Electrochemical Synthesis of Quinolines

Abstract

This report outlines an intramolecular oxidative annulation process involving N-substituted o-amino phenylacetylene, performed under electrochemical conditions, which yields substituted quinoline in an undivided cell at room temperature. The reaction features mild conditions, requiring neither external oxidants nor metals, and achieves yields that range from good to excellent. Moreover, the synthetic potential of quinoline has been demonstrated resulting in the synthesis of substituted polycyclic isoindolinone and (aza-)isoindolinone compounds.

Aromatic aza-heterocyclic compounds represent one of the most important structural motifs that is omnipresent owing to their wide range of application in fields of pharmaceuticals, natural alkaloids, and organic materials.[1] [2] They have an important contribution towards the fundamental framework in medicinal chemistry.[3,4] Among various heterocyclic compounds, substituted quinoline represents one of the privileged classes of N-containing heterocycles due to its increase demand.[5] Functionalization of this moiety has allowed to develop new drugs to detect various pharmacological activities and are widely studied as fluorescent probe.[5] [6]

In addition to this, the acylated quinoline unit has various structural importance as it is widely present in biologically active molecule as well as natural product.[7] In particular, a class of molecules containing the 4-carbonyl quinoline moiety exhibits various biological activities such as antiplasmodial, antibacterial, antifungal, anti-inflammatory, and cytotoxic activity.[8] [9] [10] Owing to such important activities, the increasing demand towards the synthesis of such compound has garnered considerable attention employing milder and sustainable strategy.

Considerable efforts have been devoted towards the synthesis of the heterocyclic motif.[6] [11] [12] Such transformation has previously been reported by several groups. In 2012, Liang and coworkers developed a method towards the synthesis of 4-carbonyl-quinolines using copper in the presence of oxygen (Scheme [1a]).[13]

In 2017, Zhu and co-workers reported the synthesis of quinoline derivatives in copper-catalyzed conditions under visible light in the presence of oxygen atmosphere and TBHP oxidant (Scheme [1b]).[14] Also in 2019, Wang and coworkers reported the synthesis of 4-carbonyl quinolines using oxidant and additive under oxygen conditions (Scheme [1c]).[15] In 2023, Thongsornkleeb and group reported the synthesis of 2-substituted quinolines using Mn(OAc)₃ under oxidative annulation of 2-alkynylanilines and 1,3-ketoesters under acidic conditions (Scheme [1d]).[16]

In our approach, we have developed an intramolecular oxidative cyclization using an electrochemical method under metal- and oxidant-free conditions in an undivided cell at room temperature (Scheme [1e]).

There have been several approaches towards the synthesis but the rising demand for the novel and versatile methodology still persists through a readily available starting material. From the viewpoint of green and sustainable chemistry, electrosynthesis has emerged as an effective and straightforward approach.[17] Organic reactions promoted by electrosynthesis has attracted researchers owing to its milder, eco-friendly, and sustainable reach.[18] [19] It holds a great potential due to its recognition as an economically attractive method as it employs electrical energy to facilitate the redox reaction under metal-, oxidant-, and reductant-free conditions for new chemical bond construction.[20] Hence an increase in the influx of interests in electrosynthesis is observed nowadays.[21]

With our continuous interest in electropromoted radical reactions, we developed a straightforward construction of substituted quinoline derivatives at room temperature in an undivided cell under metal- and oxidant-free conditions. This methodology features sustainable chemistry and avoids the formation of undesired byproducts.

