Proline selective labeling via on-site construction of naphthoxazole (NapOx).

Chemoselective construction of naphthoxazoles (NapOx) via a three-component annulation reaction enables proline selective labeling of peptides in solution or in solid-phase synthesis. The fluorogenic peptides possess low cytotoxicity, efficient cell membrane permeability and excellent bioimaging potential for biomedical applications.

Acid mediated coupling of aliphatic amines and nitrosoarenes to indoles.

Traditionally, amines react with nitrosoarenes to provide the corresponding imines or azo compounds. Herein, we report an acid mediated annulation reaction of aliphatic amines and nitrosoarenes to provide indole derivatives. The elusive direct annulation of aliphatic amines and nitrosoarenes via simultaneous C-C and C-N bond formation was achieved under metal free conditions. This conceptually novel method for indole synthesis does not require pre-functionalization steps for the new C-C and C-N bond formation. The method has been applied for an elegant synthesis of nor-neocryptolepine and neocryptolepine.

Metal free direct C(sp2)-H arylaminations using nitrosoarenes to 2-hydroxy-di(het)aryl amines as multifunctional Aß-aggregation modulators.

An unprecedented metal free arylamination reaction involving nitrosoarenes as the electrophilic aminating agents is reported. The direct arylamination of a broad range of substrates, such as naphthols, hydroxyquinolines, hydroxyquinones, coumarins and 1,3-cyclohexadienones was achieved under operationally simple and mild conditions without the aid of additional reagents/steps for N-O bond reduction. Interestingly, novel 2-hydroxydiaryl amines were found to act as Aß-aggregation inhibitors.

Metal-Free Sequential C(sp2)-H/OH and C(sp3)-H Aminations of Nitrosoarenes and N-Heterocycles to Ring-Fused Imidazoles.

Hydrogen bond assisted ortho-selective C(sp2)-H amination of nitrosoarenes and subsequent α-C(sp3)-H functionalization of aliphatic amines is achieved under metal-free conditions. The annulation of nitrosoarenes and 2-hydroxy-C-nitroso compounds with N-heterocycles provides a facile excess to a wide range of biologically relevant ring-fused benzimidazoles and structurally novel polycyclic imidazoles, respectively. Nucleophilic aromatic hydrogen substitution (SNArH) was found to be preferred over classical SNAr reaction during the C(sp2)-H amination of halogenated nitrosoarenes.

Regio- and Diastereoselective and Enantiospecific Metal-Free C(sp(3) )-H Arylation: Facile Access to Optically Active 5-Aryl 2,5-Disubstituted Pyrrolidines.

Optically active 5-aryl 2,5-disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio- and diastereoselective and enantiospecific method for direct C-H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single-step three-component reaction under metal- and oxidant-free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin-converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp(3) C-H arylation reaction. Preference for a given regio- and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re-aromatization step. The calculated energies reveals that the re-aromatization step is essentially rate determining, accompanying an activation barrier of Δ(≠) G=25.6 kcal mol(-1) .