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DOI: 10.1055/a-2176-1840
Direct Electrochemical C(sp3)–H Amidation Enabled by Hexafluoroisopropanol (HFIP)
Abstract
A direct electrochemical amidation of xanthene was readily achieved under direct anodic oxidation. The reactivity of benzamides was significantly enhanced by the virtue of the solvent effect of hexafluoroisopropanol (HFIP). An obvious hydrogen bonding between HFIP and benzamide was detected, and the proton-coupled electron-transfer (PCET) effect was proposed for the enhancement effect of HFIP. In this transformation, a broad range of primary and secondary amides were readily used as amidating reagents, including l-proline-, naproxen-, and probencid-derived amides. We proposed a plausible reaction mechanism for this direct amidation based on the experimental observations.
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Amides are prevalent in bioactive molecules. As mentioned by Ertl in the corresponding review:[1] ‘The most frequent FG in bioactive molecules is the amide, in either its secondary or tertiary disposition, and this FG is present in 40.3% of all molecules.’ Consequently, tremendous attention has been devoted to the synthesis of amides. Conventional approaches commonly require activated acylation reagents.[2] Growing concerns related to sustainable chemistry has shifted attention to the direct amidation of C(sp3)–H, which would provide an approach to upgrade primary or secondary amides to secondary or tertiary amides, respectively.
In the area of the intermolecular C(sp3)–H amidation, two main strategies involving C–H activation[3] and nitrene insertion[4] were developed (Scheme [1a]). A range of sophisticated amidating reagents, such as dioxazolones, acyl azides, and hydroxamate were devised for these transformations. In the sharp contrast, primary amide as one of the most accessible amidating reagents has received far less attention due to its weak acidity and nucleophilicity. As depicted in the Scheme [1b], the pK a [5] of benzenesulfonamide and benzamide ranges from 16.1 to 23.3.
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The past decade has witnessed the explosive progress in synthetic electrochemistry[6] since it provides distinct and efficient solutions for conventionally challenging transformations. Electrochemical oxidative amination of C(sp3)–H has received tremendous attention. Sulfonamide as amidating reagent was explored by some groups. For instance, Lei[7] and coworkers used acidic sulfonimide as an amidating reagent in the reaction with arenes (Scheme [1c]). A remarkable breakthrough in the site-selective C(sp3)–H amination was recently achieved by the Xu[8] group with benzenesulfonamide as nitrogen source (Scheme [1d]). At almost the same time, Ackermann[9] independently developed an electrochemical approach for allylic C(sp3)–H sulfonamidation (Scheme [1e]). Despite this impressive progress, using benzamide derivatives as a direct amidating reagent still suffer from formidable challenges. Very recently, we reported a paired-electrolysis strategy for the electrochemical amidation,[10] in which alkoxyamide was used as the precursor of primary amide (Scheme [1f]). In our line of research[11] in synthetic chemistry, we questioned whether hexafluoroisopropanol (HFIP)[12] could enhance the reactivity of benzamide via proton-coupled electron-transfer (PCET)[13] effect to enable the direct electrochemical C(sp3)–H amidation. Indeed, a direct electrochemical amidation of C(sp3)–H was readily achieved by virtue of unique property[12] of HFIP.
At the outset, we probe the solvent effect of HFIP on the redox property of benzamide (1a). As shown in the cyclic voltammogram of benzamide (Figure [1a]), a new oxidation peak at 1.12 V was detected upon introducing 1 equivalent of HFIP. This result suggests that the HFIP could significantly enhance the anodic oxidation of benzamide as compared to the former peak at 2.09 V. Additionally, a uniform enhancement effect of HFIP on the oxidation of other amides has also been recorded (see the Supporting Information for details). To rationalize the effect of HFIP, nuclear magnetic resonance (1H NMR) study was conducted (Figure [1b]). Mixing HFIP with benzamide lead to obvious variation of peaks of benzamide. Specifically, peaks of N–H shift to low field (δ = 5.92–6.08 ppm), indicating a hydrogen-bonding effect between HFIP and benzamide. Taken together, proton-coupled electron transfer (PCET) was proposed for the enhancement effect of HFIP on the oxidation of benzamide.
