A Photochemical Strategy for ortho‐Aminophenol Synthesis via Dearomative‐Rearomative Coupling Between Aryl Azides and Alcohols

Abstract

Abstractortho‐Aminophenols are aromatic derivatives featuring vicinal N‐ and O‐based functionalities commonly found in the structures of many high‐value materials. These molecules are generally prepared using multistep strategies that follow the rules of electrophilic aromatic substitution (SEAr) chemistry. Despite their high fidelity, such approaches cannot target substrates featuring a “contra‐SEAr” arrangement of N‐ and O‐groups. Here we report an alternative strategy for the preparation of such ortho‐aminophenols using aryl azides as the precursors. The process utilizes low‐energy photoexcitation to trigger the decomposition of aryl azides into singlet nitrenes that undergo a dearomative‐rearomative sequence. This allows the incorporation of alcoholic nucleophiles into a seven‐membered ring azepine intermediate via temporary disruption of aromaticity, followed by electrophile‐induced re‐aromatization. The net retrosynthetic logic is that the alcohol displaces the azide, which, in turn, moves to its ortho position and furthermore is converted into an amide. The synthetic value and complementarity of this strategy has been demonstrated by the coupling of aryl azides with complex, drug‐like alcohols and phenols as well as amines, thiols and thiophenols, which provides a general platform for the fast and selective heterofunctionalization of aromatics.

Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines

“…In fact, the bicyclic diazanorcaradiene was often proposed as its ring-opening can be explained due to the high ring strain. Although the latter has never been observed, it is a rather reasonable hypothesis and is in fair agreement with other processes furnishing 7-membered rings. ,,− Preliminary NMR experiments were conducted at −60 °C in order to monitor the transient species. At this temperature, the rearrangement proceeds at a very slow rate, but the diazepine as well as the starting ylides only were detected (see the Supporting Information for details and additional experiments).…”

“…Electron-withdrawing groups in the C4 position inhibited the rearrangement; 48 we could nonetheless isolate the unreacted ylide 52 with a good yield. In the case of 2vinylpyridine, the double bond was well tolerated, as we could not notice any side reactivity on the pending olefin (53). In contrast, the ethynyl derivative leads to the unexpected formation of a 1,2-diazepine bonded with a fused pyrazolo-[1,5-a]pyridine ring in 80% yield (54).…”

Visible photons as ideal reagents for the activation of coloured organic compounds

“…A similar process involved irradiation of aryl azides in the presence of alcohols followed by treatment with trifluoroacetic anhydride (TFAA), resulting in the formation of ortho -aminophenols via a dearomative-rearomative sequence. 219…”

Effects of the Solvent and the Nucleophile on the Photochemical Synthesis of Azepines

“…These aim to expand the benzene ring during the intramolecular rearrangement of aryl nitrenes or the addition of carbenes to pyridines. Precursors such as aryl azides, [13][14][15][16] nitrobenzenes, [17][18][19] 3-phenylbenzo[c]isoxazoles [20] and diazo compounds [21] are used (Scheme 1). Using this approach, methods for the synthesis of 2-alkoxy-3H-azepines [14] and 2-oxo-3H-azepines [15] have been developed.…”