Reductive etherification

Reductive Etherification. As indicated earlier, aldehydes as well as ketones often give very good yields of ethers when they are treated with Br0nsted acids or other electrophilic species in the presence of organosilicon hydrides (Eq. 172). In the absence of added alcohols, symmetrical ethers are obtained. 

Unsymmetrical ethers may be produced from the acid-promoted reactions of aldehydes and organosilicon hydrides when alcohols are introduced into the reaction medium (Eq. 173).327,328 An orthoester can be used in place of the alcohol in this transformation.327 335 A cyclic version of this conversion is reported.336 Treatment of a mixture of benzaldehyde and a 10 mol% excess of triethylsilane with methanol and sulfuric, trifluoroacetic, or trichloroacetic acid produces benzyl methyl ether in 85-87% yields.328 Changing the alcohol to ethanol, 1-propanol, 2-propanol, or 1-heptanol gives the corresponding unsymmetrical benzyl alkyl ethers in 45-87% yield with little or no side products.328 A notable exception is the tertiary alcohol 2-methyl-2-propanol, which requires 24 hours.328 1-Heptanal gives an 87% yield of //-lie ply I methyl ether with added methanol and a 49% yield of benzyl n-heptyl ether with added benzyl alcohol under similar conditions.328 

The yield of ethyl n -pentyl ether formed from the reduction of 1-pentanal by Et3SiH/TFA in ethanol is 57% after 6-8 hours at 50-60°.327 The yield of product increases to 72% when one equivalent of ethyl orthoformate and some anhydrous hydrogen chloride are added to the reaction medium.327 Presumably, this reduces the amount of free water in the reaction medium. 

Various chemical species with Lewis acid properties are also effective in promoting the direct conversion of aldehydes into ethers by organosilicon hydrides. 

Superior yields of ethers from aldehydes are obtained by the use of several other electrophilic species. The addition of 5 mol% of trityl perchlorate to a mixture of triethylsilane and 3-phenylpropanal in dichloromethane at 0° produces an 83% yield of bis-(3-phenylpropyl) ether within 10 minutes (Eq. 176),329 Reductive polycondensation of isophthalaldehyde occurs with two equivalents of triethylsilane in the presence of 10 mol% of trityl perchlorate to give 40-72% yields of polyether with average molecular weights ranging from 6,500 to 11,400 daltons (Eq. 177).337 Addition of one equivalent of an alkoxytrimethylsilane to the reaction mixture produces unsymmetrical ethers in good to excellent yields. Thus, a mixture of (ii)-cinnamaldehyde, 3-phenylpropoxytrimethylsilane, and triethylsilane in dichloromethane reacts under the influence of a catalytic amount of trityl perchlorate to give the unsymmetrical ether in 88% yield (Eq. 178).329 

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Oriyama and coworkers reported an iron-catalyzed reductive etherification of carbonyl compounds with triethylsilane and alkoxytriaUcylsilane [149, 150] and alcohols (Scheme 48) [151]. 

Scheme 48 Iron-catalyzed reductive etherification of carbonyl compounds...

Although some methods for reductive etherifications of carbonyl compounds have been reported [152-162], the iron-catalyzed version possesses several advantages (1) fairly short reaction times are needed, (2) not only trimethylsilyl ether but also triethylsilyl and butyldimethylsilyl ethers and alcohols are adaptable, and (3) a broad substrate scope. 

Cyclic ethers can also be formed in a fashion similar to that of the reactions described previously (Eq. 186),306,342 and also result from the reductive etherification of bis(trimethylsilylated) diols and dialdehydes (Eq. 187).343... 

Electrogenerated acid (EG acid), aldehyde to alcohol reduction, etherification, 65-69... 

Et3SiH reduces aldehydes or ketones in alcoholic acidic media to ethers.6 The mechanism of the reductive etherification involves the following steps. After activation of the aldehyde 7 attack of the nucleophilic crotyl alcohol takes place. Elimination of water provides cation 26, which is reduced by Et3SiH to ether 8. 

DFT has been used to explore the mechanism of reductive etherification of aromatic aldehydes by alcohols, using BH3 as catalyst and reductant.312 The reaction is suggested to proceed by addition (rate controlling), followed by reduction, and is expected to be feasible in polar solvents such as acetonitrile. 

A high-yielding stereoselective intramolecular reductive etherification of the 5-silyloxy substituted ketone 310 provides the final step in a total synthesis of the antibiotic (—)-centrolobine 311 (Equation 134) <2003OL3883>. 

R,5R)-( — )-l and (2S,5S)-( + )-l are obtained from ( )-fran4-N-benzylpyrrolidine-2,5-dicarboxylic acid (resolution, reduction, etherification). 