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Having identified the solvent effect of HFIP, we selected xanthene as a reaction partner with benzamide (Figure [1c]), which would allow a direct access to a broad range of bioactive scaffolds.[14] After a series of optimizations, the electrochemical C(sp3)–H amidation between xanthene and benzamide was readily achieved using mixed solvent (CH3CN/HFIP), platinum anode, and graphite cathode; the desired product was accessed in 99% yield. Removal of HFIP or replacing it with methanol led to diminished yields.
With the optimal conditions in hand, a broad range of amides was examined to illustrate the reaction generality (Scheme [2]).[15] First, electronic property effect was explored by using para-substituted benzamides as substrates (3b–h). It showed that the redox-labile iodine group (3f) and the strongly electron-withdrawing cyano group (3h) resulted in lower yields. Second, it was found that changing the para substitution to meta (3i) or ortho (3j) substitution marginally affected the reaction efficiency. Third, other aromatic amides (3k–m), alkenyl amides (3n–o), and aliphatic amides (3p–q) were also amenable to afford the desired amidation products, although aliphatic amides led to diminished yields due to its inactive redox property. It is noteworthy that the bioactive molecule XAA (3o)[14a] can be directly accessed with this electrochemical protocol. Subsequently, secondary amides (3r–t), carboxamide (3u), phosphinamide (3v), and sulfinamide (3w) were also employed as the amidating reagents, and the corresponding products (3r–w) were delivered in moderate to good yields. To demonstrate the synthetic utility of this approach, amides derived from natural product (l-proline) and pharmaceuticals (naproxen, probenecid) were subjected to the optimal conditions. To our delight, the desired amidated xanthenes (3x–z) were successfully accessed in satisfactory yields. Replacing xanthene with thioxanthene (3aa) caused a significant drop in the reaction yield, while substituted oxanthenes (3ab–ad) were well tolerated with good yields. This result might attribute to the overoxidation of the product 3aa. Remarkably, this electrochemical protocol can be readily scaled up, and gram-scale product 3a was readily accessed in 72% yield.
To get insight into the reaction mechanism, control experiments and a cyclic voltammogram experiment were conducted. As shown in the Figure [2a], some radical scavengers were introduced to the reaction conditions. Obvious suppression effect was observed, although the desired product 3a still can be accessed in 13–78% yield. This result suggests that the radical species is involved in this reaction. The kinetic isotope effect was also studied (Figure [2b]), and it indicates that the cleavage of C(sp3)–H is the rate-determining step in the reaction. Finally, a cyclic voltammogram experiment (Figure [2c]) showed that closed onset-waves were detected for the substrates benzamide (1a) and xanthene 2a in the mixed solution of acetonitrile and HFIP. This result supports that two substrates are oxidized simultaneously over the surface of the anode.
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Based on the experimental observations and previous report,[16] a plausible reaction mechanism was proposed (Scheme [3]). Under cathodic reaction, acidic solvent HFIP is reduced to hydrogen and the conjugated base A. With the PCET assistance of base A, benzamide 1a is oxidized to amidyl radical B. Simultaneously, xanthene 2a proceeds with a sequential single-electron transfer and deprotonation to afford a persistent radical C, which is immediately intercepted by B to give the final product 3a. Alternatively, radical C can be further oxidized to carbocation D (path II). Under nucleophilic attack of 1a, the desired product 3a is delivered.
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In conclusion, a direct electrochemical amidation between xanthene and benzamides was reported. In this transformation, a significant enhancement effect of HFIP on the reaction performance was observed. Proton-coupled electron-transfer effect was proposed for the role of HFIP in the reaction according to the 1H NMR study. Further investigation on the solvent effect of HFIP is ongoing in our laboratory.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2176-1840.
