Currently, few pharmaceutical or aromatic chemicals are produced without the use of organometallic reagents. In particular, organolithium reagents, which are the most commonly used commercially available organometallic compounds in synthetic laboratories worldwide, are characterized by their ultra-high reactivity. However, this high reactivity prevents such reagents from being in contact with air or water, and harsh conditions are required for use, such as anhydrous and oxygen-free, toxic organic solvents, and extremely low temperatures (<-50 °C). In recent years, the limitation of anhydrous and oxygen-free environment for organometallic reagents is being removed by replacing conventional solvents with green, nontoxic, and biorenewable deep eutectic solvents (DES).
Recently, researchers used a microfluidic two-phase segmented flow reactor and DES to conduct continuous, stable, and safe organometallic reactions based on flow chemistry at room temperature, achieving the addition of several organometallic species to different ketones/imines. The reaction system can withstand the presence of moisture and is not easily clogged.
First, researchers tested a customized microflow reactor using the addition reaction of PhLi with 2'- methoxyacetophenone. This reaction produces a lithium alcohol intermediate, which is then hydrolyzed to obtain the desired tertiary alcohol (a component of a variety of drug molecules) and release lithium hydroxide. When the ratio of PhLi to substrate is 1.25 equivalents, the reaction yield is as high as 98% (separation yield after recrystallization in Et2O: 90%), and the selectivity is 100% within a residence time of 35 seconds without the need for oxygen free conditions. In contrast, previous studies using RLi for flow synthesis in conventional organic solvents require low temperature conditions (requiring a considerable residence time in minutes), and are prone to clogging due to solid formation.
Due to the formation of insoluble lithium salt by-products during the reaction process, the previously reported continuous reactions of organometallides with ketones and imines often result in clogging, and insoluble LiOH can also be formed when the reaction is conducted under less stringent anhydrous conditions. In contrast, this reaction can operate stably for a long time even at room temperature, not only due to the presence of DES (such as ChCl/2Gly), but also because segmented flow promotes the transfer of insoluble compounds (such as lithium salts) from the organic phase to the DES phase, increasing the contact area between the two phases.
In addition, the reaction system can also be extended to a range of different substrates and organometallic compounds. Using commercially available phenyl lithium, n-butyl lithium, and vinyl magnesium bromide, it was found that the addition reaction of 2 '- methoxyacetophenone could proceed smoothly and yield phenylalcohol (yield: 73%), n-butanol (yield: 56%), and vinyl alcohol (yield: 55%). In contrast, phenyl Grignard reagent generates phenylalcohol in only 20% yield. Subsequently, the researchers also screened different ketones and imines. For acetophenone substrates, PhLi has a better reaction effect. In addition, a similar high yield was observed for a series of imines.
This method pioneered the use of organometallic reagents to produce alcohols and amines from ketones and imines through flow chemistry. The segmented flow between the immiscible DES containing carrier phase and the dispersed substrate organic phase contributes to stable operation at room temperature without lithium salt clogging.
Related Products & Services
Reference
- Continuous, stable, and safe organometallic reactions in flow at room temperature assisted by deep eutectic solvents
Florian F. Mulks, Bruno Pinho, Andrew W.J. Platten, M. Reza Andalibi, Antonio J. Expo´sito, Karen J. Edler, Eva Hevia, Laura Torrente-Murciano
