New perspectives in aromatic aminations using hypervalent iodine(iii) reagents

Resumo

Aromatic amines are compounds of relevant industrial and commercial importance. They are used as intermediates in the syntheses of numerous organic compounds such as azo dyes and antioxidants in consumer goods. As important structural fragments, these aminated compounds often show significant biological properties. For this reason, they have been prominent in synthetic, material and medicinal chemistry. A particular important example of innovative C−N bond installation is the synthesis of anilines by transition-metal-catalysed couplings between amino sources and pre-functionalised arenes. In this field, palladium and copper have received most attention since the mid-1990s. The main objective of this doctoral thesis, in contrast to the established methodologies, is the development of new stoichiometric and catalytic methods for the metal-free aminations of aromatic and heteroaromatic cores. Our approach relies only on the inherent reactivity of these substrates, without the presence of directing groups to drive the regioselectivity. The first example of reductive elimination at an iodine(III) centre using diaryliodonium salts and imides as nitrogen sources has been reported. The proposed reaction mechanism was supported by the isolation of reaction intermediates, which were also characterised by X-ray diffraction. The study of the kinetic profile of the transformation by 19F-NMR allowed the calculation of the energetic parameters leading to Arrhenius and Eyring plots. The reaction reported is of unusual broad scope in respect to the sterically congested arenes and nitrogen sources (51-95% yields). The synthetic utility was demonstrated by a short two-step-synthesis of the N,N’-diarylated pyrrolidinone carboxamide (45% overall yield after two steps). This compound belongs to a family of binding inhibitors of the chemo-attractant peptide chemerin to the G-protein coupled receptor ChemR23. A new metal-free approach was developed for the synthesis of anilines utilising 1,2-diiodobenzene as pre-catalyst. The mechanism of the reaction, contrary to the iodonium(III) salts previously used, involved an electrophilic nitrogen intermediate. In contradiction to the reported mechanistic proposals, we assumed an active role of both iodine centres on the bis(iodo)arene. This was confirmed by the isolation and X-rays structural analysis of the oxidised iodine(III) intermediate, which showed a strained μ-oxo-bridged conformation. A value for the kinetic isotopic effect (KIE) of 1.18 suggested that the arylation step is rather fast and that the C−H bond cleavage is not rate-determining. A variety of nitrogen-protecting groups including sulphonamides, carbamates, and hydrazines were well tolerated. The turnover numbers (TON) and the regioselectivities of the new catalytic system were superior compared to all other reported protocols with a regioselectivity of 66/1.