- Supporting Information
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References and Notes
- 1 Ertl P, Altmann E, McKenna JM. J. Med. Chem. 2020; 63: 8408
- 2a Montalbetti CA. G. N, Falque V. Tetrahedron 2005; 61: 10827
- 2b Ojeda-Porras A, Gamba-Sánchez D. J. Org. Chem. 2016; 81: 11548
- 2c Pattabiraman VR, Bode JW. Nature 2011; 480: 471
- 3a Wang H, Tang G, Li X. Angew. Chem. Int. Ed. 2015; 54: 13049
- 3b Tan PW, Mak AM, Sullivan MB, Dixon DJ, Seayad J. Angew. Chem. Int. Ed. 2017; 56: 16550
- 3c Antien K, Geraci A, Parmentier M, Baudoin O. Angew. Chem. Int. Ed. 2021; 60: 22948
- 4a Knecht T, Mondal S, Ye J.-H, Das M, Glorius F. Angew. Chem. Int. Ed. 2019; 58: 7117
- 4b Burman JS, Harris RJ, Farr CM. B, Bacsa J, Blakey SB. ACS Catal. 2019; 9: 5474
- 4c Lei H, Rovis T. J. Am. Chem. Soc. 2019; 141: 2268
- 4d Tang J.-J, Yu X, Wang Y, Yamamoto Y, Bao M. Angew. Chem. Int. Ed. 2021; 60: 16426
- 4e Bakhoda A, Jiang Q, Badiei YM, Bertke JA, Cundari TR, Warren TH. Angew. Chem. Int. Ed. 2019; 58: 3421
- 5a Breugst M, Tokuyasu T, Mayr H. J. Org. Chem. 2010; 75: 5250
- 5b Kütt A, Tshepelevitsh S, Saame J, Lõkov M, Kaljurand I, Selberg S, Leito I. Eur. J. Org. Chem. 2021; 1407
- 6a Francke R, Little RD. Chem. Soc. Rev. 2014; 43: 2492
- 6b Yan M, Kawamata Y, Baran PS. Chem. Rev. 2017; 117: 13230
- 6c Jiang Y, Xu K, Zeng C.-C. Chem. Rev. 2018; 118: 4485
- 6d Yoshida J.-i, Shimizu A, Hayashi R. Chem. Rev. 2018; 118: 4702
- 6e Moeller KD. Chem. Rev. 2018; 118: 4817
- 6f Waldvogel SR, Lips S, Selt M, Riehl B, Kampf CJ. Chem. Rev. 2018; 118: 6706
- 6g Yuan Y, Lei A. Acc. Chem. Res. 2019; 52: 3309
- 6h Xiong P, Xu H.-C. Acc. Chem. Res. 2019; 52: 3339
- 6i Jiao K.-J, Xing Y.-K, Yang Q.-L, Qiu H, Mei T.-S. Acc. Chem. Res. 2020; 53: 300
- 6j Gandeepan P, Finger LH, Meyer TH, Ackermann L. Chem. Soc. Rev. 2020; 49: 4254
- 6k Novaes LF. T, Liu J, Shen Y, Lu L, Meinhardt JM, Lin S. Chem. Soc. Rev. 2021; 50: 7941
- 6l Cheng X, Lei A, Mei T.-S, Xu H.-C, Xu K, Zeng C. CCS Chem. 2022; 4: 1120
- 7 Hu X, Zhang G, Nie L, Kong T, Lei A. Nat. Commun. 2019; 10: 5467
- 8 Hou Z.-W, Liu D.-J, Xiong P, Lai X.-L, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2021; 60: 2943
- 9 Wang Y, Lin Z, Oliverira JC. A, Ackermann L. J. Org. Chem. 2021; 86: 15935
- 10 Li F, Liang Y, Zhan X, Zhang S, Li M.-B. Org. Chem. Front. 2022; 9: 5571
