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Article

Persulfate-Promoted Carbamoylation/Cyclization of Alkenes: Synthesis of Amide-Containing Quinazolinones

by
Jia-Jun Tang
,
Meng-Yang Zhao
,
Ying-Jun Lin
,
Li-Hua Yang
and
Long-Yong Xie
*
College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425100, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(5), 997; https://doi.org/10.3390/molecules29050997
Submission received: 25 January 2024 / Revised: 22 February 2024 / Accepted: 24 February 2024 / Published: 25 February 2024
(This article belongs to the Special Issue Cyclization Reactions in Organic Synthesis: Recent Developments)
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Versions Notes

Abstract

:
The incorporation of amide groups into biologically active molecules has been proven to be an efficient strategy for drug design and discovery. In this study, we present a simple and practical method for the synthesis of amide-containing quinazolin-4(3H)-ones under transition-metal-free conditions. This is achieved through a carbamoyl-radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. Notably, the carbamoyl radical is generated in situ from the oxidative decarboxylative process of oxamic acids in the presence of (NH4)2S2O8.

1. Introduction

Quinazolinones, nitrogen-containing heterocycles, are widely present in natural products and pharmaceuticals [1,2,3]. In particular, 2,3-fused quinazolin-4(3H)-ones display a wide spectrum of pharmacological and biological properties, including anti-inflammatory, antimicrobial, antiviral, antitumor, and other activities (Figure 1), and have attracted the extensive attention of chemists [4,5,6,7,8].
Consequently, remarkable efforts have been devoted to their efficient synthesis in the past few years [9,10,11,12,13,14,15]. Traditionally, 2,3-fused quinazolin-4(3H)-ones can be prepared through multiple pathways, such as dehydrogenative cross-coupling reactions [16,17,18,19,20,21], oxidative ring-opening reactions [22,23,24,25,26,27,28], cycloaddition reactions [29,30,31,32], etc. However, these methods suffer from the use of complicated starting materials, harsh reaction conditions, and complex reaction procedures. In recent years, the radical cascade cyclization reaction of N3-alkenyl-tethered quinazolinones has emerged as an attractive strategy for the synthesis of functionalized ring-fused quinazolinone derivatives [33]. In this regard, several important functional groups, including alkyl [34,35,36,37], acyl [38], fluoralkyl [39,40,41,42,43], sulfonyl [44], and sulfonamidation groups [45], were smoothly incorporated into quinazolinone scaffolds (Scheme 1a). Despite these advances, the development of efficient and facile methods for the introduction of some other valuable groups to quinazolinone scaffolds is still in high demand.
On the other hand, amide compounds frequently exist in natural products, pharmaceuticals, and various functional materials [46,47,48]. In contrast to conventional methods for the construction of amide bonds via condensation [49,50] or cross-coupling reaction [51,52,53], which often suffer from the prefunctionalization of substrates and environmentally unfriendly coupling reagents, the radical carbamoylation reaction has been regarded as one of the most efficient approaches to directly introduce an amide group into an organic molecule [54]. In this context, obvious achievements have been made, especially in the carbamoylation of N-heterocycles through a Minisci-type reaction process [55,56,57,58]. In recent years, radical difunctionalization reactions of alkenes employing oxamic acids or other carbamoylating reagents such as carbamoyl radical precursors have also provided a promising strategy to introduce amide groups to various complex molecules [59,60]. For instance, in 2021, Wang and co-workers reported persulfate-promoted difunctionalization reactions of ortho-cyanoarylacrylamides with oxamic acids to access a variety of carbamoyl quinoline-2,4-diones [61]. Li and co-workers developed a convenient and practical method for carbamoylated benzimidazo [2,1-a]isoquinolin-6(5H)-ones from 2-arylbenzoimidazoles and oxamic acids [62]. Very recently, Anand Singh et al. developed a visible-light-induced cascade carbamoylation/cyclization of acrylamides with 4-carbamoyl-1,4-dihydropyridines as carbamoylation reagents [63]. However, to our knowledge, the carbamoyl-radical-triggered cascade cyclization reaction of N3-alkenyl-tethered quinazolinones to afford amide-containing quinazolinones has never been reported. With our continuing interest in radical chemistry [64,65,66,67,68], herein, we report a metal-free protocol for the synthesis of amide-substituted polycyclic quinazolinones through the cascade radical carbamoylation/cyclization reaction of N3-alkenyl-tethered quinazolinones with oxamic acids as a readily available carbamoyl radical source (Scheme 1b).

