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Article

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

by
Xueyan Lv
1,
Lili Lv
2,
Shichen Li
1,
Chengcheng Ding
1,
Bingchuan Yang
3,* and
Chen Ma
1,*
1
Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
2
China Petroleum Planning and Engineering Institute, Dongying 257237, China
3
College of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250013, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(21), 7391; https://doi.org/10.3390/molecules28217391
Submission received: 29 September 2023 / Revised: 24 October 2023 / Accepted: 25 October 2023 / Published: 2 November 2023
(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications)
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Abstract

:
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.

Graphical Abstract

1. Introduction

N-heterocycles are inseparable from our life for use as drug molecules, functional materials and dyes [1,2,3]. Pyrrolo [1,2-a]quinoxalines and quinazolin-4-ones are two essential heterocyclic skeletons with outstanding biological properties for antimalarial, anticancer, anti-HIV, antibacterial, etc [4,5,6,7,8,9,10,11,12,13,14]. As shown in Figure 1, compound I exhibits excellent activity towards the 5-HT3 receptor, and compounds II and III have anticancer and antileishmanial properties, respectively. Glycosminine (Figure 1, IV) and alkaloid bouchardatine (Figure 1, V) are present in natural products. Compound VI has anticonvulsant activity. Given their excellent applications, especially in medicinal chemistry, their efficient and green synthesis has been a long-pursued research topic in the field of organic synthetic chemistry. In 1966, Cheeseman and Tuck [15] first synthesized pyrrolo [1,2-a]quinoxalines using 1-(2-aminophenyl)-pyrrole as the starting material with aqueous formic acid under reflux conditions. Since then, a number of groups have made tremendous efforts to construct these compounds [16,17,18,19,20,21,22,23,24,25]. In 2022, Ma [16] reported a Cu(II)-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines using N,N-dimethylethanolamine (DMEA) as a C1 synthon. In addition, the method of Ma’s group was also applicable to the synthesis of quinazolin-4-one and benzo[4,5]imidazoquinazoline. During the preparation of our manuscript, by means of an I2-DMSO synergistic system, Lin [17] reported a method for the synthesis of acyl-substituted pyrrolo[1,2-a]quinolines using epoxides as acyl precursors. As part of our research interest in the green synthesis of nitrogen-containing heterocycles under metal-free conditions, PEG-400 [18], DMF [19] and DMSO [20] as carbon synthons have been reported (Scheme 1).
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 H2O 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.
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,N′-dioxide/ScIII 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.

2. Results and Discussion

2.1. Optimization

We commenced our exploration with 1-(2-aminophenyl)-pyrrole (1a; 0.5 mmol) and styrene oxide (2a; 1.0 mmol) as the model substrates. In the presence of I2 (0.5 mmol) and AcOH (0.5 mmol) in CH3CN (1.0 mL) at 120 °C, the target product 4-benzylpyrrolo[1,2-a]quinoxaline (3a) was obtained in 52% yield. Then, we screened several common Brønsted acids, such as HCOOH, trifluoromethanesulfonic acid (TfOH) and p-toluenesulfonic acid (TsOH) (Table 1, entries 1–5), and 3a had the best yield (76%) when TsOH was used (Table 1, entry 5). In addition, we found that in the absence of iodine or acid, yields showed a significant decline (Table 1, entries 6–7). It can be noted that iodine and acid play a crucial role in this reaction system. Furthermore, when the acid was reduced to 0.5 equivalents, the yield decreased; when the acid equivalent was increased to 1.5 equivalents, the yield did not increase significantly (Table 1, entries 8–9). In addition, common solvents, such as 1,2-dichloroethane (DCE), EtOH, toluene, N-methylpyrrolidone (NMP) and PhCl, were selected, and CH3CN was the best (Table 1, entries 10–14). Lowering the reaction temperature did not improve the reaction yield (Table 1, entries 15–16). For the sake of economy and safety, we did not raise the temperature further. We finally determined that subsequent experiments will be performed with I2 (0.5 mmol) and TsOH (0.5 mmol) in CH3CN at 120 °C for 4 h (Table 1, entry 5).

2.2. Scope of Substrates

With the optimal reaction conditions in hand, various substituted 1-(2-aminophenyl)-pyrroles were first explored, and the results are shown in Table 2. For monosubstituted 1-(2-aminophenyl)-pyrroles, some bearing electron-donating groups (EDGs), like methyl, methoxy or tert-butyl, work well in this method (3b–3c, 3e–3f and 3k). The method was also compatible with substrates containing electron-withdrawing groups (EWGs), such as fluoro, chloro, bromo and iodine (3d, 3g–3j and 3l). Disubstituted 1-(2-aminophenyl)-pyrroles were also well tolerated under these conditions; for 4,5-dimethyl-2-(1H-pyrrol-1-yl)aniline, 4,5-difluoro-2-(1H-pyrrol-1-yl)aniline and 4,5-dichloro-2-(1H-pyrrol-1-yl)aniline, the target products 3m, 3n and 3o were obtained with the yields of 64%, 76% and 65%, respectively. When we replaced the pyrrole ring with indole, the reaction still proceeded with 35–48% yields (3p–3r). The reaction also proceeds smoothly when alkyl epoxides, such as 1,2-epoxybutane, were used (3s); when 3,4-epoxy-1-butene was used, the product 3t’ was expected to suffer a facile double-bond migration, affording the conjugated structure 3t.
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 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.

2.3. 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 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 Fe3+ and Ag+ metal ions.

2.4. 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 I2, 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 I2, 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 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).
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.

3. Materials and Methods

3.1. 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. 1H NMR (400 MHz or 500 MHz) and 13C 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.

3.2. General Experimental Procedures for 2-(1H-Pyrrol-1-yl) Anilines (1)

The substituted 2-nitroaniline (2.7626 g, 20 mmol, 1 equiv.) and 2, 5-dimethoxytetrahydrofuran (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, Na2CO3 aqueous solution was added and extracted three times with EtOAc. The organic layer was then dried with anhydrous Na2SO4 and the residue was obtained after vacuum evaporation. Iron powder (4.4680 g, 80 mmol, 5 equiv.) and NH4Cl (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 Na2SO4, and the residue was obtained after vacuum evaporation. The residue was subsequently purified by silica gel chromatography to yield the desirable compounds.