In order to investigate the feasibility of the approach discussed above, we chose N-substituted o-amino phenylacetylene as the model substrate towards the optimization of our reaction conditions (Table [1]). Gratifyingly, under standard reaction conditions which includes graphite electrode as both anode as well as cathode material with a constant current of 10 mA in the presence of KI (1 equiv) as an electrolyte and DMF–H₂O as a solvent, 1a gave substituted 2a in 69% yield.[22] To begin with, firstly different electrode materials were scrutinized that showed an effect towards the reaction efficiency. Reactions using other electrodes such as C/Pt, C/Ni showed decrease in yields (31% and 37%, respectively, entries 2 and 3). On using a Pt/C electrode, no intended product was observed (entry 4) while on a Pt/Pt electrode, yield was observed to be 43% (entry 5). After looking upon the effect of electrodes, the effect of electrolyte was also taken into consideration and was observed to be playing an important key role towards the reaction efficiency. With electrolytes such as NaI, KI (0.5 equiv), and TBAI a decrease in yield was observed (67%, 55%, and 60%, respectively, entries 6–8) while with other electrolytes such as NaBr, tetrabutylammonium tetrafluoroborate, LiClO₄, tetrabutylammonium hexafluorophosphate, and NaCl no intended product was observed (entries 9–13).

Variation in current flow was also evaluated as it was observed that it also created an impact on the yield on the product. With change in current from 5 mA, 7 mA to 15 mA afforded the desired product in 60%, 65%, and 58% yield, respectively (entries 14–16). In order to improve the yield, other solvents such as DMSO and MeCN–H₂O were tested, but these also did not improve the yield of the reaction (36% and 29%, respectively, entries 17 ad 18). At the end, the reaction was carried out in the absence of electricity but no required product 2a was formed indicating that electricity is important for this reaction to occur.

Table 1 Optimization of Reaction Conditions^a

Entry	Deviation from standard conditions	Yield (%)b
1	none	69
2	C (+) and Pt (–)	31
3	C (+) and Ni (–)	37
4	Pt (+) and C (–)	ND
5	Pt (+) and Pt (–)	43
6	NaI	67
7	KI (0.5 equiv)	55
8	TBAI	60
9	NaBr	ND
10	Bu4NBF4	ND
11	LiClO4	ND
12	Bu4NPF6	ND
13	NaCl	ND
14	5 mA	60
15	7 mA	65
16	15 mA	58
17	DMSO	36
18	MeCN–H2O	29
19	no electricity	ND

^a Reaction conditions: 1a (0.1 mmol, 1 equiv), KI (0.1 mmol, 1 equiv), 5 ml DMF–H₂O (99:1), rt, undivided cell.

^b Isolated yields based on 1a. ND = not detected.

After having the optimized reaction conditions in hand, we diverted our attention towards the generality of this electrochemical approach by investigating the substrate scope towards the synthesis of substituted quinolines (Scheme [2]). As discussed in Scheme [2, a] wide range of N-substituted o-amino phenylacetylenes were evaluated in order to determine the scope of this methodology. A variety of substituted aromatic enamines were used to afford substituted quinolines from good to excellent yields (69–93% yield, Scheme [2]). Reactants bearing electron-donating as well as electron-withdrawing groups are well tolerated under these electrochemical reaction conditions. Molecules containing methyl and phenyl groups afforded the products in moderate yields (2a = 69%, 2b = 79%). Electron-withdrawing substituents such as F, Cl, and Br could also be well tolerated (2c–e, 84–88%). With an electron-donating group present on the aromatic ring, the yields vary from moderate to good (2f–l, 76–89%) while the electron-withdrawing groups present on the aromatic ring resulted in yields from good to excellent (2m–u, 88–93%).

Substrate containing heteroatom (2v, 2w) are also well tolerated for this transformation affording the product in 90% and 79% yield, respectively. Unfortunately, in the presence of an isopropyl group, only trace amount of the product (2x) was formed. After this, we also paid our attention towards the substrate scope for intramolecular oxidative cyclization with 2y and 2z in 69% and 70% yield, respectively.

In order to further demonstrate the synthetic utility of this strategy, extended transformations were carried out for different substituted quinolines with hydrazine hydrate and hydroxylamine hydrochloride affording substituted polycyclic moieties with yields varying from moderate to good (70–79%, Scheme [3]).[23] [24] [25] In the case of reaction with hydrazine hydrate with a ketone group ortho to the ester group based on the literature, it was anticipated to obtain a phthalazinone derivative[26] but instead we got an isoindolinone derivative. Similarly, with hydroxylamine hydrochloride, (aza-)isoindolinone is obtained.[27] [28] Crystal structures of 2aa and 2ab have been taken (Scheme [3]) for the structural proof.

