Mitsunobu phenols

Hydroxyl group of 7-hydroxymethylperhydropyrido[l,2-u]pyrazines 382 was arylated by Mitsunobu coupling with phenols and 4-fluorothiophenol... 

Representative Procedure for Silicon Promoted Glycosylation with Cl-Hemiacetal Donors Using Me3SiBr and CoBr2 129 Representative Procedure for Mitsunobu-Type Glycosylation with Cl-Hemiacetal Donors and Phenol Glycosyl Acceptors 129 Representative Procedure for Appel-Type Glycosylation with Cl-Hemiacetal Donors 129... 

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... 

Although aliphatic alcohols are typically poor acceptors in the Mitsunobu-type glycosylation, Szarek and coworkers have highlighted one advance to this end [95]. For the triphenylphosphine and diethylazodicarboxylate promoted glycosylation of a monosaccharide acceptor, the addition of mercuric bromide is necessary to promote the reaction. For example, the (1,6)-disaccharide 44 was obtained in 80% yield using this modified Mitsunobu protocol. Unlike previous examples with phenol or N-acceptors, preactivation of the hemiacetal donor was performed for 10 min at room temperature prior to addition of the aliphatic alcohol nucleophile. 

Representative Procedure for Mitsunobu-Type Glycosylation with Cl-Hemiacetal Donors and Phenol Glycosyl Acceptors [90]... 

Preparation of the donor 46 was started from 4,6-0-benzylidene protected thiomannoside 47 (Scheme 7.24). Alkylation with p-allyloxybenzyl chloride under phase transfer conditions78 was followed by 3-O-silylation and Pd(0)-mediated deallylation79 to give 48. The phenolic OH group was alkylated with ethyl 6-bromohexanoate and carboxylic acid, liberated by alkaline hydrolysis, was reacted with PEG monomethyl ether (MW -5000) under Mitsunobu conditions to afford 46. 

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-... 

Both aliphatic alcohols and phenols have been immobilized as esters of support-bound carboxylic acids. The esterification can be achieved by treatment of resin-bound acids with alcohols and a carbodiimide, under Mitsunobu conditions, or by acylation of alcohols with support-bound acyl halides (see Section 13.4). 

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]. 

The Mitsunobu etherification of polystyrene-bound phenols is usually conducted in THF or NMP, simply by adding the alcohol, the phosphine, and DEAD. Some authors claim that the addition of tertiary amines is beneficial [148], but this seems not always to be the case [146], It is, of course, important that neither the support nor any of the... 

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. 

Mitsunobureaction.1 Two intermediates have been isolated from the Mitsunobu esterification of carboxylic acids with phenols. One is the betaine 1, which has been generally assumed to be involved the other is the phosphorane 2.2... 

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],... 

Figure 2.34 shows the mechanism of this reaction. A key intermediate is the alkylated phosphine oxide A, with which the carboxylate ion reacts to displace the leaving group 0=PPh3. Figure 2.34 also shows that this carboxylate ion results from the deprotonation of the carboxylic acid used by the intermediate carbamate anion B. Nucleophiles that can be deproto-nated by B analogously, i.e., quantitatively, are also alkylated under Mitsunobu-like conditions (see Figure 2.36). In contrast, nucleophiles that are too weakly acidic cannot undergo Mitsunobu alkylation. Thus, for example, there are Mitsunobu etherifications of phenols, but not of alcohols.

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. 

A stereoselective synthesis of (-)-gallocatechin illustrates a general approach to flavan-3-ols. Mitsunobu coupling of a phenol and an epoxyalcohol provides access to a l-aryl-3-bromo-2-hydroxypropyl 2-iodoaryl ether which is cyclised to the flavanol by a halogen-metal exchange (Scheme 13) <06CL1006>. 

An unusual method for the preparation of TBS ethers of phenols and alcohols involves reaction with /m-butyldimethylsilano] under Mitsunobu conditions [Scheme 4.69],115... 

The enhanced acidity conferred upon / acyl phenols is sufficient for their participation in Mitsunobu displacements. Scheme 4.171 shows an example in which selective 0-benzyIation of the p-hydroxyl in the orcinol derivative 171 1 took place in preference to the o-hydroxyl.319... 

Phenols readily react with fluorinated and nonfluorinated alcohols under Mitsunobu conditions (vide siipra)d or with other phosphates, c.g. coupling of dichlorophosphate 12 with pcntafluorophenol 13 to yield ether 14." or related reagents. " ... 

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... 

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