Defluorosilylation of fluoroarenes and fluoroalkanes

Abstract

Direct activation of carbon–fluorine bonds (C–F) to introduce the silyl or boryl groups and generate valuable carbon–silicon (C–Si) or carbon–boron (C–B) bonds is important in the development of synthetically useful reactions, owing to the unique opportunities for further derivatization to achieve more complex molecules. Despite considerable progress of C–F bond activation to construct carbon–carbon (C–C) and carbon–heteroatom (C–X) bond formation, the defluorosilylation via C–F cleavage has been rarely demonstrated. Here, we report an ipso-silylation of aryl fluorides via cleavage of unactivated C–F bonds by a Ni catalyst under mild conditions and without the addition of any external ligand. Alkyl fluorides are also directly converted into the corresponding alkyl silanes under similar conditions, even in the absence of the Ni catalyst. Applications of this protocol in late-stage defluorosilylation of potentially bioactive pharmaceuticals and in further derivatizations are also carried out.

In Situ Generation of Silyl Anion Species through Si−B Bond Activation for the Concerted Nucleophilic Aromatic Substitution of Fluoroarenes

“…It has been reported that R 3 Si−B(pin) can efficiently form a silyl‐borate complex with alkoxides, but it was not clear whether a highly reactive silyl anion equivalent could be generated from the silyl‐borate species and practically utilized. We selected the defluorosilylation reaction of Ph−F as a model reaction, based on the experimental observation by Würthwein and Studer that the S N Ar (nucleophilic aromatic substitution) reaction of unactivated fluoroarenes with silyllithiums proceeds smoothly without any transition metal (TM) catalyst . S N Ar reaction has long been considered to proceed in a stepwise manner via the Meisenheimer intermediate, though more recently an in‐depth mechanistic study by Jacobsen demonstrated that S N Ar reaction also occurs via a concerted pathway…”

Strategies for Developing CRISPR‐Based Gene Editing Methods in Bacteria

“…[35,36] This phenomenon also indicated the reason why off-target bindings frequently occurred in dSpCas9. [37] However, the extent of the heteroduplex toward the PAM-distal region determines the activity of DNA cleavage. [35,36,38] Upon the occurrence of the DNA binding event, a simultaneous movement of the HNH domain is triggered, bringing the HNH domain to the scissile phosphate site on the target DNA strand.…”

“…Comparing to the construction of the single-gene knockout library in bacteria, building a CRISPR-dCas9 based single-gene knockdown library costs much less labor, time, and budget (Table S2, Supporting Information). [37,[188][189][190] For instance, the essential genes in S. pneumoniae have been identified from previous transposon sequencing (Tn-seq) works. [189] However, the insertion of a transposon into an essential gene leads to cell death.…”

“…Generally, dCas9-mediated DNA binding requires fewer base pairings between sgRNA and target DNA than Cas9-led cleavage, since dCas9 do not require complete binding over seed region to trigger the conformational change, which leads to DNA cleavage. [36] Cui et al [37] demonstrated that when dCas9 was expressed constitutively at a high level in E. coli, sgRNAs with specific 5-bp seed sequences at the PAM-proximal region would produce substantial fitness defect, even when the other 15-bp in sgRNAs were completely different or the targeted gene was nonessential. These 5-bp seed sequences have been characterized as 5′-ACCCA-3′, 5′-ATACT-3′, and 5′-TGGAA-3′, and designated as "bad seed."…”

Impact of CRISPR interference on strain development in biotechnology

“…Moreover, inherent problems such as ambiguous interpretation of CRISPRi results when targeting a bidirectional promoter or upstream versus downstream genes in operons exist [135,136] and require caution and further experimentation for full comprehension. Several studies reported dCas9 protein off-target effect, besides toxicity in bacterial cells [137][138][139][140][141][142]. In E. coli, it was observed that a high level of dCas9 expression led to abnormal cell morphology [137].…”