- 11a Zhang S, Li L, Zhang J, Zhang J, Xue M, Xu K. Chem. Sci. 2019; 10: 3181
- 11b Zhang S, Li L, Li J, Shi J, Xu K, Gao W, Zong L, Li G, Findlater M. Angew. Chem. Int. Ed. 2021; 60: 7275
- 11c Zhang S, Shi J, Li J, Li M.-B, Li G, Findlater M. CCS Chem. 2022; 4: 1938
- 11d Liang Y, Zhan X, Li F, Bi H, Fan W, Zhang S, Li M.-B. Chem. Catal. 2023; 3: 100582
- 11e Zhang S, Liang Y, Liu K, Zhan X, Fan W, Li M.-B, Findlater M. J. Am. Chem. Soc. 2023; 145: 14143
- 11f Zhang S, Findlater M. ACS Catal. 2023; 13: 8731
- 12 Colomer I, Chamberlain AE. R, Haughey MB, Donohoe TJ. Nat. Rev. Chem. 2017; 1: 0088
- 13 Murray PR. D, Cox JH, Chiappini ND, Roos CB, McLoughlin EA, Hejna BG, Nguyen ST, Ripberger HH, Ganley JM, Tsui E, Shin NY, Koronkiewicz B, Qiu G, Knowles RR. Chem. Rev. 2022; 122: 2017
- 14a Luo L, Jia B.-Z, Wei X.-Q, Xiao Z.-L, Wang H, Sun Y.-M, Shen Y.-D, Lei H.-T, Xu Z.-L. Sens. Actuators, B 2021; 332: 129561
- 14b Park I.-S, Seo HR, Kim K, Lee H, Shum D, Choi I, Kim J. Biochem. Biophys. Res. Commun. 2020; 527: 709
- 14c Watterson KR, Hansen SV. F, Hudson BD, Alvarez-Curto E, Raihan SZ, Azevedo CM. G, Martin G, Dunlop J, Yarwood SJ, Ulven T, Milligan G. Mol. Pharmacol. 2017; 91: 630
- 15 General Procedure for the Electrochemical Amidation (3a as an Example) An undivided cell was equipped with a magnet stirrer, platinum plate (1.5 × 1.5 cm2), and graphite rod (0.6 × 10 cm), as anode and cathode, respectively (the electrolysis setup is shown in Figure S1). Substrate benzamide (1a, 61 mg, 0.5 mmol), 9H-xanthene (2a, 137 mg, 0.75 mmol), and n-Bu4NClO4 (342 mg, 1 mmol) were added to the solvent MeCN/HFIP (9/1 mL). The resulting mixture was allowed to stir and electrolyze under constant current conditions (15 mA) at room temperature for 3 h. The reaction mixture was condensed with a rotary evaporator. The residue was purified by column chromatography (PE/EtOAc = 20/1 to10/1, V/V) on silica gel to afford the desired product 3a (149 mg) in 99% yield. N-(9H-Xanthen-9-yl)benzamide (3a) 149 mg, 99% yield; white solid, mp 227–228 °C. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.33 (t, J = 8.0 Hz, 2 H), 7.16–7.10 (m, 4 H), 6.78 (d, J = 12.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 166.5, 151.1, 134.0, 131.8, 129.7, 129.4, 128.6, 127.0, 123.7, 121.0, 116.7, 44.3.
