Mitsunobu reaction ether formation

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

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. 

All characteristic last steps in the synthesis of EDOT, i.e. the ring closure to the dioxane structure, are also sufficient for the formation of the analogous seven-membered rings (1,3-dioxepanes), the 3,4-propylenedioxythiophenes (ProDOTs) Williamson ether synthesis [13], transetherification [30] and Mitsunobu reaction [25]. The analogous basic five-membered ring compound 3,4-methylenedioxythiophene (MDOT, a 1,3-dioxolane derivative) is also accessible by Williamson ether synthesis using bro-mochloromethane [31]. 

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]. 

The sulfonamide betaine 26 has occasionally been employed as a surrogate for TPP/DEAD in Mitsunobu reactions in solution and on solid support. Tamaka et al. have employed 2,4,4,6-tetrabromo-2,5-cyclohexandione (27) as a DEAD equivalent. The couple has been used to convert alcohols and THP ethers into the corresponding bromides. Use of the reagent combination in the presence of zinc(II) azide leads to the efficient formation of azides from alcohols in 70% or higher yields. ... 

In a related application of a phenol-like ether formation via Mitsunobu reaction, Deleris et al. prepared a series of Z-ascorbic acid derivatives using the unprotected acid. The reaction was selective for the 3 position of ascorbic acid 90, the most acidic of the four alcohol substituents of the acid. Use of the A iiV.iV .iV -tetramethylaza-dicarboxylate/tributylphos-phine reagent combination did not improve the yield of the reaction. 

The Mitsunobu reaction has been extensively used for the formation of aziridines. Recently, Cossy et al. were interested in inverting the benzylic hydroxyl group in 167 to prepare a precursor of (phenol derivative 169. Increasing the concentration of 2-ethoxyphenol to 20 equiv led to the formation of the desired phenol ether in good yield. The Mitsunobu reaction has also been used for the preparation of amino acid derived aziridines these compounds can then be used for the synthesis of pseudopeptides. 

Synthetic highlights A critical step in the synthesis of the compound involves non-hydrolytic anomalous lactone ring-opening by TMSl. To avoid racemization, the Mitsunobu reaction was applied in the formation of the ether bond. Optimization of the Mitsunobu reaction was finally achieved without loss of enantiomeric purity. 

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