Pinacol rearrangement aldehydes

The pinacol rearrangement reaction is of limited synthetic importance although it can be a useful alternative to the standard methods for synthesis of aldehydes and ketones." Especially in the synthesis of ketones with special substitution pattern—e.g. a spiro ketone like 5—the pinacol rearrangement demonstrates its synthetic potential ... 

The Prins cyclization can also be coupled with a ring-contraction pinacol rearrangement, as illustrated in Scheme 1.6. This allows a smooth conversion of alkyl-idene-cyclohexane acetal 1-16 to single bond-joined cyclohexane cyclopentane aldehyde 1-17 [le]. 

Isomerization of substituted styrene oxides allows the synthesis of aldehydes in high yields726 [Eq. (5.275)]. Cycloalkene oxides do not react under these conditions, whereas 2,2,3-trimethyloxirane gives isopropyl methyl ketone (85% yield). Isomerization of oxiranes to carbonyl compounds is mechanistically similar to the pinacol rearrangement involving either the formation of an intermediate carbocation or a concerted mechanism may also be operative. Glycidic esters are transformed to a-hydroxy-/3,y-unsaturated esters in the presence of Nafion-H727 [Eq. (5.276)]. 

The pinacol rearrangement is a dehydration of an alcohol that results in an unexpected product. When hot sulfuric acid is added to an alcohol, the expected product of dehydration is an alkene. However, if the alcohol is a vicinal diol, the product will be a ketone or aldehyde. The reaction follows the mechanism shown, below. The first hydroxyl group is protonated and removed by the acid to form a carboca-tion in an expected dehydration step. Now, a methyl group may move to fonn an even more stable carbocation. This new carbocation exhibits resonance as shown. Resonance Structure 2 is favored because all tire atoms have an octet of electrons. The water deprotonates Resonance Structure 2, forming pinacolone and regenerating the acid catalyst. 

The proposed mechanism for the reaction is shown in Scheme 13.75. In the first step, the oxonium cation 208, formed by TfOH-catalyzed condensation of an aldehyde with alcohol 206, undergoes an intramolecular cyclization to form the tertiary carbocation 209. In a subsequent step, cation 209 undergoes a pinacol rearrangement, leading to the observed tetrahydropyran 205. 

The most general method for the synthesis of tetrahydrofurans based upon the IMSC methodology was developed by Overman et al. [53, 54, 94—96] For example, condensation of alcohol 221 with an aldehyde or a ketone in the presence of a Lewis acid leads to the formation of the carbocations 222a,b. The tertiary carboca-tion 222a undergoes a pinacol rearrangement and forms the desired heterocycle 224 (Scheme 13.82). Overman et al. used this approach during the synthesis of the various cladiellin diterpenes, which possess the core skeleton 224 [53]. 

The inter- and intramolecular coupling of two carbonyl groups of aldehydes or ketones in the presence of a low-valent titanium species produces a C-C bond with two adjacent stereocenters, a 1,2-diol (a pinacol). These may be further elaborated into ketones by the pinacol rearrangement or be deoxygenated to alkenes (McMurry reaction). 

The Prins-pinacol rearrangement was utilized during the first enantioselective total synthesis of briarellin diterpenes by L.E. Overman and co-workers. The cyclohexadienyl diol substrate was condensed with a (Z)-a,p-unsaturated aldehyde at low temperature in the presence of catalytic amounts of acid and MgS04 as dehydrating agent. The initially formed acetal was then exposed to 10 mol% of SnCU to afford the desired tetrahydroisobenzofuran as a single stereoisomer that was later converted to briarellin F. 

The important study of Berti et al. (also discussed in the context of the pinacol rearrangement see equations 8 to 11 of Chapter 3.2 in this volume) included BFs-induced reactions of the cis- and transepoxides (85 equation 36) and (91 equation 37), respectively. These very informative reactions show that, at least under the particular reaction conditions used in this work (benzene as solvent), the Coxon mechanism must be expanded to include an appreciable antiperiplanar geometrical feature. Unlike the pinacol rearrangements of the related diols, which gave only ketone (89) and aldehyde (90) under the same conditions, epoxide (85) gives, in addition to these same products, a significant amount of aldehyde (87). This appears to require the involvement of the twist boat conformer (86), which is the expected intermediate if the shown starting material conformer opens at the tertiary benzylic center with antiperiplanar constraints. Subsequent rotation of (86) to the chair conformer (88) allows formation of the ketone (89) and the aldehyde (90). 

The cleaner reactions of the halohydrins show that these, if formed by anti opening and not subsequently epimerized, cannot account for the product mixtures from the epoxides. House proposed a competing carbenium ion route for both epoxides, leading to the normal pinacol rearrangement (carbenium ion) product, the aldehyde (202). 

Dihydroxylation of the stilbene double bond in the trans isomers of Combretastatin A-1 and A-4 produced diols which by treatment with boron trifluoride in ethyl ether [44] or with trifluoroacetic acid [17] resulted in pinacolic rearrangement to produce an aldehyde. The aldehyde was converted in a variety of derivatives, as illustrated in the Scheme 20, via the following reaction sequence reduction with sodium borohydride to primary alcohol which was derivatized to the corresponding mesylate or tosylate, substitution with sodium azide and final reduction to amine with lithium aluminum hydride. Alternatively the aldehyde was converted to oxime which was catalitically hydrogenated to amine [17]. 

Oxonium intermediates resulting from the pinacol rearrangement of a-sulfonate acetal derivatives can be intercepted with nucleophilic reagents, affording protected ketones or aldehydes. Rearrangement of acetals in the presence of excess bis(2-methylpropyl)aluminum hydride affords the acetal products31. 

A change of a polarity from a polar to nonpolar state (reverse polarity change) can be accomplished by the pinacol-pinacolone rearrangement and has been exploited in chemically amplified lithographic imaging [151, 348-350]. The pinacol rearrangement involves conversion of vie-diols to ketones or aldehydes with an acid as a catalyst (Fig. 115). 

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