- 16a Lin M.-Y, Xu K, Jiang Y.-Y, Liu Y.-G, Sun B.-G, Zeng C.-C. Adv. Synth. Catal. 2018; 360: 1665
- 16b Yang Y.-Z, Song R.-J, Li J.-H. Org. Lett. 2019; 21: 3228
- 16c Wei B, Qin J.-H, Yang Y.-Z, Xie Y.-X, Ouyang X.-H, Song R.-J. Org. Chem. Front. 2022; 9: 816
- 16d Chen X, Liu H, Gao H, Li P, Miao T, Li H. J. Org. Chem. 2022; 87: 1056
For the synthesis of amides, see:
For the approaches involving C(sp3)–H activation, see:
For the approaches involving nitrene insertion, see:
For reviews of synthetic electrochemistry, see:
For bioactive xanthene, see:
Corresponding Authors
Publication History
Received: 01 August 2023
Accepted after revision: 14 September 2023
Accepted Manuscript online:
14 September 2023
Article published online:
18 October 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References and Notes
- 1 Ertl P, Altmann E, McKenna JM. J. Med. Chem. 2020; 63: 8408
- 2a Montalbetti CA. G. N, Falque V. Tetrahedron 2005; 61: 10827
- 2b Ojeda-Porras A, Gamba-Sánchez D. J. Org. Chem. 2016; 81: 11548
- 2c Pattabiraman VR, Bode JW. Nature 2011; 480: 471
- 3a Wang H, Tang G, Li X. Angew. Chem. Int. Ed. 2015; 54: 13049
- 3b Tan PW, Mak AM, Sullivan MB, Dixon DJ, Seayad J. Angew. Chem. Int. Ed. 2017; 56: 16550
- 3c Antien K, Geraci A, Parmentier M, Baudoin O. Angew. Chem. Int. Ed. 2021; 60: 22948
- 4a Knecht T, Mondal S, Ye J.-H, Das M, Glorius F. Angew. Chem. Int. Ed. 2019; 58: 7117
- 4b Burman JS, Harris RJ, Farr CM. B, Bacsa J, Blakey SB. ACS Catal. 2019; 9: 5474
- 4c Lei H, Rovis T. J. Am. Chem. Soc. 2019; 141: 2268
- 4d Tang J.-J, Yu X, Wang Y, Yamamoto Y, Bao M. Angew. Chem. Int. Ed. 2021; 60: 16426
- 4e Bakhoda A, Jiang Q, Badiei YM, Bertke JA, Cundari TR, Warren TH. Angew. Chem. Int. Ed. 2019; 58: 3421
- 5a Breugst M, Tokuyasu T, Mayr H. J. Org. Chem. 2010; 75: 5250
- 5b Kütt A, Tshepelevitsh S, Saame J, Lõkov M, Kaljurand I, Selberg S, Leito I. Eur. J. Org. Chem. 2021; 1407
- 6a Francke R, Little RD. Chem. Soc. Rev. 2014; 43: 2492
- 6b Yan M, Kawamata Y, Baran PS. Chem. Rev. 2017; 117: 13230
- 6c Jiang Y, Xu K, Zeng C.-C. Chem. Rev. 2018; 118: 4485
- 6d Yoshida J.-i, Shimizu A, Hayashi R. Chem. Rev. 2018; 118: 4702
- 6e Moeller KD. Chem. Rev. 2018; 118: 4817
- 6f Waldvogel SR, Lips S, Selt M, Riehl B, Kampf CJ. Chem. Rev. 2018; 118: 6706
- 6g Yuan Y, Lei A. Acc. Chem. Res. 2019; 52: 3309
- 6h Xiong P, Xu H.-C. Acc. Chem. Res. 2019; 52: 3339
- 6i Jiao K.-J, Xing Y.-K, Yang Q.-L, Qiu H, Mei T.-S. Acc. Chem. Res. 2020; 53: 300
- 6j Gandeepan P, Finger LH, Meyer TH, Ackermann L. Chem. Soc. Rev. 2020; 49: 4254
- 6k Novaes LF. T, Liu J, Shen Y, Lu L, Meinhardt JM, Lin S. Chem. Soc. Rev. 2021; 50: 7941
- 6l Cheng X, Lei A, Mei T.-S, Xu H.-C, Xu K, Zeng C. CCS Chem. 2022; 4: 1120
- 7 Hu X, Zhang G, Nie L, Kong T, Lei A. Nat. Commun. 2019; 10: 5467
- 8 Hou Z.-W, Liu D.-J, Xiong P, Lai X.-L, Song J, Xu H.-C. Angew. Chem. Int. Ed. 2021; 60: 2943
- 9 Wang Y, Lin Z, Oliverira JC. A, Ackermann L. J. Org. Chem. 2021; 86: 15935