To evaluate the scalability of the reaction, we carried out the reaction with 0.5 g of the starting material 1a under the standard reaction conditions for 8 h, furnishing the corresponding quinoline in 72% yield indicating the practicality of the electrochemical reaction for gram-scale synthesis.

In order to shed some light on mechanistic insight, whether the reaction is occurring via radical mechanism or not some control experiments were conducted using 2 equiv of TEMPO or BHT (Scheme [4]). In both the cases no intended product was formed indicating that the reaction solely goes through the radical pathway.

On the basis of the above experimental results and previous literature reports,[15] [29] a plausible reaction mechanism is proposed (Scheme [5]). Initially, iodonium cation (I⁺) is formed by double oxidation at the anode. After this, 1a reacts with I⁺ to form the N-iodo intermediate A. Homolysis of this bond takes place leading to the generation of radical-forming intermediate B. This radical is stabilized by the presence of an electron-withdrawing group (–COOEt) forming C.

This radical then attacks the alkyne in an intramolecular way forming intermediate D that further undergoes oxidation forming E. The resulting intermediate E is captured by H₂O forming F that rearranges to form substituted quinoline 2a. Meanwhile, the generated iodine radical can be oxidized by the anode to regenerate the hyperiodide intermediate. Here KI does not only play the role of an electrolyte but also participates in an oxidative cyclization.

In conclusion, we have demonstrated the concept of a direct intramolecular oxidative cyclization for the synthesis of substituted quinolines via electrochemically generated N-center radical followed by further transformation affording polycyclic compounds. Notably, this current method offers a simple, efficient, and convenient way towards the synthesis of quinoline derivatives under milder conditions in an undivided cell at room temperature avoiding the usage of metals as well as toxic oxidants.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

M.F. expresses gratitude to MOE for offering a fellowship and the Indian Institute of Technology Hyderabad for providing facilities.

