Arylations of Esters

Due to their relatively high acidity, the challenges in the arylation of esters are represented by the disposition of the ester enolates to uncatalyzed condensation reactions, or thermal decompositions. In order to suppress any undesired selfcondensation reactions, t-butyl-substituted esters are often used as substrates. 

For example, Hartwig used Pd(dba)2 in combination with P(LBu)3 or carbene-type hgands as catalysts, whilst LHMDS, NaHMDS or IiNCy2 proved to be effec- 

In 2001, Buchwald reported the a-arylation of esters using not only biphenyl-type ligands but also t-Bu-MAP [217]. The t-butyl acetates could be successfully arylated using DavePhos as ligand and LHMDS as base, and the same system was employed for the formation of a-aryl propionic esters and for the a-arylation of ethyl phenyl acetates. Aryl chlorides could also be used as coupling partners for 

A synthetically attractive approach is found in the arylation of amino acid esters, because this leads to a-aryl amino acids in a simple, yet modular fashion. This was reahzed using protected amino acid esters, most often the corresponding imines. Hartwig reported this reaction using P( Bu)3 as active ligand with K3PO4 

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Several biphenylphosphines with 2 -amino substituents are also effective in arylation of ester enolates.174 Among the esters that were successfully arylated were f-butyl acetate, /-butyl propanoate, and ethyl phenylacetate. The ester enolates were generated with LiHMDS. 

Most recently, Bentz and co-workers established that the Pd-catalyzed a-arylation of esters and amides, using Reformatsky reagents and the corresponding aryl bromides, can be successfully performed under microwave conditions.417 The reported yields are somewhat lower than those reported by Hartwig 414 however, this approach does not require the use of Q-phos and can be considered as valuable alternative for a-arylation. 

Scheme 6.43 Palladium-catalyzed a-arylation of esters and amides with organozinc reagents.

Carbonyl compounds other than ketones have been even less studied. Only Hartwig and co-workers have shown the effectiveness of the combination Pd(II)/SIPr for the a-arylation of esters [34] and amides [35] at room tem-... 

The exact mechanism of this process, however, remains unclear. It should be noted that the C-H activation in this case involves a C-H bond that is fairly acidic due to the carbonyl group, and the palladium-catalyzed a-arylation of esters by aryl halides is a well known process [68-71], Thus, one might argue that activation of this specific homobenzylic C-H bond may involve formation of a five-membered ring palladacycle, which undergoes P-hydride elimination, rather than palladium migration. 

Functionalization of pyridines from the corresponding bromo substrates has been achieved by use of Reformatsky reagents and a microwave-accelerated reaction procedure [65]. This approach utilizes Pd(0)-catalyzed a-arylation of esters and amides (Scheme 10.29). The Reformatsky reagent was prepared by microwave irradiation of tert-butyl bromoacetate or dibenzyl bromoacetamide with Zn in THF for 5 min at 100 °C. 

The arylation of esters is of importance as a synthetic method of arylacetic acids and 2-arylpropionic acids, which may exhibit antiinflammatory activity. Use of relatively bulky and strong bases such as hexamethyldisilazides has been reported to allow satisfactory results (Eqs. 18 and 19) [62-64]. The arylation of trimethylsilyl enolates of esters has also been described to occur effectively in the presence of a zinc(II) species, which proceeds via zinc enolates [65]. 

The cross-coupling of aryl halides and enolates is a powerful method to generate new C-C bonds and it has been extensively investigated using various palladium catalysts [70]. Extremely active NHC/Pd systems have been reported for the a-arylation of esters at room temperature [71] and for the arylation of amides [72]. Ketones that possess a-protons can be deprotonated in the presence of strong bases, a-Arylation of ketones can be performed in the presence of a catalytic amount of (NHC)Pd(allyl)Cl as catalyst and NaO Bu as base (Scheme 19). 

