Potassium tert-Butoxide Promoted α-Keto Ester Synthesis through C(O)–N Bond Cleavage of Isatins

Tridev Ghosh; Soumya Jyoti Basak; Jyotirmayee Dash

doi:10.1055/a-2413-0350

Synlett, Table of Contents

Synlett 2024; 35(20): 2532-2536
DOI: 10.1055/a-2413-0350

letter

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

Authors

Tridev Ghosh
Soumya Jyoti Basak
Jyotirmayee Dash∗

Abstract

All articles of this category

Dedicated to Professor Brindaban Chandra Ranu on the occasion of his 75^th 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.

Key words

keto esters - isatins - benzoyl chloride - C–N bond cleavage - transition-metal-free reaction

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References

References and Notes

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16 α-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.

Supplementary Material