that could overcome these limitations. ... 

Direct Arylation of Imidazo[l,2-a]pyrazines. A sequential arylation of the C-3 and C-5 positions of imidazo[ l,2-a]pyrazines was developed in the presence of Pd(OAc)2 (eq 177). The first functionalization employs pivalic acid as the proton shuttle, while the second arylation occurs under air using phen as the ligand for Pd. A one-pot, sequential reaction employing the conditions in eq 177 is also possible. Moreover, C-6 arylation oecurs with >100 1 selectivity over the C-5 and C-2 positions for a substituted imidazopyrazine under CMD conditions (eq 178). ... 

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. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

Regioselective arylation of substituted isoquinolines was also viable. Notably, by switching Irom pivalic acid to 2,2-dimethylhexanoic acid, less reactive pyridine substrates, such... 

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