Organometallic Nucleophilic Reagents in Organic Synthesis. Theory and Applications

The synthesis of organic molecules relies on the controlled formation of carbon-carbon bonds to build up the basic skeleton of the target molecule from simple, available precursors. This task is made difficult by the stability of carbon groups in the ground state and the difficulty of creating covalent bonds between identical atoms.

The difference in electronegativity that exists within an organometallic reagent between a metal atom and a carbon group gives the latter a nucleophilic character that was discovered as early as the end of the 19th century, notably following the work of Philippe Barbier, Paul Sabatier and Victor Grignard. The latter two were awarded the Nobel Prize in Chemistry in 1912, one for the hydrogenation of organic compounds on finely divided metals and the other for the discovery of organomagnesium reagents. Organometallic reagents were subsequently exploited to form carbon-carbon bonds by attacking electrophilic carbon compounds. The latter can be chosen from carbonyl derivatives (aldehydes, ketones, esters, amides, carboxylic acids, acyl chlorides, carbonates, carbon dioxide) and their equivalents (imines, Schiff bases, nitriles), under certain conditions, alkyl halides RX (X=Cl, Br, I) and their equivalents (alkyl tosylates and other reactants with nucleofugal groups) and, in some cases, unsaturated hydrocarbons (mainly alkynes). This diversity of partners is combined with the diversity of organometallic reagents available or easily prepared, such as organolithiums and organomagnesiums from the corresponding halides and metal in the zero oxidation state, by halogen-metal exchange or acid-base reaction.

These organometallic nucleophilic reagents thus represent the most direct form of nucleophilic grouping, and are relatively easily accessible (and sometimes even commercial). However, their strong base behavior makes them incompatible with wet conditions. As a result, they must be processed using anhydrous solvents and reactors. On the other hand, reactions involving organometallic reagents are generally exothermic, which imposes particular constraints when scaling up for industrial applications.

All these aspects will be covered. The first part will present the main nucleophilic organometallic reagents (definition, terminology, preparation, physicochemistry and stability), followed by a second part dealing with reactivity, and a third part focusing on metallocatalyzed reactions involving these reagents. Finally, a section on industrial applications, and in particular applications for the synthesis of active pharmaceutical ingredients, illustrating issues of scale-up, safety and compliance, will be proposed.