Ethers, Mitsunobu reaction

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

A new Ullmann ether protocol to install the pyrrolidinylethanol 10 was developed, obviating the need for the 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]. 

A PEG-star supported triphenylphosphine analog (66) was synthesized and employed in Mitsunobu reactions. Four phenolethers were prepared within 3-18 h reaction time and 68-93% yield. Upon completion of the reactions, the formed polymer supported triphenylphosphine oxide was isolated by precipitation from diethyl ether in > 85% yield. The reagent could be recycled by means of alane reduction (73%). 

Fluoroalkyl Glycosides (RFn-(CH2)2-n-0-sugar) and Perfluor-oalkylidene Acetals Derived from Sugars The very low nucleophilicity of fluoroalcohols makes it difficult to substitute of a hydroxyl (anomeric or not). ° This is the reason why this type of ether is not very common. Such ethers have only been isolated in very small quantities in solvolysis reactions, or in carben insertions, performed in fluorous alcohols.Preparation of these ethers has been solved by means of the Mitsunobu reaction. This reaction is known to be dependent on the pA a of the acceptor of the glycosyl the acidity of fluorous alcohols allows a much easier deprotonation than with non fluorinated alcohols." ... 

Below -ester products 85-92 via CALB-catalyzed acylation of rac-alcohols, isopropenyl acetate, room temp, until 50% conversion. Then Mitsunobu reaction ( DIAD, TPP, CH3COOH, ether 0 -> 20 °C, 24 h) ... 

The PEG3400-linked triarylphosphine 33 was developed as a liquid-phase polymeric reagent for use in Staudinger and Mitsunobu reactions.48 Precipitation of the PEG polymer with cold diethyl ether, filtration, and evaporation afforded the purified products. 

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. 

Sulfonamides can also be alkylated by support-bound electrophiles (Table 8.10). Polystyrene-bound allylic alcohols have been used to N-alkylate sulfonamides under the conditions of the Mitsunobu reaction. Oxidative iodosulfonylamidation of support-bound enol ethers (e.g. glycals Entry 3, Table 8.10) has been used to prepare /V-sulfonyl aminals. Jung and co-workers have reported an interesting variant of the Baylis-Hillman reaction, in which tosylamide and an aromatic aldehyde were condensed with polystyrene-bound acrylic acid to yield 2-(sulfonamidomethyl)acrylates (Entry 4, Table 8.10). 

Protection of primary alcohols p-Anisyl ethers are readily prepared from primary alcohols by the Mitsunobu reaction [P(C6H5)3 DEAD]. The ethers are stable to 3 N HC1 or 3 N NaOH at 100°, to Jones or PCC oxidation, and to LiAlH4. Deprotection is effected in 85-95% yield by oxidation with CAN in aqueous CH3CN. 

Enantiopure 72 was converted to 73 by performing the Mitsunobu reaction. An exchange of protecting groups was then carried out (for reasons outlined in previous sections) and the free alcohol 74 generated. Subsequent O-silylation formed the RRM precursor 71 in a 90% yield. The metathesis and the subsequent silyl ether cleavage were performed in a one pot procedure to give 69 (Scheme 23). 

Novel nor-seco baccatin 99 was synthesized in 92% yield through oxidative cleavage of the A ring of 14-OH-DAB (75) with periodic acid via the hydroxy ketone intermediate 100 (Scheme 19). Protection of the 7-hydroxyl of 99 as TES ether followed by reduction of the aldehyde with sodium borohydride yielded nor-seco baccatin alcohol 101 in 80% yield. Nor-seco 13-amino-baccatins 102 and 103 were synthesized from 101 and 99a via the Mitsunobu reaction and reductive amination, respectively, in high yields (Scheme 20). 

The Mitsunobu Reaction allows the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers and various other compounds. The nucleophile employed should be acidic, since one of the reagents (DEAD, diethylazodicarboxylate) must be protonated during the course of the reaction to prevent from side reactions. 

The hydroxymethyl derivative of 2-azabicyclo[2.2.0]hexane 199 (R = H) has been converted into the 2-chloropyr-idin-5-yl ether 199 (R = 2-CIG5H3N) by Mitsunobu reaction with 2-chloro-5-hydroxypyridine <2000T9227>. 

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. 

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