Synthesis of Biaryls Having a Piperidylmethyl Group Based on Space Integration of Lithiation, Borylation, and Suzuki–Miyaura Coupling

In a flow microreactor, aryllithiums bearing a piperidylmethyl group were generated using nBuLi by precise residence time control and effective temperature control, and then selectively borylated with boronic esters such as 2‐isopropoxy‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (BpinOiPr) and trimethy...

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Published in:European journal of organic chemistry 2020-02, Vol.2020 (5), p.618-622
Main Authors: Takahashi, Yusuke, Ashikari, Yosuke, Takumi, Masahiro, Shimizu, Yutaka, Jiang, Yiyuan, Higuma, Ryosuke, Ishikawa, Susumu, Sakaue, Hodaka, Shite, Ibuki, Maekawa, Kei, Aizawa, Yoko, Yamashita, Hiroki, Yonekura, Yuya, Colella, Marco, Luisi, Renzo, Takegawa, Toshihiro, Fujita, Chiemi, Nagaki, Aiichiro
Format: Article
Language:English
Subjects:
Borylation
Coupling (molecular)
Cross coupling
Esters
Flow microreactors
Lithiation
Piperidylmethyl groups
Synthesis
Temperature control
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Summary:In a flow microreactor, aryllithiums bearing a piperidylmethyl group were generated using nBuLi by precise residence time control and effective temperature control, and then selectively borylated with boronic esters such as 2‐isopropoxy‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (BpinOiPr) and trimethyl borate B(OMe)3 by fast mixing. Moreover, the direct integration with Suzuki–Miyaura cross coupling were successfully achieved to obtain nitrogen‐containing biaryl compounds. The present method could be applied for the straightforward synthesis of the key intermediate of a bioactive component bearing a piperidylmethyl‐biphenyl framework. A flow microreactor enabled the generation of aryllithiums bearing a piperidylmethyl group and their selective borylation with boronic esters. Moreover, lithiation, borylation, and Suzuki–Miyaura cross‐coupling were integrated to obtain nitrogen‐containing biaryl compounds such as a synthetic intermediate of a compound with histone deacetylase (HDAC) inhibitory activity.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201901729