Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery

Ogasahara R., Ban K., Mae M., et al. Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery. ChemMedChem , (2024); https://doi.org/10.1002/cmdc.202400201.Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C−H bonds with more stable C−D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C−H bonds to C−D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years. Although various deuterated drug candidates undergo clinical trials, approved deuterated drugs possess CD3 groups in the same molecule. However, less diversification, except for the CD3 group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (dn-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using D2O as an inexpensive deuterium source to introduce CD3, CH3CD2, and ArCH2CD2 groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD3 group, and our newly developed electrophilic dn-alkyl reagents are discussed

Versatile Biaryls and Fused Aromatics through Oxidative Coupling of Hydroquinones with (Hetero)Arenes

Aijima T., Ueda R., Nakane T., et al. Versatile Biaryls and Fused Aromatics through Oxidative Coupling of Hydroquinones with (Hetero)Arenes. ChemistrySelect 9, e202400647 (2024); https://doi.org/10.1002/slct.202400647.Hydroquinones bearing an electron-withdrawing group at the C2-position can effectively underwent oxidative coupling with (hetero)arenes (e. g., indoles, electron-rich benzene derivatives) in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and FeCl3 to produce the corresponding biaryl products. In the present reactions, the DDQ-mediated oxidation of hydroquinone derivatives produce benzoquinone intermediate, which subsequently underwent FeCl3-catalyzed nucleophilic addition of (hetero)arenes to the α,β-unsaturated carbonyl moiety to give the biaryl product in a one-pot manner. Especially, the indole-based biaryl products were further converted into tetracyclic aromatics through DDQ-mediated oxidation followed by FeCl3-catalyzed intramolecular cyclization. Thiophene derivatives were also applicable to give the tetracyclic aromatics. Moreover, the photophysical properties of the indole- and thiophene-based tetracyclic aromatics in the solution and the solid states were investigated

パラジウム炭素を触媒とした檜山クロスカップリング反応

檜山クロスカップリング反応は、フッ化物塩や塩基により活性化された有機ケイ素化合物と有機ハライド、あるいは有機ハライド等価体とのパラジウム（Pd）を触媒とした交差縮合反応である。本反応の基質である有機ケイ素化合物は毒性が低く、またグリニャール試薬などの求核剤と異なり空気中安定で取り扱いやすい。また、反応後に副生するケイ素化合物は、燃焼により無害な二酸化ケイ素に変換・処理されるため、檜山カップリングは医薬品を始めとした機能性物質の量産化反応に適している。従来法では均一系Pd 触媒を使用し、ゼロ価Pd の安定・活性化のためにリガンドが添加されるが、生成物中への残存や混入は避けることができず除去工程が別途必要となる。一方、不均一系Pd 触媒はPd が担体に保持されており化学的に安定であることから、均一系Pd 触媒を使用した際に生じる処理工程の回避が期待される。我々は接触水素化反応における汎用不均一系触媒であるパラジウム炭素（Pd/C）に着目し「Pd/C による檜山クロスカップリング反応」の開発並びにPd/C を触媒とした「リガンドを全く使用しない檜山クロスカップリング反応」の開発に成功した。特に後者はリガンドの添加を全く必要とせず、汎用されているPd/C を極微量使用するだけで効率良く進行する点で、操作性とコストに優れておりプロセス化学的適用が期待される。The Hiyama cross-coupling reaction, a palladium-catalyzed carbon–carbon bond formation between organosilanes andorganohalides or their equivalents, has been popularized as a useful synthetic method to construct unsymmetrical biphenyls asstructural components of various functional materials. The use of organosilanes as organometallic compounds, which was initiallyexplored by Hiyama, is one of the most attractive approaches, since organosilanes are easy to handle and environmentally friendlydue to their air-stability and low toxicity. Hiyama coupling has generally been achieved by the combined use of a homogeneouspalladium catalyst and a phosphine ligand. Recently, the development of heterogeneously palladium-catalyzed cross-couplingreactions has attracted significant attention from both environmental and economical points of view, since the catalysts can be readilyrecovered from the reaction mixture. Efficient methods are demonstrated for the palladium on carbon (Pd/C)-catalyzed Hiyamacross-coupling reactions and the first ligand-free Pd/C-catalyzed Hiyama cross-coupling reaction between a variety of aryl halidesand aryltriethoxysilanes

Construction of Functionalized ortho-Naphthoquinone Methides via Site-Selective Ring Opening of 1-Siloxy-1,4-epoxy-1,4-dihydronaphthalenes

1-Siloxy-4-(benzyloxy)methyl-1,4-epoxy-1,4-dihydronaphthalenes, generated from benzynes and furans, underwent automatic site-selective ring opening because of the synergetic effect of the steric strain of the 1,4-epoxy moiety and the electron-donating ability of the siloxy group on the acetal structure to afford the precursors of ortho-naphthoquinone methides (o-NQMs). Subsequent Lewis acid-facilitated o-NQM formation and annulation with olefins afforded multi-fused heterocycles. Notably, the consecutive hexacyclic skeleton of rubioncolin B was constructed via solvent-dependent regioselective annulation of naphthofuran derivatives.This is the peer reviewed version of the following article: Aijima T., Komagawa S., Akai S., et al. Construction of Functionalized ortho-Naphthoquinone Methides via Site-Selective Ring Opening of 1-Siloxy-1,4-epoxy-1,4-dihydronaphthalenes. Advanced Synthesis and Catalysis 365, 3981 (2023), which has been published in final form at https://doi.org/10.1002/adsc.202300968. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited

Palladium on Carbon-Catalyzed Suzuki-Miyaura Coupling Reaction Using an Efficient and Continuous Flow System

The continuous flow Suzuki-Miyaura reaction between various haloarenes and arylboronic acids was successfully achieved within only ca. 20 s during the single-pass through a cartridge filled with palladium on carbon (Pd/C). No palladium leaching was observed in the collected reaction solution by atomic absorption spectrometry (detection limit: 1 ppm)