3.3. 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 Na2SO4 and a solid was obtained after vacuum evaporation. Iron powder (5.6850 g, 100 mmol, 5 equiv.) and NH4Cl (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 Na2SO4. 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.

3.4. 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 CH3CN (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 Na2S2O3 and extracted three times with EtOAc and H2O, followed by drying with anhydrous Na2SO4. The product was purified by silica gel column chromatography to give the desired compounds 3a–3t and 5a–5m.

3.5. Characterization Data

  • 4-benzylpyrrolo[1,2-a]quinoxaline (3a), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3a as a light yellow solid (98.2 mg, 76% yield); 1H NMR (400 MHz, CDCl3): δ 7.86–7.84 (m, 1 H), 7.65 (dd, J = 2.9, 1.4 Hz, 1 H), 7.60–7.57 (m, 1 H), 7.31–7.24 (m, 4 H), 7.14 (t, J = 8.0 Hz, 2 H), 7.10–7.03 (m, 1 H), 6.69 (dd, J = 4.0, 1.2 Hz, 1 H), 6.62–6.62 (m, 1 H), 4,23 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 154.1, 136.9, 134.7, 128.5, 127.8, 127.8, 127.4, 126.1, 125.5, 124.7, 124.0, 113.2, 112.6, 112.5, 106.1, 41.5. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H15N2+: 259.1229; found: 259.1233.
  • 4-benzyl-8-methylpyrrolo[1,2-a]quinoxaline (3b), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3b as a yellow solid (84.4 mg, 62% yield); 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.2 Hz, 1 H), 7.72 (dd, J = 2.7, 1.3 Hz, 1 H), 7.50 (s, 1 H), 7.32 (d, J = 7.4 Hz, 2 H), 7.20–7.10 (m, 4 H), 6.71 (dd, J = 4.0, 1.3 Hz, 1 H), 6.67 (dd, J = 4.0, 2.7 Hz, 1 H), 4.26 (s, 2 H), 2.43 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 153.2, 137.1, 136.6, 132.8, 128.3, 127.8, 127.4, 126.0, 125.5, 125.3, 124.9, 112.8, 112.6, 112.5, 105.7, 41.5, 20.7. HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17N2+: 273.1385; found: 273.1381.
  • 4-benzyl-8-methoxypyrrolo[1,2-a]quinoxaline (3c), purification on a silica gel (petroleum ether/ethyl acetate = 8:1) afforded compound 3c as a yellow solid (85.1 mg, 59% yield); 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.9 Hz, 1 H), 7.57 (dd, J = 2.8, 1.3 Hz, 1 H), 7.29 (d, J = 6.8 Hz, 2 H), 7.14 (t, J = 7.4 Hz, 2 H), 7.08–7.03 (m, 2 H), 6.88 (dd, J = 8.9, 2.7 Hz, 1 H), 6.66–6.61(m, 2 H), 4.21 (s, 2 H), 3.75 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 157.7, 151.5, 137.2, 129.8, 129.2, 127.8, 127.4, 126.9, 125.4, 124.7, 112.7, 112.6, 111.5, 105.5, 96.4, 54.6, 41.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17ON2+: 289.1335; found: 289.1339.
  • 4-benzyl-8-fluoropyrrolo[1,2-a]quinoxaline (3d), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3d as a yellow solid (102.3 mg, 74% yield); 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J = 2.8, 1.3 Hz, 1 H), 7.56–7.50 (m, 2 H), 7.31 (d, J = 7.2 Hz, 2 H), 7.16 (t, J = 7.5 Hz, 2 H), 7.11–7.00 (m, 2 H), 6.74 (d, J = 4.0 Hz, 1 H), 6.64 (dd, J = 4.1, 2.7 Hz, 1 H), 4.22 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 158.7 (d, JC-F = 243.4 Hz), 155.4, 136.7, 136.0 (d, JC-F = 11.4 Hz), 127.65 (d, JC-F = 34.6 Hz), 125.6, 124.5, 122.86 (d, JC-F = 2.3 Hz), 113.9 (d, JC-F = 22.2 Hz), 113.7 (d, JC-F = 21.1 Hz), 113.6, 113.5, 113.4, 112.7, 106.4, 41.4. 19F NMR (377 MHz, CDCl3): δ −116.7 (s). HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14FN2+: 277.1135; found: 277.1132.
  • 4-benzyl-7-methylpyrrolo[1,2-a]quinoxaline (3e), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3e as a yellow solid (84.4 mg, 62% yield); 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 1.5 Hz, 2 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.31 (d, J = 7.2 Hz, 2 H), 7.18–7.12 (m, 3 H), 7.08 (t, J = 7.3 Hz, 1 H), 6.70 (dd, J = 4.0, 1.3 Hz, 1 H), 6.63 (dd, J = 4.0, 2.7 Hz, 1 H), 4.24 (s, 2 H), 2.36 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 154.1, 137.0, 134.8, 133.8, 128.5, 127.8, 127.4, 127.2, 125.5, 124.7, 124.1, 112.9, 112.3, 112.2, 105.7, 41.5, 20.0. HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17N2+: 273.1385; found: 273.1384.
  • 4-benzyl-7-(tert-butyl)pyrrolo[1,2-a]quinoxaline (3f), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3f as a yellow solid (114.8 mg, 73% yield); 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1 H), 7.68 (dd, J = 2.8, 1.3 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.40 (dd, J = 8.6, 2.3 Hz, 1 H), 7.30 (d, J = 6.8 Hz, 2 H), 7.14 (t, J = 7.5 Hz, 2 H), 7.08–7.04 (m, 1 H), 6.69 (d, J = 4.0 Hz, 1 H), 6.63 (dd, J = 4.0, 2.7 Hz, 1 H), 4.25 (s, 2 H), 1.30 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ 154.0, 147.3, 137.0, 134.5, 127.7, 127.4, 125.5, 125.0, 124.7, 124.0, 123.8, 112.9, 112.4, 112.1, 105.8, 41.6, 33.7, 30.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2+: 315.1855; found: 315.1859.