• References and Notes

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• 17 Möhle S, Zirbes M, Rodrigo E, Gieshoff T, Wiebe A, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 6018
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• 22 General Procedure for Electrochemical Quinoline Synthesis Into the undivided cell were taken N-substituted o-amino phenylacetylene 1a, KI (1 equiv), 5 mL of DMF–H₂O (99:1). The mixture was stirred under constant current (10 mA) with a C anode and a C cathode in an undivided cell at room temperature for 6 h. After the completion of reaction as monitored on TLC, the reaction was quenched with cold water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as solvent as eluent.Compound 2: 84% yield, yellow solid, mp 124–126 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 8.6 Hz, 1 H), 7.87–7.81 (m, 3 H), 7.75 (t, J = 1.7 Hz, 1 H), 7.64 (ddd, J = 8.7, 6.0, 1.1 Hz, 2 H), 7.57–7.38 (m, 6 H), 3.91 (q, J = 7.1 Hz, 2 H), 0.86 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 195.46, 166.74, 155.93, 148.13, 147.48, 141.97, 136.58, 134.56, 134.52, 131.96, 130.21, 129.75, 129.16, 129.06, 128.94, 128.40, 126.95, 125.96, 123.36, 123.27, 62.16, 13.35. IR (neat): 3062, 2982, 1722, 1672, 1581 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₅H₁₈ClNO₃: 416.1048; found: 416.1060.
• 23 Mitobe K, Kawasaki-Takasuka T, Agou T, Kubota T, Yamazaki T. J. Fluorine Chem. 2019; 218: 36
  CrossrefSearch in Google Scholar
• 24 Chollet A, Stigliani J, Pasca MR, Mori G, Lherbet C, Constant P, Quémard A, Bernadou J, Pratviel G, Bernardes-Génisson V. Chem. Biol. Drug Des. 2016; 88: 740
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• 25 Viña D, del Olmo E, Lopez-Pérez JL, San Feliciano A. Tetrahedron 2009; 65: 1574
  CrossrefSearch in Google Scholar
• 26 Aitha A, Payili N, Rekula SR, Yennam S, Anireddy JS. ChemistrySelect 2017; 2: 7246
  CrossrefSearch in Google Scholar
• 27 General Procedure for the Synthesis of IsoindolinoneInto the RB were taken substituted quinoline 2aa, 2ad, 2ae, or 2af and hydrazine hydrate (5 equiv). To this EtOH was added and kept under reflux. The reaction was stirred for 12–24 h. After completion of the reaction as monitored on TLC, it was quenched with water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as eluent. Compound 2aa: 71% yield, yellow solid, mp 252–254 °C. ¹H NMR (600 MHz, DMSO): δ = 8.15 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J = 6.5, 2.9 Hz, 2 H), 7.91–7.81 (m, 2 H), 7.60–7.56 (m, 1 H), 7.51 (ddd, J = 15.4, 8.3, 3.6 Hz, 5 H), 7.18 (t, J = 8.9 Hz, 2 H), 4.38 (s, 2 H). ¹³C NMR (150 MHz, DMSO): δ = 163.66, 162.71, 161.09, 160.45, 155.02, 154.93, 149.02, 141.50, 137.42, 134.99, 131.66, 130.40, 129.17, 128.68, 127.63, 127.45, 124.46, 120.27, 120.03, 115.36, 115.21, 88.41. IR (neat): 3399, 3060, 2920, 1720, 1656, 1570 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₃H₁₆FN₃O₂: 386.1300; found: 386.1271.
• 28 General Procedure for the Synthesis of (Aza-)Isoindolinone Into the RB were taken substituted quinoline 2ab, 2ac, or 2ag and hydroxylamine hydrochloride (10 equiv). To this, Et₃N (10 equiv) was added followed by addition of ethanol under reflux conditions. The reaction was stirred for 12 h. After completion of the reaction as monitored on TLC, it was quenched with water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as eluent.Compound 2ab: 79% yield, white solid, mp 210–212 °C. ¹H NMR (400 MHz, DMSO): δ = 9.98 (s, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.90 (dt, J = 15.0, 10.4 Hz, 5 H), 7.63–7.41 (m, 8 H). ¹³C NMR (100 MHz, DMSO): δ = 161.54, 154.81, 153.48, 149.08, 137.29, 137.23, 133.14, 131.88, 131.47, 130.37, 130.02, 129.28, 128.78, 128.54, 128.47, 127.87, 127.57, 124.31, 120.09, 119.37, 88.11. IR (neat): 3450, 3063, 2922, 1705, 1618, 1564 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₃H₁₅ClN₂O₃: 403.0844; found: 403.0827.
• 29 Tang S, Gao X, Lei A. Chem. Commun. 2017; 53: 3354
  CrossrefPubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 31 July 2024

