Phenolic nucleophiles

When phenolic nucleophiles were used, either potassium hydroxide or potassium f-butoxide was generally chosen as the base. When aliphatic hydroxyls constituted the nucleophiles, a stronger base was required and sodium hydride was generally chosen. 

Relaxation kinetics. In the course of a study of hemiacetal formation with a phenol nucleophile, an equation was given for the relaxation time in the system ... 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Reactions of a wide range of substituted phenyl acetates with six a-effect nucleophiles have revealed little or no difference, compared with phenolate nucleophiles, in the values of the Leffler parameters. As a result, the case for a special electronic explanation of the a-effect is considered unproven. Studies of the kinetics and mechanism of the aminolysis and alkaline hydrolysis of a series of 4-substituted (21) and 6-substituted naphthyl acetates (22) have revealed that, for electron-withdrawing substituents, aminolysis for both series proceeds through an unassisted nucleophilic substitution pathway. 

Nucleophilic addition of phenolic nucleophiles to l,l-dicyano-2-arylethenes in the gas phase and in water has been studied theoretically" using the semiempirical AMI method and the Cramer-Truhlar solvation model SM2.1. The difference between the Brpnsted coefficients (a" = 0.81 and P" =0.65) determined for the gas-phase reaction is indicative of a small positive transition state imbalance of / = 0.16. For reaction in water the estimates (a" = 0.61 and P" = 0.36, giving I = 0.25) are close to the experimental values (a" = 0.55 and P" = 0.35) obtained with amine bases, and the small imbalance is as expected for a reaction involving no hybridization change at the incipient carbanion site. 

Shibasaki and coworkers have applied heterobimetalhc gallium complexes to the desymmetrization of meso epoxides using phenolic nucleophiles. Complex 35 is... 

DIPC has been used as a benzyne precursor17 into which it decomposes at 160— 220 °C. At lower temperatures (80-100°C) and in the presence of copper(n) acetate, it reacts with amino and phenolic nucleophiles to give ort/io-substituted benzoic acids.16... 

In principle, the construction of 198 may proceed either as a tandem Sn )avo-SnI I heterocyclization or as an SNH-SN ipso sequence. Since 2-aryloxyquinoxalines 197 do not cyclize under the above conditions, only the former possibility seems to be realized. Similar uncertainty exists with the phenolate nucleophile. It may react as a C-nucleophile (Scheme 60, path a ) or this transformation may start from O-nucleophilic attack (path b ). In both cases the same cycloaddition product 201... 

The products of the asymmetric alkylation have been used as key building blocks in syntheses of morphanes, phyllanthocin, and periplanone B natural products. In the case of the synthesis of the morphane skeleton, a phenolic nucleophile was reacted with cyclohexenyl methyl carbonate and the resulting ether was subjected to a europium-induced Claisen rearrangement followed by an intramolecular aldehyde-ene reaction to generate the key tricyclic intermediate. Scheme 27 [56]. 

Aryloxy alcohols. These glycol monoethers are formed by epoxide opening. From meso-epoxides, chiral products are obtained in the presence of the linked BINOL complex. Reaction with simple BINOLs is complicated by erosion of enantioselectivity due to phenolate exchange (i.e., BINOL and phenolate nucleophile). 

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

Certain compounds (electrophilic) can react with phenols (nucleophilic). The nucleophilic activity can be either in the iaromatic ring or the oxygen in the hydroxyl group. Examples of electrophilic aromatic substitution include nitration, halogenation, Friedel-Crafts reactions (alkylation and acylation), and sulfonation. The halogenation example shown below is a polysubstitution reaction involving bromine. The polysubstitution usually occurs when polar solvents are used. 

The (l )-(-)-COP-OAc dimer enantiomer [849592-74-1] M 1512.2, m 241-251" dec. is prepared in the same way but using the enantiomeric starting material. [Stevens Richards Organometallics 18 1346 1999, Anderson et al. Org Synth 84 148 2007.] The reactions of trichloroacetimidate derivatives of Z-2-alken-l-ols with phenolic nucleophiles in the presence of chiral COP-OAc dimer catalysts yield 3-aryloxy-l-alkenes in high yield (63-90%) and high enantiomeric purity (90-97% ee) and are compatible with the presence of base-labile substituents in either reactant [Kirsch, Overman and White Org Lett 9 911 2007],... 

It has been speculated that the mechanism of copper-mediated (stoichiometric in copper) arylations of phenols involves the following elemental steps (i) transmetal-lation of Cu(II) with the arylboronic acid (ii) coordination of the phenol nucleophile to copper(II) and (iii) reductive elimination, slowly via the Cu(II) species or via air oxidation to the Cu(III) species which can be expected to undergo reductive eUmination more rapidly, thereby regenerating a potentially catalyticaUy active copper(I) species (Scheme 4.2). A plausible catalytic mechanism (not illustrating the potential role of substrates as copper ligands) is also shown. 

Shortly after, Merschaert et al. developed a new asymmetric synthesis of simple 2-substituted chiral chromanes by the intramolecular addition of a phenolic nucleophile to an a,p-unsaturated ester catalysed by Cinchona alkaloids.The best ee values (80%) were obtained with cinchonine and its C-3 modified derivatives. 

Spectroscopic and X-ray crystal structure analysis has shown that (/ )- -methylheptyl phenyl ether formed in the reaction between phenol and the isourea derivative of (2S)-octan-2-ol proceeds via the carbenium ion intermediate (9). It is suggested that only 0 the (IJ)-l-methylheptyl phenyl ether (99.4% ee) is formed because attack by the phenol nucleophile on the carbenium ion intermediate can only occur from one direction because of strong shielding by the two bulky cyclohexylamino groups. 

The 7,8-dihydroxyflavan-3,4-diols (teracacidins and melacacidins) posed another interesting question about their function in the plant. Here these flavan-3,4-diols also can readily react with phenolic nucleophiles to produce dimeric proanthocyanidins (28, 112). Until recently it was considered that the or- Ao-hydroxylation pattern reduced the nucleophilicity of the A-ring so that further condensation to polymeric proanthocyanidins did not occur. This conclusion was supported by observation of the free flavan-3,4-diols in natural plant extracts. 

The vast majority of recent works on the reactions of flavan-3,4-diols has centered on their role as precursors to flavan-4-carbocations or quinone methide electrophiles in proanthocyanidin syntheses. The regioselectivity of their condensation with flavan-3-ols or oligomeric proanthocyanidins is discussed in Sect. 7.6.3.1.2. Our concern here is with the factors governing the stability of the electrophile and the stereospecificity or stereoselectivity of its reaction with phenolic nucleophiles. Roux and coworkers have made extensive studies of these reactions and have prepared reviews of their recent results (316, 317). The intent here is to summarize some of the more important principles that have been developed. 

Monomethylation of catechol and resorcinol is best achieved under conditions (i) and (ii) above and using a two phase system with a water immiscible solvent such as nitrobenzene. For more complex phenols small differences in the acidity of the phenol, nucleophilicity of the phenol or its anion and steric factors may be exploited to achieve partial alkylation. 

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