Allylic alkylation phenols

Total syntheses of callipeltoside A [147] and the vitamin E core [148] have been published in which one of the key steps is an asymmetric allylic alkylation of this class of substrate using a phenol derivative as nucleophile. 

The palladium(0)-catalyzed asymmetric O-allylation of phenols has been described using five-, six- and seven-membered ring allylic carbonates and acyclic allylic carbonates (eq 9). The products from these reactions were subjected to a Claisen rearrangement to provide C-alkylated phenols. A study of various ligands for the reaction of phenol with 2-cyclohexenyl-l-methyl carbonate clearly showed that the Trost ligand is superior. ... 

A significant study of the synthesis of chiral chromans by the Pd-catalysed intramolecular asymmetric allylic alkylation of readily available phenol allyl carbonates has established the optimum conditions for this highly efficient method and demonstrated its value by the total syntheses of (+)-clusifoliol and (-)-siccanin (Scheme 6) <04JA11966>. A biomimetic enantioselective synthesis of (-)-siccanin also features this approach to the chroman moiety <04JA12565>. 

Allylic alkylations. Highly regiosi nucleophiles (phenolates, sulfonamides, ami also possible with the Rh catalyst modiho seems to play an important role in the di branched allylic ethers thus, reaction with 1 the product yields are low. The best comprot... 

The reactivity of alcohols and phenols with ethylene oxide varies in the order primary > alkyl phenol > secondary > tertiary [13]. However, tertiary alcohols can be made to react with ethylene oxide [14]. Some linear secondary alcohols have been reacted with ethylene oxide to give nonionic surfactants (Union Carbide) [15]. Some typical alcohols used to give the nonionic surfactants (polyoxyethylenealkyl ethanols) are allyl, lauryl, cetyl, stearyl, tridecyl, myristyl, C12-C15 primary linear, tallow, and trimetfaylnonyl [16]. 

Seheme 6.88 Asymmetric intramolecular AFC-type allylic alkylation of phenols reported by You and by Hamada. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

MBH diene adducts have also been employed successfully in a palladium-catalyzed asymmetric allylic alkylation reactions with various phenols in good regio- and enantioselectivity. These high enantioselectivities are even more substantial considering the ambiguity introduced by the additional double bond in the allylic system (Scheme 3.139). ... 

The allylic alkylation with weak nucleophiles employing nickel catalysts is generally not as efficient as the corresponding palladium-catalyzed methods. However, allylic acetates, allyl phenyl ethers, and allylic carbonates undergo efficient couplings with amines, phenols, and malonates in the presence of nickel(O) catalysts (Scheme 25). ... 

SCHEME 5.10 Stereoselective synthesis of tetrahydroisoquinoline via [Ir(I)]-catalyzed asymmetric allylic alkylation of phenols. 

In 2011, a metal-free asymmetric intramolecular allylic alkylation promoted by a chiral A(-triflylphosphoramide 12b was achieved by Rueping et al. (Scheme 2.29). The phenol 96 was believed to undergo organic ion-pair catalytic procedure to furnish optically active 2/f-chromenes 97 in good yields and excellent enantioselectivities [40]. 

The Tsuji-Trost reaction is the palladinum-catalyzed substitution of allylic leaving groups by carbon nucleophiles. The nucleophile can be carbon-, nitrogen-, or oxygen- based compounds such as alcohols, enolates, phenols, and enamines, and the leaving group can be a halide or an acetate. This emerged as a powerful procedure for the formation of C—C, C—O and C—N bonds. The reaction, also known as Trost allylation or allylic alkylation, was named after Jiro Tsuij, who first reported the method in 1965 [42], and Barry Trost, who introduced an asymmetric version in 1973 [43]. 

O-Methylation of phenolic compotmds can be efficiently carried out by tetra-methylammonium chloride in diglyme or poly ethyleneglycol (PEG) at temperatures of 150-160 °C and in the presence of either NaOH or K COj. The benzylation and methylation of phenols occiu, where the benzylation product was always predominating. With allyl-substituted phenols as substrates and using NaOH as a base, it was feasible to achieve both the alkylation and the double-bond isomerization of the allyl group to obtain (E/Z)-propenyl-substituted methyl and benzyl aryl ethers in a single preparative step (Maras et al., 2010). 

