A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor

An iodine-mediated one-pot synthesis of pyrrolo/indolo [1,2-a]quinoxalines and quinazolin-4-one via utilizing epoxides as alkyl precursors under metal-free conditions has been described. Both 1-(2-aminophenyl)-pyrrole and 2-aminobenzamide could be applied to this protocol. A total of 33 desired products were obtained with moderate to good yields. This methodology was suitable for wide-scale preparation and the obtained products could be further modified into promising pharmaceutically active reagents.

On the other hand, the synthesis of quinazolin-4-ones has also attracted much attention from chemists.In traditional synthesis methods, quinazolinone was obtained by an acid/base facilitated condensation reaction of esters, aldehydes or carboxylic acids with amides by means of some homogeneous catalytic systems and expensive raw materials [26][27][28][29][30].In 2018, Wang [31] reported a novel synthetic strategy for the synthesis of quinazolinones from olefins, carbon monoxide and amines over a heterogeneous Ru cluster/cerium oxide catalyst under acid/ base-free and oxidant-free conditions with H 2 O as the only by-product.In 2019, Zheng [32] developed a visible light-mediated intramolecular C-N cross-coupling reaction to synthesize a series of fused N-substituted polycyclic quinazolinone derivatives under mild reaction conditions via long-lived photoactive photoisomer complexes.In 2023, Fan [33] reported a method for the synthesis of 5H-phthalazino [1,2-b]quinazolin-8(6H)-one derivatives via a t-BuOK-catalyzed intramolecular hydrogen amination reaction of quinazolinones.Also in 2023, Zhu [34] reported a cobalt homeostatic catalysis system for the synthesis of quinazolinones from the coupling of enaminones and oxadiazolones.On the other hand, the synthesis of quinazolin-4-ones has also attracted much attention from chemists.In traditional synthesis methods, quinazolinone was obtained by an acid/base facilitated condensation reaction of esters, aldehydes or carboxylic acids with On the other hand, the synthesis of quinazolin-4-ones has also attracted much attention from chemists.In traditional synthesis methods, quinazolinone was obtained by an acid/base facilitated condensation reaction of esters, aldehydes or carboxylic acids with Epoxides are well-known electrophiles that can react with various nucleophiles.They are readily available from olefins or ketones and are usually air-stable and easily stored.The Meinwald rearrangement [35] is an acid-catalyzed rearrangement reaction in which epoxides form aldehydes or ketones via ring-opening followed by a 1,2-shift of the hydride or alkyl group.Aldehydes, especially enolizable aliphatic aldehydes, are susceptible to self-condensation which makes them unstable and hard to store in pure form.Therefore, it is more desirable to utilize epoxides to replace the original aldehydes.In 2023, Moran [36] synthesized a series of functionalized isochromans using epoxides as an alternative to aldehydes.In 2021, Feng [37] reported the first catalytic asymmetric multi-insertion olefin addition reaction triggered by an epoxy-vinyl Meinwald rearrangement using a chiral N,Ndioxide/Sc III complex catalyst.Encouraged by these discoveries and to further explore the applications of epoxides [38][39][40][41][42], herein, we developed a method for synthesizing pyrrolo [1,2-a]quinoxalines and quinazolin-4-ones via a tandem Meinwald rearrangement and cyclization in one pot.

Large Scale Reaction and Synthetic Applications
Subsequently, several synthetic applications were performed to demonstrate the practicality of this methodology (Scheme 2).Under standard conditions, the gram-scale synthesis of 3a and 5a was carried out.Pleasantly, the desired product was successfully obtained in 60% and 62% yields, respectively, making the procedure suitable for a broad-scale preparation.Of these, 5a can be used as a cardiovascular agent [14].In addition, the 2benzylquinazolin-4(3H)-one (5a) obtained in this protocol could be further modified into an active antiurease reagent [43], molecular antagonists of CCR 4 [44] and a photoluminescent probe [45].The photoluminescent probe could be used for the label-free, highly selective and sensitive detection of Fe 3+ and Ag + metal ions.

