Etherification of phenols

A number of examples have been cited by Chakrabarti and Sharma (1993) and Sharma (1995). The example of etherification of phenols, substituted phenols, cresols, naphthols, etc., with isobutylene and isoamylene may be empahsized where homogeneous catalysts lead to... 

Figure 2.34 shows the mechanism of this reaction. A key intermediate is the alkylated phosphine oxide A, with which the carboxylate ion reacts to displace the leaving group 0=PPh3. Figure 2.34 also shows that this carboxylate ion results from the deprotonation of the carboxylic acid used by the intermediate carbamate anion B. Nucleophiles that can be deproto-nated by B analogously, i.e., quantitatively, are also alkylated under Mitsunobu-like conditions (see Figure 2.36). In contrast, nucleophiles that are too weakly acidic cannot undergo Mitsunobu alkylation. Thus, for example, there are Mitsunobu etherifications of phenols, but not of alcohols.

Substitutions. Etherification of phenols with alkylating agents, a base, and phase transfer catalyst in dry media under microwave irradiation can be an effective method. For preparation of alkyl azides from alkyl bromides one can use surfactant pillared clays as catalyst. ... 

Aryl 1,1-dimethylpropargyl ethers. An improved procedure for the etherification of phenols uses CuCU 2H2O and DBU in MeCN at 0°C. 

The fluoroisopropenyl etherification of phenols results through 1,3-bis(Bu Me2SiO)prop-2-yl-2,5-dichlorobenzene sulphonate, PhCOCH23r gives... 

Diazomethane is a valuable reagent for one-carbon extension of acyl halides and anhydrides, as well as for ring expansion reactions of cyclic ketones " . It is also widely used in small-scale organic synthesis for the esterification of carboxylic acids and the etherification of phenols, enols and alcohols " . In these reactions, however, CH2N2 installs the label in positions that are potentially metabolically labile and usually unsuitable for use in metabolism smdies. For in vitro studies where metabolism is not an issue, tritiated diazomethane is usually preferred because of its higher specific activity. 

Although palladium catalysts have played the most prominent role in this area, other metals have also been found to catalyze allylic etherification reactions, often providing complementary stereochemical outcomes. A few ruthenium catalyst systems have been used for the O-allylation of phenols,143,144 including an enantioselective version utilizing [Cp Ru(MeCN)3]PF6 that provides promising ee s, albeit with diminished control of regioselectivity (Equation (25)).145... 

Important advances in propargylic etherification have come from the use of copper-based systems that achieve efficient, catalytic O-progargylation of phenols (Scheme 8).245,246 While the mechanism of this transformation remains unclear, the products of these reactions have been readily converted into chromenes through subsequent Claisen rearrangement,... 

An example for the synthesis of poly(2,6-dimethyl-l,4-phenylene oxide) - aromatic poly(ether-sulfone) - poly(2,6-dimethyl-1,4-pheny-lene oxide) ABA triblock copolymer is presented in Scheme 6. Quantitative etherification of the two polymer chain ends has been accomplished under mild reaction conditions detailed elsewhere(11). Figure 4 presents the 200 MHz Ir-NMR spectra of the co-(2,6-dimethyl-phenol) poly(2,6-dimethyl-l,4-phenylene oxide), of the 01, w-di(chloroally) aromatic polyether sulfone and of the obtained ABA triblock copolymers as convincing evidence for the quantitative reaction of the parent pol3rmers chain ends. Additional evidence for the very clean synthetic procedure comes from the gel permeation chromatograms of the two starting oligomers and of the obtained ABA triblock copolymer presented in Figure 5. 

Catalysts lacking phosphorus ligands have also been used as catalysts for allylic substitutions. [lr(COD)Cl]2 itself, which contains a 7i-accepting diolefin ligand, catalyzes the alkylation of allylic acetates, but the formation of branched products was only favored when the substitution reaction was performed with branched allylic esters. Takemoto and coworkers later reported the etherification of branched allylic acetates and carbonates with oximes catalyzed by [lr(COD)Cl]2 without added ligand [47]. Finally, as discussed in Sect. 6, Carreira reported kinetic resolutions of branched allylic carbonates from reactions of phenol catalyzed by the combination of [lr(COE)2Cl]2 and a chiral diene ligand [48]. 

This methodology was applied to a two-step sequence for the preparation of enantio-merically enriched dihydrobenzo[h]furans (Scheme 10.11) [46]. Rhodium-catalyzed allylic etherification of (S)-47 (>99% ee), with the sodium anion of 2-iodo-6-methyl-phenol, furnished the corresponding aryl allyl ethers (S)-48/49 as a 28 1 mixture of regioisomers favoring (S)-48 (92% cee). Treatment of the aryl iodide (S)-48 with tris(trimethylsilyl)silane and triethylborane furnished the dihydrobenzo[h]furan derivatives 50a/50b as a 29 1 mixture of diastereomers [43]. 

