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

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

Publication History

Received: 29 July 2024

Accepted after revision: 10 September 2024

Accepted Manuscript online:
10 September 2024

Article published online:
30 September 2024

• References and Notes

• 1a Han W, Hu Z, Jiang X, Decicco D. Bioorg. Med. Chem. Lett. 2000; 10: 711
• 1b Elsebai MF, Kehraus S, Lindequist U, Sasse F, Shaaban S, Gütschow M, Josten M, Sahl H.-G, König GM. Org. Biomol. Chem. 2011; 9: 802
• 1c Nie Y, Xiao R, Xu Y, Montelione GT. Org. Biomol. Chem. 2011; 9: 4070
• 1d Aoki Y, Tanimoto S, Takahashi D, Toshima K. Chem. Commun. 2013; 49: 1169
• 1e Shimizu Y, Yasuda K, Kanai M. Heterocycles 2014; 88: 919
• 2a Xiao X, Xie Y, Su C, Liu M, Shi Y. J. Am. Chem. Soc. 2011; 133: 12914
• 2b Boughton BA, Hor L, Gerrard JA, Hutton CA. Bioorg. Med. Chem. 2012; 20: 2419
• 2c Sarabu R, Bizzarro FT, Corbett WL, Dvorozniak MT, Geng W, Grippo JF, Haynes N.-E, Hutchings S, Garofalo L, Guertin KR, Hilliard DW, Kabat M, Kester RF, Ka W, Liang Z, Mahaney PE, Marcus L, Matschinsky FM, Moore D, Racha J, Radinov R, Ren Y, Qi L, Pignatello M, Spence CL, Steele T, Tengi J, Grimsby J. J. Med. Chem. 2012; 55: 7021
• 2d Liu J, Liu Q, Yi H, Qin C, Bai R, Qi X, Lan Y, Lei A. Angew. Chem. Int. Ed. 2014; 53: 502
• 2e Xuan Q, Zhao C, Song Q. Org. Biomol. Chem. 2017; 15: 5140
• 3a Moriyama K, Takemura M, Togo H. Org. Lett. 2012; 14: 2414
• 3b Zhang Z, Su J, Zha Z, Wang Z. Chem. Eur. J. 2013; 19: 17711
• 3c Nagaki A, Ichinari D, Yoshida J.-i. Chem. Commun. 2013; 49: 3242
• 3d Sagar A, Vidyacharan S, Sharada DS. RSC Adv. 2014; 4: 37047
• 3e Xie Y, Liu J, Huang Y, Yao L. Tetrahedron Lett. 2015; 56: 3793
• 3f Kumar Y, Jaiswal Y, Kumar A. J. Org. Chem. 2016; 81: 12247
• 3g Laha RM, Khamarui S, Manna SK, Maiti DK. Org. Lett. 2016; 18: 144
• 3h Jiang X, Gan B, Liu J, Xie Y. Synlett 2016; 27: 2737
• 3i Liang Y.-F, Jiao N. Acc. Chem. Res. 2017; 50: 1640
• 3j Saha P, Ray SK, Singh VK. Tetrahedron Lett. 2017; 58: 1765
• 3k Meng X, Bi X, Chen G, Chen B, Zhao P. Org. Process Res. Dev. 2018; 22: 1716
• 3l Guo C, Xu C, Zhang N.-N, Li X.-j, Ge Y.-q, Diao P.-h. Synlett 2018; 29: 1065
• 4 Shimizu H, Murakami M. Chem. Commun. 2007; 2855
• 5 Su Y, Zhang L, Jiao N. Org. Lett. 2011; 13: 2168
• 6a Zhang C, Feng P, Jiao N. J. Am. Chem. Soc. 2013; 135: 15257
• 6b Zhang C, Jiao N. Org. Chem. Front. 2014; 1: 109
• 7a Zhou M, Song Q. Synthesis 2014; 46: 1853
• 7b Xu X, Ding W, Lin Y, Song Q. Org. Lett. 2015; 17: 516
• 7c Huang X, Li X, Zou M, Pan J, Jiao N. Org. Chem. Front. 2015; 2: 354
• 8 Das DK, Kumar Pampana VK, Hwang KC. Chem. Sci. 2018; 9: 7318
• 9 Wang Y.-q, Zou J.-x, Wang H.-h, Peng X, Lu Y.-m, Feng Y.-y, Chen C, Shi T, Wang Z. Asian J. Org. Chem. 2019; 8: 1354
• 10a de la Torre A, Kaiser D, Maulide N. J. Am. Chem. Soc. 2017; 139: 6578
• 10b Kim SW, Um T.-W, Shin S. J. Org. Chem. 2018; 83: 4703
• 11 Xu W.-T, Huang B, Dai J.-J, Xu J, Xu H.-J. Org. Lett. 2016; 18: 3114
• 12a Verma A, Kumar S. Org. Lett. 2016; 18: 4388
• 12b Li G, Szostak M. Synthesis 2020; 52: 2579
• 12c Rahman MM, Szostak M. Org. Lett. 2021; 23: 4818
• 12d Amide Bond Activation: Concepts and Reactions. Szostak M. Wiley-VCH; Weinheim: 2022
• 13a Le T, Cheah WC, Wood K, Black DStC, Willcox MD, Kumar N. Tetrahedron Lett. 2011; 52: 3645
• 13b Zhu Y, Zhou L.-y, Jiang Y.-r, Zhao X.-j, Guo D. Bioorg. Med. Chem. Lett. 2017; 27: 4180
• 13c Suryanti V, Zhang R, Aldilla V, Bhadbhade M, Kumar N, Black DStC. Molecules 2019; 24: 4343
• 14 Ghosh T, Jana S, Dash J. Org. Lett. 2019; 17: 6690
• 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.
• 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.