  • 4-benzyl-7-fluoropyrrolo[1,2-a]quinoxaline (3g), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3g as a yellow solid (98.1 mg, 71% yield); 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, J = 2.8, 1.3 Hz, 1 H), 7.59 (dd, J = 9.0, 5.0 Hz, 1 H), 7.53 (dd, J = 9.5, 2.9 Hz, 1 H), 7.32 (d, J = 7.1 Hz, 2 H), 7.18 (t, J = 7.4 Hz, 2 H), 7.12–7.04 (m, 2 H), 6.76 (dd, J = 4.0, 1.3 Hz, 1 H), 6.66 (dd, J = 4.1, 2.7 Hz, 1 H), 4.23 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 158.7 (d, JC-F= 243.5 Hz), 155.4, 136.7, 136.1 (d, JC-F = 11.6 Hz), 127.8, 127.5, 125.6, 124.5, 122.9 (d, JC-F= 2.2 Hz), 114.0 (d, JC-F = 22.0 Hz), 113.8 (d, JC-F = 24.0 Hz), 113.6 (d, JC-F= 9.0 Hz), 113.4, 112.7, 106.4, 41.4. 19F NMR (377 MHz, CDCl3): δ −116.8 (s). HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14FN2+: 277.1135; found: 277.1332.
  • 4-benzyl-7-chloropyrrolo[1,2-a]quinoxaline (3h), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3h as a yellow solid (92.2 mg, 63% yield); 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 2.4 Hz, 1 H), 7.74 (d, J = 1.7 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 3 H), 7.22–7.18 (m, 2 H), 7.14–7.11 (m, 1 H), 6.81 (d, J = 4.5 Hz, 1 H), 6.73–6.72 (m, 1 H), 4.27 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 155.4, 136.6, 135.7, 129.1, 128.0, 127.8, 127.5, 126.0, 125.6, 124.8, 124.6, 113.6, 113.5, 112.9, 106.5, 41.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14ClN2+: 293.0839; found: 293.0837.
  • 4-benzyl-7-bromopyrrolo[1,2-a]quinoxaline (3i), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3i as a yellow solid (69.1 mg, 41% yield); 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 2.3 Hz, 1 H), 7.63 (d, J = 1.5 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.37 (dd, J = 8.8, 2.3 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.18 (t, J = 7.5 Hz, 2 H), 7.10 (t, J = 7.3 Hz, 1 H), 6.75 (d, J = 4.1 Hz, 1 H), 6.67–6.65 (m, 1 H), 4.23 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 155.3, 136.6, 136.0, 131.1, 128.8, 127.8, 127.5, 125.7, 125.2, 124.6, 116.5, 113.9, 113.5, 113.0, 106.6, 41.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14BrN2+: 337.0334; found: 337.0333.
  • 4-benzyl-7-iodopyrrolo[1,2-a]quinoxaline (3j), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3i as a yellow solid (76.8 mg, 40% yield); 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 2.0 Hz, 1 H), 7.69 (dd, J = 2.8, 1.4 Hz, 1 H), 7.59 (dd, J = 8.6, 2.0 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 2 H), 7.22–7.15 (m, 2 H), 7.11 (t, J = 7.3 Hz, 1 H), 6.78 (dd, J = 4.0, 1.4 Hz, 1 H), 6.70 (dd, J = 4.1, 2.7 Hz, 1 H), 4.24 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 155.2, 137.3, 136.6, 136.2, 134.5, 127.8, 127.5, 125.9, 125.7, 124.6, 114.2, 113.5, 113.0, 106.7, 87.1, 41.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14IN2+: 385.0195; found: 385.0196.
  • 4-benzyl-9-methylpyrrolo[1,2-a]quinoxaline (3k), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3k as a yellow solid (87.1 mg, 64% yield); 1H NMR (400 MHz, CDCl3): δ 8.03 (dd, J = 2.9, 1.4 Hz, 1 H), 7.72 (dd, J = 7.9, 1.8 Hz, 1 H), 7.28 (d, J = 6.8 Hz, 2 H), 7.16–7.10 (m, 3 H), 7.07–7.02 (m, 2 H), 6.72 (dd, J = 4.1, 1.3 Hz, 1 H), 6.59 (dd, J = 4.2, 2.8 Hz, 1 H), 4.21 (s, 2 H), 2.68 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 153.7, 137.0, 136.4, 129.6, 127.7, 127.4, 127.1, 126.5, 126.0, 125.4, 124.2, 123.4, 118.8, 111.8, 105.4, 41.3, 22.7. HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17N2+: 273.1385; found: 273.1390.
  • 4-Benzyl-9-chloropyrrolo[1,2-a]quinoxaline (3l). Purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3l as a yellow solid (95.2 mg, 65% yield); 1H NMR (400 MHz, CDCl3): δ 8.90 (dd, J = 2.9, 1.3 Hz, 1 H), 7.72 (dd, J = 8.0, 1.5 Hz, 1 H), 7.27 (dd, J = 8.0, 1.5 Hz, 3 H), 7.15–7.09 (m, 3 H), 7.07–7.03 (m, 1 H), 6.76 (dd, J = 4.2, 1.3 Hz, 1 H), 6.60 (dd, J = 4.2, 2.9 Hz, 1 H), 4.18(s, 2 H). 13C NMR (100 MHz, CDCl3): δ 154.6, 137.7, 136.7, 128.5, 127.8, 127.7, 127.4, 125.8, 125.6, 124.4, 123.5, 119.8, 119.8, 112.0, 106.4, 41.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14ClN2+: 293.0839; found: 293.0844.