Accepted after revision: 15 August 2024

Accepted Manuscript online:
15 August 2024

Article published online:
25 September 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1 Martins P, Jesus J, Santos S, Raposo LR, Roma-Rodrigues C, Baptista PV, Fernandes AR. Molecules 2015; 20: 16852
  CrossrefPubMedSearch in Google Scholar
• 2 Michael JP. Nat. Prod. Rep. 2008; 25: 166
  CrossrefPubMedSearch in Google Scholar
• 3 Rajendran S, Sivalingam K, Karnam Jayarampillai RP, Wang W.-L, Salas Cristian O. Chem. Biol. Drug Des. 2022; 100: 1042
  CrossrefPubMedSearch in Google Scholar
• 4 Balderas-Renteria I, Gonzalez-Barranco P, Garcia A, Banik BK, Rivera G. Curr. Med. Chem. 2012; 19: 4377
  CrossrefPubMedSearch in Google Scholar
• 5 Lewinska G, Sanetra J, Marszalek KW. J. Mater Sci.: Mater. Electron. 2021; 32: 18451
  PubMedSearch in Google Scholar
• 6 Ajani OO, Iyaye KT, Ademosun OT. RSC Adv. 2022; 12: 18594
  CrossrefPubMedSearch in Google Scholar
• 7 Zhao Y.-Q, Li X, Guo H.-Y, Shen Q.-K, Quan Z.-S, Luan T. Molecules 2023; 28: 6478
  CrossrefPubMedSearch in Google Scholar
• 8 El-Feky SA. H, Abd El-Samii ZK, Osman NA, Lashine J, Kamel MA, Thabet HK. Bioorg. Chem. 2015; 58: 104
  CrossrefPubMedSearch in Google Scholar
• 9 Soares RR, da Silva JM. F, Carlos BC, da Fonseca CC, de Souza LS. A, Lopes FV, de Paula Dias RM, Moreira PO. L, Abramo C, Viana GH. R, de Pila Varotti F, da Silva AD, Scopel KK. G. Bioorg. Med. Chem. Lett. 2015; 25: 2308
  CrossrefPubMedSearch in Google Scholar
• 10 Baragaña B, Norcross NR, Wilson C, Porzelle A, Hallyburton I, Grimaldi R, Osuna-Cabello M, Norval S, Riley J, Stojanovski L, Simeons FR. C, Wyatt PG, Delves MJ, Meister S, Duffy S, Avery VM, Winzeler EA, Sinden RE, Wittlin S, Frearson JA, Gray DW, Fairlamb AH, Waterson D, Campbell SF, Willis P, Read KD, Gilbert IH. J. Med. Chem. 2016; 59: 9672
  CrossrefPubMedSearch in Google Scholar
• 11 Li L.-H, Niu Z.-J, Liang Y.-M. Chem. Asian J. 2020; 15: 231
  CrossrefPubMedSearch in Google Scholar
• 12 Kumar A, Dhameliya TM, Sharma K, Patel KA, Hirani RV. ChemistrySelect 2022; 7: e202201059
  CrossrefSearch in Google Scholar
• 13 Xia X.-F, Zhang L.-L, Song X.-R, Liu X.-Y, Liang Y.-M. Org. Lett. 2012; 14: 2480
  CrossrefPubMedSearch in Google Scholar
• 14 Xia X.-F, Zhang G.-W, Wang D, Zhu S.-L. J. Org. Chem. 2017; 82: 8455
  CrossrefPubMedSearch in Google Scholar
• 15 Xia X, He W, Wang D. Adv. Synth. Catal. 2019; 361: 2959
  CrossrefSearch in Google Scholar
• 16 Punjajom K, Ruengsangtongkul S, Tummatorn J, Paiboonsombat P, Ruchirawat S, Thongsornkleeb C. J. Org. Chem. 2023; 88: 6736
  CrossrefPubMedSearch in Google Scholar
• 17 Möhle S, Zirbes M, Rodrigo E, Gieshoff T, Wiebe A, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 6018
  CrossrefPubMedSearch in Google Scholar
• 18 Jiang Y, Xu K, Zeng C. Chem. Rev. 2018; 118: 4485
  CrossrefPubMedSearch in Google Scholar
• 19 Wiebe A, Gieshoff T, Möhle S, Rodrigo E, Zirbes M, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 5594
  CrossrefPubMedSearch in Google Scholar
• 20 Yan M, Kawamata Y, Baran PS. Chem. Rev. 2017; 21: 13230
  CrossrefPubMedSearch in Google Scholar
• 21 Little RD. J. Org. Chem. 2020; 85: 13375
  CrossrefPubMedSearch in Google Scholar
