Preparation of Phenols Nucleophilic Aromatic Substitution

Preparation of Phenols Nucleophilic Aromatic Substitution Useful new methods for synthesizing benzene derivatives. 

General. Toluene, chlorobenzene, and o-dichlorobenzene were distilled from calcium hydride prior to use. 4-Dimethylaminopyridine (Aldrich Chemical Co) was recrystalled (EtOAc), and the other 4-dialkylaminopyridines were distilled prior to use. PEG S, PEGM s, PVP s, and crown ethers were obtained from Aldrich Chemical Co., and were used without purification. BuJ r and BU. PBr were recrystallized (toluene). A Varian 3700 VrC interfaced with a Spectraphysics SP-4000 data system was used for VPC analyses. A Dupont Instruments Model 850 HPLC (also interfaced with the SP-4000) was used for LC analyses. All products of nucleophilic aromatic substitution were identified by comparison to authentic material prepared from reaction in DMF or DMAc. Alkali phenolates or thiol ates were pre-formed via reaction of aqueous NaOH or KOH and the requisite phenol or thiophenol in water under nitrogen, followed by azeotropic removal of water with toluene. The salts were transferred to jars under nitrogen, and were dried at 120 under vacuum for 20 hr, and were stored and handled in a nitrogen dry box. 

This diazotization reaction is compatible with the presence of a wide variety of substituents on the benzene ring. Arenediazonium salts are extremely important in synthetic chemistry, because the diazonio group (N=N) can be replaced by a nucleophile in a radical substitution reaction, e.g. preparation of phenol, chlorobenzene and bromobenzene. Under proper conditions, arenediazonium salts react with certain aromatic compounds to yield products of the general formula Ar-N=N-Ar, called azo compounds. In this coupling reaction, the nitrogen of the diazonium group is retained in the product. 

Miller and coworkers prepared and investigated 2,5-bis-(sulfonyl)pyr-azines 153 as building blocks and studied their nucleophilic aromatic substitution reactions (Scheme 76) (13TL1938). In most cases, such as with phenols, alkoxides, anilines, aliphatic amines, heterocychc amines, and a carbanion formed from diethyl malonate with sodium hydride, only the monosubstituted sulfonylpyrazine was obtained. Reactions with two equivalents of either thiols or thiophenols, however, yielded only bis-thiopyrazines, such as compound 154, shown in Scheme 76. While the yields for the reactions with the other nucleophiles were good to high, those for reactions with aliphatic amines or anilines as the nucleophile were low to moderate. 

The above reaction resembles previously mentioned preparation of Meisenheimer adducts by reaction of benzofuroxan with potassium carbonate in aqueous solution. It is interesting that using 7-chlorofuroxan instead of furoxan as a starting material, under otherwise similar conditions, leads to a nucleophilic aromatic substitution and formation of fully aromatic phenol salts. The same is true for furazans (Read, Personal Communication). 

Phenols have been prepared on solid phase by aromatic nucleophilic substitution with hydroxide, by thermal rearrangement of vinylcyclobutenones, by oxidative coupling of phenols (Figure 5.20 [65]), by cyclocondensation reactions with simultaneous release of the phenols into solution (Entry 12, Table 7.6), and by Claisen rearrangement [66]. 

In principle, cyclohexadienones can be accessed through tautomerization of the corresponding phenol. However, the loss of aromatic stabilization makes this impractical in all but the most specialized of cases. In order to access an isolable cyclohexadienone, the aromaticity of the phenol must be destroyed. One way to do this is through C-alkylation, but this is mostly limited to intramolecular electrophiles. Oxidative dearomatization of the phenol is by far the most conunon method used to prepare both 2,4- and 2,5-cyclohexadienones. A variety of oxidants can be used for this transforma-tiOTi, but iodine(III)- and iodine(V)-based oxidants" have emerged as the reagents of choice in many cases. An attractive feature of these oxidants, especially those based on iodine(III), is that they can be used with a variety of different nucleophiles, thereby providing access to cyclohexadienones with different substitutents. 

The direct nucleophilic substitution of electron-rich phenol ethers using hypervalent iodine oxidants in the presence of Lewis acid or fluorinated alcohols and involving aromatic cation-radical intermediates was originally developed by Kita and coworkers in 1994 [362], Since then this procedure with some variations has been extensively applied by Kita and other researchers for various oxidative transformations. In the intermolecular mode, this reaction (Scheme 3.122) has been utilized for the preparation of the products 298 from N3, AcO , ArS, SCN , 3-dicarbony 1 compounds and other external nucleophiles [320]. The oxidative coupling reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various... 

The Ullman reaction has long been known as a method for the synthesis of aromatic ethers by the reaction of a phenol with an aromatic halide in the presence of a copper compound as a catalyst. It is a variation on the nucleophilic substitution reaction since a phenolic salt reacts with the halide. Nonactivated aromatic halides can be used in the synthesis of poly(arylene edier)s, dius providing a way of obtaining structures not available by the conventional nucleophilic route. The ease of halogen displacement was found to be the reverse of that observed for activated nucleophilic substitution reaction, that is, I > Br > Cl F. The polymerizations are conducted in benzophenone with a cuprous chloride-pyridine complex as a catalyst. Bromine compounds are the favored reactants.53,124 127 Poly(arylene ether)s have been prepared by Ullman coupling of bisphenols and... 

Sulfonated PAES random copolymers can be prepared by the by potassium carbonate mediated direct aromatic nucleophilic substitution polycondensation of disodium 3,3 -disulfonate-4,4 -dichlorodiphenyl sulfone, 4,4 -dichlorodiphenyl sulfone and BP. The condensation reaction proceeds quantitatively to high molecular weight in A-methyl-2-pyrroUdone (NMP) at 190°C. In addition, a monofunctional monomer, 4-tert-butyl-phenol, can be used as an end capping reagent. The phenol functional group has a similar reactivity as biphenol. In this way, the molecular weight can be controlled. 

Aromatic alcohols (phenols) can be prepared by treatment of a diazonium salt (ArN2 ) with water, acid, and heat. In this substitution reaction, water acts as a nucleophile and replaces the excellent nitrogen leaving group (N2) on the diazonium salt. The diazonium salt is prepared in three steps from benzene (or a substituted benzene derivative, but such compounds will be addressed in a later part of this book). First, nitration of benzene with HNO3 and H2SO4... 

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