Alcohols allylic, primary

Isomerization of allylic alcohols. Primary and secondary allylic alcohols and their silyl ethers are equilibrated in the presence of (Me3Si0)Re02. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

The slow oxidation of primary alcohols, particularly MeOH, is utilized for the oxidation of allylic or secondary alcohols with allyl methyl carbonate without forming carbonates of the alcohols to be oxidized. Allyl methyl carbonate (564) forms 7r-allylpalladium methoxide, then exchange of the methoxide with a secondary or allylic alcohol 563 present in the reaction medium takes place to form the 7r-allylpalladium alkoxide 565, which undergoes elimination of j3-hydrogen to give the ketone or aldehyde 566. The lactol 567 was oxidized selectively with diallyl carbonate to the lactone 568 without attacking the secondary alcohol in the synthesis of echinosporin[360]. 

The trimethoxy derivative is too labile for most applications, but the mono and diderivatives have been used extensively in the preparation of oligonucleotides and oligonucleosides. The monomethoxy derivative has been used for the selective protection of a primary allylic alcohol over a secondary allylic alcohol (MMTr, Pyr, -10°). ... 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

Nickel peroxide is a solid, insoluble oxidant prepared by reaction of nickel (II) salts with hypochlorite or ozone in aqueous alkaline solution. This reagent when used in nonpolar medium is similar to, but more reactive than, activated manganese dioxide in selectively oxidizing allylic or acetylenic alcohols. It also reacts rapidly with amines, phenols, hydrazones and sulfides so that selective oxidation of allylic alcohols in the presence of these functionalities may not be possible. In basic media the oxidizing power of nickel peroxide is increased and saturated primary alcohols can be oxidized directly to carboxylic acids. In the presence of ammonia at —20°, primary allylic alcohols give amides while at elevated temperatures nitriles are formed. At elevated temperatures efficient cleavage of a-glycols, a-ketols... 

BzCl or BZ2O, Pyr, 0°. Benzoyl chloride is the most common reagent for the introduction of the benzoate group. Reaction conditions vary, depending on the nature of the alcohol to be protected. Cosolvents such as CH2CI2 are often used with pyridine. Benzoylation in a polyhydroxylated system is much more selective than acetylation. A primary alcohol is selectively protected over a secondary allylic alcohol, and an equatorial alcohol can... 

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

With respect to the olefinic substrate, various functional groups are tolerated, e.g. ester, ether, carboxy or cyano groups. Primary and secondary allylic alcohols, e.g. 14, react with concomitant migration of the double bond, to give an enol derivative, which then tautomerizes to the corresponding aldehyde (e.g. 15) or ketone ... 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

Table 6.2 Examples of epoxides generated by AE, applied to different primary allylic alcohols showing all eight basic substitution patterns.

The AE reaction catalyzed by titanium tartrate 1 and with alkyl hydroperoxide as terminal oxidant has been applied to a large variety of primary allylic alcohols containing all eight basic substitution patterns. A few examples are presented in Table 6.2. 

The empirical rule described above for the enantiofacial differentiation in AE of primary allylic alcohols also applies to secondary allylic alcohols. The new aspect that needs to be taken into consideration in this case is the steric hindrance arising from the presence of a substituent (R4) at the carbon bearing the hydroxy group (Figure 6.3). This substituent will interfere in the process of oxygen delivery, making the oxidation of one enantiomer much faster than the reaction of the other one. The phenomenon is so acute that in practice kinetic resolution is often achieved (Figure 6.4) [27]. 

The reaction gives good yields with primary, secondary, and tertiary alcohols, and with alkyl and aryllithium reagents.Allylic alcohols also couple with certain... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

Trifluoromethanesulfonates of alkyl and allylic alcohols can be prepared by reaction with trifluoromethanesulfonic anhydride in halogenated solvents in the presence of pyridine.3 Since the preparation of sulfonate esters does not disturb the C—O bond, problems of rearrangement or racemization do not arise in the ester formation step. However, sensitive sulfonate esters, such as allylic systems, may be subject to reversible ionization reactions, so appropriate precautions must be taken to ensure structural and stereochemical integrity. Tertiary alkyl sulfonates are neither as easily prepared nor as stable as those from primary and secondary alcohols. Under the standard preparative conditions, tertiary alcohols are likely to be converted to the corresponding alkene. 

The scope of the reaction of Ph3P-Cl3CCOCCl3 with allylic alcohols has been studied. Primary and some secondary alcohols, such as 14A and 14B, give good... 

Organozinc reagents have been used in conjunction with a-bromovinylboranes in a tandem route to Z-trisubstituted allylic alcohols. After preparation of the vinylborane, reaction with diethylzinc effects migration of a boron substituent with inversion of configuration and exchange of zinc for boron.176 Addition of an aldehyde then gives the allylic alcohol. The reaction is applicable to formaldehyde alkyl and aryl aldehydes and to methyl, primary, and secondary boranes. 

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

The isoquinolinium ylide 241 reacts with allyl alcohol in a [3+2] cycloaddition to give the tetracyclic product 242 (Equation 32) the primary cycloaddition product spontaneously undergoes an intramolecular transesterification to give the isolated furanone. Similarly, reaction of such ylides with vinylene carbonate gives the tetracycles 243 (Equation 33) <1988BCJ2513>. 

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