Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu
Potassium tert-Butoxide Promoted α-Keto Ester Synthesis through C(O)–N Bond Cleavage of Isatins
Tridev Ghosh
,
Soumya Jyoti Basak
,
Jyotirmayee Dash∗
JD thanks the Wellcome Trust DBT India Alliance [Grant Number IA/S/18/2/503986] and DST CRG for funding. S.B. thanks CSIR India for a senior research fellowship.
Dedicated to Professor Brindaban Chandra Ranu on the occasion of his 75th birthday
Abstract
We present a novel and cost-effective method for synthesizing biologically important α-keto esters in a single-step reaction. This approach involves a sequential cascade process within a single reaction vessel facilitated by t-BuOK, which promoted the cleavage of the sp2 C(O)–N bond of an isatin and the formation of a new N–C(sp2)(O) bond with benzoyl chloride. To the best of our knowledge, this is the first instance of the construction of an α-keto ester scaffold adjacent to an amide group through a one-pot process. In comparison to existing methods, our protocol offers several advantages: readily available starting materials, mild reaction conditions, a concise synthetic pathway, high sustainability, and excellent tolerance towards various functional groups. Given these strengths, we anticipate widespread use of this method in the synthesis of related α-keto ester scaffolds.
15 CCDC 2366607 contains the supplementary crystallographic data for compound 1ga. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures ; see also the Supporting Information.
16α-Keto Ester Synthesis: General Procedure
A clean, oven-dried, screw-capped, 20 mL reaction tube was charged with the appropriate isatin derivative 2 (1 equiv, 0.5 mmol), benzoyl chloride 3 (2 equiv, 1 mmol), and t-BuOK (2 equiv, 1 mmol) in t-BuOH (4 mL) under an open-air environment. The solution was then stirred at 90 °C in an oil bath for 12 h until the reaction was complete (TLC). The solvent was removed under vacuum and the concentrated reaction mixture was diluted with aq KHSO4 and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure, and the resulting crude mixture was purified by column chromatography (silica gel, hexane–EtOAc).
tert-Butyl [2-(Benzoylamino)-5-tolyl](oxo)acetate (1ba)
Purified by column chromatography [silica gel, hexane–EtOAc (95:5)] to give a yellow solid; yield: 93.3 mg (55%). 1H NMR (300 MHz, CDCl3): δ = 12.03 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 8.06 (dd, J = 8.1, 1.5 Hz, 2 H), 7.55–7.48 (m, 5 H), 2.38 (s, 3 H), 1.66 (s, 9 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 191.4, 166.1, 149.0, 141.0, 141.0, 138.1, 133.7, 132.4, 132.3, 129.0, 127.6, 120.9, 117.4, 85.6, 28.2, 20.9. HRMS (ESI-TOF): m/z [M + H] + calcd for C20H22NO4: 340.1549; found: 340.1548.