  • 4-benzyl-7,8-dimethylpyrrolo[1,2-a]quinoxaline (3m), purification on a silica gel (petroleum ether/ethyl acetate = 10:1) afforded compound 3m as a yellow solid (91.6 mg, 64% yield); 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1 H), 7.62 (s, 1 H), 7.41 (d, J = 5.3 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.15 (t, J = 7.4 Hz, 2 H), 7.07 (t, J = 7.3 Hz, 1 H), 6.67 (dd, J = 4.0, 1.4 Hz, 1 H), 6.62–6.60 (m, 1 H), 4.23 (s, 2 H), 2.29 (s, 3 H), 2.25 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 153.1, 137.2, 135.5, 133.0, 132.8, 128.8, 127.8, 127.4, 125.4, 124.8, 124.2, 113.0, 112.6, 112.2, 105.4, 41.5, 19.1, 18.5. HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H19N2+: 287.1542; found: 287.1540.
  • 4-benzyl-7,8-difluoropyrrolo[1,2-a]quinoxaline (3n), purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3n as a yellow solid (108.8 mg, 76% yield); 1H NMR (400 MHz, CDCl3): δ 7.68 (dd, J = 11.0, 8.1 Hz, 1 H), 7.62 (dd, J = 2.7, 1.3 Hz, 1 H), 7.48 (dd, J = 10.5, 7.3 Hz, 1 H), 7.32 (d, J = 6.9 Hz, 2 H), 7.22–7.17 (m, 2 H), 7.14–7.11 (m, 1 H), 6.80 (dd, J = 4.1, 1.3 Hz, 1 H), 6.73 (dd, J = 4.0, 2.8 Hz, 1 H), 4.25 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 154.8 (d, JC-F = 2.9 Hz), 148.3 (dd, JC-F = 248.7, 14.4 Hz), 146.9 (dd, JC-F = 245.2, 13.7 Hz), 136.6, 129.9, 127.8, 127.5, 125.7, 124.4, 122.6 (d, JC-F = 8.7 Hz), 116.2 (d, JC-F = 19.6 Hz), 113.5, 113.2, 106.6, 101.1 (d, JC-F = 22.2 Hz), 41.3. 19F NMR (377 MHz, CDCl3): δ -135.1 (s), -140.2 (s). HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H13F2N2+: 295.1041; found: 295.1039.
  • 4-benzyl-7,8-dichloropyrrolo[1,2-a]quinoxaline (3o), purification on a silica gel (petroleum ether/ethyl acetate = 25:1) afforded compound 3o as a yellow solid (106.3 mg, 65% yield); 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1 H), 7.75 (s, 1 H), 7.64 (dd, J = 2.8, 1.3 Hz, 1 H), 7.31 (d, J = 6.9 Hz, 2 H), 7.22–7.11 (m, 3 H), 6.80 (dd, J = 4.0, 1.3 Hz, 1 H), 6.71 (dd, J = 4.0, 2.8 Hz, 1 H), 4.23 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 155.6, 136.4, 134.3, 129.6, 129.6, 127.8, 127.6, 127.5, 125.7, 125.4, 124.5, 114.1, 113.8, 113.4, 107.1, 41.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H13Cl2N2+: 327.0450; found: 327.0455.
  • 6-benzylindolo[1,2-a]quinoxaline (3p), purification on a silica gel (petroleum ether/ethyl acetate = 25:1) afforded compound 3p as a yellow solid (74.1 mg, 48% yield); 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 15.8, 8.6 Hz, 2 H), 7.89 (dd, J = 7.9, 1.8 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.42–7.23 (m, 6 H), 7.17 (t, J = 7.8 Hz, 2 H), 7.09 (t, J = 8.1 Hz, 1 H), 6.95 (s, 1 H), 4.30 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 155.6, 136.6, 134.7, 131.7, 129.2, 128.9, 128.1, 127.9, 127.7, 127.5, 127.0, 125.6, 123.1, 122.9, 121.6, 121.4, 113.5, 113.4, 99.5, 41.6. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H17N2+: 309.1385; found: 309.1382.
  • 6-qenzyl-3-methylindolo[1,2-a]quinoxaline (3q), purification on a silica gel (petroleum ether/ethyl acetate = 20:1) afforded compound 3q as a yellow solid (61.3 mg, 38% yield); 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.6 Hz, 1 H), 8.14 (s, 1 H), 7.79 (dd, J = 16.9, 8.0 Hz, 2 H), 7.42–7.27 (m, 3 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.23–7.06 (m, 4 H), 6.98 (s, 1 H), 4.33(s, 2 H), 2.51(s, 3 H). 13C NMR (100 MHz, CDCl3): δ 154.6, 137.5, 136.7, 132.7, 131.7, 129.1, 128.7, 128.3, 128.0, 127.7, 127.5, 125.6, 124.0, 122.9, 121.6, 121.5, 113.9, 113.6, 99.4, 41.6, 21.1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H19N2+: 323.1542; found: 323.1546.
  • 6-Benzyl-7-methylindolo[1,2-a]quinoxaline (3r). Purification on a silica gel (petroleum ether/ethyl acetate = 15:1) afforded compound 3r as a yellow solid (56.4 mg, 35% yield); 1H NMR (400 MHz, CDCl3): δ 8.44 (t, J = 7.9 Hz, 2 H), 7.99 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.56 (q, J = 7.1 Hz, 2 H), 7.41 (dt, J = 14.1, 7.1 Hz, 2 H), 7.27–7.25 (m, 4 H), 7.20 (q, J = 4.3 Hz, 1 H), 4.64 (s, 2 H), 2.63 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 156.8, 137.9, 132.1, 130.6, 130.0, 129.5, 128.9, 128.6, 128.5, 128.4, 128.2, 126.5, 124.8, 124.0, 123.8, 122.0, 120.7, 114.5, 114.4, 29.7, 11.0. HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H19N2+: 323.1542; found: 323.1543.