2. Results and Discussion

Initially, 3-(but-3-en-1-yl)quinazolin-4(3H)-one (1a) and 2-oxo-2-(phenylamino)acetic acid (2a) were selected as the model substrates to screen the optimized reaction conditions, as shown in Table 1. When the reaction was performed at 80 °C under N2 atmosphere for 6 h with (NH4)2S2O8 as an oxidant in DMSO solvent, the corresponding radical cyclization product 3a was obtained in 42% isolated yield (entry 1). Then, some other oxidants, including K2S2O8, Na2S2O8, PhI(OAc)2, selectfluor reagent, and potassium peroxomonosulfate (Oxone) were investigated, among which K2S2O8 and Na2S2O8 gave low yields in contrast to (NH4)2S2O8 (entries 2 and 3 vs. entry 1), and other oxidants failed to give the desired product. Furthermore, various commonly used organic solvents, including CH3CN, DCE, DMF, THF, 1,4-dioxane, and NMP were examined. Beyond our expectation, only DMSO was valid for the current transformation and other investigated organic solvents were found unsuitable for this reaction. In addition, water as a solvent also gave 27% yield of 3a (entry 4). Then, various ratios of DMSO-H2O mixed solvents were tested to further enhance the reaction efficiency (entries 5–7). We found an appropriate amount of water is beneficial for the reaction, likely due to the addition of water to DMSO obviously improving the solubility of ammonium persulfate in solvents, while too much water may reduce the solubility of the reactants and result in a worse yield. When the volume ratio of DMSO to H2O is 100:1 (v/v), the yield of 3a reached a yield of 57% (entry 6). The reaction temperature has a significant influence on the reaction yield. Increasing the reaction temperature to 90 and 100 °C, the yield of 3a was obtained in 64 and 76% yields, respectively (entries 8 and 9). Further increasing the reaction temperature did not improve the yield (entry 10), while reducing the temperature to 70 °C only gave 3a in 16% yield (entry 11). We also investigated the amounts of (NH4)2S2O8 to the reaction (entries 12–14). We found the yield of 3a was improved to 82% when the amounts of (NH4)2S2O8 was increased to 3.5 equiv. based on 1a (entry 13). Finally, no reaction occurred in the absence of any oxidant, demonstrating that oxidant was essential for the present reaction (entry 15).
With the optimal reaction conditions in hand (Table 1, entry 22), the substrate scope and limitations of the present reaction were investigated by the reaction of 3-(but-3-en-1-yl)quinazolin-4(3H)-one (1a) with various oxamic acids. As depicted in Scheme 2, N-aryl oxamic acids bearing either electron-donating groups or electron-withdrawing groups at the different positions of aryl rings all reacted well with substrate 1a to give the corresponding products in 58–83% yields (3b–3k). Other important functional groups, such as methyl groups (3b), halogen atoms (3c–3e, 3i and 3k), trifluoromethyl groups (3g), and trifluoromethylthio groups (3h), were compatible with the current transformation. In addition, some N-alkyl oxamic acids were also found suitable for the reaction and gave the desired products in satisfactory yields (3l–3o). However, using N-disubstituted oxamic acid 2p as a potential substrate, the expected product was not observed (3p). In addition, some N-dialkyl oxamic acids obtained from dialkyl amines, such as morpholine, piperidine, and diethylamine, were used for the present reaction, while no reaction occurred to give the corresponding amide products.
We then turned to investigate the reactions of 2a with other quinazolinones, as shown in Scheme 3. We found these investigated quinazolinones substituted with several important functional groups, such as methyl (3r), fluoro (3q and 3u), chloro (3s and 3v), and trifluoromethyl (3t and 3w) groups at the C5–C7 positions of the benzene ring were all compatible with the present reaction under standard conditions and provided the corresponding products in 66–82% yields. Furthermore, di-substituted quinazolinones also gave the expected products 3x and 3y in 66 and 67% yields, respectively. To our satisfaction, six-ring-fused quinazolinone product 3z could also be obtained in a good yield. However, 3-(2-(prop-1-en-2-yl)phenyl)quinazolin-4(3H)-one failed to give the cyclization product (4a).
The synthetic application of the present reaction was demonstrated via a gram-scale experiment, as shown in Scheme 4. The reaction of 3-(but-3-en-1-yl)quinazolin-4(3H)-one (1a, 4 mmol) with 2-oxo-2-(phenylamino)acetic acid 2a could proceed well to provide the desired product 3a in 79% isolated yield under standard reaction conditions. In addition, when the reaction was carried out in air atmosphere condition, a slightly decreased product was obtained in 76% yield.
To better understand the reaction process of the present reaction, several control experiments were carried out, as shown in Scheme 5. First, the model reaction was performed under standard conditions with two equiv. of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger, and no desired product 3a was observed (Scheme 5a), indicating a free radical might be involved in the current transformation. Furthermore, a reaction of 1a and 2l was conducted with the addition of two equiv. of 2,6-di-tert-butyl-4-methylphenol (BHT) or 1,1-diphenylethylene, and 3l was not observed. Meanwhile, radical-adducts 5a and 5b were detected through GC-MS analysis (Scheme 5b,c). These results implied that a carbamoyl radical might generate during the reaction process.
Based on the control experiment and relevant reports [69,70,71,72], we speculated a possible reaction pathway, as shown in Scheme 6. Initially, compound 2a might give a key carbamoyl radical TM-1 through a successive oxidative, hydrogen atom transfer (HAT), and decarboxylative process in the presence of SO4−•, which can be generated via the heat-promoted homolytic cleavage of (NH4)2S2O8 in DMSO at high temperature. The radical TM-1 further attacks the carbon–carbon double bond of 1a to form a carbon radical intermediate TM-2. Then, the radical intermediate TM-2 adds to the C=N bond to afford a nitrogen radical TM-3, which undergoes a 1,2-hydrogen atom transfer (1,2-HAT) process to deliver another carbon radical intermediate TM-4. Finally, the target product 3a is generated through oxidative dehydrogenation of TM-4 in the presence of radical anion SO4−•.

3. Experimental Section

3.1. General Information

Unless otherwise specified, all reagents and reaction solvents were obtained from commercial suppliers and used without further purification. The NMR spectra were recorded (Supplementary Materials Figures S1–S50) on an NMR spectrometer (Bruker, Rheinstetten, Germany, 1H NMR at 400 MHz, 13C NMR at 100 MHz and 19F NMR at 376 MHz, respectively). Chemical shifts were calibrated in ppm using residual CDCl3 as an internal reference (δ 7.26 ppm for 1H and 77.0 ppm for 13C). The high-resolution mass spectra (HRMS) were recorded on a spectrometer operating on ESI-TOF. Melting points were measured on a melting point apparatus and are uncorrected.

