Mild Homologation of Esters through Continuous Flow Chloroacetate Claisen Reactions

Abstract

The selective chloromethylenation of functionalized esters using chloroacetic acid (CA) and LiHMDS (HMDS = hexamethyldisilazide) in ac ontinuous-flows etup is reported. This Claisen homologation is for the first time extended to bischloromethylenation using dichloroacetic acid (DCA), thus giving access to under-explored a,a'-bis-chloroketones.T he use of flow conditions enables efficient generation and reaction of the unstable chloroacetate dianion intermediates,leading to unprecedented mild and scalable reaction conditions at an economical reagent stoichiometry (À10 8 8C, < 1min, 1.0-2.4 equiv dianion). The clean reaction profiles allows ubsequent use of the unpurified crude products,w hichi sd emonstrated in the synthesis of various heterocycles of broad interest. Furthermore,wereport anovel, catalyst-free substitution of the obtained monochloro ketone products with (hetero)aryl zinc enolates to give valuable 1,4-diketones.Mono-andbis-a-chloroketonesareusefulbis-electrophiles (C À Cl and C = O; compare 1,X= Cl and 2,X= H, Scheme 1), which accounts for their widespread use,p articularly in cyclocondensations to give heterocycles. [1] Such cyclizations of functionalized precursors are cost-economic,a void challenging cross-coupling steps and transition-metal purging, [2,3] thus making novel approaches to pre-functionalized a-chloro [*] M. A. Ganiek,D r. M. V. Ivanova, Prof.

Fast and Efficient Continuous Flow Method for the Synthesis of Ynones and Pyrazoles

“…1,1‐Dichloro‐4‐phenylbut‐3‐yn‐2‐one (3i): 1 H‐NMR (400 MHz, CDCl 3 ): δ = 7.65 (dd, J = 8.5, 1.1 Hz, 2H), 7.52 (tt, J = 7.6, 1.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 5.99 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 168.4, 128.1, 126.3, 123.3, 113.4, 92.4, 77.9, 64.5.…”

“…(3g): [31] 1 H-NMR (400 MHz, CDCl 3 ): δ = 7.65-7.59 (m, 3H), 7.45-7.34 (m, 4H), 6.57 (dd, J =3.6, 1.6 Hz 1H). 13 [33] [34] [35] Phenyldodec-1-yn-3-one(3m): [ [30] The solution was passed throw preheating unit R3 (Φ = 1.0 mm, L = 500 cm, 2514 μL) at 70°C. After a steady state was reached (after 1 min), the final product solution was collected for 60 seconds.…”

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…”

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…A different approach, for the introduction of a dihalomethylenic unit, was recently reported by Knochel, who developed a continuous flow tactic for homologation of esters using dichloroacetic acid 13 . The reported strategy, was an unprecedented mild and scalable Claisen reaction that used an unstable chloroacetate dianion tamed using flow technology (Scheme ) …”