Ethers from hydroalkoxylation

Hydroalkoxylation reactions refer to the addition of an alcohol over an insaturation. This highly atom economical process is potentially a straightforward and clean access to ethers, and the reaction is successfully applied at the industrial level for the production of MTBE (methyl terf-butyl ether) and ETBE (ethyl tert-butyl ether) from isobutylene and methanol or ethanol. If this transformation is well known with activated olefins (reaction referred to a Michael addition), a real challenge is the synthesis of ethers from unactivated olefins. Veiy few reactions involving carbohydrates or polyols have been reported to date and most of them involve isobutylene as this substituted olefin is prompt to generate stabilized carbenium ion under acidic conditions. Dimerization reactions of the alcohol or isobutylene are the main side reactions that have to be avoided in order to reach high selectivities into the desired ethers. ... 

Scheme 23 Synthesis of glycerol ethers from an hydroalkoxylation reaction.

Scheme 25 Synthesis of isosorbide ethers from a hydroalkoxylation reaction.

Phenyl-1-propyne (55) underwent facile formal intermolecular hydroamination, affording the allylic amine 56 in high yield at 0 "C in the presence of AcOH or benzoic acid. In this reaction, at first, Pd-catalyzed isomerization of 55 to pheny-lallene (57) occurs by addition-elimination of H-Pd-OAc to internal alkyne 55, and then the allene 57 is converted to jr-allylpalladium intermediate 58 by hydropal-ladation. The final step is a well-known amination to produce the allylic amine 56. As an intramolecular version, 2-(2-phenylpropenyl)pyrrole (60) was obtained from l-phenyl-7-amino-l-hexyne 59 [16,16a]. Similarly Pd/benzoic acid-catalyzed hydroalkoxylation of 55 with (—)-menthol (61) afforded the allylic ether 62 [17]. 

The corresponding reaction of but-3-yn-l-ols or pent-4-yn-l-ols with primary or secondary alcohols in the presence of catalytic amounts of Ph3PAuBF4 and p-TsOH afforded tetrahydrofuranyl ethers (Scheme 4-76). This tandem 5-endo-cycloisomerization/hydroalkoxylation proceeds via 2,3-dihydrofurans, which then undergo an intermolecular Bronsted acid-catalyzed addition of the external alcohol. The transformation is not restricted to internal alkynols but can be applied to terminal acetylenes as well. Application of the method to the s thesis of bicyclic heterocycles with a P-lactam structure was reported recently.Under the same conditions, epoxyalkynes undergo a sequence of epoxide opening, 6-exo-cycloisomerization, and nucleophilic addition to afford tetrahydropyranyl ethers. In a closely related transformation, cyclic acetals were obtained from alk-2-ynoates bearing a hydroxy group in 6- or 7-position by treatment with AuCU and MeOH. ... 

Gold-catalyzed intermolecular hydroalkoxylations of allenes have received much less attention than their intramolecular counterpart. Nishina and Yamamoto performed the addition of primary or secondary alcohols using 5 mol% each of PhsPAuCl and AgOTf without any solvent and obtained the allylic ethers resulting from attack of the alcohol at the less substituted allenic terminus with moderate to high yield. The best results were obtained for aryl-substituted allenes. Unfortunately, enantiomerically enriched allenes provided only racemic addition products under these conditions. In the presence of a gold(I) catalyst and iV-iodosuccinimide, 2-iodoallylic ethers were obtained in a regioselective and stereoselective manner. 

Intramolecular hydroalkoxylation of unactivated olefins can be achieved in the presence of iron(III) triflate that is formed in situ from iron(III) chloride and silver(I) triflate under mild conditions (Scheme 4-284). The corresponding cyclic ethers are obtained in excellent yield. However, the stereoselectivity is low. ... 

Sigman reported a particular hydrochlorination/hydroalkoxylation reaction catalyzed by Pd(ll) in combination with Cu(ll), starting from styrenes. The first formed hydrochlorinated product in the presence of an alcohol was converted in situ to benzylic ethers [96] (Scheme 47). 

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