Science of Synthesis

Ayaz, M.; De Moliner, F.; Morales, G. A.; Hulme, C., Science of Synthesis: Multicomponent Reactions, (2014) 1, 116.

According to the multicomponent reaction union concept,[‌98‌] merging a multicomponent reaction into another one represents a powerful tool to achieve increased structural variety. Therefore, an extension of the three-component Strecker reaction, which entails its combination with an Ugi-type process, is particularly valuable. Hulme and co-workers[‌91‌] have described a protocol for the synthesis of imidazo[1,2-a]pyridin-3-amines utilizing trimethylsilyl cyanide as an alternative to an isocyanide.[‌99‌–‌101‌] Interestingly, three groups independently reported the preparation of analogous chemotypes with isocyanides in what may be viewed as a variant of the Ugi reaction.[‌99‌–‌101‌] However, replacement of the isocyanide with a cyanide source and the resulting methodology represent what is essentially an intramolecular variant of the Strecker reaction. Indeed, by using an extra equivalent of aldehyde, the initial Strecker product ‌20‌, which bears a primary amine, is immediately converted into Schiff base ‌21‌ (‌Scheme 21‌). The Schiff base then undergoes a second sequential Strecker reaction driven by an extra equivalent of trimethylsilyl cyanide present in the system. The overall one-pot tandem Strecker protocol results in the efficient formation of 2-(imidazo[1,2-a]pyridin-3-ylamino)alkanenitriles ‌22‌. It is worth noting that changing the stoichiometry of the reaction components leads to the formation of two different scaffolds (i.e., ‌20‌ and ‌21‌).[‌91‌]

‌Meeeee 88‌ Meeeeeeeee Meeee-Meeeee Meee-Meeeeeeee Mee/Meeeeeee Meeeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeeee Meeeeeeee

8-(Meeeeee[8,8-e]eeeeeee-8-eeeeeee)eeeeeeeeeeeeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeeeee eeeeeee eee eee eeeeeeeeee eeeeeeee eee eeeeeeeee eeeee.

Me e eeeeeeee eeeeeee ee ee eeeeeeeeeeeee (8.8 eeee, 8 eeeee), ee eeeeeeee (8 eeee, 8 eeeee), eee eeeeeee-eeeee Me(MMe)8 (8.888 eeee, 8.88 eeeee) ee MeMM (8 eM) eee eeeee MMMMM (8.8 eeee, 8 eeeee). Mee eeeeeee eee eeee eeeeeeeee eeeeeeeeee ee e Meeeeee Meeeeeeee 88 ee 888 °M eee 88 eee. Meeee eeeeeee ee ee, eee eeeeeeee eee eeeeeee eeee eee eeeeeee ee eeeeeeeeee eee eee eeeeeee eee eeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeee eeeeeeee eee eeeeeeee ee eeeeeeeeeee MMMM.

References