François Couty

The von Braun reaction, discovered at the dawn of the past century, consists of the reaction between a tertiary amine and cyanogen bromide. It leads to the cleavage of a C─N bond with the formation of an N‐dialkylcyanamide and an alkyl bromide and has been extensively used in organic synthesis. A detailed in silico study (PCM/density functional theory [DFT]/B3LYP/6‐31++G(d,p) calculations) of this venerable reaction has shown that in the first stage a zwitterionic adduct with a multibonded bromine atom is formed. The widely accepted mechanism involving an S_N2 reaction occurs in the second step, thus accounting for its selectivity. Quantum chemical calculations were performed for the von Braun‐like reactions in systems formed by cyclic tertiary amines (N‐alkyl azetidines). In these cases, the first stage is almost the same as in the classical von Braun processes, and selective S_N2 mechanisms can occur in the second step.

α‐Amino acid residues with a ϕ,ψ constrained conformation are known to significantly bias the peptide backbone 3D structure. An intriguing member of this class of compounds is (αMe)Aze, characterized by an N^α‐alkylated four‐membered ring and C^α‐methylation. We have already reported that (S)‐(αMe)Aze, when followed by (S)‐Ala in the homochiral dipeptide sequential motif ‐(S)‐(αMe)Aze‐(S)‐Ala‐, tends to generate the unprecedented γ‐bend ribbon conformation, as formation of a regular, fully intramolecularly H‐bonded γ‐helix is precluded, due to the occurrence of a tertiary amide bond every two residues. In this work, we have expanded this study to the preparation and 3D structural analysis of the heterochiral (S)‐Ala/(R)‐(αMe)Aze sequential peptides from dimer to hexamer. Our conformational results show that members of this series may fold in type‐II β‐turns or in γ‐turns depending on the experimental conditions.

3‐Bromo N‐alkyl cyanamides are accessible in one simple synthetic operation from N‐alkyl azetidines reacting with cyanogen bromide. These unexplored building blocks combine two extremely useful electrophilic moieties: an alkyl bromide and a cyanamide. We demonstrate herein that they can be transformed into a range of nitrogen‐containing molecules, and especially cyclic guanidines, accessible in enantiomerically pure form. Considering the large structural diversity of available azetidines, this contribution complements the use of these strained heterocycles in diversity‐oriented synthesis.

Unlike the extensively investigated relationship between the peptide β-bend ribbon and its prototypical 3₁₀-helix conformation, the corresponding relationship between the narrower γ-bend ribbon and its regular γ-helix counterpart still remains to be studied, as the latter 3D-structures have not yet been experimentally authenticated. In this paper, we describe the results of the first characterization, both in the crystal state and in solution, of the γ-bend ribbon conformation using X-ray diffraction and FT-IR absorption, electronic CD and 2D-NMR spectroscopies applied to an appropriate set of synthetic, homo-chiral, sequential dipeptide oligomers based on (S)-Ala and the known γ-bend inducer, C^α-tetrasubstituted, N-alkylated α-amino acid residue (S)-C^α-methyl-azetidine-carboxylic acid.

This article focuses on the dehydration of α‐hydroxy‐tetrazoles, leading to tetraazafulvenes and then to vinylic carbenes that rearrange into ethynyl moieties through the Fritsch–Buttenberg–Wiechell rearrangement. Each step of this sequence was scrutinized, either by examination of the substrate and/or dehydrating agent scope, or through AM1 calculations, in order to understand the limiting step of this process. This underrated transformation appears to be a viable alternative to existing methods used for transforming aldehydes into alkynes.

The von Braun reaction (the reaction of cyanogen bromide with tertiary amines) was applied to a series of functionalized N‐alkyl‐substituted azetidines. This reaction mainly led to the cleavage of the strained four‐membered ring to produce 3‐bromo N‐alkyl cyanamides in good yields with variable regioselectivity. The resulting cyanamide products were then employed as original building blocks for the synthesis of nitrogen heterocycles.

An efficient and general iodocarbamation of benzyl N‐homopropargylcarbamates has been developed by using iodine as the electrophilic agent. This regio‐ and stereoselective cyclization yielded (E)‐6‐iodomethyleneoxazinan‐2‐ones, which can be further transformed through palladium cross‐coupling reactions followed by hydrogenation to produce 1,3‐oxazinan‐2‐ones.

We describe herein the use of α-hydroxy-β-azidotetrazoles, easily prepared in one step from α,β-epoxynitriles, as new scaffolds for orthogonal CuAAC reactions performed on the same carbon atom.

2-Cyanoazetidines, easily accessible from β-amino alcohols, undergo ring-cleavage upon reaction with trimethylsilylazide and catalytic amounts of Bu₂SnO, to give the corresponding homopropargylamines which are isolated as their N-Boc protected derivatives. The scope of this reaction, which constitutes a new way to access these highly relevant building blocks, is examined in detail. The proposed mechanism involves a tin-catalyzed cycloaddition of the nitrile moiety with the azide to give the corresponding tetrazole, which decomposes with the extrusion of two molecules of dinitrogen to produce an intermediate vinylidene carbene that finally evolves to give the alkyne.