Chapter 12 Phosphorus reagents Topics: –For conventional Wittig reaction and developed Wittig reaction. –For conversion of hydroxy into halogen and for the formation of esters and amides from carboxylic acids. –For some reductive transformations.

 Nomenclature for phosphorus reagents

4  Phosphorus reagents for conventional Wittig reaction

6

7 In general: –Stabilized ylides (R 1 = -M group, e.g. an ester. E-isomer usually predominates. –Non-stabilized ylides (R, R 1 = hydrogen or simply alkyl, a mixture of E- and Z-isomers) –The ‘salt-Free’ wittig reaction of non-stabilized ylides gives the Z-alkene as the major product. –NaNH 2 or NaN(SiMe 3 ) 2 as bases yield increased Z-isomers. –Lithium halides present yield more of E-isomers.

For stabilized ylides, E-isomer usually predominates.

 Unstabilized ylides yield most Z-isomers:

 Adding salts to unstabilized ylides yield most E-isomers:

Another modification: the ylide is prepared by using PhLi and the addition to the aldehyde is carried out at –78 o C. Then a second mol. PhLi is added.

Azoylides

 Phosphorus reagents for developed Wittig reaction Horner-Wadsworth-Emmons Reaction

 Transition State Model (Compare stabilized ylides)

 Advantages for this reaction over the Wittig procedure include the following: Wittig reactions involving stabilized ylides are slow and, since additional stabilization by an electron-withdrawing group is required in almost all successful P=O stabilized carbanion reactions, the latter is the preferred procedure in such cases. A major problem in the Wittig procedure is the separation of the proceduct from the phosphine oxide; with P=O stabilized carbanion reactions the phosphorus is eliminated as a water-soluble phosphate anion.

A. Lattanzi et al. /Tetrahedron Letters 44 (2003) 1333–1337 D. L. Comins, C. G. Ollinger /Tetrahedron Letters 42 (2001) 4115–4118

 The Horner-Wittig reaction

R’COOR’’

Reactions of Carbon Nucleophiles with Carbonyl Groups. Wittig reaction The Aldol Condensation incl. Claisen cond. Robinson annulation Mannich reaction

Phosphorus( Ⅲ ) reagents Mitsunobu esterification Reaction Mechanism:

Mechanism: Side reaction:

Summary Phosphorus( Ⅲ ) reagents are nucleophilic but unlike their nitrogen analogues they are weakly basic. Trisubstituted phosphines and phosphites react with electrophiles of various kinds: –Alkylation of trialkyl- and triarylphosphines gives phosphonium salts, which may be precursors of ylides for use in the wittig reaction. –Alkylation of phosphites gives phosphonate esters (the Michaelis- Arbusov reaction), which may be the precursors of carbanions for use in the Horner-Wadsworth-Emmons alternative to the Wittig reaction: this variants yields predominantly the E-alkene. Other variants of the classical Wittig procedure may lead to cycloalkenes and alkynes.

Phosphorus( Ⅲ ) reagents can be used for conversion of hydroxy into halogen and for the formation of esters and amides from carboxylic acids. Phosphorus( Ⅲ ) reagents readily abstract oxygen, sulfur and halogen from organic compounds. This property is used to effect the following reductive transformations: –thiiranes alkenes –1,2-diols alkenes –R 3 N + － O R 3 N –ArNO 2 ArN=O ArN:(a nitrene) various insertion products –R 2 S=O R 2 S –ArCl or ArBr ArH