Phenols have been documented to serve as a versatile class of 0-nucleophiles in asymmetric allylic alkylation events. Even a sterically hindered ortho-disubstituted phenol such as 59 participated in a palladium-catalyzed allylic displacement reaction with carbonate 60 (Scheme 14.12) [69]. Product 62 was obtained in 88% ee and subsequently converted into (-)-galantha-mine (63), a selective inhibitor of acetylcholinesterase with potential in the treatment of Alzheimer s disease [69, 70). 

Allyl ethers of perfluoroaromatic phenols have been observed to alkylate the aromatic nucleus [106] or to undergo Claisen rearrangement [1071 (equation 54). 

DIBAL, NiCl2(dppp), toluene, CH2CI2, THF, or ether, 80-97% yield. These conditions are chemoselective for simple alkyl and phenolic allyl ethers. More highly substituted allyl ethers are unreactive. 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previous section, which is general to all ethers, the Claisen rearrangement is specific to allyl aryl ethers, Ar—O—CH2CH = CH2. Treatment of a phenoxide ion with 3-bromopropene (allyl bromide) results in a Williamson ether synthesis and formation of an allyl aryl ether. Heating the allyl aryl ether to 200 to 250 °C then effects Claisen rearrangement, leading to an o-allylphenol. The net result is alkylation of the phenol in an ortho position. 

Heteropoly acids can be synergistically combined with phase-transfer catalysis in the so-called Ishii-Venturello chemistry for oxidation reactions such as oxidation of alcohols, allyl alcohols, alkenes, alkynes, P-unsaturated acids, vic-diols, phenol, and amines with hydrogen peroxide (Mizuno et al., 1994). Recent examples include the epoxidations of alkyl undecylenates (Yadav and Satoskar, 1997) and. styrene (Yadav and Pujari, 2000). 

The solvent can also affect regioselectivity. Consider O- vs C-alkylation of phenoxide ion with allyl chloride or bromide. In water, with allyl chloride the O- to C-alkylation ratio is 49 41 with phenol as a solvent it is 22 78 with methanol, dimethylformamide, and dioxane 100% O-alkylation is achieved. The selective solvation of the more electronegative O by the more protic solvents perhaps leads to some C-alkylations. 

Aryl alcohol oxidase from the ligninolytic fungus Pleurotus eryngii had a strong preference for benzylic and allylic alcohols, showing activity on phenyl-substituted benzyl, cinnamyl, naphthyl and 2,4-hexadien-l-ol [103,104]. Another aryl alcohol oxidase, vanillyl alcohol oxidase (VAO) from the ascomycete Penicillium simplicissimum catalyzed the oxidation of vanillyl alcohol and the demethylation of 4-(methoxymethyl)phenol to vanillin and 4-hydro-xybenzaldehyde. In addition, VAO also catalyzed deamination of vanillyl amine to vanillin, and hydroxylation and dehydrogenation of 4-alkylphenols. For the oxidation of 4-alkylphenol, the ratio between the alcohol and alkene product depended on the length and bulkiness of the alkyl side-chain [105,106]. 4-Ethylphenol and 4-propylphenol, were mainly converted to (R)-l-(4 -hydroxyphenyl) alcohols, whereas medium-chain 4-alkylphenols such as 4-butylphenol were converted to l-(4 -hydroxyphenyl)alkenes. 

Monomer Synthesis. 4-Allyloxystyrene was prepared by the Wittig reaction of 4-allyloxybenzaldehyde and methyltriphenylphosphonium bromide, under basic conditions. The allyloxybenzaldehyde was prepared, in turn, by the alkylation of 4-hydroxybenzaldehyde with allyl bromide. This method, which provides high purity monomer in high overall yield, is outlined in Scheme 1 and has been previously described (2). Alternatively, the monomer may be prepared by the direct alkylation of p-vinylphenol with allyl bromide (8,9), although this method is less convenient due to the difficulties in synthesizing and storing the highly reactive vinyl phenol (10). 

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