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.

α-Keto esters are key building blocks in many bioactive natural compounds, biomolecules, and pharmaceuticals.[1] They are also widely employed as versatile precursors for various functional groups of interest.[2] Recent advances in α-keto ester synthesis have garnered considerable attention, due to their immense potential.[3] For instance, in 2007, Murakami and co-workers achieved a synthesis through rhodium-catalyzed reactions of arylboronic acids with a cyanoformate (Scheme [1a]).[4] Subsequently, in 2011, Jiao’s group reported a ruthenium-catalyzed oxidation of α-aryl halo derivatives to obtain α-keto esters (Scheme [1b]).[5] They further developed procedures using 1,3-diketones and α-carbonyl aldehydes (Schemes 1c and 1d).[6] Song and co-workers used Cu(OTf) for the oxidative esterification of acetophenone (Scheme [1e]),[7] and Hawang et al. achieved a synthesis of α-keto esters by a CuI-catalyzed oxidative esterification of terminal alkynes (Scheme [1f]).[8] Later, the Wang group developed an oxidative esterification of α-amino carbonyl by using tert-butyl hydroperoxide and cumene hydroperoxide under radical conditions (Scheme [1g]).[9]

Despite this notable progress, the synthesis of α-keto esters remains constrained by the use of metal catalysts, issues with compatibility, and the requirement for additives.[10] These limitations not only increase the complexity of the process, but also add to the costs associated with obtaining α-keto esters. There has been extensive research on transition-metal-catalyzed C–N bond cleavage.[2d] [11] However, transition-metal-free C–N bond cleavage and the formation of new C–N bonds remains a fascinating area in organic synthesis, due to its environmental and economic benefits.[12] The two-step processes for α-keto ester formation reported by Kumar (2011), Guo (2017), and Black (2019) involve a base-mediated acylation, followed by ring opening using an alcohol (Scheme [1h]).[13] We recently reported a t-BuOK-mediated transition-metal-free transamidation of amides with primary amines.[14]

Here, we report an unprecedented base-promoted chemoselective cleavage of the C(CO)–N bond of isatins to produce α-keto esters, as well as the subsequent formation of a new C–N bond using tert-butanol as the solvent.

We attempted the reaction using 5-bromoisatin (2h) and benzoyl chloride (3a) as model substrates, and we obtained the desired α-keto ester 1ah in 60% yield by using two equivalents of t-BuOK as a base at 90 °C (Table [1], entry 1). Benzoic acid was formed as the byproduct. Interestingly, changing the base from t-BuOK to t-BuONa or t-BuOLi resulted in lower yields of 54 and 42%, respectively (entries 2 and 3). Therefore, the potassium cation plays an important role in this reaction. Further screening of various other bases did not yield the desired product, with only the starting material remaining (entries 4–11). After these preliminary tests, we screened other reaction parameters such as the solvent, the stoichiometry of the base, the temperature, and the time. Various solvents were tested (DMF, DMSO, toluene, mesitylene, 1,4-dioxane, NMP, and PhCF₃) (entries 12–18). Traces of the product were obtained in NMP, mesitylene, and PhCF₃ (entries 16–18). With DMSO, toluene, or 1,4-dioxane, the product was obtained in considerably lower amounts (entries 13–15). We then optimized the temperature by reducing it from 90 °C to room temperature, which dramatically reduced the product yield (entries 19 and 20). Next, we screened the base loading and found that increasing it from 0.5 to 2.0 equivalents increased the yield of the product (entries 21–23). Extending the reaction time from 3 to 12 hours led to an increase in yield (entries 24–26). After analyzing the various parameters, we determined that the optimal conditions for obtaining the desired product 1ah in 60% yield involved the use of using 5-bromoisatin (2h) (1 equiv), benzoyl chloride (3a) (2 equiv), and t-BuOK (2 equiv) in t-BuOH (4 mL) as the solvent at 90 °C for 12 hours (Table [1], entry 1).

Table 1 Optimization of the Reaction Conditions^a,b

Entry	Base (equiv)	Solvent	Temp (°C)	Time (h)	Yieldb (%)
1	t-BuOK (2)	t-BuOH	90	12	60
2	NaO t Bu (2)	t-BuOH	90	12	54
3	LiO t Bu (2)	t-BuOH	90	12	42
4	K2CO3 (2)	t-BuOH	90	12	NRc
5	Cs2CO3 (2)	t-BuOH	90	12	NR
6	Na2CO3 (2)	t-BuOH	90	12	NR
7	NaOH (2)	t-BuOH	90	12	NR
8	KOH (2)	t-BuOH	90	12	NR
9	K3PO4 (2)	t-BuOH	90	12	NR
10	Et3N (2)	t-BuOH	90	12	NR
11	DBU (2)	t-BuOH	90	12	NR
12	t-BuOK (2)	DMF	90	12	NR
13	t-BuOK (2)	DMSO	90	12	50
14	t-BuOK (2)	toluene	90	12	53
15	t-BuOK (2)	1,4-dioxane	90	12	47
16	t-BuOK (2)	NMP	90	12	trace
17	t-BuOK (2)	mesitylene	90	12	trace
18	t-BuOK (2)	PhCF3	90	12	trace
19	t-BuOK (2)	t-BuOH	rt	12	25
20	t-BuOK (2)	t-BuOH	45	12	41
21	t-BuOK (0.5)	t-BuOH	90	12	32
22	t-BuOK (1)	t-BuOH	90	12	46
23	t-BuOK (2)	t-BuOH	90	12	60
24	t-BuOK (2)	t-BuOH	90	3	28
25	t-BuOK (2)	t-BuOH	90	6	46
26	t-BuOK (2)	t-BuOH	90	12	60

