Aryl ethers, Mitsunobu reaction

For the synthesis of perfectly dendronized sohd-phase polymers (Fig. 7.4) various dendritic structures were prepared based on amide connections [6]. For example, the naturally occurring amino acid lysine was used as a building block in creating a dendritic scaffold [33]. The synthesis of symmetrical tri-branching den-drimers on aminomethyl polystyrene macrobeads was also described in literature [34]. Recently, aryl ether dendrimers were prepared on hydroxymethyl polystyrene using a Mitsunobu reaction with 3,5-bis(acetoxymethyl)phenol [35]. 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

Rano TA, Chapman KT, Solid phase synthesis of aryl ethers via the mitsunobu reaction, Tetrahedron Letters, 36 3789-92, 1995, Solid phase synthesis (aryl resin coupling) TMAD Bu3P. 

O-Aryl glycidol ethers can be prepared from glycidol by the Mitsunobu reaction with phenols (see eq 3) and are also made from direct displacement by glycidol on activated haloaryls. ... 

In 1992, Parker and Fokas reported the short step (11 steps) synthesis of racemic dihydroisocodeine, which completes a formal synthesis of codeine and morphine [58]. The key feature of their synthesis are (1) a construction of an aryl ether moiety (connection of the A and C rings) by Mitsunobu reaction, (2) a tandem radical cyclization of aryl bromide possessing the C-ring precursor to generate the A-B-C-E ring of morphine, and (3) a hydroamination for the construction of the D-ring by the reaction of a tosylamide with Li/NH3. In 2006, they reported the chiral version of the synthesis of dihydrocodeinone [59]. 

The Mitsunobu reaction proved to be useful for the synthesis of aryl alkyl ethers from alcohols and phenols. The method proceeds under mild conditions and tolerates many functional groups with inversion of configuration, as exemplified by the reactions of lactate and ewrfo-5-norbornen-2-ol (equations 4 and Neighboring group participation,... 

Table 1 shows the experimental conditions for the synthesis of azocellulose polymers through alkyl aryl ether formation via Mitsunobu reaction (Scheme 1). Samples AZOEST21 and AZOEST49 were prepared from ESTERCELL cellulose, and Sample AZOVIS69 was prepared from VISCOCELL cellulose. The degrees of substitution (DS) for these samples are 0.21, 0.49 and 0.69, respectively. 

The most common preparative method to prepare the aryl allyl ether is the Williamson s ether synthesis [la,b]. Typically, aryl allyl ethers can be obtained from phenol derivatives and allylic halide under basic conditions (KjCOj) in refluxing acetone. This method is convenient for the preparation of simple allyl aryl ethers. However, some side reactions such as a competitive C-allylation (Sn2 type reaction) often accompany the formation of undesired byproducts. Mitsunobu reaction of phenol derivatives with allylic alcohols instead of allylic halides can be used under mild conditions [13]. In particular, when the allyl halide is unstable, this procedure is effective instead of the Williamson s ether synthesis. This method is also useful for the preparation of chiral allyl aryl ether from chiral allylic alcohol with inversion at the chiral center. Palladium catalyzed O-allylation of phenols is also applicable, but sometimes a lack of site-selectivity with unsymmetrical allylic carbonate [14] may be a problematic issue. 

Rearrangement of propargyl aryl ether 19 smoothly proceeds under thermal conditions to afford chromene derivatives 22 [23, 24]. The mechanism involves the formation of ortho allenyl phenol 20 followed by a 1,5-hydrogen shift and elec-trocyclic ring closure sequence via 21. For example, the Claisen rearrangement of propargyl aryl ether 23 prepared by the Mitsunobu reaction smoothly took place at 180 °C to give a flav-3-ene derivative 24 in excellent yield [25]. 

Solid-supported triphenylphosphine, first reported by Havens et al. in 1983 for an esterification reaction, has found extensive applications in Mitsunobu chemistry. For example, the preparation of aryl ethers from amino alcohols has been carried out interestingly, addition of triethylamine led to better conversion in some cases. " More recently, Pelletier et al. prepared a series of primary amines by reaction of a primary alcohol in the presence of (Boc)2NH, TBAD and solid-supported TPP. Typical reported yields were in excess o l5% ... 

Mitsunobu and Wada first reported the use of the Mitsunobu reaction in the preparation of ethers in 1972. Since then, the Mitsunobu reaction has become a useful alternative to the reaction of phenols with alkyl halides. Other sufficiently acidic alcohols with a p a of less than 13 may also react under the Mitsunobu reaction conditions. Interestingly, unactivated, less acidic alcohols will form ethers when reacting in an intramolecular manner. The figures below show a number of applications of the Mitsunobu reaction in the preparation of alkyl and aryl ethers. 

The general scheme of the Mitsunobu reaction in the synthesis of aryl-alkyl ethers reveals the complexity of the reacting system (Scheme 3.4). 

Ran1995 Rano, T.A. and Chapman, K.T., Solid Phase Synthesis of Aryl Ethers via the Mitsunobu Reaction, Tetrahedron Lett., 36 (1995) 3789-3792. 

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