Organic synthesis Kamil Paruch Masaryk University, Brno • C electrophiles: C-alkylations usually predominate • O alkylations: very reactive (hard) electrophile (e.g. ROTf); K+ a Na+ enolates Enolates: preparation, structure, reactivity C-C bonds ACIDOBASIC PROPERTIES OF CARBONYL COMPOUNDS ACIDOBASIC PROPERTIES OF CARBONYL COMPOUNDS malonic ester synthesis acetoacetate synthesis selenation of carbonyl compounds • preparation of a,b-unsaturated carbonyl compounds oxidation of enolates J. Am. Chem. Soc. 1988, 110, 649. J. Am. Chem. Soc. 1990, 112, 6679. J. Am. Chem. Soc. 1974, 96, 5944. ACIDOBASIC PROPERTIES OF CARBONYL COMPOUNDS KINETIC VS. THERMODYNAMIC ENOLATE Formation of kinetic product (k1 > k2; k1 >> k-1) is typically observed under these conditions: • aprotic solvent; • strong non-nucleophilic base; • low temperature; • short reaction time (equilibrium not established). Formation of thermodynamic product (k1 ~ k-1) is typically observed under these conditions: • protic solvent (deprotonation-reprotonation); • weaker bases; • higher temperature; • longer reaction time (sufficient for establishing equilibrium). ACIDOBASIC PROPERTIES OF CARBONYL COMPOUNDS KINETIC VERSUS THERMODYNAMIC PRODUCT enamines • “nitrogenous enolates“; some can be isolated • enamines react well with C-electrophiles Tetrahedron 1958, 3, 314. planar geometry  formation of kinetic isomer silyl enol ethers • formation of Si-O bond; irreversible • silyl enol ethers are relatively stable J. Org. Chem. 2000, 65, 7602. Mukaiyama (aldol) reaction J. Am. Chem. Soc. 1974, 96, 7503.L. A. : TiCl4, SnCl4, BF3.OEt2 Sakurai allylation J. Am. Chem. Soc. 1977, 99, 1673. Chem. Lett. 1985, 977. 10 000 more nucleophilic than propene Org. Lett. 2000, 2, 945. • quite universal, mild conditions (cf. addition of organometalic reagents) Saegusa oxidation J. Org. Chem. 1978, 43, 1011. • very mild conditions J. Org. Chem. 2002, 67, 2735. recent review: Organic Reactions 98. Aldol reaction: 2 new stereogenic centers can be created • sterochemistry of products depends on the configuration of the starting enolates Z vs. E enolate GEOMETRY OF ENOLATES - IRELAND MODEL small R1 E large R1 Z GEOMETRY OF ENOLATES - EFFECT OF BASE GEOMETRY OF ENOLATES – EFFECT OF SUBSTITUENT • enolates often form clusters J. Am. Chem. Soc. 1986, 108, 462. Helv. Chim. Acta 1981, 64, 2617. SELECTIVE FORMATION OF E OR Z ENOL BORINATES R2BCl with large alkyls (e.g. cyclohexyl) + small base (Et3N) -> E enolates R2BOTf with small alkyls (e.g. n-butyl) + large base (DIPEA) -> Z enolates