Scheme 10.11 Stereoselective construction of benzo[b]furans using allylic etherification with phenols.

Amiodarone (16) has been the center of much interest because of its activity as a cardiac depressant useful in treating ventricular arrhythmia and many analogues have been prepared [4. I he originally patented procedure concludes simply by etherification of benzofuran-containing iodonated phenol 15 with 2-halodiethylaminoethane to give amiodarone (16) [5]. The synthesis t)f 15 is not detailed in the reference but the synthesis of benzbromarone contains closely analo-goii.s steps [6]. 

The etherified hardwood lignin model II reacted at a similar rate as the phenolic model indicating the etherification of the phenolic group has a small effect on the reaction rate. When this reaction was repeated at 55°C with an excess formaldehyde, some mefa-hydroxymethylated products were obtained (Fig. 4B). 

Only a few examples have been reported of the etherification of alcohols with resin-bound diarylmethyl alcohols (Entry 5, Table 3.30 Entry 5, Table 3.31 [564]). Diarylmethyl ethers do not seem to offer advantages over the more readily accessible trityl ethers, which are widely used as linkers for both phenols and aliphatic alcohols. Attachment of alcohols to trityl linkers is usually effected by treating trityl chloride resin or 2-chlorotrityl chloride resin with the alcohol in the presence of a base (phenols pyridine/THF, 50 °C [565] or DIPEA/DCM [566] aliphatic alcohols pyridine, 20-70 °C, 3 h-5 d [567-572] or collidine, Bu4NI, DCM, 20 °C, 65 h [81]). Aliphatic or aromatic alcohols can be attached as ethers to the same type of light-sensitive linker as used for carboxylic acids (Section 3.1.3). 

The Mitsunobu etherification of polystyrene-bound phenols is usually conducted in THF or NMP, simply by adding the alcohol, the phosphine, and DEAD. Some authors claim that the addition of tertiary amines is beneficial [148], but this seems not always to be the case [146], It is, of course, important that neither the support nor any of the... 

The etherification of support-bound phenols with alkyl halides is usually performed in dipolar aprotic solvents (DMF, NMP, DMSO) in the presence of bases such as DBU, KN(SiMe3)2, phosphazenes [149], or cesium carbonate (Entries 6 and 7, Table 7.11). 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

It has been reported that tertiary amines (as additives or as the solvent) lead to increased yields when etherifying tyrosine derivatives with polystyrene-bound benzyl alcohols [175]. Nevertheless, other phenols react smoothly without the addition of a base [47,176], When only a slight excess of phenol is used for the etherification of support-bound alcohols, AyV -bi s (eth oxycarbonyl)hydrazi n e (the by-product of the Mit-sunobu reaction) can compete with the phenol to a significant extent and become attached to the support. This reaction can be suppressed by the use of a greater excess of phenol [168]. 

The etherification of alcohols or phenols and their subsequent Claisen Rearrangement under thermal conditions makes possible an extension of the carbon chain of the molecule. 

The extent of C-alkylation as a side reaction in etherification varies about 1% of allyl 2-allylphenyl ether is formed when phenol is used in the acetone and potassium carbonate method with allyl bromide with cinnamyl bromide or 7,7-dimethylallyl bromide the extent of C-alkylar tion is greater.16 A complicated mixture of C- and O-alkylation products results from the treatment of phenol with 4-bromo-2-hexene and 4-chloro-2-hexene. 9 4-Hexenylresordnol has been obtained in about 40% yield from the reaction of l-bromo-2-hexene, resorcinol, and potassium carbonate in boiling acetone.99 An appreciable amount of C-alkylation occurs when 2,6-dimethyIphenol is treated with allyl bromide and sodium ethoxide in ethanol.70 Since, in general, the ampunt of C-alkylation is greatly increased by carrying out the alkylation on the sodium salt of the phenol in benzene,16 this method is unsuitable for the preparar tion of allyl aryl ethers. 

A history of ether and etherification is a welcome, and now rare, focus on an individual compound.72 It covers work by Berzelius, Gerhardt, Hennell, Kolbe, Liebig, and of course Williamson. Acetoacetic ester has received detailed historical notice in a biography,73 as have salicylic acid and the salicylates.74 Apart from natural products, few heterocyclic substances have been recently the subject of historical enquiry. An impressive exception is that of pyrrole, a simple molecule explored by Dippel, Reichenbach, Runge and others, and manufactured by Du Pont.75 There is also an account of the structural problems posed by piperidine.76 Accounts have been given of the discovery of aniline from crystallin (a product of the thermal decomposition of indigo),77 of the history of phenol over the last two centuries,78 and of organic nitrates and their uses in medicine.79... 

---