A Unified Approach for Divergent Synthesis of Heterocycles via TMSOTf‐Catalyzed Formal [3+2] Cycloaddition of Electron‐Rich Alkynes

Abstract

We present a synthetic protocol for the construction of polysubstituted five‐membered heterocycles via TMSOTf‐catalyzed formal [3+2] cycloaddition of electron‐rich alkynes, which features free from any metal, atom economy and water as the main by‐product. Furthermore, alkenyl ether adduct has been verified as the key intermediate. Notably, by utilizing this approach, we can synthesize a broad range of polysubstituted furans, thiophenes and pyrroles, and extend this transformation to deliver fused‐polyheterocycles. This reaction can be achieved on a gram scale and the corresponding products are intermediates for producing diverse potentially useful scaffolds.

Synthesis of Polysubstituted Furans: An Update Since 2019

“…[107][108][109][110][111] Inspired by these reports on electron-rich alkyne chemistry, Shi et al in the year 2021 demonstrated a practical strategy for the synthesis of polysubstituted furans 205 via TMSOTf-catalyzed formal [3 + 2] cycloaddition of electron-rich alkynes in good to excellent yields. [112] The mechanism starts with the transformation of TMSOTf into TfOH by reaction with a trace amount of water in the reaction system. intramolecular nucleophilic attack towards the acid-activated carbonyl afforded iminium ion 203.…”

Cascade Cyclization/Amination of para‐Quinone Methides with β‐Ketodinitriles: Synthesis of Polysubstituted Furans

“…[8] In 2021, Shi et al provided a protocol for synthesizing a wide range of polysubstituted furans through TMSOTf-catalyzed [3 + 2] cycloaddition reaction of electron-rich alkynes with benzoin and its derivatives. [9] In 2018, Li and colleagues developed a one-pot cascade heterocyclization protocol to generate furo [2,3-d]pyrimidines from linear γ-and βketomalononitriles. [10] Very recently, Patel and coworkers developed a Pd(II)-catalyzed synthesis of furo [2,3-b]pyridines from β-ketodinitriles and alkynes via cyclization and NÀ H/C annulation.…”

“…In 2021, Shi et al . provided a protocol for synthesizing a wide range of polysubstituted furans through TMSOTf‐catalyzed [3+2] cycloaddition reaction of electron‐rich alkynes with benzoin and its derivatives [9] . In 2018, Li and colleagues developed a one‐pot cascade heterocyclization protocol to generate furo[2,3‐ d ]pyrimidines from linear γ ‐ and β ‐ketomalononitriles [10] .…”

Research Progress of Reactions Participated by α-Hydroxy Ketones

“…图式 37 α-羟基酮与炔烃的环加成反应 Scheme 37 Cycloaddition reaction of α-hydroxyl ketones with alkynes 反应, 形成中间体 124, 124 异构化得到中间体 125, 然后 通过中间体 126 进行分子内酯化得到相应的产物 121. 如果产物 121 的芳基是 2-喹啉基、未取代或 4-/5-取代 的 2-吡啶基时, 则在碱性条件下, 由氮原子的孤对电子 对酯基上的羰基碳原子进行亲核进攻, 进一步发生环化, 消除一分子甲醇从而得到产物 122 (Scheme 38).2021 年, 史大永课题组[52] 报道了通过三氟甲基磺酸 三甲基硅酯(TMSOTf)催化富电子炔烃与 α-羟基酮 130[53] 报道了 Wittig 试剂 133中的硫醇酯与 α-羟基酮 132 在 Cu(II)盐的催化作用下, 通过 push-pull 理论, 在中性条件下首次实现催化的醇酰 化反应(Scheme 40). 该方法作为铜催化酰亚胺一锅法内 酯化的新方法, 对天然产物的合成具有一定的实用价值.…”