Phenolic ethers nucleophilic cleavage

Strategies that lead to the formation of isoxazoles during cleavage from an insoluble support include the oxidative cleavage of /V-(4-alkoxybenzyl)isoxazolidincs with DDQ to yield isoxazolines (Entry 14, Table 15.16), the nucleophilic cleavage of 2-acyl enamines with hydroxylamine (Entry 15, Table 15.16), and the acidolysis of 2-cyano-phenols etherified with an oxime resin (Entry 17, Table 15.16). The required oxime ethers for the latter synthesis were prepared by reaction of the corresponding 2-fluorobenzonitriles with Kaiser oxime resin [203],... 

Fig. 7-12. Reactions of phenolic /8-aryl ether and a-ether structures (1) during neutral sulfite pulping (Gierer, 1970). R = H, alkyl, or aryl group. The quinone methide intermediate (2) is sulfonated to structure (3). The negative charge of the a-sulfonic acid group facilitates the nucleophilic attack of the sulfite ion, resulting in /8-aryl ether bond cleavage and sulfonation. Structure (4) reacts further with elimination of the sulfonic acid group from a-position to form intermediate (5) which finally after abstraction of proton from /8-position is stabilized to a styrene-/8-sulfonic acid structure (6). Note that only the free phenolic structures are cleaved, whereas the nonphenolic units remain essentially unaffected.

Intramolecular reaction with nucleophilic groups can also lead to heterocycles. For example, good yields of 3-acylbenzofurans result from cyclization caused by intramolecular substitution of the tertiary amino group by a phenol formed by cleavage of a phenol ether by boron tribromide251 (equation 182). 0-Hydroxy benzyl alcohols were used to obtain 4//-chromenes by their reaction with 4-morpholino-3-buten-2-one in acetic acid-acetic anhydride187. 

The nucleophilic cleavage of aryl alkyl ethers gives the corresponding phenol with only 1 equiv. of thiophenol in the presence of N-methyl-2-pyrrolidinone (NMP) in a catalytic amount of potassium carbonate. The aromatic nitro and chloro substituents which are displaced with stoichiometric thiolates are preserved by this method. Moreover, a(B-unsaturated carbonyl compounds do not undergo Michael addition of thiolate under these conditions. 

O-Demethylation has been observed as well as, or instead of, nucleophilic displacement on reaction of 3,4,5-chloro/methoxy pyridazines and 4,5-chloro/methoxy-2-methyl-3(2//)-py-ridazinones with morpholine (e.g.. Scheme 63). Demethylation was observed at all ring positions, but usually adjacent to chlorine or a carbonyl group, and A -methylmorpholine was isolated, consistent with demethylation rather than hydrolysis. The demethylation can also occur with other primary and secondary amines such as diethylamine, butylamine, and piperidine, but not with pyrrolidine and aniline <87H(26)1 >. 3-Phenolic ethers of pyridazines are resistant to reductive cleavage of the aryl ether bond under the conditions of phase transfer catalytic hydrogenolysis <82T3775>. 

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). 

Free Phenolic Structures Containing /3-Ary I Ether Bonds The first step of the reaction involves the formation of a quinone methide from the phenolate anion by the elimination of a hydroxide, alkoxide, or phenoxide ion from the a-carbon (Fig. 7-25). The subsequent course of reactions depends on whether hydrosulfide ions are present or not. In the latter case (soda pulping), the dominant reaction is the elimination of the hydroxymethyl group from the quinone methide with formation of formaldehyde and a styryl aryl ether structure without cleavage of the /8-ether bond (Fig. 7-26). When hydrosulfide ions are present (strong nucleophiles) they react with the... 

Fig. 7-25. Main reactions of the phenolic /8-aryl ether structures during alkali (soda) and kraft pulping (Gierer, 1970). R = H, alkyl, or aryl group. The first step involves formation of a quinone methide intermediate (2). In alkali pulping intermediate (2) undergoes proton or formaldehyde elimination and is converted to styryl aryl ether structure (3a). During kraft pulping intermediate (2) is instead attacked by the nucleophilic hydrosulfide ions with formation of a thiirane structure (4) and simultaneous cleavage of the /3-aryl ether bond. Intermediate (5) reacts further either via a 1,4-dithiane dimer or directly to compounds of styrene type (6) and to complicated polymeric products (P). During these reactions most of the organically bound sulfur is eliminated as elemental sulfur.

Cleavage of ethers. This combination cleaves methyl ethers of primary and secondary 2ilcohols readily. With the latter substrates, retention of configuration obtains. Aryl methyl ethers are cleaved very slowly by this method. Benzyl ethers of both alcohols and phenols are also cleaved and in high yield the former ethers are cleaved more readily. Presumably BFj coordinates with the ethereal oxygen to form n oxonium intermediate that is then attacked by the thiol (a soft nucleophile). ... 

In the case of the acid cleavage of ethers, which can be achieved with either concentrated hydriodic acid or hydrobromic acid, this proceeds by protonalion of the oxygen atom, followed by nucleophilic displacement of phenol as shown in Scheme 4.5. 

In another case, 1 was used to deprotect the 2-(allyloxy)phenylacetyl group, employed as a protecting functionality in carbohydrate chemistry242. Thus, heating compound 266 with a palladium catalyst/proton sponge system results in an almost quantitative yield of compound 268 (equation 29). In accordance with a postulated relay mechanism, the phenolic allyl ether is cleaved by the transition metal followed by intramolecular ester cleavage by nucleophilic attack of the released hydroxyl. The aforementioned conditions... 

Finally, the data related to the application of ionic liquids for the cleavage of ethers are also notable. Chloroaluminates [44], anhydrous hydrobromic acid in 1-methylimidazole [45] and concentrated hydrobromic acid in [BMIM][BF4] or p-TsOH/[BMIM][Br] in [BMIM][BF4] [46] have been used to regenerate phenols from the corresponding aryl alkyl ethers. In ionic liquids, in the presence of an efficient proton donor (HBr or TsOH), the bromide anion behaves as a strong nucleophile able to cleave ethers. These latter reactions seem, therefore, to indicate that, as opposed to the situation in the absence of adds, the nudeophihcity of the bromide anion in ionic liquids in the presence of proton donors is higher than in molecular solvents (both pro tic and aprotic). This behavior may be a consequence of a... 

---