3.2. General Procedure for the Preparation of 3

To an oven-dried reaction vessel equipped with a magnetic stir bar was added quinazolin-4(3H)-one 1 (0.3 mmol, 1 eq.), oxamic acid 2 (0.6 mmol, 2 eq.), and (NH4)2S2O8 (1.05 mmol, 3.5 eq.) in DMSO-H2O mixed solvent (3 mL, v/v 100:1). The reaction mixture was stirred at 100 °C under N2 atmosphere for about 6–8 h, which was monitored by thin-layer chromatography (TLC). After completion, the reaction was allowed to cool to room temperature and then H2O (5 mL) was added to the mixture, which was further extracted with CH2Cl2 three times (10 mL × 3). The organic phase was then dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography using a mixture of solvent consisting of petroleum ether and ethyl acetate as eluent (PE/EA 3:1–1:1) to obtain the desired product 3.

3.3. Gram-Scale Synthesis of 3a

To an oven-dried reaction vessel equipped with a magnetic stir bar was added 3-(but-3-en-1-yl)quinazolin-4(3H)-one 1a (4 mmol, 0.800 g), 2-oxo-2-(phenylamino)acetic acid 2a (8 mmol, 1.320 g), and (NH4)2S2O8 (14 mmol, 3.195 g) in DMSO-H2O mixed solvent (40 mL, v/v 100:1). The reaction mixture was stirred at 100 °C under N2 atmosphere for about 6 h. After completion, the reaction was allowed to cool to room temperature and then H2O (30 mL) was added to the mixture, which was further extracted with CH2Cl2 three times (30 mL × 3). The organic phase was then dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography using a mixture solvent consisting of petroleum ether and ethyl acetate as eluent (PE/EA 3:1–1:1) to obtain 1.009 g of 3a.

