Selective Acylation of Aryl- and Heteroarylmagnesium Reagents with Esters in Continuous Flow

Abstract

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.

Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents

“…Indeed, a number of quinoline derivatives have been obtained under flow conditions through chlorination, trihalomethylation, and Suzuki–Miyaura arylation . Moreover, microreactor technology has proved its value for the functionalization of several heteroarenes using organometallic intermediates. − …”

“…In contrast, using the same flow conditions for cyclohexanone and DMF as the electrophiles, compounds 10b and 10f were isolated in low yields (28 and 22%, respectively). Therefore, modifications regarding the electrophile concentration, volume of the second coil, and flow rate, the latter two generating different residence times, were investigated. , According to results, which are shown in Table , longer residence times may be used as an interesting alternative to afford quinoline derivatives in high conversions from less reactive electrophiles (Table , entries 1–3). Thus, an improved yield (37%) was obtained from a more concentrated solution of cyclohexanone (1.2 mol·L –1 , 6 equiv), larger coil reactor (18 mL), and high residence time (2.5 min).…”

Continuous-Flow Reactions Mediated by Main Group Organometallics

“…Similar batch reactions often give tertiary alcohols or symmetric ketones as byproducts. [41][42][43] Scheme 17 Continuous-flow synthesis of ketones from carbon dioxide…”

Green production of 9-aryl-fluoren-9-ols achieved through process intensification of the Grignard reaction using continuous flow at room temperature

“…To date, continuous flow technology has been extensively applied in nitration reactions, 31,32 catalytic hydrogenation reactions, 33,34 the Friedel-Crafts reaction, 35,36 the Grignard reaction, 37,38 the Suzuki reaction, 39,40 oxidation reactions 41,42 and other reactions. 43,44 Moreover, continuous flow synthesis can also achieve the "end-to-end" synthesis of drug molecules by combining multi-step reactions in series, without the need for intermediate product separation and purification.…”