Geminal dialkyl substitution

Alkylene chains with geminal dialkyl substitution have been shown to cyclize more readily than the corresponding unsubstituted compounds (Scheme 9.12). This effect can be used to achieve cyclization which might not occur without geminal disubstitution (see, e.g., Scheme 9.21) [32]. The magnitude of this effect is, however, highly dependent on the type of reaction and product, as illustrated by the examples in Scheme 9.12. 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

A number of functionalities at the four-position of the heterocyclic ring were also investigated. Geminal dialkyl substitution was found to be essential for activity. Maximum effectiveness was... 

Scheme 10. Reaction sequence for the synthesis of tri-, tetra-, and penta(isopropyl)cyclo-pentadienes (34,35) from di(isopropyl)-Cp (59) via a series of metallations/alkylations. Tri(isopropyl)-Cp is obtained in a 4 1 mixture of the 1,2,4- and 1,2,3-substituted isomers. The C—H acidic tetra(isopropyl) isomers are separated from the 5,5 -geminal dialkylated forms by their transformation in the sodium salt and evaporation of the nonmetallated components. Subsequent hydrolysis yields l,2,3,4-tetra(isopropyl)cyclopentadiene in an iso-merically pure form. Similarly, l,2,3,4,5-penta(isopropyl)-Cp is purified after separation of the 1,2,3,S,5 derivative as the main alkylation product. For more details and the respective yields, see Refs. 34 and 35.

Ethylene dithioacetals of benzophenone and its 4-fluoro-, 4-bromo-, 4,4 -difluoro-, 4,4 -dichlo-ro-, and 3,5-dimethyl-substituted analogs react with sulfuryl chloride or sttlfuryl chloride fluoride in hydrogen fluoride/ pyridine at — 78 C to room temperature to give the corresponding geminal difluorides in 85-90% yield. The reaction is, however, not applicable to dialkyl or alkyl aryl ketones as they undergo chlorination under these conditions.73... 

Double substitution of geminal dibromides is best accomplished by treatment with an organocuprate, followed by the addition of an alkyl iodide to the crude reaction mixture. " The reaction has found especial application for the synthesis of dimethylcyclopropanes, ubiquitous in natural product chemistry. Excellent yields are often obtained with Me2CuLi, but with less reactive substrates higher order cyano-and thiocyano-cuprates sometimes provide better results. Spiro dialkylation of geminal dibromides has also been accomplished. Vicinal dibromides, on the other hand, afford alkenes upon treatment with dialkyl cuprates. ... 

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