Aryl halides nucleophilic coupling

A variety of substituted aromatic compounds have been prepared through addition of anionic nucleophiles to arynes generated from readily accessible precursors.1 Most of the laboratory preparations start with aryl halides. The coupling yields are usually good to modest (equations 13-15) but can be poor (equation 16).83 Sometimes, a dramatic improvement in reaction efficiency can be achieved by the change of the base/solvent pair or other reaction conditions. For instance, in arylation of phenoxides and benzenethiolates, a switch over to DMSO as the solvent boosted the yield considerably (equation 17).86 Another example, illustrative of this point, is the reaction of N-methylpyrrolidone with aryl halides where an acceptable yield could not be obtained under a variety of conditions except with LICA in THF (equation 18).71... 

Today microemulsions are used in catalysis, preparation of submicron particles, solar energy conversion, extraction of minerals and protein, detergency and lubrication [58]. Most studies in the field of basic research have dealt with the physical chemistry of the systems themselves and only recently have microemulsions been used as a reaction medium in organic synthesis. The reactions investigated to date include nucleophilic substitution and additions [59], oxidations [59-61], alkylation [62], synthesis of trialkylamines [63], coupling of aryl halides [64], nitration of phenols [65], photoamidation of fluoroolefins [66] and some Diels-Alder reactions. 

Aryldiazonium salts, usually obtained from arylamines, undergo replacement of the diazonium group with a variety of nucleophiles to provide advantageous methods for producing aryl halides, cyanides, phenols and arenes by reductive removal of the diazo group. Coupling reaction of aryldiazonium salts with phenols or arylamines give rise to the formation of azo dyes. 

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

Instead of quenching with deuterium chloride, the intermediary organomonozinc compound can be used as a new nucleophile. Not only allylic halide but also alkenyl or aryl halide can be used as the first electrophile with bis(iodozincio)methane (3). In Scheme 23, examples for sequential coupling are summarized. In the case of coupling with bromoalkene, a nickel catalyst is more effective than a palladium catalyst. 

The coupling of aryl halides and classical carbon nucleophiles, such as malonates, is also feasible in the presence of a properly selected palladium or copper catalyst. Diethyl malonate and 3-iodopyridine, for example, gave diethyl 2-(3 -pyridyl)malonate in 73% yield (7.84.), The optimal catalyst in this process consisted of copper(I) iodide and 2-hydroxylbiphenyl.106... 

Substitutions by the SRn 1 mechanism (substitution, radical-nucleophilic, unimolecular) are a well-studied group of reactions which involve SET steps and radical anion intermediates (see Scheme 10.4). They have been elucidated for a range of precursors which include aryl, vinyl and bridgehead halides (i.e. halides which cannot undergo SN1 or SN2 mechanisms), and substituted nitro compounds. Studies of aryl halide reactions are discussed in Chapter 2. The methods used to determine the mechanisms of these reactions include inhibition and trapping studies, ESR spectroscopy, variation of the functional group and nucleophile reactivity coupled with product analysis, and the effect of solvent. We exemplify SRN1 mechanistic studies with the reactions of o -substituted nitroalkanes (Scheme 10.29) [23,24]. 

This reaction allows the alkylation of aryl halides. The more reactive alkyl halide forms an organosodium first, and this reacts as a nucleophile with an aryl halide as the electrophile. Excess alkyl halide and sodium may be used if the symmetric coupled alkanes formed as a side product may be separated readily. 

S. Kozuch, A. Jutand, C. Amatore, S. Shaik, Organometallics 24, 2139 (2005). What Makes for a Good Catalytic Cycle A Theoretical Study of the Role of Anionic Palladium(O) in the Cross-Coupling Reaction of An Aryl Halide with an Anionic Nucleophile. 

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