Alkylation of Cyclic Ethers

The alkylation of cyclic ethers by thermal processes has been reported by several groups (67, 68, 75, 76,39). The photochemical alkylation has also been reported, and in some cases seems to give higher yields of 2-alkylated fcyclic ethers, due to the preservation of the ether ring dining the photochemical process. It has been shown that photocyanation of both open chain and cyclic ethers can be effected by irradiation of a mixture of an ether and C1CN (46). 

SCHEME 5.48 Nickel-catalyzed alkylation of cyclic ethers with grignard reagents. 

Ethers are widely used in solid-phase synthesis, either as linkers for alcohols or as target compounds. Almost all reported solid-phase syntheses of ethers are O-alkyla-tions or O-arylations of alcohols, which differ only in the type of alkylating/arylating agent used and in the precise reaction conditions. This section covers mainly syntheses of acyclic ethers. Preparations of cyclic ethers are considered in Chapter 15. 

The preparation and properties of the oxonium salts have been considered here in some detail because of their great importance in the polymerization of cyclic ethers by Friedel Crafts catalysts. From the point of view of this review the most important reactions of these salts are those with ethers and alcohols with ethers they exchange alkyl groups in an equilibrium process,... 

Schurig, V., Biirkle, W., Hintzer, K, and Weber R. (1989a) Evaluation of nickel(II) bis[a-(heptafluorobutanoyl)-terpeneketonates] as chiral stationary phases for the enantiomer separation of alkyl-substituted cyclic ethers by complexation gas chromatography, J. Chromatogr. 475, 23-44. 

This process makes some of the alkylation reactions of cyclic ethers at elevated temperatures unsuitable for the preparation of alkylated alpha-cyclic ethers. Ring cleavage of cyclic ethers hardly takes place at room temperature, and thus cyclic ethers can be alkylated under these conditions without undergoing ring cleavage. Once these radicals are produced at room temperature they participate in reactions as cyclic radicals (8, 21,39). 

Such reactions of hydroperoxide alkyl radicals are of importance during the oxidation of hydrocarbons in the gaseous phase where they give a relatively high yield of cyclic ethers. 

In the presence of monomers, all discussed initiators form the corresponding onium ions by alkylation or acylation, as shown schematically below, for the polymerization of cyclic ethers ... 

Covalent compounds, which are strong alkylating or acylating agents may initiate the cationic polymerization of heterocycles. Again, as in the case of acids, classification of these agents is relative for example, alkyl bromide will efficiently alkylate strongly nucleophilic monomers like cyclic amines or oxazolines and thus initiate their polymerization whereas it will be uneffective in the polymerization of cyclic ethers. 

Esters of very strong protonic acids (trifluoromethanesulfonic, fluoro-sulfonic, perchloric), however, are sufficiently strong alkylating agents to initiate the polymerization of even weakly nucleophilic monomers (cyclic acetals, ethers) [2-6], Also their anhydrides (e.g., triflic anhydride) are efficient initiators. This last compound is especially interesting, because in the polymerization of cyclic ethers it leads to macromolecules with two identical growing chain ends (difunctional initiator) [30] ... 

Reactions of cycloalkadiene monoepoxides have received considerable attention. In general, cyanocu-prates have provided better Sn2 selectivity than lithium homocuprates, and the alternative Sn2 reaction is more competitive with vinyl- or phenyl-cuprates than with alkylcuprate reagents. Reactions of cy-clopentadiene monoepoxides with cyanocuprates have found application in prostaglandin synthesis. Effective electrophilic a -alkylation of cyclic enones can be accomplished by Sn2 cuprate addition to the corresponding epoxy enolate, enol phosphate or silyl enol ether. ... 

Scheme 26 Oxidative alkylation of cyclic benzyl ethers with malonates using oxygen gas as the terminal oxidant...

Heterocyclics containing P-atoms are usually strong nucleophiles. For example the basicity of 2-methoxy-ODP (pKa = 3.1) is much higher than that of cyclic ethers or sulfides. Therefore, a wide range of initiators, i.e., carbenium or oxonium salts, Lewis and protonic acids, and relatively nonreactive alkyl halides and organoalu-minum compounds have been used. Usually, reactions were carried out in a N2 atmosphere, although no special precautions (e.g. vacuum) were used to avoid contamination with water. 

Miscellaneous Reactions. - p-Toluenesulfonaraide undergoes Mitsunobu-type reactions in the presence of alcohols and cyanomethylenetriphenyl-phos-phorane (56) to give predominantly mono-N-alkylation products. This reaction has also been applied to the synthesis of cyclic ethers from diols and cyclic amines from amino alcohols and to carbon-carbon bond formation. Examples of cyclic amine synthesis include that of (+)-a-skytanthine (57). A comparative study of the reactions of active methine compounds (58) as nucleophiles using... 

Alkylation of mesitylene by 2-propanol gives 100% selectivity for 1-isopropyl-2,4,6-trimethylbenzene 22 at a conversion of 50% (Scheme 37). Compared with liquid-phase or gas-phase reactions, SCCO2 reduces the mass transport restrictions at the catalytic surface, which increases the residence time of the substrate and reduces coking of the catalysts. This reaction method is also successful in the formation of cyclic ethers, acetals, linear alkyl ethers and aryl ethers. For example, when synthesizing THF from 1,4-butanediol in SCCO2 at 100°C, increasing the pressure from 100 to 200 bar increases the yield from 63 to 87% (Scheme 38). 

Compared to the well-known BBrj-mediated cleavage of aryl alkyl ethers, reactions of cyclic ethers have rarely been investigated. One known example is the cleavage of cyclic ethers to generate (D-bromoalkanols after treatment with BBrj/MeOH. Recently, this methodology has been successfully used in the synthesis of 3,4-disubstituted isoxazole and haloconduritoP derivatives (Scheme 23.8). 

Alkyl derivatives of cyclic ethers behave in a similar manner yielding surface active sulfates valuable as detergents. 

Stork, G. Danheiser, R. L. Regiospecific Alkylation of Cyclic j3-Diketone Enol Ethers. General Synthesis of 4-Alkylcyclohexenones /. Or. Chem. 1973, 38, 1775-1776. 

---