3.4. Characterization Data of Products 3a–3z

2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)-N-phenylacetamide (3a):
White solid; mp 172–173 °C; 78.5 mg (isolated yield 82%); 1H NMR (400 MHz, Chloroform-d) δ 9.86 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 4.45–4.26 (m, 1H), 4.02–3.86 (m, 1H), 3.83–3.64 (m, 1H), 3.16 (dd, J = 15.1, 7.7 Hz, 1H), 2.73 (dd, J = 15.1, 4.3 Hz, 1H), 2.63 (dt, J = 13.8, 7.5 Hz, 1H), 2.08–1.97 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.9, 161.3, 160.5, 148.2, 138.3, 134.5, 129.0, 126.8, 126.7, 126.4, 124.1, 120.7, 119.7, 44.8, 40.9, 40.0, 27.7. HRMS (ESI) m/z calcd for C19H18N3O2 [M + H]+: 320.1394; found: 320.1397.
2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)-N-(p-tolyl)acetamide (3b):
White solid; mp 167–168 °C; 82.9 mg (isolated yield 83%); 1H NMR (400 MHz, Chloroform-d) δ 9.64 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 6.8 Hz, 1H), 7.68 (d, J = 7.7 H, 1H), 7.51–7.42 (m, 3H), 7.11 (d, J = 7.5 Hz, 2H), 4.34 (t, J = 10.4 Hz, 1H), 3.99–3.89 (m, 1H), 3.76–3.65 (m, 1H), 3.20–3.10 (m, 1H), 2.74–2.68 (m, 1H), 2.67–2.58 (m, 1H), 2.30 (s, 3H), 2.08–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.8, 161.2, 160.6, 148.3, 135.7, 134.4, 133.7, 129.5, 126.7,126.6, 126.5, 120.7, 119.7, 44.8, 40.9, 39.9, 27.6, 20.8. HRMS (ESI) m/z calcd for C20H20N3O2 [M + H]+: 334.1550; found: 334.1552.
N-(4-fluorophenyl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3c):
White solid; mp 198–199 °C; 74.8 mg (isolated yield 74%); 1H NMR (400 MHz, Chloroform-d) δ 10.00 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.58–7.48 (m, 3H), 7.02 (t, J = 8.3 Hz, 2H), 4.49–4.29 (m, 1H), 4.02–3.94 (m, 1H), 3.82–3.65 (m, 1H), 3.15 (dd, J = 14.9, 7.8 Hz, 1H), 2.77 (d, J = 14.8 Hz, 1H), 2.71–2.55 (m, 1H), 2.09–2.01 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.9, 161.3, 160.5, 159.1 (d, JC-F = 242.1 Hz), 148.1, 134.5, 134.4 (d, JC-F = 2.4 Hz), 126.8, 126.7, 126.3, 121.3 (d, JC-F = 7.8 Hz), 120.7, 115.6 (d, JC-F = 22.3 Hz), 44.8, 40.8, 39.9, 27.6; 19F NMR (376 MHz, Chloroform-d) δ -118.24. HRMS (ESI) m/z calcd for C19H17FN3O2 [M + H]+: 338.1299; found: 338.1304.
N-(4-chlorophenyl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3d):
White solid; mp 215–216 °C; 76.3 mg (isolated yield 72%); 1H NMR (400 MHz, Chloroform-d) δ 10.16 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60–7.44 (m, 3H), 7.32–7.26 (m, 2H), 4.49–4.30 (m, 1H), 4.06–3.91 (m, 1H), 3.74 (d, J = 7.6 Hz, 1H), 3.15 (dd, J = 15.1, 8.0 Hz, 1H), 2.78 (d, J = 15.0 Hz, 1H), 2.72–2.57 (m, 1H), 2.11–2.00 (d, J = 21.4 Hz, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.0, 161.3, 160.5, 148.0, 137.0, 134.5, 129.0, 128.9, 126.9, 126.7, 126.3, 120.8, 120.7, 44.8, 40.8, 40.0, 27.7. HRMS (ESI) m/z calcd for C19H17ClN3O2 [M + H]+: 354.1004; found: 354.1006.
N-(4-bromophenyl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3e):
White solid; mp 213–214 °C; 85.8 mg (isolated yield 72%); 1H NMR (400 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52–7.45 (m, 3H), 7.42 (d, J = 8.7 Hz, 2H), 4.36 (t, J = 10.4 Hz, 1H), 4.02–3.89 (m, 1H), 3.80–3.66 (m, 1H), 3.14 (dd, J = 15.1, 8.0 Hz, 1H), 2.72 (dd, J = 15.1, 4.1 Hz, 1H), 2.66–2.57 (m, 1H), 2.07–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.0, 161.3, 160.4, 148.0, 137.5, 134.5, 131.9, 126.8, 126.7, 126.3, 121.2, 120.7, 116.5, 44.8, 40.8, 40.1, 27.7. HRMS (ESI) m/z calcd for C19H17BrN3O2 [M + H]+: 398.0499; found: 398.0494.
2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-(4-phenoxyphenyl)acetamide (3f):
White solid; mp 197–198 °C; 80.2 mg (isolated yield 65%); 1H NMR (400 MHz, Chloroform-d) δ 9.89 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 7.04–6.86 (m, 4H), 4.37 (t, J = 10.5 Hz, 1H), 3.97 (q, J = 11.1, 10.7 Hz, 1H), 3.81–3.67 (m, 1H), 3.16 (dd, J = 15.1, 7.7 Hz, 1H), 2.75 (dd, J = 15.1, 3.6 Hz, 1H), 2.70–2.58 (m, 1H), 2.10–2.00 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.8, 161.3, 160.5, 157.5, 153.2, 148.1, 134.5, 133.9, 129.7, 126.8, 126.7, 126.4, 123.0, 121.3, 120.7, 119.7, 118.3, 44.8, 40.9, 39.9, 27.6. HRMS (ESI) m/z calcd for C25H22N3O3 [M + H]+: 412.1656; found: 412.1662.
2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (3g):
