Monodentate Transient Directing Group-Assisted Palladium-Catalyzed Direct ortho-C–H Iodination of Benzaldehydes for Total Synthesis of Hernandial

Abstract

The first palladium-catalyzed direct o-C–H iodination of benzaldehydes was successfully developed with the assistance of commercially available 2,5-bis­(trifluoromethyl)­aniline as the optimal monodentate transient directing group (MonoTDG). Moderate to excellent yields and good selectivity were achieved for a broad substrate scope under mild conditions. More importantly, the synthetic application was demonstrated by a concise two-step total synthesis of the natural product hernandial, which was accomplished by merging this new MonoTDG-assisted C–H iodination and subsequent copper-catalyzed cross-coupling.

Metal-free iodination of arylaldehydes for total synthesis of aristogins A–F and hernandial

“…The bis-iodinated product was only detected in a trace amount when 3,4,5-trimethoxybenzaldehyde was used as a substrate (14). The system demonstrated good performance in the iodination of naphthaldehyde (15-17), 6-methoxynicotinaldehyde (18), and thiophene-2-carbaldehyde (19,20), yielding moderate to good product yields. Additionally, in the synthesis of the aristogin family, methyl 4-methoxybenzoate was also used and it afforded the iodination product 21 in 94% yield.…”

“…4,5 Due to these factors, numerous highly efficient methods have been developed for the synthesis of aryl iodides 6 including the Sandmeyer reaction, 7 aromatic Finkelstein reaction, 8 metalcatalyzed reactions, [9][10][11][12][13] direct electrophilic iodination, 14 chelated directing-group-assisted metal-catalyzed halogenation [15][16][17] and decarboxylative iodination. 18 Among these options, iodine is a notable environmentally friendly reagent due to its easy accessibility and low cost, making it an extensively used reagent in the iodination of aromatic rings. However, due to the limited electrophilicity of iodine, it is necessary to introduce an oxidant in order to facilitate the iodization.…”

“…[42][43][44][45] Among them, the synthesis of hernandial reported by Zhou's group stands out as the most convenient method due to their successful integration of a palladium catalyzed C-H iodination of benzaldehydes and subsequent copper-catalyzed cross-coupling. 18 The palladium-catalyzed direct C-H iodination of benzaldehydes, assisted by a monodentate transient directing group, plays a major role. Inspired by these studies, we aim to broaden the range of applications of PIDA mediated oxidative iodination of arylaldehydes.…”

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

“…In 2021, Zhang and Zhou reported a palladium‐catalyzed ortho ‐C−H iodination of aromatic aldehydes involving a monodentate TDG (Scheme 3). [13] Very useful 2‐iodobenzaldehydes 9 were obtained in good yields and the methodology was applied to a two‐step synthesis of hernandial through a copper‐catalyzed coupling reaction with 2‐iodo‐4,5‐dimethoxybenzaldehyde.…”

Aryl Sulfoxides: A Traceless Directing Group for Catalytic C−H Activation of Arenes

“…The coordination of such groups to the catalytic species not only drives the selectivity but also improves the reaction efficiency. As a result, this strategy has been successfully implemented in the synthesis of natural products [2] or organic electronic materials, [3] taking advantage of its sustainable and economic character.…”