  • 4-propylpyrrolo[1,2-a]quinoxaline (3s), purification on a silica gel (petroleum ether/ethyl acetate = 10:1) afforded compound 3s as a yellow solid (42.1 mg, 40% yield); 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J = 7.9, 1.5 Hz, 1 H), 7.81–7.79 (m, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.35 (dtd, J = 21.0, 7.4, 1.4 Hz, 2 H), 6.82 (dd, J = 3.9, 1.2 Hz, 1 H), 6.75 (dd, J = 3.8, 2.8 Hz, 1 H), 2.91 (dd, J = 8.5, 7.1 Hz, 2 H), 1.86 (dq, J = 15.0, 7.4 Hz, 2 H), 1.00 (t, J = 7.4 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ 156.4, 135.0, 128.4, 126.2, 125.8, 125.1, 124.0, 113.0, 112.6, 112.4, 105.2, 36.8, 20.9, 13.3. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H15N2+: 211.1229; found: 211.1233.
  • (E)-4-(prop-1-en-1-yl)pyrrolo[1,2-a]quinoxaline (3t), purification on a silica gel (petroleum ether/ethyl acetate = 10:1) afforded compound 3t as a yellow solid (52.1 mg, 40% yield); 1H NMR (500 MHz, CDCl3): δ 7.90–7.82 (m, 2 H), 7.77–7.72 (dd, J = 8.0, 1.0 Hz, 1 H), 7.42–7.29 (m, 2 H), 7.18–7.09 (qd, J = 13.5, 7.0 Hz, 1 H), 6.93–6.90 (dd, J = 4.0, 1.0 Hz, 1 H), 6.80 (dd, J = 4.0, 1.5 Hz, 1 H), 6.78 (dd, J = 7.0, 2.5 Hz, 1 H), 1.98 (dd, J = 6.8, 1.7 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ 149.2, 135.1, 134.4, 128.6, 126.2, 125.9, 125.7, 124.6, 124.2, 113.3, 112.6, 112.5, 105.0, 17.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2+: 209.1072; found: 209.1071.
  • 2-benzylquinazolin-4(3H)-one (5a), purification on a silica gel (petroleum ether/ethyl acetate = 2:1) afforded compound 5a as a white solid (82.7 mg, 70% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1 H), 8.09 (dd, J = 7.9, 1.6 Hz, 1 H), 7.78 (ddd, J = 8.4, 7.0, 1.6 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.50–7.44 (m, 1 H), 7.39 (d, J = 7.9 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.28–7.22 (m, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 167.1, 161.2, 154.1, 141.8, 139.6, 134.1, 133.7, 132.2, 132.0, 131.4, 130.9, 126.0, 46.0. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13ON2+: 237.1002; found: 237.1005.
  • 2-benzyl-6-methylquinazolin-4(3H)-one (5b), purification on a silica gel (petroleum ether/ethyl acetate = 5:1) afforded compound 5b as a white solid (92.6 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.32 (s, 1 H), 7.87 (s, 1 H), 7.59 (dd, J = 8.3, 2.2 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 1 H), 7.38 (d, J = 6.8 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 7.24 (t, J = 7.2 Hz, 1 H), 3.92 (s, 2 H), 2.42 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 162.3, 155.5, 147.4, 137.1, 136.3, 136.1, 129.3, 129.0, 127.3, 127.2, 125.5, 121.0, 41.2, 21.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15ON2+: 251.1178; found: 251.1177.
  • 2-benzyl-6-methoxyquinazolin-4(3H)-one (5c), purification on a silica gel (petroleum ether/ethyl acetate = 1:1) afforded compound 5c as a white solid (77.3 mg, 58% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.38 (s, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.48 (d, J = 2.9 Hz, 1 H), 7.41–7.36 (m, 3 H), 7.32 (d, J = 15.0 Hz, 2 H), 7.24 (t, J = 7.2 Hz, 1 H), 3.92 (s, 2 H), 3.85 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ 162.2, 157.8, 154.1, 143.9, 137.2, 129.3, 129.1, 129.0, 127.2, 124.3, 122.0, 106.2, 56.0, 41.1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H15ON2+: 267.1127; found: 267.1123.
  • 2-benzyl-6-fluoroquinazolin-4(3H)-one (5d), purification on a silica gel (petroleum ether/ethyl acetate = 5:1) afforded compound 5d as a white solid (90.3 mg, 71% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1 H), 7.76 (dd, J = 8.6, 2.7 Hz, 1 H), 7.71–7.65 (m, 2 H), 7.39 (d, J = 6.9 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 161.8 (d, JC-F = 3.3 Hz), 160.2 (d, JC-F = 244.9 Hz), 156.0 (d, JC-F = 2.2 Hz), 146.2 (d, JC-F = 1.8 Hz), 136.9, 130.2 (d, JC-F = 8.0 Hz), 129.4, 129.0, 127.3, 123.3 (d, JC-F = 24.0 Hz), 122.4 (d, JC-F = 8.4 Hz), 110.8 (d, JC-F = 23.3 Hz), 41.1. 19F NMR (377 MHz, DMSO-d6): δ −114.1 (s). HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OFN2+: 255.0927; found: 255.0928.
  • 2-benzyl-6-chloroquinazolin-4(3H)-one (5e), purification on a silica gel (petroleum ether/ethyl acetate = 5:1) afforded compound 5e as a white solid (101.55 mg, 75% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1 H), 8.01 (d, J = 2.5 Hz, 1 H), 7.80 (dd, J = 8.8, 2.6 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.38 (d, J = 6.8 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 161.4, 157.1, 148.1, 136.8, 135.0, 130.9, 129.7, 129.4, 129.0, 127.3, 125.2, 122.5, 41.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OClN2+:271.0632; found: 271.0635.