White solid; mp 224–225 °C; 88.3 mg (isolated yield 76%); 1H NMR (400 MHz, Chloroform-d) δ 10.48 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.74–7.64 (m, 3H), 7.56 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 4.44–4.29 (m, 1H), 4.01–3.86 (m, 1H), 3.79–3.67 (m, 1H), 3.17 (dd, J = 15.1, 8.1 Hz, 1H), 2.76 (dd, J = 15.1, 3.4 Hz, 1H), 2.63 (dt, J = 14.4, 7.6 Hz, 1H), 2.09–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.3, 161.4, 160.4, 147.8, 141.5, 134.6, 127.0, 126.7, 126.3, 126.1, 124.1 (q, JC-F = 269.8 Hz), 125.7 (q, JC-F = 34.0 Hz), 120.6, 119.2, 44.8, 40.7, 40.1, 27.7; 19F NMR (376 MHz, Chloroform-d) δ -62.07. HRMS (ESI) m/z calcd for C20H17F3N3O2 [M + H]+: 388.1267; found: 388.1275.
2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-(4-((trifluoromethyl)thio)phenyl)acetamide (3h):
White solid; mp 206–207 °C; 78.0 mg (isolated yield 62%); 1H NMR (400 MHz, Chloroform-d) δ 10.51 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.74–7.65 (m, 3H), 7.61 (d, J = 7.9 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 4.44–4.33 (m, 1H), 4.02–3.93 (m, 1H), 3.78–3.66 (m, 1H), 3.17 (dd, J = 15.0, 8.1 Hz, 1H), 2.78 (d, J = 15.2 Hz, 1H), 2.71–2.58 (m, 1H), 2.11–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.3, 161.4, 160.4, 147.8, 141.0, 137.5, 134.6, 129.5 (d, JC-F = 306.5 Hz), 127.0, 126.8, 126.1, 120.6, 120.1, 118.4, 44.8, 40.8, 40.2, 27.7; 19F NMR (376 MHz, Chloroform-d) δ −43.35. HRMS (ESI) m/z calcd for C20H17F3N3O2S [M + H]+: 420.0988; found: 420.0992.
N-(2-bromophenyl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3i):
White solid; mp 197–198 °C; 69.1 mg (isolated yield 58%); 1H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.36–8.15 (m, 2H), 7.78–7.65 (m, 2H), 7.55–7.41 (m, 2H), 7.35–7.27 (m, 1H), 7.03–6.92 (m, 1H), 4.48–4.24 (m, 1H), 4.11–3.90 (m, 1H), 3.88–3.68 (m, 1H), 3.35–3.14 (m, 1H), 3.00–2.80 (m, 1H), 2.76–2.59 (m, 1H), 2.16–1.99 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.9, 160.6, 148.4, 135.6, 134.3, 132.4, 128.2, 126.7, 126.6, 126.5, 125.7, 123.0, 120.7, 114.1, 44.9, 40.7, 39.3, 27.0. HRMS (ESI) m/z calcd for C19H17BrN3O2 [M + H]+: 398.0499; found: 398.0495.
2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)-N-(m-tolyl)acetamide (3j):
White solid; mp 238–239 °C; 63.9 mg (isolated yield 64%); 1H NMR (400 MHz, Chloroform-d) δ 9.71 (s, 1H), 8.39 (d, J = 7.9 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 4.44 (t, J = 10.5 Hz, 1H), 4.04 (q, J = 10.7 Hz, 1H), 3.78 (d, J = 18.6 Hz, 1H), 3.23 (dd, J = 14.9, 7.2 Hz, 1H), 2.83 (d, J = 14.7 Hz, 1H), 2.77–2.66 (m, 1H), 2.41 (s, 3H), 2.17–2.06 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.8, 161.3, 160.5, 148.2, 138.9, 138.2, 134.4, 128.8, 126.8, 126.7, 126.4, 124.9, 120.7, 120.4, 116.7, 44.8, 40.9, 40.0, 27.6, 21.5. HRMS (ESI) m/z calcd for C20H20N3O2 [M + H]+: 334.1550; found: 334.1557.
N-(3-bromophenyl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3k):
White solid; mp 234–235 °C; 79.8 mg (isolated yield 67%); 1H NMR (400 MHz, Chloroform-d) δ 10.21 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 20.1, 7.6 Hz, 2H), 7.25–7.14 (m, 2H), 4.47–4.25 (m, 1H), 4.09–3.89 (m, 1H), 3.78–3.61 (m, 1H), 3.15 (dd, J = 15.0, 8.2 Hz, 1H), 2.73 (dd, J = 15.1, 3.4 Hz, 1H), 2.64 (dt, J = 14.1, 7.7 Hz, 1H), 2.08–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.1, 161.3, 160.5, 148.0, 139.7, 134.6, 130.3, 127.0, 126.9, 126.7, 126.3, 122.6, 122.6, 120.7, 118.0, 44.8, 40.8, 40.1, 27.8. HRMS (ESI) m/z calcd for C19H17BrN3O2 [M + H]+: 398.0499; found: 398.0494.
N-butyl-2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)acetamide (3l):
White solid; mp 167–168 °C; 69.1 mg (isolated yield 77%); 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 6.85 (s, 1H), 4.33 (t, J = 10.5 Hz, 1H), 4.01–3.91 (m, 1H), 3.74–3.57 (m, 1H), 3.31- 3.24 (m, 2H), 2.97 (dd, J = 14.9, 6.2 Hz, 1H), 2.59 (dd, J = 14.6, 6.2 Hz, 2H), 2.02 (d, J = 11.6 Hz, 1H), 1.52–1.44 (m 2H), 1.34 (dt, J = 14.8, 7.4 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ 170.4, 161.1, 160.7, 148.5, 134.2, 126.6, 126.5, 120.7, 44.8, 41.0, 39.3, 38.5, 31.6, 27.1, 20.1, 13.7. HRMS (ESI) m/z calcd for C17H22N3O2 [M + H]+: 300.1707; found: 300.1714.
N-cyclopentyl-2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)acetamide (3m):
White solid; mp 206–207 °C; 67.2 mg (isolated yield 72%); 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.02 (s, 1H), 4.32 (t, J = 10.2 Hz, 1H), 4.24–4.15 (m, 1H), 4.00–3.90 (m, 1H), 3.67–3.59 (m, 1H), 2.92 (dd, J = 14.9, 6.4 Hz, 1H), 2.68–2.48 (m, 2H), 2.10–1.86 (m, 4H), 1.71- 1.53 (m, 4H), 1.45–1.34 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 170.0, 161.1, 160.7, 148.5, 134.3, 126.6, 126.5, 120.7, 51.3, 44.8, 41.1, 38.7, 33.1, 27.2, 23.7. HRMS (ESI) m/z calcd for C18H22N3O2 [M + H]+: 312.1707; found: 312.1712.