- 10 Li F, Liang Y, Zhan X, Zhang S, Li M.-B. Org. Chem. Front. 2022; 9: 5571
- 11a Zhang S, Li L, Zhang J, Zhang J, Xue M, Xu K. Chem. Sci. 2019; 10: 3181
- 11b Zhang S, Li L, Li J, Shi J, Xu K, Gao W, Zong L, Li G, Findlater M. Angew. Chem. Int. Ed. 2021; 60: 7275
- 11c Zhang S, Shi J, Li J, Li M.-B, Li G, Findlater M. CCS Chem. 2022; 4: 1938
- 11d Liang Y, Zhan X, Li F, Bi H, Fan W, Zhang S, Li M.-B. Chem. Catal. 2023; 3: 100582
- 11e Zhang S, Liang Y, Liu K, Zhan X, Fan W, Li M.-B, Findlater M. J. Am. Chem. Soc. 2023; 145: 14143
- 11f Zhang S, Findlater M. ACS Catal. 2023; 13: 8731
- 12 Colomer I, Chamberlain AE. R, Haughey MB, Donohoe TJ. Nat. Rev. Chem. 2017; 1: 0088
- 13 Murray PR. D, Cox JH, Chiappini ND, Roos CB, McLoughlin EA, Hejna BG, Nguyen ST, Ripberger HH, Ganley JM, Tsui E, Shin NY, Koronkiewicz B, Qiu G, Knowles RR. Chem. Rev. 2022; 122: 2017
- 14a Luo L, Jia B.-Z, Wei X.-Q, Xiao Z.-L, Wang H, Sun Y.-M, Shen Y.-D, Lei H.-T, Xu Z.-L. Sens. Actuators, B 2021; 332: 129561
- 14b Park I.-S, Seo HR, Kim K, Lee H, Shum D, Choi I, Kim J. Biochem. Biophys. Res. Commun. 2020; 527: 709
- 14c Watterson KR, Hansen SV. F, Hudson BD, Alvarez-Curto E, Raihan SZ, Azevedo CM. G, Martin G, Dunlop J, Yarwood SJ, Ulven T, Milligan G. Mol. Pharmacol. 2017; 91: 630
- 15 General Procedure for the Electrochemical Amidation (3a as an Example) An undivided cell was equipped with a magnet stirrer, platinum plate (1.5 × 1.5 cm2), and graphite rod (0.6 × 10 cm), as anode and cathode, respectively (the electrolysis setup is shown in Figure S1). Substrate benzamide (1a, 61 mg, 0.5 mmol), 9H-xanthene (2a, 137 mg, 0.75 mmol), and n-Bu4NClO4 (342 mg, 1 mmol) were added to the solvent MeCN/HFIP (9/1 mL). The resulting mixture was allowed to stir and electrolyze under constant current conditions (15 mA) at room temperature for 3 h. The reaction mixture was condensed with a rotary evaporator. The residue was purified by column chromatography (PE/EtOAc = 20/1 to10/1, V/V) on silica gel to afford the desired product 3a (149 mg) in 99% yield. N-(9H-Xanthen-9-yl)benzamide (3a) 149 mg, 99% yield; white solid, mp 227–228 °C. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.33 (t, J = 8.0 Hz, 2 H), 7.16–7.10 (m, 4 H), 6.78 (d, J = 12.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 166.5, 151.1, 134.0, 131.8, 129.7, 129.4, 128.6, 127.0, 123.7, 121.0, 116.7, 44.3.
- 16a Lin M.-Y, Xu K, Jiang Y.-Y, Liu Y.-G, Sun B.-G, Zeng C.-C. Adv. Synth. Catal. 2018; 360: 1665
- 16b Yang Y.-Z, Song R.-J, Li J.-H. Org. Lett. 2019; 21: 3228
- 16c Wei B, Qin J.-H, Yang Y.-Z, Xie Y.-X, Ouyang X.-H, Song R.-J. Org. Chem. Front. 2022; 9: 816
- 16d Chen X, Liu H, Gao H, Li P, Miao T, Li H. J. Org. Chem. 2022; 87: 1056
For the synthesis of amides, see:
For the approaches involving C(sp3)–H activation, see:
For the approaches involving nitrene insertion, see:
For reviews of synthetic electrochemistry, see:
For bioactive xanthene, see:
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