  • 2-benzyl-6-bromoquinazolin-4(3H)-one (5f), purification on a silica gel (petroleum ether/ethyl acetate = 5:1) afforded compound 5f as a white solid (93.0 mg, 59% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 7.92 (dd, J = 8.7, 2.4 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.38 (d, J = 6.9 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 3.94 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 161.2, 157.2, 148.4, 137.7, 136.8, 129.8, 129.4, 129.0, 128.3, 127.3, 122.9, 119.0, 41.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OBrN2+: 315.0127; found: 315.0124.
  • 2-benzyl-7-methylquinazolin-4(3H)-one (5g), purification on a silica gel (petroleum ether/ethyl acetate = 2:1) afforded compound 5g as a white solid (75.2 mg, 60% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.31 (s, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.47–7.37 (m, 3 H), 7.35–7.20 (m, 4 H), 3.93 (s, 2 H), 2.43 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ 162.2, 156.5, 149.5, 145.3, 137.1, 129.3, 128.9, 128.0, 127.2, 127.1, 126.0, 118.8, 41.2, 21.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15ON2+: 251.1178; found: 251.1175.
  • 2-benzyl-7-fluoroquinazolin-4(3H)-one (5h), purification on a silica gel (petroleum ether/ethyl acetate = 2:1) afforded compound 5h as a white solid (85.2 mg, 67% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1 H), 8.15 (dd, J = 8.9, 6.4 Hz, 1 H), 7.42–7.37 (m, 3 H), 7.36–7.30 (m, 3 H), 7.25 (t, J = 7.3 Hz, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ = 166.2 (d, J C-F = 250.7 Hz), 161.6, 158.0, 151.6 (d, J C-F = 13.2 Hz), 136.8, 129.4, 129.2, 129.0, 127.3, 118.3 (d, JC-F = 1.8 Hz), 115.2 (d, JC-F = 23.6 Hz), 112.5 (d, JC-F = 21.8 Hz), 41.2. 19F NMR (377 MHz, DMSO-d6): δ −104.5 (s). HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OFN2+: 255.0927; found: 255.0930.
  • 2-benzyl-7-chloroquinazolin-4(3H)-one (5i), purification on a silica gel (petroleum ether/ethyl acetate = 2:1) afforded compound 5i as a white solid (88.1 mg, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 2.1 Hz, 1 H), 7.50 (dd, J = 8.6, 2.1 Hz, 1 H), 7.39 (d, J = 7.0 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 161.8, 158.1, 150.5, 139.5, 136.8, 129.4, 129.0, 128.3, 127.3, 127.0, 126.6, 120.1, 41.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OClN2+: 271.0632; found: 271.0630.
  • 2-benzyl-7-bromoquinazolin-4(3H)-one (5j), purification on a silica gel (petroleum ether/ethyl acetate = 3:1) afforded compound 5j as a white solid (100.9 mg, 64% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 2.1 Hz, 1 H), 7.62 (dd, J = 8.4, 2.0 Hz, 1 H), 7.39 (d, J = 6.8 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 161.9, 158.1, 150.6, 136.8, 129.7, 129.7, 129.4, 129.0, 128.5, 128.3, 127.3, 120.4, 41.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OBrN2+: 315.0127; found: 315.0131.
  • 2-(4-chlorobenzyl)quinazolin-4(3H)-one (5k), purification on a silica gel (petroleum ether/ethyl acetate = 2:1) afforded compound 5k as a white solid (89.4 mg, 66% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1 H), 8.09 (dd, J = 7.9, 1.6 Hz, 1 H), 7.78 (ddd, J = 8.6, 7.1, 1.6 Hz, 1 H), 7.60 (dd, J = 8.3, 1.1 Hz, 1 H), 7.50–7.45 (m, 1 H), 7.44–7.37 (m, 4 H), 3.95 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 162.3, 156.1, 149.3, 136.0, 134.9, 132.0, 131.3, 128.9, 127.4, 126.8, 126.2, 121.3, 40.4. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OClN2+: 271.0632; found: 271.0633.
  • 2-(4-bromobenzyl)quinazolin-4(3H)-one (5l), purification on a silica gel (petroleum ether/ethyl acetate = 3:1) afforded compound 5l as a white solid (99.3 mg, 63% yield); 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1 H), 8.09 (d, J = 9.6 Hz, 1 H), 7.82–7.73 (m, 1 H), 7.60 (d, J = 7.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 2 H), 3.93 (s, 2 H). 13C NMR (100 MHz, DMSO-d6): δ 162.3, 156.0, 149.3, 136.4, 134.9, 131.8, 131.7, 127.4, 126.8, 126.2, 121.3, 120.5, 40.5. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12OBrN2+: 315.0127; found: 315.0125.
  • (E)-2-(prop-1-en-1-yl)quinazolin-4(3H)-one (5m). Purification on a silica gel (petroleum ether/ethyl acetate = 1:1) afforded compound 5m as a white solid (44.7 mg, 48% yield); 1H NMR (500 MHz, DMSO-d6): δ 12.17 (s, 1 H), 8.14–8.01 (m, 1 H), 7.82–7.72 (m, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.21–7.04 (m, 1 H), 6.27 (dd, J = 15.7, 1.7 Hz, 1 H), 1.92 (dd, J = 6.9, 1.5 Hz, 3 H). 13C NMR (125 MHz, DMSO-d6): δ 162.3, 151.6, 149.5, 138.7, 134.9, 127.5, 126.4, 126.2, 125.1, 121.4, 18.7. HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H11ON2+: 187.0865; found: 187.0867.

