Mechanochemical Approach for Air-Tolerant and Extremely Fast Lithium-Based Birch Reductions in Minutes
Dr. Yunpeng Gao
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
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Prof. Dr. Koji Kubota
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, 060-0021 Sapporo, Hokkaido, Japan
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Prof. Dr. Hajime Ito
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, 060-0021 Sapporo, Hokkaido, Japan
Search for more papers by this authorDr. Yunpeng Gao
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
Search for more papers by this authorCorresponding Author
Prof. Dr. Koji Kubota
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, 060-0021 Sapporo, Hokkaido, Japan
Search for more papers by this authorCorresponding Author
Prof. Dr. Hajime Ito
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, 060-8628 Sapporo, Hokkaido, Japan
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, 060-0021 Sapporo, Hokkaido, Japan
Search for more papers by this authorGraphical Abstract
A mechanochemical Birch reduction is reported for the first time. The newly developed ball-milling method does not require an inert atmosphere or other special precautions. Notably, the reaction reached completion within one minute for most of the investigated substrates. The present study thus provides a novel, operationally simple, rapid, and scalable alternative to conventional solution-based Birch reduction.
Abstract
Birch reduction has been widely used in organic synthesis for over half a century as a powerful method to dearomatize arenes into 1,4-cyclohexadiene derivatives. However, the conventional Birch reduction reaction using liquid ammonia requires laborious procedures to ensure inert conditions and low temperatures. Although several ammonia-free modifications have been reported, the development of an operationally simple, efficient, and scalable protocol remains a challenge. Herein, we report an ammonia-free lithium-based Birch reduction in air without special operating conditions using a ball-milling technique. This method is characterized by its operational simplicity and an extremely short reaction time (within 1 min), probably owing to the in situ mechanical activation of lithium metal, broad substrate scope, and no requirement for dry bulk solvents. The potential of our flash Birch reaction is also demonstrated by the efficient reduction of bioactive target molecules and gram-scale synthesis.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
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- 25Although we did not encounter any hazards in the gram-scale mechanochemical Birch reduction in air, anyone who wants to scale up should pay attention to the safety issues. On one hand, organolithiums and lithium metal are commonly considered to be pyrophoric. On the other hand, Birch reduction is an exothermic reaction that might release flammable vapors. Risk management must be done to avoid fire and explosion hazards before any attempts to scale up this reaction in air.