Nucleophilic Grignard reagents

A soft (nucleophilic) Grignard reagent has been developed (82—84). The value of this reaction is demonstrated ia acylation reactions (82). 

Thus It appears that the more nucleophilic Grignard reagents, or higher reaction temperatures, favor the formation of compounds II and III, while weaker nucleophiles undergo the metal-halogen exchange reaction, a reaction that Is also preferred at low temperatures. 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

The mechanism resembles earlier reactions of nucleophilic Grignard reagents with carbonyl groups, as shown in Mechanism 20.8. 

In Step [1], the nucleophilic Grignard reagent attacks the electrophilic carbon atom of CO2, cleaving a n bond and forming a new carbon-carbon bond. 

The use of other mixed reagents to promote acylation and subsequent enolization of the ketone during its formation have been reported by Fehr. The success of the method depends on the ease of ketone deprotonation and thus was limited to substituted allylic nucleophiles. The final product was obtained entirely in the form of the a. -unsaturated ketone. A combination of the nucleophilic Grignard reagent and the nonnucleophilic base lithium diisopropylamide converts sterically hinder ester (50) into a-damas-cone (52) via (51) (Scheme 16). The ratio of ketone to tertiary alcohol was 98 2 (many cases gave selectivity greater than 9 1) however, a few examples showed a substantial amount of tertiary alcohol formation. 

This product (4-chlorotetrahydropyran, 4-C1-THP) 193 may not look very useful but the chlorine atom can be converted into a nucleophilic Grignard reagent or used in a Friedel-Crafts reaction to give 197 while the ether ring may be cleaved to give a doubly electrophilic unit 198. One useful application is the synthesis of 4-phenyl piperidine 199, a structural unit found in medicinal compounds. 

The strongly nucleophilic Grignard reagent uses its electron pair to form a bond to the carbon atom. One electron pair of the carbonyl group shifts out to the oxygen. This reaction is a nucleophilic addition to the carbonyl group, and it results in the formation of an alkoxide ion associated with Mg + and X. ... 

---