Functionalizations pivalic acid

Carboxylic mixed anhydrides are very important for the rapid synthesis of peptides by the stepwise procedure,however the use of carboxylic mixed anhydrides,e.g.those derived from pivalic acid and a protected amino acid (1),suffers from two disadvantages. Firstly,regiospecificity of attack at the desired carboxyl function is largely determined by steric effects and will not be 100% for all coupling reactions.Secondly,such mixed anhydrides have a propensity towards disproportionation to symmetric anhydrides which is highly undesirable in terms of reaction efficiency.This latter process can be depressed by operation of the reaction at -15 °C, but with the concurrent decrease in reaction rate and,on large scale manufacture,increased costs. 

In an approach to direct C-functionalization of triazolo[4,5-c]pyridines, shown in Scheme 3, 1-methyl (or phenyl)[l,2,3]triazolo[4,5-c]pyridines (26,33) are alkylated exclusively at C-4 by radicals generated by decarboxylation of carboxylic acids (ammonium persulfate-sulfuric acid-silver nitrate) <90ZOB683>. However, with /-butanol various products are obtained depending on the catalyst employed. For example, with ammonium persulfate-sulfuric acid-silver nitrate, exclusive C(4)-methylation (34) was observed, while ammonium persulfate-sulfuric acid gave exclusively C(4)-/ -hydroxy-/ ,/ -dimethylethylation (cf. (36)). The /-butyl analogue (35) was obtained by decarboxylation of pivalic acid. 

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],... 

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],... 

An exceptional case of an acylphosphonate in which nucleophiles react at the phosphorus rather than at the carbonyl is that of the mixed anhydride of pivalic acid and pivaloylphosphonyl monoester of 5 0-DMT-2 -deoxythymidine (equation 54). In this compound the keto function is especially unreactive, because of steric hindrance, while the phosphorus is unusually electrophilic, being both a mixed anhydride and an acylphos-phonyl function at the same time. As a consequence of these structural features, this compound reacts at the phosphorus with nucleophiles, such as water, ethanol or pyridine, to give products resulting from P—O bond cleavage (equation 54). 

When the fully functionalized, stereochemically pure side chain and the fully substituted diketone were treated under very carefully defined conditions (1 equiv. pivalic acid, 1 4 1 toluene/heptanesyTHF), a 75% yield of the penta-substitued pyrrole was obtained.Deprotection and formation of the hemi-calcium salt produced stereochemically pure atorvastatin calcium in a convergent, high-yielding, and commercially viable manner. 

Considerable effort in the past few years has been devoted to the development and the study of rapid and efficient analytical methods for the determination of functionality in coal and coal derived products (2-11). The determination of phenol and alcohol moieties by acetylation has been used routinely for several years (1,3-7). Recently several groups have used silylation in combination with Infrared,(10) proton NMR (2) and atomic adsorption spectroscopy (3) to determine phenolic and alcoholic content of coal and coal derived products. Triethylborane activated by pivalic acid has been used very recently as a reagent for the determination of hydroxyl groups in lignites (11). 

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). ... 

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. 

Silver(I) carbonate functioned as an oxidant in combination with TBAI to provide optimal yields. Pivalic acid was superior to pyridine as an additive. Thiazole, pyrazole, thiophene, and pyrrole substrates could be cross-coupled however, heteroarenes bearing electron-donating substituents afforded better yields compared with electron-withdrawing groups. The reactions proceeded in high regioselectivity at the C2/C5 position. 

Direct Alkenylation of Heteroarenes. Pivalic acid enhanced both yield and selectivity for the C2-selective olefination of pyridine. Other acid additives performed inferiorly to pivalic acid 2.5 equiv of PivOH was the ideal amount to maximize product yield. Silver(I) acetate functioned as a terminal oxidant and also positively influenced yield and selectivity. Only small amounts of C3 product were detected. 

Silver(I) salts can also function as an terminal oxidant in the C2-selective olefination of pyridine improvements in both yield and C2 selectivity were observed when less basic AgOAc was employed in place of Ag2C03 as an oxidant. Maximal yields were achievable when pivalic acid was added. Of note, only small amounts of C3 product were detected. 

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. ... 

C5-arylation of iV-protected L-histidine could be achieved using microwave irradiation via a Pd-catalyzed process employing pivalic acid and tricyclohexylphosphine (eq 2 ) Other phosphines, such as PPhs and P(2-furyl)3, produced diminished conversions. Moderate yields could be obtained without a ligand (54%), albeit tricyclohexylphosphine was required to maximize product formation. Good functional group tolerance was observed for aryl iodide coupling partners orf/zo-substitution and sensitive groups, such as cyano, nitro, ester, and chloro substrates, were compatible. Aryl bromides could also be employed, albeit with diminished yields (10-18%). 

There is still another effect which might contribute to anomalous behaviour, and this is the intermolecular interaction of proton donor and proton acceptor which can occur as these two come together to form a transition state [53]. Steric hindrance is a common manifestation of this effect [54]. It is well-known, for example, that, although alkyl substitution at the 2- and 6-positions of pyridines raises the basicity of these substances, it often lowers their ability to function as proton acceptors [55]. Hydrophobic interactions can also be significant, and the fact that pivalic acid is sometimes a better acid catalyst than its pK would suggest has been attributed to this effect [56]. Polar interactions are another source of the intermolecular effect. In the acid-catalysed hydrolysis of ethyl vinyl ether, for example,... 

Various functional alkenes were similarly synthesized with high regio and E-stereoselective manner via [RuCl2(p-cymene)]2/AgSbF6 catalysed hydroarylation of phenyl or ester substituted alkynes with aromatic carbamates. The addition of 5 equiv. of pivalic acid improves the reaction in 1,4-dioxane. The alkenyl ester is converted into carboxylic acid by using 2 equiv. of LiOH, whereas phenol derivatives were deprotected by addition of 10 equiv. of LiOH [(Eq. 82)] [166]. 

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