N-(adamantan-1-yl)-2-(9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)acetamide (3n):
White solid; mp 85–86 °C; 88.2 mg (isolated yield 78%); 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 6.46 (s, 1H), 4.32 (t, J = 10.4 Hz, 1H), 4.02–3.89 (m, 1H), 3.65–3.58 (m, 1H), 2.90 (dd, J = 14.8, 5.9 Hz, 1H), 2.65–2.54 (m, 1H), 2.49 (dd, J = 14.8, 6.3 Hz, 1H), 2.11–1.93 (m, 10H), 1.70–1.59 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ 169.6, 161.1, 160.7, 148.7, 134.2, 126.6, 126.5, 126.4, 120.7, 52.0, 44.8, 41.6, 41.2, 39.6, 36.3, 29.4, 27.1. HRMS (ESI) m/z calcd for C23H28N3O2 [M + H]+: 378.2176; found: 378.2179.
N-benzyl-2-(9-oxo-1,2,3,9-tetrahydropyrrolo
[2,1-b]quinazolin-3-yl)acetamide (3o):
White solid; mp 174–175 °C; 65.0 mg (isolated yield 65%); 1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.49–7.34 (m, 3H), 7.26 (s, 5H), 4.56–4.37 (m, 2H), 4.37–4.26 (m, 1H), 4.01–3.86 (m, 1H), 3.74–3.61 (m, 1H), 3.00 (dd, J = 15.0, 6.5 Hz, 1H), 2.72–2.54 (m, 2H), 2.11–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 170.4, 160.8, 160.7, 148.5, 138.1, 134.1, 128.7, 127.8, 127.5, 126.6, 126.5, 126.5, 120.7, 44.7, 40.9, 38.5, 27.2. HRMS (ESI) m/z calcd for C20H20N3O2 [M + H]+: 334.1550; found: 334.1557.
2-(8-fluoro-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3q):
White solid; mp 202–203 °C; 74.8 mg (isolated yield 74%); 1H NMR (400 MHz, Chloroform-d) δ 9.45 (s, 1H), 7.68 (q, J = 8.1 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.17–7.05 (m, 2H), 4.42–4.27 (m, 1H), 4.01–3.86 (m, 1H), 3.71 (d, J = 15.0 Hz, 1H), 3.15 (dd, J = 15.1, 7.2 Hz, 1H), 2.73 (dd, J = 15.1, 4.7 Hz, 1H), 2.67–2.56 (m, 1H), 2.09–1.98 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.7, 162.8, 162.1, 158.9 (d, JC-F = 249.5 Hz), 150.6, 138.1, 134.8 (d, JC-F = 10.4 Hz), 129.0, 124.2, 122.4 (d, JC-F = 4.2 Hz), 119.7, 113.3 (d, JC-F = 20.8 Hz), 110.5 (d, JC-F = 6.9 Hz), 44.8, 40.9, 39.7, 27.3; 19F NMR (376 MHz, Chloroform-d) δ -110.23. HRMS (ESI) m/z calcd for C19H17FN3O2 [M + H]+: 338.1299; found: 338.1292.
2-(7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3r):
White solid; mp 217–218 °C; 71.0 mg (isolated yield 71%); 1H NMR (400 MHz, Chloroform-d) δ 10.03 (s, 1H), 8.10 (s, 1H), 7.65–7.53 (m, 4H), 7.34 (d, J = 6.6 Hz, 2H), 7.10 (t, J = 6.7 Hz, 1H), 4.37 (t, J = 10.7 Hz, 1H), 3.95 (q, J = 11.3, 10.6 Hz, 1H), 3.71 (d, J = 17.3 Hz, 1H), 3.25–3.10 (m, 1H), 2.73 (d, J = 15.2 Hz, 1H), 2.63 (dt, J = 15.0, 8.0 Hz, 1H), 2.50 (s, 3H), 2.07–1.97 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.0, 160.6, 160.4, 146.2, 138.4, 137.0, 135.9, 129.0, 126.2, 126.1, 124.1, 120.5, 119.6, 44.7, 40.8, 40.2, 27.8, 21.3. HRMS (ESI) m/z calcd for C20H20N3O2 [M + H]+: 334.1550; found: 334.1556.
2-(7-chloro-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3s):
White solid; mp 238–239 °C; 80.5 mg (isolated yield 76%); 1H NMR (400 MHz, Chloroform-d) δ 9.36 (s, 1H), 8.27 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 4.49–4.31 (m, 1H), 4.05–3.93 (m, 1H), 3.81–3.67 (m, 1H), 3.15 (dd, J = 15.2, 7.2 Hz, 1H), 2.75 (dd, J = 15.2, 4.6 Hz, 1H), 2.71–2.59 (m, 1H), 2.12–2.02 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.7, 161.5, 159.5, 146.8, 138.1, 134.8, 132.6, 129.1, 128.1, 126.1, 124.3, 121.8, 119.7, 44.9, 40.9, 39.7, 27.5. HRMS (ESI) m/z calcd for C19H17ClN3O2 [M + H]+: 354.1004; found: 354.1002.
2-(9-oxo-7-(trifluoromethyl)-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3t):
White solid; mp 191–192 °C; 84.8 mg (isolated yield 73%); 1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.57 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 4.46–4.28 (m, 1H), 4.04–3.93 (m, 1H), 3.74 (d, J = 15.5 Hz, 1H), 3.17 (dd, J = 15.3, 6.6 Hz, 1H), 2.76 (dd, J = 15.3, 5.3 Hz, 1H), 2.73–2.58 (m, 1H), 2.12–2.01 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.6, 163.3, 159.8, 150.6, 137.9, 130.6 (q, JC-F = 3.2 Hz), 129.0, 128.6 (q, JC-F = 33.3 Hz), 127.5, 124.5 (q, JC-F = 4.0 Hz), 124.3, 123.6 (q, JC-F = 270.5 Hz), 120.7, 119.7, 45.0, 41.0, 39.4, 27.2; 19F NMR (376 MHz, Chloroform-d) δ -62.27. HRMS (ESI) m/z calcd for C20H17F3N3O2 [M + H]+: 388.1267; found: 388.1261.
2-(6-fluoro-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3u):
