Phosphorus(III)-assisted regioselective C–H silylation of heteroarenes

Abstract

Heteroarenes containing carbon–silicon (C–Si) bonds are important building blocks that play an important role in the construction of natural products, pharmaceuticals, and organic materials. In this context, the C–H silylation of heteroarenes is a topic of intense interest. Indole C–H silylation can preferentially occur at the nucleophilic C3 and C2 position (pyrrole core), while accessing the C4-C7 positions (benzene core) of the indole remains highly challenging. Here, we show a general strategy for the regioselective C7-H silylation of indole derivatives. Mainly, the regioselectivity is determined by strong coordination of the palladium catalyst with phosphorus (III) directing group. Using this expedient synthetic strategy, the diverse C7-silylated indoles are synthesized effectively which exhibits the broad functional group compatibility. Moreover, this protocol also been extended to other heteroarenes such as carbazoles. The obtained silylated indoles have been employed in various transformations to enable the corresponding differently functionalized indole derivatives. Significantly, a cyclopalladated intermediate is successfully synthesized to test the hypothesis about the P(III)-directed C–H metalation event. A series of mechanistic experiments and density functional theory (M06-2X) calculations has shown the preferred pathway of this directed C–H silylation process.

C–H Bond Silylation of Heteroarenes

“…In 2021, the Shi group reported an efficient method for the regioselective C7 silylation of indoles 23 assisted by a phosphine-directing group in the presence of a palladium catalyst under oxidative conditions, whilst avoiding the addition of any exogenous ligands (Scheme 7 ). 18 The key to obtaining a high level of regioselective silylation was the appropriate choice of an N -protected phosphine directing group. It was found that the N -P t Bu 2 group was the best choice as a directing group for achieving both high reactivity and selectivity in this reaction.…”

From C4 to C7: Innovative Strategies for Site-Selective Functionalization of Indole C–H Bonds

“…Recently, we have reported the palladium-catalyzed P­(III)-directed C7-selective C–H silylation of indoles 5 with hexamethyldisilane using 2,5-dimethyl-1,4-benzoquinone (DMBQ) as an external oxidant (Scheme ). Diverse C7-silylated indoles 24 were constructed efficiently, exhibiting broad functional group compatibility. In addition, this developed strategy could also be extended to C–H germanylation with hexamethyldigermane.…”

“…We found that the diverse indoles 42 bearing pivaloyl groups at the C3-position were also capable of participating in C–H borylation at C4-position to access the corresponding borylated indoles 43 in the presence of simple BBr 3 (Scheme ). The choice of the N -Ts group in the indole substrates as a protecting group showed the best reactivity.…”

KOtBu-Catalyzed 1,2-Silaboration of N-Heteroarenes to Access 2-Silylheterocycles: A Cooperative Model for the Regioselectivity

“…Transformative functionalization of prevalent heteroarenes is an attractive strategy to access valuable synthons with the original heterocyclic skeletons having high synthetic and medicinal utility. − Among various functionalities being able to be installed into the heteroaromatics, a silyl group offers special benefits in that it can serve either as a versatile intermediate for further oxidative conversions or as a robust final-stage motif in pharmaceutical, material, and polymer science. − In this context, a number of site-selective silylation transformations of heteroarenes were developed by employing readily available silyl sources such as hydrosilanes, − silylboranes, − or silyl cations. , In this line, transition-metal-catalyzed C–H silylation offers an attractive route to silylated compounds.…”