Phenols Mitsunobu reaction

The glycosylation based on the Mitsunobu reaction has been most commonly directed to the synthesis of O-aryl glycosides, a structural motif found in a variety of natural products [80-82], Early work by Grynkiewicz [83,84], among others [85-87], established the viability of triphenylphosphine and diethylazodicarboxylate to promote the glycosylation of phenol acceptors at ambient temperature. More recently, Roush and coworkers have discovered that the glycosylation performed well in the... 

The second reaction uhhzed with this reagent was the Mitsunobu reaction ]97], a reachon known to require chromatographic purification to obtain pure product because side-products are formed. An insoluble polymer approach to this problem is known [98], however, the nature of the support means that the reachon is inherently heterogeneous (see above). The reaction between phenol and a series of alco-... 

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]. 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

Phenols attached to insoluble supports can be etherified either by treatment with alkyl halides and a base (Williamson ether synthesis) or by treatment with primary or secondary aliphatic alcohols, a phosphine, and an oxidant (typically DEAD Mitsu-nobu reaction). The second methodology is generally preferred, because more alcohols than alkyl halides are commercially available, and because Mitsunobu etherifications proceed quickly at room temperature with high chemoselectivity, as illustrated by Entry 3 in Table 7.11. Thus, neither amines nor C,H-acidic compounds are usually alkylated under Mitsunobu conditions as efficiently as phenols. The reaction proceeds smoothly with both electron-rich and electron-poor phenols. Both primary and secondary aliphatic alcohols can be used to O-alkylate phenols, but variable results have been reported with 2-(Boc-amino)ethanols [146,147]. 

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. 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

Fukumoto, S. Fukushi, S. Terao, S. Shiraishi, M. Direct and enantiospecific ortho-benzyla-tion of phenols by the Mitsunobu reaction. 

Chemists from Merck [25] have also described the use of the Mitsunobu reaction for the functionalization of either phenols or benzyl alcohols using TMAD/Bu3P. Similar chemistry has been applied successfully to intermediate phenols prepared using the Mimo-tope pin technology [26],... 

As shown in Equation (19), l-(2-dimethylaminoethyl)-8,9-dihydropyrano[3,2-e]indoles (44), rotationally restricted phenolic analogues of the neurotransmitter serotonin, were prepared in good yield from 5-hydroxyindoles in a cyclization reaction using an intramolecular variant of the Mitsunobu reaction <91TL3345, 92T1039). The borane complex could be dissociated with CsF and Na2C03 in refluxing EtOH. 

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. ... 

As the Mitsunobu reaction requires weakly acidic nucleophiles, and since phenols have the necessary acidity, aryl glycosides [409-411] have been prepared this way. However, alcohols are... 

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,... 

Oxidation phenol - biphenyl derivatives with VOCl.i [218], synthesis of oligonucleotide [219], Mitsunobu reaction [220]. 

The Mitsunobu reaction [26] with phenols was carried out under standard reaction conditions. 

Carboxylic acids can be attached to these linkers using methods of ester bond formation such as carbodiimide/DMAP [23] and acid chloride/base. For the loading of N-protected-a-amino acids in particular, an array of different methods has been developed to minimize enantiomerizahon and dipeptide formation during the esterification reaction. These include the use of MSNT/N-methylimidazole [24], mixed anhydrides generated with 2,6-dichlorobenzoyl chloride [25], esters of 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene [26] and acid fluorides [27]. Phenols and N-protected hydroxylamines have been immobilized using the Mitsunobu reaction [28, 29], The latter are particularly useful for the preparation of hydroxamates [29, 30],... 

Various solutions to the problem have been suggested. In a straightforward synthesis of aryl (3-D-mannopyranosides, 2,3 4,6-di-0-cyclohcxylidcnc-a-o-mannopyranose was treated with diethyl azodicarboxylate, triphenylphosphine, and a phenol in toluene (Mitsunobu reaction conditions) to give, after hydrolytic removal of the two cyclohexylidene groups, the (3-mannosidcs in good yield.37... 

The elegant formal total synthesis of morphine, accomplished by Parker, shows some similarities to that of Fuchs through analogous disconnections. In both syntheses, the core of the molecule was formed as a result of a tandem process in this case as a result of a radical cascade.79 80 The immediate cyclization precursor 191 was prepared via a Mitsunobu reaction between monoprotected cw-diol 189 (prepared in 8 steps from 2-((3-methoxyphenyl)ethylamine) in 47% overall yield) and phenol 188, followed by cleavage of the silyl ether, Scheme 21. The key step, homolytic cleavage of the Ci2-Br... 

Alkylations. The reagent effects reductive Af-alkylation of A -tosylamines and indole derivatives with alcohols. The Mitsunobu reaction of 2-(l-hydroxy-alkyl)-acrylic esters and that of glycals with phenols follow an Sn2 course. The reaction has been applied to the inversion of configuration at an a-cyanohydrin center, whereas alkyl nitriles are prepared by this method using acetonitrile cyanohydrin as the source of nucleophile. The C-alkylation of o-nitroarylacetonitriles at the ben-zylic position is easily controlled. 

Nucleophilic Attack at Other Atoms. The mechanism of reactions involving alcohols (or phenols) with the triphenylphosphine-diethyl azodicarboxylate (DAD) reagent (the Mitsunobu reaction) has now been reconsidered in the light of a number of spectroscopic and preparative studies in the past year. In an... 

Thus, the triisopropylsilyl ether of the 4-aminophenol 25 was treated with 2-(4-biphenyl)isopropyl phenyl carbonate in THF followed by addition of excess KH to provide the Bpoc derivative 26. The trimethyltin group was then introduced by directed orf/io-metalation followed by reaction with trimethyltin chloride. Treatment of 27 with BU4NF provided the free phenol, which was then coupled to the cyanomethyl ester of 4-(hydroxymethyl)phenoxyacetic acid under standard Mitsunobu reaction conditions to give the active ester 28 (Scheme 4.1.6). 

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