White solid; mp 181–182 °C; 68.8 mg (isolated yield 68%); 1H NMR (400 MHz, Chloroform-d) δ 9.36 (s, 1H), 8.42–8.18 (m, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.7 Hz, 3H), 7.18 (t, J = 8.4 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 4.43–4.27 (m, 1H), 4.00–3.89 (m, 1H), 3.84–3.66 (m, 1H), 3.15 (dd, J = 15.2, 6.9 Hz, 1H), 2.73 (dd, J = 15.2, 5.1 Hz, 1H), 2.67–2.58 (m, 1H), 2.13–1.99 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.7, 166.4 (d, JC-F = 252.9 Hz), 162.5, 159.9, 150.6 (d, JC-F = 12.8 Hz), 138.0, 129.3 (d, JC-F = 10.6 Hz), 129.0, 124.2, 119.7, 117.4, 115.4 (d, JC-F = 23.3Hz), 112.0 (d, JC-F = 22.0Hz), 44.8, 40.9, 39.6, 27.4; 19F NMR (376 MHz, Chloroform-d) δ -103.09. HRMS (ESI) m/z calcd for C19H17FN3O2 [M + H]+: 338.1299; found: 338.1303.
2-(6-chloro-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3v):
White solid; mp 187–188 °C; 76.3 mg (isolated yield 72%); 1H NMR (400 MHz, Chloroform-d) δ 9.24 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 4.41–4.27 (m, 1H), 4.02–3.90 (m, 1H), 3.81–3.68 (m, 1H), 3.15 (dd, J = 15.2, 6.9 Hz, 1H), 2.73 (dd, J = 15.2, 5.1 Hz, 1H), 2.69–2.59 (m, 1H), 2.09–2.00 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.7, 162.5, 160.0, 149.4, 140.6, 138.0, 129.1, 128.0, 127.3, 126.1, 124.3, 119.7, 119.2, 44.9, 40.9, 39.6, 27.4. HRMS (ESI) m/z calcd for C19H17ClN3O2 [M + H]+: 354.1004; found: 354.1007.
2-(9-oxo-6-(trifluoromethyl)-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3w):
White solid; mp 203–204 °C; 85.9 mg (isolated yield 74%); 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 4.45–4.30 (m, 1H), 4.02–3.94 (m, 1H), 3.77 (d, J = 8.4 Hz, 1H), 3.18 (dd, J = 15.4, 6.1 Hz, 1H), 2.76 (dd, J = 15.3, 5.7 Hz, 1H), 2.72–2.60 (m, 1H), 2.17–2.04 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.6, 162.5, 159.8, 148.5, 137.9, 135.8 (q, JC-F = 32.8 Hz), 129.0, 127.7, 124.4, 124.1 (q, JC-F = 3.9 Hz), 123.3 (q, JC-F = 271.3 Hz), 123.0, 122.6 (q, JC-F = 3.4 Hz), 119.7, 45.0, 40.8, 39.3, 27.1; 19F NMR (376 MHz, Chloroform-d) δ −63.14. HRMS (ESI) m/z calcd for C20H17F3N3O2 [M + H]+: 388.1267; found: 388.1270.
2-(6,7-difluoro-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3x):
White solid; mp 220–221 °C; 70.3 mg (isolated yield 66%); 1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.05 (t, J = 9.2 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.45 (dd, J = 10.4, 7.1 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 4.43–4.27 (m, 1H), 4.04–3.90 (m, 1H), 3.81–3.68 (m, 1H), 3.14 (dd, J = 15.3, 6.5 Hz, 1H), 2.75 (dd, J = 15.3, 5.4 Hz, 1H), 2.69–2.61 (m, 1H), 2.13–2.02 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 168.6, 162.0, 159.2 (d, JC-F = 2.5 Hz), 154.8 (dd, JC-F = 256.7 Hz, 14.8 Hz), 147.2 (dd, JC-F = 205.7 Hz, 13.8 Hz), 137.9, 129.1, 124.4, 119.7, 117.7 (d, JC-F = 7.6 Hz), 114.5, 114.3, 114.0 (dd, JC-F = 18.8 Hz, 1.7 Hz), 45.0, 40.9, 39.4, 27.3; 19F NMR (376 MHz, Chloroform-d) δ -126.08 (d, J = 21.6 Hz), -136.11 (d, J = 21.6 Hz). HRMS (ESI) m/z calcd for C19H16F2N3O2 [M + H]+: 356.1205; found: 356.1209.
2-(5,6-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b]quinazolin-3-yl)-N-phenylacetamide (3y):
White solid; mp 233–234 °C; 69.8 mg (isolated yield 67%); 1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.35–7.24 (m, 3H), 7.10 (t, J = 7.3 Hz, 1H), 4.44–4.25 (m, 1H), 4.01–3.85 (m, 1H), 3.79–3.70 (m, 1H), 3.17 (dd, J = 15.1, 7.2 Hz, 1H), 2.75 (dd, J = 15.1, 4.7 Hz, 1H), 2.70–2.57 (m, 1H), 2.51 (s, 3H), 2.42 (s, 3H), 2.09–1.93 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 169.3, 161.1, 159.6, 146.8, 143.4, 137.9, 132.8, 128.9, 128.6, 124.3, 123.4, 120.3, 118.6, 44.5, 41.0, 39.8, 27.6, 21.0, 13.5. HRMS (ESI) m/z calcd for C21H22N3O2 [M + H]+: 348.1707; found: 348.1708.
2-(11-oxo-7,8,9,11-tetrahydro-6H-pyrido
[2,1-b]quinazolin-6-yl)-N-phenylacetamide (3z):
White solid; mp 122–123 °C; 73.0 mg (isolated yield 73%); 1H NMR (400 MHz, Chloroform-d) δ 9.40 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (dd, J = 19.9, 7.9 Hz, 4H), 7.29 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 4.57–4.37 (m, 1H), 3.81 (t, J = 13.8 Hz, 1H), 3.34 (d, J = 11.1 Hz, 1H), 3.18 (dd, J = 14.2, 7.5 Hz, 1H), 2.77 (dd, J = 14.2, 3.5 Hz, 1H), 2.34–2.21 (m, 1H), 2.08–1.97 (m, 2H), 1.76–1.64 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 170.0, 161.5, 157.7, 146.4, 138.2, 134.4, 129.0, 127.0, 126.6, 126.1, 123.9, 120.3, 119.5, 40.8, 40.6, 37.9, 26.0, 20.7. HRMS (ESI) m/z calcd for C20H20N3O2 [M + H]+: 334.1550; found: 334.1553.

