Van Leusen Reaction
The Van Leusen Reaction allows the conversion of a ketone into a nitrile with one additional carbon atom in a single pot using tosylmethyl isocyanide (TosMIC) as a synthon.
Mechanism of the Van Leusen Reaction
TosMIC is a unique one-carbon synthon that can be easily deprotonated and alkylated. The sulfinyl group not only enhances the acidity of the α-protons, but is also a good leaving group. In addition, TosMIC features the unique properties of the isocyanide group in which the oxidation of the carbon atom is a driving force for multiple reactions.
For example, TosMIC can be used as a C-N=C synthon for the synthesis of various heterocycles, such as oxazoles (Van Leusen Oxazole Synthesis), imidazoles (Van Leusen Imidazole Synthesis), pyrroles, 1,2,4-triazoles and many more.
The conversion of ketones to the homologous nitriles can also be formally described as a "reductive nitrilation", as after addition of TosMIC to the ketone, the resulting α-hydroxy group is removed. Indeed, the carbon atom in the isocyanide group is oxidized in the course of the reaction.
In the formation of the nitrile, the deprotonated form of the alcohol that has been added to the reaction mixture now plays a crucial role as a nucleophile in deformylating the ketimine:
Although the reaction would still lead to nitriles without adding a primary alcohol, the process is considerably speeded up in the presence of MeOH or EtOH. Unfortunately, the use of an excess of a primary alkyl alcohol also favors the formation of a 4-alkoxy-2-oxazoline, so that the amount of primary alcohol must be controlled judiciously - typically in the range of 1-2 eq.
For a detailed mechanistic discussion, please refer to a publication by Van Leusen (J. Org. Chem., 1977, 42, 3114-3118. Abstract).
Chemistry of sulfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unit
O. H. Oldenziel, D. Van Leusen, A. M. Van Leusen, J. Org. Chem., 1977, 42, 3114-3118.