Mechanism Investigation
To shed light on the mechanism of the reaction, several control experiments were performed (Scheme 3).When the radical scavengers 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO, 3.0 equiv.)and 2,6-di-tert-butyl-4-methylphenol (BHT, 3.0 equiv.)were added to the reaction system under standard conditions, the desired product was obtained in 65% and 68% yields (Scheme 3a), respectively.This indicated that the conversion was a non-radical process.When the reaction was carried out without the addition of I 2 , the yield exhibited a significant decrease (27%).When the reaction system was performed without the addition of TsOH, the target product was obtained with a 50% yield; we presumed that it is the I 2, as a Lewis acid, that plays a role in the conversion process (Table 1, entries 6-7).To investigate the reaction mechanism in more depth, we used 2-phenylacetaldehyde to react with 1a under standard conditions to obtain the target product in 65% yield (Scheme 3b).This indicated that 2-phenylacetaldehyde may be a key intermediate in the reaction.In the absence of I 2 , the yield decreased significantly, indicating that iodine plays a key role in the subsequent cyclization reaction.Under standard conditions, aniline and 1-(2-aminophenyl)pyrrole were reacted with styrene oxide (2a), respectively, and the intermediate imide was detected with HRMS (Scheme 3c,d).
Based on the aforementioned control experiments and related literature studies, a plausible mechanism of this reaction is described in Scheme 4. Initially, in the presence of TsOH, styrene oxide (2a) underwent a Meinwald rearrangement to afford 2-phenylacetaldehyde.   a Reaction conditions: 1a (0.5 mmol, 1 equiv.),2a (1.0 mmol, 2 equiv.),I2 (0.5 mmol, 1 equiv.)and acid in solvent (1.0 mL) were stirred in a sealed tube and allowed to react for 4 h.b Isolated yield.c Without I2.
Inspired by the experimental results in Table 2, we then turned our focus to the synthesis of quinazolin-4-ones.We attempted to react 2-aminobenzamide (4a) with styrene oxide (2a) under optimal conditions and successfully obtained 2-benzylquinazolin-4(3H)one (5a) in 70% yield (Table 3).Whether the R3 group of 2-aminobenzamide was EDG or EWG participated successfully in the reaction with yields ranging from 58% to 74% (5a-5j).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could 3q, 38% 3r, 35% 3s, 40% 3t' 3t, 50% a 1 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.),I 2 (0.5 mmol, 1 equiv.)and acid (0.5 mmol, 1 equiv.) in solvent (1.0 mL) were stirred in a sealed tube, and allowed to react for 4 h.b Isolated yield.5j).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.
).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.
).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.5j).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.
).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.
).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.
).Whether the R3 group of the 2-aminobenzamide was an EDG or EWG and could smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.smoothly participate in this reaction, were demonstrated with yields ranging from 58% to 74% (5a-5j).The reaction also performed well when styrene oxide (2a) was attached to EWGs, such as chloro and bromo (5k-5l).When we used 3,4-epoxy-1-butene to react with 4a, the expected product quinazolinone 5m' suffered an easy double-bond migration to give the conjugated product 5m.Unfortunately, we did not obtain the desired products 5n and 5o when the R4 group was replaced with an alkyl or aryl group.a 4 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.),I 2 (0.5 mmol, 1 equiv.)and acid (0.5 mmol, 1 equiv.) in solvent (1.0 mL) were stirred in a sealed tube and allowed to react for 4 h.b Isolated yield.

Large Scale Reaction and Synthetic Applications
Subsequently, several synthetic applications were performed to demonstrate the practicality of this methodology (Scheme 2).Under standard conditions, the gram-scale synthesis of 3a and 5a was carried out.Pleasantly, the desired product was successfully obtained in 60% and 62% yields, respectively, making the procedure suitable for a broadscale preparation.Of these, 5a can be used as a cardiovascular agent [14].In addition, the 2-benzylquinazolin-4(3H)-one (5a) obtained in this protocol could be further modified into an active antiurease reagent [43], molecular antagonists of CCR4 [44] and a photoluminescent probe [45].The photoluminescent probe could be used for the label-free, highly selective and sensitive detection of Fe 3+ and Ag + metal ions.
Scheme 2. Large-scale reaction and synthetic applications.

Mechanism Investigation
To shed light on the mechanism of the reaction, several control experiments were performed (Scheme 3).When the radical scavengers 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO, 3.0 equiv.)and 2,6-di-tert-butyl-4-methylphenol (BHT, 3.0 equiv.)were added to the reaction system under standard conditions, the desired product was ob-Scheme 2. Large-scale reaction and synthetic applications.entries 6-7).To investigate the reaction mechanism in more depth, we used 2-phenylacetaldehyde to react with 1a under standard conditions to obtain the target product in 65% yield (Scheme 3b).This indicated that 2-phenylacetaldehyde may be a key intermediate in the reaction.In the absence of I2, the yield decreased significantly, indicating that iodine plays a key role in the subsequent cyclization reaction.Under standard conditions, aniline and 1-(2-aminophenyl)-pyrrole were reacted with styrene oxide (2a), respectively, and the intermediate imide was detected with HRMS (Scheme 3c,d).

Scheme 3. Control experiments (a-d).
Based on the aforementioned control experiments and related literature studies, a plausible mechanism of this reaction is described in Scheme 4. Initially, in the presence of TsOH, styrene oxide (2a) underwent a Meinwald rearrangement to afford 2-phenylacetaldehyde.The 2-phenylacetaldehyde reacted with 1-(2-aminophenyl)-pyrrole (1a) accompanied by the elimination of H2O to generate the intermediate imine I. Afterwards, intramolecular cyclization was accomplished with the assistance of molecular iodine to afford the dihydropyrrolo[1,2-a]quinoxaline II, which was ultimately aromatized to afford the target product 3a.