4. Conclusions

In summary, we have developed a convenient method for the incorporation of an amide group to 2,3-fused quinazolin-4(3H)-ones via the radical cascade reaction of N3-alkenyl-tethered quinazolinones with readily available oxamic acids as amide sources. The reaction was performed well under transition-metal-free conditions with wide functional group compatibility, making it an attractive method for the construction of amide-containing quinazolinone derivatives.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29050997/s1, Figure S1: MS spectra of compound 4a; Figure S2: MS spectra of compound 4b; Figures S3–S52: Copies of the 1H NMR and 13C NMR spectra.

Author Contributions

J.-J.T., M.-Y.Z. and Y.-J.L. performed the experiments. L.-H.Y. analyzed the data. L.-Y.X. wrote the original draft and was responsible for reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Science and Technology Innovation Program of Hunan Province (2022RC1119), the Science and Technology Program of Yong Zhou (2021-YZKJZD-002), and the construct program of applied characteristic discipline in Hunan Province.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 00997 g001
Figure 1. Representative bioactive polycyclic quinoxalin-2(1H)-one derivatives.
Figure 1. Representative bioactive polycyclic quinoxalin-2(1H)-one derivatives.
Molecules 29 00997 g001
Molecules 29 00997 sch001
Scheme 1. Radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. (a) Diverse radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. (b) The carbamoyl-radical-triggered cascade cyclization reaction of N3-alkenyl-tethered quinazolinones.
Scheme 1. Radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. (a) Diverse radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. (b) The carbamoyl-radical-triggered cascade cyclization reaction of N3-alkenyl-tethered quinazolinones.
Molecules 29 00997 sch001
Molecules 29 00997 sch002
Scheme 2. Preparation of 3b–3p. Conditions: 1a (0.3 mmol, 1 eq), 2 (0.6 mmol, 2 eq), (NH4)2S2O8 (1.05 mmol, 3.5 eq), DMSO-H2O (3 mL, v/v 100:1), 100 °C, under N2 atmosphere for 6–8 h. Isolated yields were given.
Scheme 2. Preparation of 3b–3p. Conditions: 1a (0.3 mmol, 1 eq), 2 (0.6 mmol, 2 eq), (NH4)2S2O8 (1.05 mmol, 3.5 eq), DMSO-H2O (3 mL, v/v 100:1), 100 °C, under N2 atmosphere for 6–8 h. Isolated yields were given.
Molecules 29 00997 sch002
Molecules 29 00997 sch003
Scheme 3. Preparation of 3a, 3q–3z. Conditions: 1 (0.3 mmol, 1 eq), 2a (0.6 mmol, 2 eq), (NH4)2S2O8 (1.05 mmol, 3.5 eq), DMSO-H2O (3 mL, v/v 100:1), 100 °C, under N2 atmosphere for 6–8 h. Isolated yields were given.
Scheme 3. Preparation of 3a, 3q–3z. Conditions: 1 (0.3 mmol, 1 eq), 2a (0.6 mmol, 2 eq), (NH4)2S2O8 (1.05 mmol, 3.5 eq), DMSO-H2O (3 mL, v/v 100:1), 100 °C, under N2 atmosphere for 6–8 h. Isolated yields were given.
Molecules 29 00997 sch003
Molecules 29 00997 sch004
Scheme 4. Gram-scale synthesis of 3a.
Scheme 4. Gram-scale synthesis of 3a.
Molecules 29 00997 sch004
Molecules 29 00997 sch005
Scheme 5. Control experiments. (a) The reaction of 1a and 2a in the presence of TEMPO. (b) The reaction of 1a and 2a in the presence of BHT. (c) The reaction of 1a and 2a in the presence of 1,1-diphenylethylene.
Scheme 5. Control experiments. (a) The reaction of 1a and 2a in the presence of TEMPO. (b) The reaction of 1a and 2a in the presence of BHT. (c) The reaction of 1a and 2a in the presence of 1,1-diphenylethylene.
Molecules 29 00997 sch005
Molecules 29 00997 sch006
Scheme 6. Possible mechanism.
Scheme 6. Possible mechanism.
Molecules 29 00997 sch006
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 00997 i001
EntryOxidantSolventTempYield of 3a b
1(NH4)2S2O8DMSO8042%
2K2S2O8DMSO8018%
3Na2S2O8DMSO8024%
4(NH4)2S2O8H2O8027%
5(NH4)2S2O8DMSO/H2O (500:1)8043%
6(NH4)2S2O8DMSO/H2O (100:1)8057%
7(NH4)2S2O8DMSO/H2O (10:1)8046%
8(NH4)2S2O8DMSO/H2O (100:1)9064%
9(NH4)2S2O8DMSO/H2O (100:1)10076%
10(NH4)2S2O8DMSO/H2O (100:1)11073%
11(NH4)2S2O8DMSO/H2O (100:1)7016%
12 c(NH4)2S2O8DMSO/H2O (100:1)10067%
13 d(NH4)2S2O8DMSO/H2O (100:1)10082%
14 e(NH4)2S2O8DMSO/H2O (100:1)10080%
15NoneDMSO/H2O (100:1)1000%
a General conditions, unless otherwise noted: 1a (0.3 mmol, 1 equiv.), 2a (0.6 mmol, 2 equiv.), oxidant (0.9 mmol, 3 equiv.), solvent (3 mL), 6 h, N2 atmosphere. b Isolated yields. c 2.5 equiv. of (NH4)2S2O8 was used. d 3.5 equiv. of (NH4)2S2O8 was used. e 4 equiv. of (NH4)2S2O8 was used.
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Tang, J.-J.; Zhao, M.-Y.; Lin, Y.-J.; Yang, L.-H.; Xie, L.-Y. Persulfate-Promoted Carbamoylation/Cyclization of Alkenes: Synthesis of Amide-Containing Quinazolinones. Molecules 2024, 29, 997. https://doi.org/10.3390/molecules29050997

AMA Style

Tang J-J, Zhao M-Y, Lin Y-J, Yang L-H, Xie L-Y. Persulfate-Promoted Carbamoylation/Cyclization of Alkenes: Synthesis of Amide-Containing Quinazolinones. Molecules. 2024; 29(5):997. https://doi.org/10.3390/molecules29050997

Chicago/Turabian Style

Tang, Jia-Jun, Meng-Yang Zhao, Ying-Jun Lin, Li-Hua Yang, and Long-Yong Xie. 2024. "Persulfate-Promoted Carbamoylation/Cyclization of Alkenes: Synthesis of Amide-Containing Quinazolinones" Molecules 29, no. 5: 997. https://doi.org/10.3390/molecules29050997

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