4. 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 N-heterocycles 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.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules28217391/s1, Figure S1: 1H NMR spectrum of compound 3a in CDCl3 (400 MHz); Figure S2: 13C {1H} NMR spectrum of compound 3a in CDCl3 (100 MHz); Figure S3: 1H NMR spectrum of compound 3b in CDCl3 (400 MHz); Figure S4: 13C {1 H} NMR spectrum of compound 3b in CDCl3 (100 MHz); Figure S5: 1H NMR spectrum of compound 3c in CDCl3 (400 MHz); Figure S6: 13C {1 H} NMR spectrum of compound 3c in CDCl3 (100 MHz); Figure S7: 1H NMR spectrum of compound 3d in CDCl3 (400 MHz); Figure S8: 13C {1 H} NMR spectrum of compound 3d in CDCl3 (100 MHz); Figure S9: 19F {1 H} NMR spectrum of compound 3d in CDCl3 (377 MHz); Figure S10: 1H NMR spectrum of compound 3e in CDCl3 (400 MHz); Figure S11: 13C {1 H} NMR spectrum of compound 3e in CDCl3 (100 MHz); Figure S12: 1H NMR spectrum of compound 3f in CDCl3 (400 MHz); Figure S13: 13C {1 H} NMR spectrum of compound 3f in CDCl3 (100 MHz); Figure S14: 1H NMR spectrum of compound 3g in CDCl3 (400 MHz); Figure S15: 13C {1 H} NMR spectrum of compound 3g in CDCl3 (100 MHz); Figure S16: 19F {1H} NMR spectrum of compound 3g in CDCl3 (377 MHz); Figure S17: 1H NMR spectrum of compound 3h in CDCl3 (400 MHz); Figure S18: 13C {1 H} NMR spectrum of compound 3h in CDCl3 (100 MHz); Figure S19: 1H NMR spectrum of compound 3i in CDCl3 (400 MHz); Figure S20: 13C {1 H} NMR spectrum of compound 3i in CDCl3 (100 MHz); Figure S21: 1H NMR spectrum of compound 3j in CDCl3 (400 MHz); Figure S22: 13C {1 H} NMR spectrum of compound 3j in CDCl3 (100 MHz); Figure S23: 1H NMR spectrum of compound 3k in CDCl3 (400 MHz); Figure S24: 13C {1 H} NMR spectrum of compound 3k in CDCl3 (100 MHz); Figure S25: 1H NMR spectrum of compound 3l in CDCl3 (400 MHz); Figure S26: 13C {1 H} NMR spectrum of compound 3l in CDCl3 (100 MHz); Figure S27: 1H NMR spectrum of compound 3m in CDCl3 (400 MHz); Figure S28: 13C {1 H} NMR spectrum of compound 3m in CDCl3 (100 MHz); Figure S29: 1H NMR spectrum of compound 3n in CDCl3 (400 MHz); Figure S30: 13C {1 H} NMR spectrum of compound 3n in CDCl3 (100 MHz); Figure S31: 19F {1 H} NMR spectrum of compound 3n in CDCl3 (377 MHz); Figure S32: 1H NMR spectrum of compound 3o in CDCl3 (400 MHz); Figure S33: 13C {1 H} NMR spectrum of compound 3o in CDCl3 (100 MHz); Figure S34: 1H NMR spectrum of compound 3p in CDCl3 (400 MHz); Figure S35: 13C {1 H} NMR spectrum of compound 3p in CDCl3 (100 MHz); Figure S36: 1H NMR spectrum of compound 3q in CDCl3 (400 MHz); Figure S37: 13C {1 H} NMR spectrum of compound 3q in CDCl3 (100 MHz); Figure S38: 1H NMR spectrum of compound 3r in CDCl3 (400 MHz); Figure S39: 13C {1 H} NMR spectrum of compound 3r in CDCl3 (100 MHz); Figure S40: 1H NMR spectrum of compound 3s in CDCl3 (500 MHz); Figure S41: 13C {1 H} NMR spectrum of compound 3s in CDCl3 (125 MHz); Figure S42: 1H NMR spectrum of compound 3t in CDCl3 (500 MHz); Figure S43: 13C {1 H} NMR spectrum of compound 3t in CDCl3 (125 MHz); Figure S44: 1H NMR spectrum of compound 5a in DMSO-d6 (400 MHz); Figure S45: 13C {1 H} NMR spectrum of compound 5a in DMSO-d6 (100 MHz); Figure S46: 1H NMR spectrum of compound 5b in DMSO-d6 (400 MHz); Figure S47: 13C {1 H} NMR spectrum of compound 5b in DMSO-d6 (100 MHz); Figure S48: 1H NMR spectrum of compound 5c in DMSO-d6 (400 MHz); Figure S49: 13C {1 H} NMR spectrum of compound 5c in DMSO-d6 (100 MHz); Figure S50: 1H NMR spectrum of compound 5d in DMSO-d6 (400 MHz); Figure S51: 13C {1 H} NMR spectrum of compound 5d in DMSO-d6 (100 MHz); Figure S52: 19F {1 H} NMR spectrum of compound 5d in DMSO-d6 (377 MHz); Figure S53: 1H NMR spectrum of compound 5e in DMSO-d6 (400 MHz); Figure S54: 13C {1 H} NMR spectrum of compound 5e in DMSO-d6 (100 MHz); Figure S55: 1H NMR spectrum of compound 5f in DMSO-d6 (400 MHz); Figure S56: 13C {1 H} NMR spectrum of compound 5f in DMSO-d6 (100 MHz); Figure S57: 1H NMR spectrum of compound 5g in DMSO-d6 (400 MHz); Figure S58: 13C {1 H} NMR spectrum of compound 5g in DMSO-d6 (100 MHz); Figure S59: 1H NMR spectrum of compound 5h in DMSO-d6 (400 MHz); Figure S60: 13C {1 H} NMR spectrum of compound 5h in DMSO-d6 (100 MHz); Figure S61: 19F {1 H} NMR spectrum of compound 5h in DMSO-d6 (377 MHz); Figure S62: 1H NMR spectrum of compound 5i in DMSO-d6 (400 MHz); Figure S63: 13C {1 H} NMR spectrum of compound 5i in DMSO-d6 (100 MHz); Figure S64: 1H NMR spectrum of compound 5j in DMSO-d6 (400 MHz); Figure S65: 13C {1 H} NMR spectrum of compound 5j in DMSO-d6 (100 MHz); Figure S66: 1H NMR spectrum of compound 5k in DMSO-d6 (400 MHz); Figure S67: 13C {1 H} NMR spectrum of compound 5k in DMSO-d6 (100 MHz); Figure S68: 1H NMR spectrum of compound 5l in DMSO-d6 (400 MHz); Figure S69: 13C {1 H} NMR spectrum of compound 5l in DMSO-d6 (100 MHz); Figure S70: 1H NMR spectrum of compound 5m in DMSO-d6 (500 MHz); Figure S71: 13C {1 H} NMR spectrum of compound 5m in DMSO-d6 (125 MHz); Figure S72. HRMS of intermediate.

