Ligand-assisted nucleophilic addition

A striking exaple of the influence of the Schlenk equilibrium on the progress of reactions of organomagnesium compounds was observed in, what was named, a ligand-assisted nucleophilic addition reaction (LANA), in which the substrate was a lithium quinol alkoxide [29]. In a typical LANA reaction (Scheme 14) the lithium quinol alkoxide is first prepared in situ, after which follows the sequential addition of l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidone (DPMU) and a Grignard reagent. 

Scheme 16.11 Hydroamination of alkynes using ligand assisted nucleophilic addition.

For attack of F on acrylic acid, first a hydrogen bonded complex is formed which then proceeds to the transition state and then to a stable carbanion. The methyl in the methacrylic acid reduces stabilization of the carbanion as predicted. Subsequent studies using ammonia as the nucleophile indicated that attack proceeded by a rate-determining intramolecular proton transfer from the nucleophile to the ligand, assisted by a discrete water molecule that acts as a catalyst17. They predicted that acrolein underwent 1,4-addition, acrylic acid either 1,2- or 1,4-addition and acrylonitrile 1,2-addition. 

Lithiated epoxides are more commonly trapped by electrophiles, generating elaborated oxiranes. In this arena, Hodgson and co-workers <04OL4187> have optimized the lithiation of non-stabilized terminal epoxides with iec-hutylhthium assisted by diamine ligands, such as dibutylbispidine (DBB, 99) or (-)-sparteine 100. The oxiranyl anions thus formed engage in smooth nucleophilic addition onto aldehydes to form epoxyalcohols e.g., 101) the same conditions can be used for the stannylation of epoxides e.g., 84 102). Similarly,... 

As discussed in a recent review, there are four modes of C-H bond metalation (l) oxidative addition with eleetron-rich late transition metals (2) a-bond metathesis with early transition metals (3) electrophilic activation with electron-deficient late transition metals and (4) earboigrlate-directed metalation. The last mode has been only recently reported and proceeds via a continuum of electrophilic, ambiphilic, and nucleophilic interactions with the assistance of a bifunetional ligand bearing an additional Lewis-basic heteroatom, such as carbojgrlate. Possible mechanisms for the C-H bond palladation are shown in Seheme 2.12. 

The highest enantiomeric excess in the palladium(0)-assisted enantiosclcctive alkylation of racemic 3-cycloalkenyl acetate has so far been observed with the chiral ligands 2, 3a and 3b60-61 (Table 17). The addition of tetrahexylammonium bromide dramatically increases enantioselec-tivity in the case of ligand 2, as does changing the solvent from tetrahydrofuran to dichloro-methane. which is believed to enhance the formation of dimeric ionic salts of the nucleophile. In contrast, additives such as tetraalkylammonium salts or crown ethers diminish the enantiomeric excess in reactions catalyzed by the phosphinoaryl oxazoline ligands 3a and 3b. bearing a chiral phosphorus on the aryl moiety. 

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