Benzylic alcohol etherification

Substitution Reactions on Side Chains. Because the benzyl carbon is the most reactive site on the propanoid side chain, many substitution reactions occur at this position. Typically, substitution reactions occur by attack of a nucleophilic reagent on a benzyl carbon present in the form of a carbonium ion or a methine group in a quinonemethide stmeture. In a reversal of the ether cleavage reactions described, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers by acid-catalyzed etherifications or transetherifications with alcohol or phenol. The conversion of a benzyl alcohol or ether to a sulfonic acid group is among the most important side chain modification reactions because it is essential to the solubilization of lignin in the sulfite pulping process (17). 

In order to prepare multi-kilogram quantities of 1 our efforts were strictly focused on the development of an asymmetric route. Our retrosynthetic approach was centered on the preparation of cyclopentenone 27 which, we envisioned, could be elaborated to chiral hydroxy acid 26 through a series of asymmetric transformations (Scheme 7.4). Etherification of the hydroxy group of 26 with benzylic alcohol 25 followed by installation of (P)-nipecotate 23 at the acid position of 24, would furnish the drug candidate 1. This section will address the following ... 

Benzyl alcohol readily undergoes the reactions characteristic of a primary alcohol, such as esterification and etherification, as well as halide formation. In addition, it undergoes ring substitution. In the presence of acid, polymerization is observed, and the alcohol can be thermally dehydrated to toluene [108-88-3], Catalytic oxidation over copper oxide yields benzaldehyde benzoic acid is obtained by oxidation with chromic acid or potassium permanganate. Catalytic hydrogenation of the ring gives cyclohexylmethanol [100-49-2]. 

Most acid-labile benzyl alcohol linkers suitable for the attachment of carboxylic acids to insoluble supports can also be used to attach aliphatic or aromatic alcohols as ethers. The attachment of alcohols as ethers is less easily accomplished than esterification, and might require the use of strong bases (Williamson ether synthesis [395,552,553]) or acids. These harsh reaction conditions limit the range of additional functional groups that may be present in the alcohol. Some suitable etherification strategies are outlined in Figure 3.31. Etherifications are treated in detail in Section 7.2. 

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 most common resin-bound substrates for Mitsunobu etherification are primary benzylic alcohols, but a few non-benzylic alcohols have also been converted into aryl ethers (Table 7.13). Support-bound secondary alcohols are less suitable alkylating agents because elimination often predominates. 

Where rhenium-catalyzed deoxydehydration has attracted a lot of interest, only two reports concerning dehydration catalyzed by rhenium complexes are noteworthy in view of their application on biomass-derived substrates. The first was published in 1996 by Zhu and Espenson and uses MTO as catalyst for the dehydration reaction of various alcohols, either aliphatic or aromatic, to obtain the corresponding olefins. Using MTO in benzene or in the alcohol itself at room temperature after 3 days gives reasonable turnovers and, in the case of benzylic alcohols, good yields. In the same paper, MTO is used for the amination, etherification, and disproportionation of alcohols, which are all reactions interesting in the viewpoint of biomass transformation [123]. 

In a reversal of the ether cleavage reactions described above, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers via acid-catalyzed etherification or transetherification, respectively, by reaction with the appropriate alcohol or phenol (reaction R, Fig. 1.5). 

The etherification of vanillic alcohol with ethanol was compared over three large pore zeolites HBEA, HFAU and HMOR and over an average pore size zeolites (HMFI) with different Si/Al ratios. Whatever the large pore zeolite and its Si/Al ratio, a total conversion of the benzylic alcohol and a 100% yield in ether are obtained. With the HMFI samples, conversion and yields were equal to 55% only for an Si/Al ratio of 15 and to approximately 70% for Si/Al = 40. It could be expected that the reaction is limited by diffusion of the bulky reactant and product molecules in the narrow pores of this zeolite. 

DBSA is also applicable to other reactions in water. Ether formation from two alcohols is such an example [40]. We tried formation of symmetric ethers from benzylic alcohols in water using 10 mol% of DBSA as a catalyst. The reactions were found to proceed smoothly in water to afford the corresponding symmetric ethers in high yields (Table 13.8, entries 1 and 2). It should be noted that the etherification of the substrate shown in entry 1 in the presence of TsOH instead of DBSA gave only a trace amount... 