• 22 General Procedure for Electrochemical Quinoline Synthesis Into the undivided cell were taken N-substituted o-amino phenylacetylene 1a, KI (1 equiv), 5 mL of DMF–H₂O (99:1). The mixture was stirred under constant current (10 mA) with a C anode and a C cathode in an undivided cell at room temperature for 6 h. After the completion of reaction as monitored on TLC, the reaction was quenched with cold water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as solvent as eluent.Compound 2: 84% yield, yellow solid, mp 124–126 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 8.6 Hz, 1 H), 7.87–7.81 (m, 3 H), 7.75 (t, J = 1.7 Hz, 1 H), 7.64 (ddd, J = 8.7, 6.0, 1.1 Hz, 2 H), 7.57–7.38 (m, 6 H), 3.91 (q, J = 7.1 Hz, 2 H), 0.86 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 195.46, 166.74, 155.93, 148.13, 147.48, 141.97, 136.58, 134.56, 134.52, 131.96, 130.21, 129.75, 129.16, 129.06, 128.94, 128.40, 126.95, 125.96, 123.36, 123.27, 62.16, 13.35. IR (neat): 3062, 2982, 1722, 1672, 1581 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₅H₁₈ClNO₃: 416.1048; found: 416.1060.
• 23 Mitobe K, Kawasaki-Takasuka T, Agou T, Kubota T, Yamazaki T. J. Fluorine Chem. 2019; 218: 36
  CrossrefSearch in Google Scholar
• 24 Chollet A, Stigliani J, Pasca MR, Mori G, Lherbet C, Constant P, Quémard A, Bernadou J, Pratviel G, Bernardes-Génisson V. Chem. Biol. Drug Des. 2016; 88: 740
  CrossrefPubMedSearch in Google Scholar
• 25 Viña D, del Olmo E, Lopez-Pérez JL, San Feliciano A. Tetrahedron 2009; 65: 1574
  CrossrefSearch in Google Scholar
• 26 Aitha A, Payili N, Rekula SR, Yennam S, Anireddy JS. ChemistrySelect 2017; 2: 7246
  CrossrefSearch in Google Scholar
• 27 General Procedure for the Synthesis of IsoindolinoneInto the RB were taken substituted quinoline 2aa, 2ad, 2ae, or 2af and hydrazine hydrate (5 equiv). To this EtOH was added and kept under reflux. The reaction was stirred for 12–24 h. After completion of the reaction as monitored on TLC, it was quenched with water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as eluent. Compound 2aa: 71% yield, yellow solid, mp 252–254 °C. ¹H NMR (600 MHz, DMSO): δ = 8.15 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J = 6.5, 2.9 Hz, 2 H), 7.91–7.81 (m, 2 H), 7.60–7.56 (m, 1 H), 7.51 (ddd, J = 15.4, 8.3, 3.6 Hz, 5 H), 7.18 (t, J = 8.9 Hz, 2 H), 4.38 (s, 2 H). ¹³C NMR (150 MHz, DMSO): δ = 163.66, 162.71, 161.09, 160.45, 155.02, 154.93, 149.02, 141.50, 137.42, 134.99, 131.66, 130.40, 129.17, 128.68, 127.63, 127.45, 124.46, 120.27, 120.03, 115.36, 115.21, 88.41. IR (neat): 3399, 3060, 2920, 1720, 1656, 1570 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₃H₁₆FN₃O₂: 386.1300; found: 386.1271.
• 28 General Procedure for the Synthesis of (Aza-)Isoindolinone Into the RB were taken substituted quinoline 2ab, 2ac, or 2ag and hydroxylamine hydrochloride (10 equiv). To this, Et₃N (10 equiv) was added followed by addition of ethanol under reflux conditions. The reaction was stirred for 12 h. After completion of the reaction as monitored on TLC, it was quenched with water and extracted with EtOAc. The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using PE and EtOAc as eluent.Compound 2ab: 79% yield, white solid, mp 210–212 °C. ¹H NMR (400 MHz, DMSO): δ = 9.98 (s, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.90 (dt, J = 15.0, 10.4 Hz, 5 H), 7.63–7.41 (m, 8 H). ¹³C NMR (100 MHz, DMSO): δ = 161.54, 154.81, 153.48, 149.08, 137.29, 137.23, 133.14, 131.88, 131.47, 130.37, 130.02, 129.28, 128.78, 128.54, 128.47, 127.87, 127.57, 124.31, 120.09, 119.37, 88.11. IR (neat): 3450, 3063, 2922, 1705, 1618, 1564 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₃H₁₅ClN₂O₃: 403.0844; found: 403.0827.
• 29 Tang S, Gao X, Lei A. Chem. Commun. 2017; 53: 3354
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material