General Information
2-(1H-pyrrol-1-yl)anilines/2-(1H-indolo-1-yl)anilines and 2-aminobenzamides were obtained based on procedures reported in the literature [46,47].All other reagents were market available and used with no further purification.We monitored the reactions using thin layer chromatography (TLC).Reactions requiring heat were performed in an oil bath. 1 H NMR (400 MHz or 500 MHz) and 13 C NMR (100 MHz or 125 MHz) spectra were recorded on a Bruker spectrometer, with CDCl3 or DMSO-d6 as a solvent and tetramethylsilane (TMS) as an internal standard (Supplementary Materials).HRMS spectra (ESI) were acquired on a Bruker impact II spectrograph in positive-ion mode with an ESI ion source.

General Information
2-(1H-pyrrol-1-yl)anilines/2-(1H-indolo-1-yl)anilines and 2-aminobenzamides were obtained based on procedures reported in the literature [46,47].All other reagents were market available and used with no further purification.We monitored the reactions using thin layer chromatography (TLC).Reactions requiring heat were performed in an oil bath. 1 H NMR (400 MHz or 500 MHz) and 13 C NMR (100 MHz or 125 MHz) spectra were recorded on a Bruker spectrometer, with CDCl 3 or DMSO-d 6 as a solvent and tetramethylsilane (TMS) as an internal standard (Supplementary Materials).HRMS spectra (ESI) were acquired on a Bruker impact II spectrograph in positive-ion mode with an ESI ion source.

General Experimental Procedures for 2-(1H-Pyrrol-1-yl) Anilines (1)
The substituted 2-nitroaniline (2.7626 g, 20 mmol, 1 equiv.)and 2, 5dimethoxytetrahydrofuran (2.9075 g, 22 mmol, 1.1 equiv.)were mixed in HOAc (30 mL) and stirred vigorously under reflux conditions for 2−3 h.To neutralize the reaction mixture, Na 2 CO 3 aqueous solution was added and extracted three times with EtOAc.The organic layer was then dried with anhydrous Na 2 SO 4 and the residue was obtained after vacuum evaporation.Iron powder (4.4680 g, 80 mmol, 5 equiv.)and NH 4 Cl (1.0698 g, 20 mmol, 1 equiv.)were added to the residue in water (40 mL) and refluxed for 4-9 h.When the reaction was complete, the mixture was extracted three times with EtOAc.The organic layer was then dried with anhydrous Na 2 SO 4 , and the residue was obtained after vacuum evaporation.The residue was subsequently purified by silica gel chromatography to yield the desirable compounds.

General Experimental Procedures for 2-(1H-Indolo-1-yl)anilines (1)
The substituted fluoro-2-nitrobenzene (2.8220 g, 20 mmol, 1 equiv.),indole (2.3430 g, 20 mmol, 1 equiv.)and NaOH (0.8000 g, 20 mmol, 1 equiv.)were mixed in DMSO (30 mL) and stirred at room temperature for 4 h.The reaction mixture was extracted with EtOAc (3 × 30 mL).The organic layer was then dried with anhydrous Na 2 SO 4 and a solid was obtained after vacuum evaporation.Iron powder (5.6850 g, 100 mmol, 5 equiv.)and NH 4 Cl (1.0700 g, 20 mmol, 1 equiv.)were added to the solvent and refluxed for 5−9 h.After cooling, the reaction mixture was extracted three times with EtOAc and brine solution and subsequently dried with anhydrous Na 2 SO 4 .After filtration, a vacuum was used to remove the solvent.The resulting solid was then purified by silica gel column chromatography to obtain the desired compound.

General Experimental Procedures for Compounds 3a-3t and 5a-5m
Various substituted amines (0.5 mmol, 1 equiv.),epoxides (1.0 mmol, 2 equiv.),iodine (0.1269 g, 0.5 mmol, 1 equiv.)and TsOH (0.0861 g, 0.5 mmol, 1 equiv.)were added to CH 3 CN (1mL) in a sealed tube.The reaction mixture was stirred vigorously at 120 • C for 4 h.After completion of the reaction, monitored by TLC, the reaction mixture was neutralized with Na 2 S 2 O 3 and extracted three times with EtOAc and H 2 O, followed by drying with anhydrous Na 2 SO 4 .The product was purified by silica gel column chromatography to give the desired compounds 3a-3t and 5a-5m.

Conclusions
To conclude, we disclosed an iodine-mediated one-pot procedure for the synthesis of pyrrolo/indolo[1,2-a]quinoxalines and quinazolin-4-ones under metal-free conditions.This methodology tandems the Meinwald rearrangement and annulation process.A series of Nheterocycles were obtained with medium to good yields.The protocol has a broad substrate scope, has a simple work-up and was suitable for wide-scale preparation.Furthermore, the obtained products could be further modified to afford promising pharmaceutical reagents.This study injects new vitality into the methodology for the synthesis of N-heterocycles.Related research is still in progress in our laboratory.
The 2-phenylacetaldehyde reacted with 1-(2-aminophenyl)-pyrrole (1a) accompanied by the elimination of H 2 O to generate the intermediate imine I. Afterwards, intramolecular cyclization was accomplished with the assistance of molecular iodine to afford the dihydropyrrolo[1,2-a]quinoxaline II, which was ultimately aromatized to afford the target product 3a.