Figure 21 Two routes for the synthesis ofCTTV-n Cyclotetramerization of 3,4-(dialkyloxy)benzyl alcohols or etherification of CTTV-OH. (From Ref. 74.)...

The cyclizations of 85 to 86 and of 87 to 88 represent the simple cases in which the internal nucleophile is the OH group of an alcohol [64,65]. An in situ generated hydroxy group, as in the addition of alcohols to carbonyl compounds, can also participate in phenylseleno-etherification reactions. This is examplified by the conversion of 89 into 90 in the presence of benzyl alcohol [66]. Another type of OH, which gives rise to these reactions is the enolic OH of /1-dicarbonyl compounds. Thus, Ley reported that compounds like 91 and 93 can be transformed into the cyclic derivatives 92 and 94 by treatment with N-PSP 11 in the presence of zinc iodide [67]. The cyclization of 95 to 96 represents a simple example of the selenolactonization process [68, 69]. It is interesting to note that the various cyclization reactions indicated in Scheme 14, which require different electrophilic selenenylating agents, can all be effected with phenyselenyl sulfate [70]. 

Chloro-a-methyl-a-phenyl benzyl alcohol is prepared by the grignardization of / -chloro-aeetophenone with phenyl magnesium bromide. This on etherification by treatment with N-(2-chloroethyl) dimethyl amine yields the chlorphenoxamine (base) which is then dissolved in an appropriate solvent and eonverted to the hydrochloride by a stream of hydrogen chloride to form the official compoimd. 

Triethylsilane can also facilitate the high yielding reductive formation of dialkyl ethers from carbonyls and silyl ethers. For example, the combination of 4-bromobenzaldehyde, trimethylsi-lyl protected benzyl alcohol, and EtsSiH in the presence of catalytic amounts of FeCls will result in the reduction and benzylation of the carbonyl group (eq 32). Similarly, Cu(OTf)2 has been shown to aid EtsSiH in the reductive etherification of variety of carbonyl compounds with w-octyl trimethylsilyl ether to give the alkyl ethers in moderate to good yields. Likewise, TMSOTf catalyzes the conversion of tetrahydrop)ranyl ethers to benzyl ethers with Ets SiH and benzaldehyde, and diphenylmethyl ethers with EtsSiH and diphenylmethyl formate. Symmetrical and unsymmetrical ethers are afforded in good yield from carbonyl compounds with silyl ethers (or alcohols) and EtsSiH catalyzed by bismuth trihalide salts. An intramolecular version of this procedure has been nicely applied to the construction of cA-2,6-di- and trisubstituted tetrahydropyrans. ... 

An interesting approach to the synthesis of unsymmetrical ethers has been reported using a ruthenium complex to catalyze a dehydrative etherification (Scheme 2.13) [18], A ruthenium hydride compound served as the catalyst for the reaction, and a vast array of alcohols were screened in this study. Primary and secondary as well as benzyl alcohols were successfully coupled with phenols. Furthermore, a number of functional groups were tolerated by this chemistry due to the lack of strong acids or bases needed to promote the... 

Esterification and etherification are the two most commonly used methods to modify HA to form a scaffold while maintaining its biocompatibility [39, 40]. The -COOH group of the glucuronic acid subunit can be reacted with an alcohol, for example benzyl alcohol, to form an ester, in this case henzyl ester (Figure 2.1a) [40]. This modification also increases the hydrophobicity of the HA macromer, thus prolonging its degradation time. These hydrophobic modified HA compounds can be made into scaffolds via electrospinning, for example, into fibres, meshes, and membranes. In particular, this chemistry is used to prepare the commercially available HYAFF 11 scaffold [39-42]. 

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

Blocking the C-l OH of D-fructose and L-sorbose (Scheme 25) was effected in excellent yields through regioselective isopropylidene acetalation of the free ketoses, followed by etherification (benzylation or allylation) of the remaining primary alcohol. Acid-catalyzed hydrolysis of the isopropylidene groups and condensation with HSCN efficiently produced a sole fused bicyclic OZT. 

Obviously, it is very desirable to substitute these modes of benzylic ether preparation by an heterogeneous catalysis process. Clays (50) and resins (51, 52) which were the first solid acid catalysts used have given low or moderate yields. The first experiments with zeolites were carried out by Rhodia (53, 54) on the etherification of vanillic alcohol (A) in a batch reactor over a HBEA zeolite with a Si/Al ratio of 12.5 ... 

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