Cascade Reductive Friedel–Crafts Alkylation Catalyzed by Robust Iridium(III) Hydride Complexes Containing a Protic Triazolylidene Ligand

The
synthesis of complex molecules like active pharmaceutical ingredients
typically requires multiple single-step reactions, in series or in
a modular fashion, with laborious purification and potentially unstable
intermediates. Cascade processes offer attractive synthetic remediation
as they reduce time, energy, and waste associated with multistep syntheses.
For example, triarylmethanes are traditionally prepared via several synthetic steps, and only a handful of cascade routes are
known with limitations due to high catalyst loadings. Here, we present
an expedient catalytic cascade process to produce triarylmethanes.
For this purpose, we have developed a bifunctional iridium system
as the efficient catalyst to build heterotriaryl synthons via reductive Friedel–Crafts alkylation from ketones,
arenes, and hydrogen. The catalytically active species were generated in situ from a robust triazolyl iridium­(III) hydride complex
and acid and is composed of a metal-bound hydride and a proximal ligand-bound
proton for reversible dihydrogen release. These complexes catalyze
the direct hydrogenation of ketones at slow rates followed by dehydration.
Appropriate adjustment of the conditions successfully intercepts this
dehydration and leads instead to efficient C–C coupling and
Friedel–Crafts alkylation. The scope of this cascade process
includes a variety of carbonyl substrates such as aldehydes, (alkyl)­(aryl)­ketones,
and diaryl ketones as precursor electrophiles with arenes and heteroarenes
for Friedel–Crafts coupling. The reported method has been validated
in a swift one-step synthesis of the core structure of a potent antibacterial
agent. Excellent yields and exquisite selectivities were achieved
for this cascade process with unprecedentedly low iridium loadings
(0.02 mol %). Moreover, the catalytic activity of the protic system
is significantly higher than that of an N-methylated
analogue, confirming the benefit of the Ir–H/N–H hydride-proton
system for high catalytic performance.

诸如活性药物成分(active pharmaceutical ingredients)这类复杂分子的合成，通常需要多步单反应串联或模块化进行，且伴随繁琐的纯化操作与中间体不稳定的风险。级联反应为合成路径提供了极具吸引力的优化方案，可显著减少多步合成所需的时间、能耗与废弃物排放。例如，三芳基甲烷类化合物传统上需经多步合成制备，目前仅报道了少数几条级联合成路线，但此类路线均存在催化剂负载量过高的局限。本研究开发了一种便捷高效的催化级联合成方法用于制备三芳基甲烷类化合物，为此我们构建了一种双功能铱基催化体系，该体系可通过酮、芳烃与氢气的还原傅-克(Friedel–Crafts)烷基化反应合成杂三芳基合成子(synthon)。该类催化活性物种可由稳定的三唑基铱(III)氢化物络合物与酸原位生成，其由金属结合氢与配体近端结合质子构成，可实现可逆的氢气释放。这类络合物可先以较低速率催化酮的直接加氢反应，随后发生脱水过程，通过合理调控反应条件可有效阻断该脱水路径，转而实现高效的C-C偶联与傅-克烷基化反应。该级联反应的底物适用范围广泛，醛、(烷基)(芳基)酮与二芳基酮等多种羰基化合物均可作为亲电前体，与芳烃、杂芳烃发生傅-克偶联反应。本方法已通过一款强效抗菌剂核心结构的快速一步合成得到验证，该级联反应在前所未有的低铱催化剂负载量(0.02 mol%)下即可实现优异的产率与极高的选择性。此外，该质子型催化体系的催化活性显著高于N-甲基化类似物，证实了Ir-H/N-H氢-质子双功能体系对提升催化性能的积极作用。