Generation of Reactive Ketenes under Flow Conditions through Zinc-Mediated Dehalogenation

 

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Dedicated to Peter Vollhardt, dear friend and academic founder of Synlett.

Abstract

Herein, we describe the generation of highly reactive monoalkyl and phenyl ketenes by using a dehalogenation procedure under flow conditions. All ketenes were generated in good yields (determined by quenching with an appropriate aniline derivative) and showed high reactivity in the [2+2] cycloaddition with imines, resulting in the formation of a range of β-lactams at room temperature in less than 10 minutes. Furthermore, initial experiments were performed by using these reactive ketenes for the synthesis of β-lactams under flow conditions.

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• 17 In-flow generation of ketenes; General procedure:A solution of α-bromo acyl halide (0.05 M) in Et₂O was passed through an Omnifit (http://www.omnifit.com/) glass column, loaded with a mixture of activated zinc (500 mg) and glass beads (1.0 g) using a Vapourtec R2 platform (http://www.vapourtec.co.uk/ products/rseriessystem). The column output was monitored by using a Mettler Toledo Flow-IR device (http://uk.mt.com/gb/en/ home/products/L1_Autochem Products/ReactIR/flow-ir-chemis.html). When freshly activated zinc was used, the formation of the corresponding ketene could be observed directly in the IR spectra. When the zinc was not sufficiently activated, ketene formation sometimes did not occur directly. However, the formation could be easily initiated by heating the zinc column for a few seconds. Once the reaction was initiated, ketene formation was stable for about 30 min. CAUTION: Although the work was conducted using low ketene concentrations, special precautions must be taken because ketenes are highly toxic. All work was carried out in a fumehood and the outcoming ketene stream was directly quenched by either the respective coupling partner or a NaOH solution. Synthesis of β-lactams; General procedure: The respective imine (0.20 mmol) was dissolved in Et₂O (1 mL) in a vial. The ketene was synthesised according to the in-flow general procedure and an aliquot of the outcoming ketene stream (0.05 M, 6 mL, 3 mmol, 1.5 equiv) was directly added to the imine solution. The mixture was stirred for another 4 min and then the reaction was quenched by adding sat. K₂CO₃ (5 mL) and the mixture was stirred for another 5 min. The organic phase was separated and the aqueous phase was extracted with Et₂O. The combined organic phases were dried over MgSO₄ and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography.

• Supplementary Material