Phenoxides, with aryl halides

Substitution between various nucleophiles (e.g. substituted phenoxides) with aryl halides. The most common of these is the Ullmann Ether Synthesis. 

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... 

Another phenoxide activating approach published by Buchwald et al. [18] is based on the reaction of cesium phenoxides with aryl bromides or iodides in the presence of catalytic amounts of copper(I) triflate and ethyl acetate in refluxing toluene (Scheme 3b). In certain cases equimolar amounts of 1-naphthoic acid have been added in order to increase the reactivity of the phenoxide. The authors assume the formation of a cuprate-like intermediate of the structure [(ArO)2Cu] Cs+ as the reactive species. In addition, diaryl ether formation between phenols and aryl halides has been achieved using a phosphazene base forming naked phenoxide in the presence of copper bromide in refluxing toluene or 1,4-dioxane [19]. 

In the preparation of substituted diaryl ethers (ArOAr ), the reaction of alkali phenoxides and aryl halides is catalyzed by copper (Ullmann). Further studies have shown that the yield varies considerably with different copper-catalyst preparations. ... 

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... 

Alkoxide or aryloxide anions are also reputed to be inactive in Sr I reactions. There is, however, one example of such a reaction at an sp carbon the nitro-derivative of 4-nitrocumyl reacts with phenoxide and 1-methyl-2-naphthoxide ions yielding the corresponding ethers (Kornblum et al., 1967). A similar reaction has been reported for halobenzenes in t-butyl alcohol upon stimulation by sodium amalgam (Rajan and Sridaran, 1977). This reaction could not, however, be reproduced (Rossi and Pierini, 1980) and other attempts to make phenoxide ions react at sp carbons have been equally unsuccessful (Ciminale et al, 1978 Rossi and Bunnett, 1973 Semmelhack and Bargar, 1980). It has been found, more recently, that phenoxide ions react with a series of aryl halides under electrochemical induction, but that the coupling occurs at the p- or o-phenolic carbon rather than at the phenolic oxygen (Alam et al, 1988 Amatore et al, 1988). This is... 

Additional studies showed that iodoferrocene was approximately as reactive as l-iodo-2-nitrobenzene under Ullmann conditions. A mixed Ullmann reaction involving these two reactive aryl halides produced 2-nitrophenylferrocene. Ullmann condensations of iodoferrocene with various sodium phenoxides and sodium arenethiolates likewise led to ferrocenyl aryl ethers and sulfides, respectively (84, 85). 

In the reaction of activated aryl halides with phenoxide and thiophenoxide in chloro- or o-dichloro-benzene at reflux, pyridinium salts (48 R, R = —-CH2CH2CHMeCH2CH2— R = Me, Bu", n-C6Hi3 R = CH2CHEtBu, CH2BU1) proved to be superior catalysts to simpler onium salts, like TBAB, due mainly to their greater thermal stability.162... 

Separation of the p-nitro-substituted aryl halide and reaction with phenoxide ion complete the synthesis. 

As noted earlier in this section, aryl halides generally do not undergo substitution reactions. However, under conditions of high temperature and pressure, these compounds can be forced to undergo substitution reactions. For example, under high temperature and pressure, chlorobenzene can be converted into sodium phenoxide when reacted with sodium hydroxide. 

Unactivated substrates also react with phenoxide ion with electrochemical catalysis in liquid NH3-Me2SO, to give diaryl ethers, presumably by the Sr I mechanism. Diaryl ethers can be prepared from activated aryl halides by treatment with a triaryl phosphate, (ArO)3PO. ... 

The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide (Sec. 15.7). Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution. 

Synthesis of aromatic ethers has been performed under solvent-free phase-transfer catalysis conditions by reaction of several aryl halides with potassium methoxide or phenoxide in the presence of a catalytic amount of 18-crown-6. The specific MW effects were shown to be very dependent on the nucleophile and on the structure of the aromatic compound (activated or nonactivated, chloride or fluoride) (Eq. (56), Table 4.17) [96, 142]. 

Phenoxides can be used in a Williamson ether synthesis by reaction with alkyl halides (Sjj2 process) to create aUg l-aryl ethers. 

An apparent exception to the generalization about the lack of reactivity of aryl halides to nucleophilic substitution is an early industrial process for the synthesis of phenol from chlorobenzene. When heated at 300°C under high pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide. Neutralization of this salt with aqueous acid gives phenol. 

The aryl ether linkage is important in many natural products and pharmaceuticals, including the antibiotic vancomycin [196]. Diaryl ethers have been efficiently prepared by the coupling of fluo-robenzonitriles with a series of phenols in DMSO using potassium carbonate as a base catalyst and with microwave irradiation [197]. A DPT study of the reaction of alkali metal phenoxides with fluo-robenzenes indicated that the role of the metal cation is to aid the binding of the aryl halide and to facilitate fluoride displacement [198]. 

It is interesting to note that the very widely used Makosza catalyst , benzyl triethyl ammonium chloride, does not show high efficiency in this study. 4) Phosphonium ions are somewhat more effective and thermally stable than the corresponding ammonium catalysts and both are better than arsonium systems. 5) Substitution of the quaternary ion by alkyl rather than aryl groups yields more effective catalysts. 6) Reaction rates are generally greater in orf/io-dichlorobenzene (and presumably in other chlorocarbon media) than in benzene, and botli are better than heptane. In connection with this latter point, Ugelstad and coworkers have studied the reactions of quaternary ammonium phenoxide ions with alkyl halides in a variety of media and concluded that the... 

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