Bulky imidazolium salts 76 and 77 were found to greatly accelerate the amination of aryl chlorides using nickel catalysts <01TL5689> and palladium catalysts <01JOC7729>. to be useful ligands in the palladium-catalyzed a-arylation of esters and protected amino acids <01JACS8410>, to be catalytic, environmentally benign solvents for the cyanide displacement... 

Direct a-arylation of esters had been regarded as impossible. New methods of facile a-arylation of esters and amides have been developed as useful synthetic methods by selection of appropriate ligands and bases [41]. Bulky and electron-rich ligands such as P(t-Bu)3 and carbene ligand XVI-6 are suitable, and NaN(TMS)2, LiN(TMS)2 and LiNCy2 are used as bases. Use of t-butyl esters is recommended to minimize a... 

Zhou SJ, Huang Z (2013) Chiral phosphines for palladium-catalyzed asymmetric alpha-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity. WO/2013/028132 http //ww w. google. com/patents/WO2013028132A1 cl=en... 

In 2003, Hartwig developed the a-arylation of esters under more neutral reaction conditions [216], and with Q-Phos or its palladium(I) dimer was able to successfully arylate zinc enolates. In contrast, P(t-Bu)3 enabled arylations with silicon-based enolates, bearing potentially reactive functional groups (Scheme 3.12). 

Pd complexes catalyze the arylation of ester enolates generated in situ in the presence of a base (Buchwald, Hartwig, Scheme 19.30b) [35]. Arylation of malonates proceeds under similar... 

Moradi and Buchwald reported an extensive study on the palladium-catalyzed a-arylation of esters [100], A number of esters could be functionalized with a wide range of aryl bromides or chlorides using PdfOAc) or Pd ldbalj as catalyst, the bulky phosphane ligands, and LiHMDS as base (Scheme 8.55). Of special importance was the use of LiHMDS as the base to obtain monoarylated products in a selective manner. Good to excellent yields were obtained on the desired arylated esters with high selectivity for monoarylation [100]. 

A few years later, Hama and Hartwig reported the palladium-catalyzed a-arylation of esters with bromo [102] and chloroarenes [103]. The coupling of esters with bromoarenes occurred under mild conditions and can be conducted easily without a drybox and on a substantial scale (a 10 g scale was described), using LiNCy as the base [102]. When chloroarenes were used, NaHMDS was the base of choice to obtain the desired products in high yield [103]. 

Pd-mediated P-arylation of esters (Scheme 3.26)," a-aminoesters, " and silyl-ketene acetals has been reported. The scope of the listed method was broad with respect to functionality on the aryl halide with the exception of weak alkyl donating substituents, which did not perform well. An extension to an asynunetric variant using a chiral davephos affords asymmetric products. Enantioselectivities were modest with 3 1 favoring the /(-enantiomer being the best for the snbstrates screened. Asynunetric arylation of fused cyclopentanes via intra-molecular C—H functionalization using Pd(0) has been accomplished. ... 

The Pd(0)-mediated a-arylation of esters is an efficient and versatile tool for the preparation of a-aryl carboxylic acids and a-aryl amino acids. Using areadily available catalyst system, e.g., Pd2(dba)3 dba and carbene precursor or t-Bu3P, many aryl halides and esters, in the presence of a strong base, react to form a series of ester-protected a-aryl carboxylic acids, e.g., 6a and 7a react to give 8a. A similar protocol facilitates the a-arylation of imine-protected glycinates with aryl halides to form ester-protected a-aryl amino acids. A useful example is the reaction of 6c and 7c to give 8c (eqs 9-11). 

The palladium-catalysed -arylation of ester enolates with aryl bromides has been studied both experimentally and computationally. The effect of the ligand on the selectivity of the a/j9-arylation reactions of ortho- and mcta-bromofluorobenzenes has been described. While / -arylation was predominantly observed with 1-bromo-2-fluorobenzene for a range of biarylphosphine ligands, a-arylation was primarily observed with l-bromo-3-fluorobenzene. It has been shown that electronic factors play a major role in the a// -arylation selectivity, with electron-withdrawing substituents favouring 0-arylation. 

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