Reactions of Aryl Halides with Phenols

As noted in the introduction to this section, UUmann also reported the formation of biaryl ethers from phenol and phenyl bromide in the presence of copper and a base. This UUmann ether synthesis has been used extensively to prepare biaryl ethers. However, the original reaction conditions involved high temperatures (150-200 C), neat phenol or highly polar aprotic solvents, and stoichiometric amounts of copper complexes. The yields for the reactions of unactivated aryl halides were often low. Conditions with catalytic amounts of copper at lower temperatures with broader scope have now been developed. 

Examples of the coupling of aryl iodides and bromides with phenols in the presence of catalytic amounts of copper are shown in Equations 19.107-19.113. The reactions of aryl iodides and bromides with a variety of phenols occur in the presence of (CuOTf), PhH as catalyst and CSjCOj as base (Equation 19.107). The air-stable [Cu(MeCN)JPF (5 mol %) also was shown to catalyze the formation of biaryl ethers. As shown in Equation 19.108, o-halo tertiary and secondary benzamides and.sulfonamides that were prepared by ortho-metallation procedures were suitable coupling partners.  

Copper catalysts for the formation of biaryl ethers have also been developed that contain diketonate ligands. Researchers at Merck Laboratories reported the coupling of aryl halides with phenols catalyzed by the combination of CuCl and 2,2,6,6-tetramethylhep-tane-3,5-dione (TMHD), which generates a copper diketonate catalyst (Equation 19.111). Catalysts containing related O-donor ligands have also been used. Two examples of reactions conducted with a polyol and with a phosphonic acid as ligand are shown in Equation 19.112 and Equation 19.113.  

CHAPTER 19 TRANSITION METAL-CATALYZED COUPLING REACTIONS 

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Another Ullmann synthesis is the syntheses of arylethers or diarylamines by the condensation reactions of aryl halides with phenols or arylamines. For example, reactions are shown in eqs. (22.16) [62] and (22.17) [63], and especially the former reaction is used for the production of polyphenylether type heat-resistant synthetic lubricants. 

Reactions of aryl halides with phenoxides or phenols (Equation (30)) and base catalyzed by complexes of these ligands occurred in significantly higher yields than did the same reactions catalyzed by complexes of DPPF or BINAP. For example, a large number of diaryl ethers have... 

In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as ffirans, thiophenes, pyrroles, oxa-zoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called heteroaryl Heck reactions [2]. 

Intermolecular arylation of carbocyclic arenes are rare. Exceptionally, phenols are easily arylated. As treated in Chapter 3.7.4, the aryl ether 48 is formed by reaction of aryl halides with hydroquinone monomethyl ether when bulky and electron-rich phosphines are used, which accelerate reductive elimination. Miura and co-workers found new completely different reactions of phenol with bromobenzene by using Pd(OAc)2, PPhs and CS2CO3 to give the unexpected pentaphenylated product 49 in 58% yield [lb, 15]. 

In none of our extensive test reactions of aryl halides with benzoic acids carried out in the presence of diverse palladium catalysts, we were able to detect even traces of the unsymmetrical biaryl. Instead, we observed mostly homocoupling and dehalogenation products in some cases along with phenol esters. The conversion of aryl triflates with potassium benzoates did not lead to the desired biaryls, either, but to the phenol esters instead. 

Venkataraman used a well-defined coordination complex as the catalyst for the crosscoupling of aryl halides with phenols. Cesium carbonate was the base for the reaction (Scheme 2.64) [92]. The synthesis of the catalyst was trivial and consisted of simply... 

The aryl ether formation was, until the late 1990s, the domain of copper-catalyzed processes, namely the Ullmann reaction. Around 15 years ago, Hartwig and Buchwald independently discovered the palladium-catalyzed alkoxylation of aryl halides with phenols. Later, these reactions were extended to aliphatic alcohols and to hydroxide as nucleophiles (vide infra. Scheme 5-159). The mechanism of the reductive elimination has been elucidated on isolated complexes. ... 

Abstract Although requiring the use of stoichiometric amounts of metal and harsh conditions, the copper-mediated coupling reactions of aryl halides with amines and phenols (Ullmann craidensatiOTis), amides and carbamates (Ullmann-Goldberg condensations), or activated methylene compounds (Ullmann-Hurtley condensations) have been for a long time useful methods for the formation of C(aryl)-N, C(aryl)-0, and C(aryl)-C bonds. In 2001, a renaissance of the Ullmann reaction has been initiated with the discovery of versatile new copper catalytic systems for C-C, C-N, or C-O coupling under mild temperature ccmditions. 

For model reactions, we chose the aromatic substitution of aryl halides with nucleophiles such as phenolates or amines. The reaction parameters particularly focused upon were reaction time, selectivity, work-up procedure, and overall processing time. 

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. 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

The SjvAr reaction is another attractive method for diaryl ether synthesis, and reactions of o-nitro- and o-cyanofluorobenzenes with phenols were reported . 7r-Complexation of aryl halides with transition metals activates the aromatic nuclei toward S fAr. Segal employed a ruthenium chlorobenzene complex in the poly(aryl ether) synthesis , and the methodology was extensively studied by Pearson, Rich and their coworkers using manganese complex and later iron and ruthenium complexes in natural product synthesis " . The intramolecular substitution of an aromatic chloride with a phenylalanine derivative takes place at room temperature without racemization (equation 27). 

Over a century ago, Ullmann reported coupling reactions catalysed by metallic copper. ° ° The harsh conditions typically involved limited its applicability, but Ullmann s work ultimately stimulated the search for milder conditions using copper catalysis. Both copper(I) and copper(II) salts can catalyse the coupling of aryl halides with a range of heteroatom nucleophiles, including phenols (Scheme 2.168, 2.169), ° alcohols (Scheme 2.170),thiols (Scheme 2.171, 2.172), amines (Scheme 2.173), anilines (Scheme 2.174)2" and A/ -heterocycles (Scheme 2.175,2.176).2i2.2i3... 

Ullman reaction The synthesis of diaryls by the condensation of aromatic halides with themselves or other aromatic halides, with the concomitant removal of halogens by a metal, e.g. copper powder thus bromobenzene gives diphenyl. The reaction may be extended to the preparation of diaryl ethers and diaryl thio-ethers by coupling a metal phenolate with an aryl halide. 

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. 

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