Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of N-acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2-a]pyridin-3-amines by a Groebke-Blackburn-Bienaymé 3CR condensation/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common N-trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations.

Cyanohydrins are versatile intermediates toward valuable organic compounds like α-hydroxy carboxylic acids, α-amino acids, and β-amino alcohols. Numerous protocols are available for synthesis of (O-protected) cyanohydrins, but all procedures invariably rely on the use of toxic cyanide sources. A novel cyanide-free synthesis of O-trityl protected cyanohydrins via a catalytic Passerini-type reaction involving aldehydes and trityl isocyanide is reported. The feasibility of a catalytic asymmetric reaction is demonstrated using chiral phosphoric acid catalysis.

An iron-catalysed carbene transfer reaction of diazo compounds to isocyanides has been developed. The resulting ketenimines are trapped in situ with various bisnucleophiles to access a range of densely functionalized heterocycles (pyrimidinones, dihydropyrazolones, 1H-tetrazoles) in a onepot process. The electron-rich Hieber anion ([Fe(CO) 3 NO] À ) facilitates efficient catalytic carbene transfer from acceptortype α-diazo carbonyl compounds to isocyanides, providing a cost-efficient and benign alternative to similar noble metalcatalysed processes. Based on DFT calculations a plausible reaction mechanism for activation of the α-diazo carbonyl carbene precursor and ketenimine formation is provided.

We report a new synthesis of the Covid-19 drug nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization and a diastereoselective multicomponent reaction as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly atom-economic process.

The application of title reagent (III) as cyanide source is demonstrated in 3 different types of reaction (Strecker, Ugi, Groebke—Blackburn—Bienaym).