^a Reaction conditions: 5-bromoisatin (2h; 1 equiv, 0.5 mmol), BzCl (3a; 2 equiv, 1 mmol), solvent (4 mL), stirring.

^b Isolated yields after column chromatography.

^c NR: no reaction.

To demonstrate the general relevance of our protocol for the synthesis of α-keto esters, we next investigated the reactions of various isatins under the optimized conditions (Scheme [2]). A series of isatins 2 were reacted with benzoyl chloride 3a, giving the corresponding the α-keto esters1ba–fa in yields of 55–71%. Isatins containing electron-withdrawing groups (e.g., F, Cl, Br, OCF₃) were converted into products more efficiently than those with electron-donating groups (e.g., Me, OMe). The structure of α-keto ester 1ga was confirmed by single-crystal x-ray analysis.[15] To broaden the substrate scope, we employed benzoyl chlorides 3b and 3c with electron-donating groups, instead of benzoyl chloride. A range of isatins 2a–f with diverse functional groups, from electron donating to electron withdrawing, were effective in amide coupling with 4-methylbenzoyl chloride (3b), furnishing the expected products 1ab–fb in moderate to good yields of 45–68%. To our delight, a wide array of isatins 2b–h were all well tolerated in reactions with 4-methoxybenzoyl chloride (3c), providing efficient access to the corresponding α-keto esters 1bc–hc (46–69%).

Next, we moved from using benzoyl chlorides with electron-donating groups to those with electron-withdrawing groups. A series of isatins 2c–h reacted with 4-chlorobenzoyl chloride (3d) to provide the corresponding α-keto esters 1cd–hd (49–63%). Similarly, in the presence of 4-nitrobenzoyl chloride (3e), isatins 2b–h furnished the expected products 1be–he in moderate to good yields (46–65%). With 4-(chloromethyl)benzoyl chloride (3f) as the substrate, isatins with both electron-donating and electron-withdrawing substituents (3b–g) also furnished the desired products 1bf–gf in yields of 51–62%. Importantly, we found that 2,6-difluorobenzoyl chloride (3g) was compatible with isatins 2a–h, albeit providing lower yields of 1bg–hg (41–55%).

To understand the reaction mechanism, a series of mechanistic experiments were carried out (Scheme [3]). First, the reaction of 5-chloroisatin (2g), benzoyl chloride (3a), and t-BuOK was performed in the presence of air and under argon. A decrease in the product yield was observed when the reaction was conducted under argon atmosphere, suggesting that the C–N bond cleavage is more efficient in the presence of air. The reaction of 5-chloroisatin (2g) with benzoyl chloride (3a) was carried out under the optimized conditions in the presence of two equivalents of a radical scavenger (TEMPO or galvinoxyl). In these reactions, the formation of α-keto esters 1ga was not inhibited, indicating that the reaction does not proceed through a radical pathway. Interestingly, under the optimized conditions, N-protected isatins (Me, Bn) 2i and 2j did not yield the product, suggesting that the N–H group is crucial for the reaction.

Based on our mechanistic experiments and relevant literature,[13] we propose a plausible mechanism for the cleavage reaction of 5-chloroisatin (2g) with benzoyl chloride (3a) as model substrates (Scheme [4]). Benzoyl chloride reacts with isatin in the presence of t-BuOK base to form the N-acylated intermediate 4 through nucleophilic acylation; this subsequently reacts with the tert-butoxide anion nucleophile to produce the desired product, the α-keto ester 1ag.

In conclusion, this robust, one-pot method of t-BuOK-mediated cleavage of isatins followed by coupling with benzoyl chloride offers an efficient route to synthesizing diverse α-keto esters.[16] This approach exhibits remarkable tolerance towards various functional groups, resulting in good yields of α-keto ester products. With its practicality and mild reaction conditions, our method provides a reliable and efficient synthetic route to α-keto esters, which are integral components in the synthesis of biologically active molecules.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank TRC IACS for the instrument facility.

• References and Notes

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

Corresponding Author

Publication History

Received: 29 July 2024

Accepted after revision: 10 September 2024

Accepted Manuscript online:
10 September 2024

Article published online:
30 September 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

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

• Supplementary Material