Nucleophilic ether cleavage

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). 

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

The use of iodotrimethylsilane for this purpose provides an effective alternative to known methods. Thus the reaction of primary and secondary methyl ethers with iodotrimethylsilane in chloroform or acetonitrile at 25—60° for 2—64 hours affords the corresponding trimethylsilyl ethers in high yield. The alcohols may be liberated from the trimethylsilyl ethers by methanolysis. The mechanism of the ether cleavage is presumed to involve initial formation of a trimethylsilyl oxonium ion which is converted to the silyl ether by nucleophilic attack of iodide at the methyl group. tert-Butyl, trityl, and benzyl ethers of primary and secondary alcohols are rapidly converted to trimethylsilyl ethers by the action of iodotrimethylsilane, probably via heterolysis of silyl oxonium ion intermediates. The cleavage of aryl methyl ethers to aryl trimethylsilyl ethers may also be effected more slowly by reaction with iodotrimethylsilane at 25—50° in chloroform or sulfolane for 12-125 hours, with iodotrimethylsilane at 100—110° in the absence of solvent, " and with iodotrimethylsilane generated in situ from iodine and trimcthylphenylsilane at 100°. ... 

Ethers can be cleaved under strongly acidic conditions by intermediate formation of dialkyloxonium salts. Hydrobromic and hydroiodic acids are especially useful for ether cleavage because both are strong acids and their anions are good nucleophiles. Tertiary alkyl ethers are very easily cleaved by acid reagents ... 

HX first protonates the oxygen atom, and halide then effects a nucleophilic displacement to form an alcohol and an organic halide. The better the nucleophile, the more effective the displacement. Since I- and Br- are better nucleophiles than Cl-, ether cleavage proceeds more smoothly with HI or HBr than with HC1. 

The initial products of ether cleavage are the alkyl halide and a borate ester, (R0)3B. The borate esters are usually inert to further displacement but, because the iodide is more nucleophilic than the other halides, warming the borate esters (60-80 °C) in the presence of BI3, will result in the complete conversion of all the alkyl residues to iodides (Eq. 6) [12]. 

By 1903, Emil Fischer had already appreciated that a proximate nucleophile can accelerate the rate of cleavage of an otherwise unreactive amide. Adaptation of such neighbouring group participation to relay deprotection is easy all that is required is a protecting group with a latent hydroxyl or amino function within easy bonding distance of the amide carbonyl, as illustrated in Scheme 8.27 by the reduction of the o-nitrophenylacetamide 27,1. The theme is capable of extensive variation. For example, 2-((/er/-butyldiphenylsilyloxy)methyl]benz-amides (27.2), 2-(acetoxymethyl)benzamides (273) and 3-methyl-3-(2,4,5-tri-methyl-3,6-dioxo-cycIohexa-l,4-dienyl) butyramides (27.4) all have latent hydroxyl nucleophiles that are released by silyl ether cleavage, ester hydrolysis and quinone reduction, respectively. 

For these reasons, nucleophilic ether cleavages are limited to good nucleophiles that are weakly basic like Br- and I-, which can exist in the presence of strong acid. (If you look back now at the reactions of alcohols, you ll see the same considerations applying there, too.) Methyl and 1° alkyl ethers react via the SN2 mechanism, whereas 3° ethers follow an SN1 pathway. Least reactive are 2° ethers (worse than 1° for SN2, and worse than 3° for Sn 1 the latter mechanism is more typical, however). 

In the reaction of 10b with piperidine in DMF, a novel methyl ether cleavage reaction of the 1-methoxy group occurs in addition to the nucleophilic substitution reaction, resulting in the formation of l-hydroxy-6-nitroindole-3-carbaldehyde (5a, 10%) and 2-piperidinyl product (109, 59%, Scheme 15) [11]. 

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