Author Contributions

Methodology: S.L. and X.L.; validation: X.L., C.D. and L.L.; investigation: S.L. and X.L.; writing—original draft preparation: X.L.; writing—review and editing: B.Y. and C.M. All authors have read and agreed to the published version of the manuscript.

Funding

Shandong Key Research Program (No. 2019JZZY021015) and Zhejiang Xin’an Chemical Group Company Basic Research Project (No. YJG202108).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The supporting data are available in the Supplementary Materials.

Acknowledgments

We are grateful for the financial support from the Shandong Key Research Program (No. 2019JZZY021015) and Zhejiang Xin’an Chemical Group Company Basic Research Project (No. YJG202108). We are also grateful for the Analytical Center for Structural Constituent and the Physical Property of Core Facilities Sharing Platform, Shandong University for their technology and service support.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 07391 g001
Figure 1. Drug Molecules Containing Quinoxalines and Quinazolines.
Figure 1. Drug Molecules Containing Quinoxalines and Quinazolines.
Molecules 28 07391 g001
Molecules 28 07391 sch001
Scheme 1. Synthesis of Pyrrolo[1,2-a]quinoxalines.
Scheme 1. Synthesis of Pyrrolo[1,2-a]quinoxalines.
Molecules 28 07391 sch001
Molecules 28 07391 sch002
Scheme 2. Large-scale reaction and synthetic applications.
Scheme 2. Large-scale reaction and synthetic applications.
Molecules 28 07391 sch002
Molecules 28 07391 sch003
Scheme 3. Control experiments (a–d).
Scheme 3. Control experiments (a–d).
Molecules 28 07391 sch003
Molecules 28 07391 sch004
Scheme 4. Proposed Mechanism.
Scheme 4. Proposed Mechanism.
Molecules 28 07391 sch004
Table 1. Optimization a.
Table 1. Optimization a.
Molecules 28 07391 i001
Entry Acid/Equiv. Solvent Temp. (°C) Yield (%) b
1AcOH/1.0CH3CN12052
2HCOOH/1.0CH3CN12055
3TFA/1.0CH3CN12056
4TfOH/1.0CH3CN12063
5TsOH/1.0CH3CN12076
6TsOH/1.0CH3CN12027 c
7-CH3CN12050
8TsOH/0.5CH3CN12056r
9TsOH/1.5CH3CN12071
10TsOH/1.0DCE12047
11TsOH/1.0EtOH12043
12TsOH/1.0toluene120trace
13TsOH/1.0NMP12048
14TsOH/1.0PhCl12026
15TsOH/1.0CH3CN10062
16TsOH/1.0CH3CN8058
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.
Table 2. Substrate Scope of 2-(1H-Pyrrolo/indolo-1-yl)anilines a,b.
Table 2. Substrate Scope of 2-(1H-Pyrrolo/indolo-1-yl)anilines a,b.
Molecules 28 07391 i002+Molecules 28 07391 i003Molecules 28 07391 i004Molecules 28 07391 i005
1 2 3
Molecules 28 07391 i006Molecules 28 07391 i007Molecules 28 07391 i008Molecules 28 07391 i009
3a, 76%3b, 62%3c, 59%3d, 74%
Molecules 28 07391 i010Molecules 28 07391 i011Molecules 28 07391 i012Molecules 28 07391 i013
3e, 62%3f, 73%3g, 71%3h, 63%
Molecules 28 07391 i014Molecules 28 07391 i015Molecules 28 07391 i016Molecules 28 07391 i017
3i, 41%3j, 40%3k, 64%3l, 65%
Molecules 28 07391 i018Molecules 28 07391 i019Molecules 28 07391 i020Molecules 28 07391 i021
3m, 64%3n, 76%3o, 65%3p, 48%
Molecules 28 07391 i022Molecules 28 07391 i023Molecules 28 07391 i024Molecules 28 07391 i025Molecules 28 07391 i026
3q, 38%3r, 35%3s, 40%3t’3t, 50%
a 1 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.), I2 (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.
Table 3. Substrate Scope of 2-Aminobenzamide a,b.
Table 3. Substrate Scope of 2-Aminobenzamide a,b.
Molecules 28 07391 i027+Molecules 28 07391 i028Molecules 28 07391 i029Molecules 28 07391 i030
4 2 5
Molecules 28 07391 i031Molecules 28 07391 i032Molecules 28 07391 i033Molecules 28 07391 i034
5a, 70%5b, 74%5c, 58%5d, 71%
Molecules 28 07391 i035Molecules 28 07391 i036Molecules 28 07391 i037Molecules 28 07391 i038
5e, 75%5f, 59%5g, 60%5h, 67%
Molecules 28 07391 i039Molecules 28 07391 i040Molecules 28 07391 i041Molecules 28 07391 i042
5i, 65%5j, 64%5k, 60%5l, 65%
Molecules 28 07391 i043Molecules 28 07391 i044Molecules 28 07391 i045Molecules 28 07391 i046
5m’5m, 48%5n, 0%5o, 0%
a 4 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.), I2 (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.
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MDPI and ACS Style

Lv, X.; Lv, L.; Li, S.; Ding, C.; Yang, B.; Ma, C. A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor. Molecules 2023, 28, 7391. https://doi.org/10.3390/molecules28217391

AMA Style

Lv X, Lv L, Li S, Ding C, Yang B, Ma C. A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor. Molecules. 2023; 28(21):7391. https://doi.org/10.3390/molecules28217391

Chicago/Turabian Style

Lv, Xueyan, Lili Lv, Shichen Li, Chengcheng Ding, Bingchuan Yang, and Chen Ma. 2023. "A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor" Molecules 28, no. 21: 7391. https://doi.org/10.3390/molecules28217391

APA Style

Lv, X., Lv, L., Li, S., Ding, C., Yang, B., & Ma, C. (2023). A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor. Molecules, 28(21), 7391. https://doi.org/10.3390/molecules28217391

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