Continuous Flow Synthesis of Ketones from Carbon Dioxide and Organolithium or Grignard Reagents

Abstract

Abstract:We describe an efficient continuous flow synthesis of ketones from CO 2 and organolithium or Grignard reagents that exhibits significant advantages over conventional batch conditions in suppressing undesired symmetric ketone and tertiary alcohol byproducts. We observed an unprecedented solvent-dependence of the organolithium reactivity, the key factor in governing selectivity during the flow process. A facile, telescoped three-step-one-flow process for the preparation of ketones in a modular fashion through the in-line generation of organometallic reagents is also established.

In Situ Reaction Monitoring of Unstable Lithiated Intermediates through Inline FTIR Spectroscopy

“…Figure 5. Hexa-(a), tetra-(b), and dimeric (c) aggregates of 2 in different solvents, according to [2,[23][24][25]. .…”

“…Concerning laboratory experiments, many authors successfully synthesized a variety of organolithium compounds within microstructured devices, by taking advantage of precisely adjustable reaction conditions to easily control those highly exothermic and fast reactions [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Key examples are studies by the groups of Yoshida, Feng, and Browne, as shown below.…”

Synthesis of Organometallic Compounds in Flow

“…Jamison and coworkers reported the preparation of ketones from carbon dioxide and organolithium or Grignard reagents ( Scheme ) …”

“…Jamison and coworkers reported the preparation of ketones from carbon dioxide and organolithium or Grignard reagents (Scheme 3). [26] In this case the introduction of CO 2 in the reaction stream was performed using a Mass Flow Controller (MCF) that allowed introducing the exact amount of gas ( Figure 6).…”

Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis

“…Carboxylation of organolithium reagents and organomagnesium bromides with CO 2 was reported by the Jamison group in 2014 (Scheme ) . In this study, two molecules of an organolithium or one equivalent of a Grignard reagent and one equivalent of an organolithium were sequentially reacted with CO 2 to synthesize ketones in a continuous flow system.…”