The classical permanent protecting group of carbohydrate hydroxyl functions is probably the benzyl ether. It is very stable and can be readily removed under essentially neutral conditions. For this reason, numerous benzylation and 0-debenzylation procedures have been described. Benzyl ether formation is usually achieved by the reaction of alcohols and benzyl halides in the presence of a base such as sodium hydride in anhydrous DMF (O Scheme 2) [11], or a mild base (Ag20) in THF using a phase-transfer catalyst [12]. Benzylation can also be accomplished by the use of an acidic catalyst with benzyltrichloroacetimidate as the reagent [13]. A method using the reductive etherification of TMS ethers under non-basic conditions has also been reported [14]. 

Triethylsilane reduces ketals to ethers in excellent yields in the presence of Nafion-H65(equation 58). When one considers the conversion of a ketone to a ketal to an ether, the overall transformation corresponds to a reductive etherification of the ketone. This general class of reduction has also been applied to the reduction of the anomeric carbon of sugars66(equation 59). 

When zeolite MCM-22 is employed as catalyst for the reaction between substituted cyclohexanones and sec-alcohols, instead of the MPV reduction obtained with Beta, a novel reductive etherification occurs to give, for example, from 4-tcrt-butylcyclohexanone and i-PrOH the isopropyl ether of 4-tert-butylcyclohexa-nol with a cisitrans isomer ratio of 60 40 [34]. It is considered that in this reaction the higher Brpnsted-acid site population relative to MPV sites favors the formation of the ether via an intermediate hemiacetal. 

Reductive etherification. Benzyl ethers are generated from ArCHO on treatment with decaborane in an alcohol (e.g., MeOH, EtOH). 

Reductive Etherifications and Acetal Reductions. Additional applications of triethylsilane in the reduction of C-0 bonds also continue to surface. The Kusanov-Pames dehydrative reduction of hemiacetals and acetals with trifluorosulfonic acid/EtsSiH has proven especially valuable. Under such conditions, 4,6-O-benzyli-dene acetal glucose derivatives can be asymmetrically deprotected to 6-0-benzyl-4-hydroxy derivatives (eq 28) and thioketone derivatives can be converted to syn-2,3-bisaryl (or heteroaryl) di-hydrobenzoxanthins with excellent stereo- and chemoselectivity (eq 29). Triethylsilane is also useful in a number of related acetal reductions, including those used for the formation of C-glycosides. For example, EtsSiH reductively opens 1,3-dioxolan-4-ones to 2-alkoxy carboxylic acids when catalyzed by HCU. Furthermore, functionalized tetrahydrofurans are generated in good yield from 1,2-0-isopropylidenefuranose derivatives with boron trifluoride etherate and EtsSiH (eq 30). These same conditions lead to 1,4- or 1,5-anhydroalditols when applied to methyl furanosides or pyranosides. ... 

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. ... 

Balakrishnan M, Sacia ER, Bell AT (2012) Etherification and reductive etherification of 5-(hydroxymethyl)furfural 5-(alkoxymethyl)furfuials and 2,5-bis(alkoxymethyl)furans as potential bio-diesel candidates. Green Chem 14 1626-1634... 

Keto-alcohols 149 participated in a stereoselective intramolecular reductive etherification process to afford differentially substituted 1,4-oxazepanes 150 in mosdy good yields with excellent diastereoselectivities. In a single example, the use of a carbon nucleophile allowed access to trisubstituted 1,4-oxazepane derivatives (13EJO2076). 

One-pot regioselective functionalization of glucopyranosides acetalation /reductive etherification... 

In this context, a one-pot regioselective protection of persilylated monosaccharides, using copper(ii) triflate as a single catalyst was able to promote acetalation-reductive etherification-acylation reactions. In the same way, the easy to handle, cheap and environment-friendly FeCls 6H2O complex was a very efficient catalyst to promote regioselective acetalation and reductive etherification on glucopyranosides. Hence, treatment of per-O-silylated a-methyl-u-glucopyranoside 50 with benzaldehyde (3 equiv) and triethylsilane (1.1 equiv) in the presence of... 

The utility of the bismuth tribromide-mediated reductive etherification for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans was also highlighted in the enantioselective total synthesis of the annonaceous acetogenin(—)-mucocin [46c]. 

Another example where a bismuth tribromide salt was found efficient is in the synthesis of the diastereomers of (6-methyltetrahydropyran-2-yl) acetic acid. Cycliza-tions of two different 5-silyloxy carbonyl compounds under either BiBrs-initiated reductive etherification (leading to the cis isomer) or tandem cyclization-addition (trans-isomer) etherification protocols from the corresponding P-keto ester or aldehyde respectively, has efficiently provide the target molecules [47]. 

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