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Article

Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines

by
Ting Chen
1,2,
Ting Huang
1,
Moudan Ye
1 and
Jinhai Shen
1,2,*
1
School of Environment and Public Health, Xiamen Huaxia University, Xiamen 361024, China
2
Xiamen Key Laboratory of Food and Drug Safety, Xiamen Huaxia University, Xiamen 361024, China
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(2), 350; https://doi.org/10.3390/molecules30020350
Submission received: 18 December 2024 / Revised: 11 January 2025 / Accepted: 14 January 2025 / Published: 16 January 2025
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Abstract

:
In this study, we present the HOAc-catalyzed selective cleavage of the C=C double bond of enaminones, enabling the formation of a new C–N bond and a new C=N bond for the one-pot synthesis of 2-substituted 3,4-dihydroquinazolines directly from ynones and 2-(aminomethyl)anilines. This method operates in ethanol under transition-metal-free and oxidant-free conditions, offering a sustainable and efficient approach for the synthesis of 3,4-dihydroquinazolines with broad functional group tolerance.

Graphical Abstract

1. Introduction

3,4-Dihydroquinazoline is a versatile nitrogen-containing heterocyclic scaffold found in many bioactive compounds with diverse biological activities (Figure 1). For example, vasicine (I), a natural alkaloid from Adhatoda vasica, exhibits various bioactivities [1,2,3]. Synthetic derivatives of 3,4-dihydroquinazoline have been developed as antiparasitic (II) [4], antiviral (III) [5,6], and antifungal (IV) [7] agents, T-type calcium channel blockers (V) [8,9], and tryptophan reductase inhibitors (VI) [10]. Consequently, various synthetic methods have been established for the construction of 3,4-dihydroquinazoline skeletons [11,12,13,14,15,16,17,18,19,20,21,22]. However, most of reported reactions need harsh conditions and require metal catalysis or special reagents, such as harmful carbodiimide, isocyanate, azide, and isocyanide derivatives. The limitations of these methods for synthesizing such alkaloids heavily impede their biological studies. Hence, the discovery of novel and more direct approaches for the synthesis of such compounds from simple starting materials is highly welcome.
Enaminones, which bear an electron-donating amino group and electron-withdrawing carbonyl group(s) at both termini of a C=C double bond, respectively, are gaining increasing interest because of their unique properties and their importance in organic synthesis as versatile building blocks [23,24,25,26,27]. Particularly, the functionalization of the enaminone via vinyl C=C double bond cleavage is gaining great attention and developing rapidly [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. On one hand, the construction of new chemical bonds has been identified as a highly beneficial strategy for the synthesis of many valuable chemical products, such as functionalized α-ketoamides [28], α-ketoesters [29], 1,2-diketones [30], and other non-cyclic compounds [31,32,33,34,35,36,37,38] (Scheme 1a). On the other hand, the construction of cyclic compounds via cyclization processes with the C=C double bond cleavage has also been achieved for the synthesis of benzoxazoles [39], benzthiazoles [40] (Scheme 1b), and 4(3H)-quinazolinones [41,42,43] (Scheme 1c). However, in order to avoid one or more of the limitations, such as harsh oxidative conditions, the use of noble metal catalysts, or a restricted substrate scope, a new strategy for oxidizing the olefin C=C double bond is still desired. As our successive efforts in enaminone chemistry [44,45], we report herein the acid-catalyzed selective cleavage of C=C double bond of β-enaminones, enabling the formation of a new C–N bond and a new C=N bond for the one-pot synthesis of 2-substituted 3,4-dihydroquinazolines directly from ynones and 2-(aminomethyl)anilines (Scheme 1d).

2. Results and Discussion

Initially, (Z)-3-((2-aminobenzyl)amino)-1,3-diphenylprop-2-en-1-one 1aa was chosen as a model substrate to begin our exploration of the reaction conditions (Table 1). Under additive-free conditions, the reaction of β-enaminone 1aa in ethanol at 100 °C for 4 h afforded the desired 2-phenyl-3,4-dihydroquinazoline 2aa with a yield of 43%, with 48% of the starting material remaining unreacted (Entry 2). To improve the reaction efficiency, we systematically screened a variety of bases and acids as catalysts, including NaOH, KOH, Et3N, HOAc, TFA, TsOH·H2O, NH4Cl, and (NH4)2S2O4 (Entries 2–9). Among these, HOAc proved to be the most effective, delivering the target 3,4-dihydroquinazoline product with an excellent yield of 96%. The effect of the solvent on the reaction was also examined. Substituting ethanol with other solvents, such as methanol, isopropanol, DMSO, DMF, acetonitrile, toluene, or dioxane, led to a noticeable decline in efficiency (Entries 10–16, 37–91%). Additionally, temperature variation revealed that reducing the reaction temperature to 90 °C slightly lowered the yield to 92%, while increasing the temperature beyond 100 °C did not result in a further improvement (Entries 17–18). Finally, we evaluated the impact of substituent variation at the R1 position. Replacing the phenyl group with p-methoxyphenyl, p-fluorophenyl, or methyl groups resulted in yields of 89%, 94%, and 46%, respectively (Entries 19–21). The optimized reaction conditions were identified as follows: 20 mol% of HOAc as the additive and EtOH as the solvent at 100 °C for 4 h (Entry 5).
As the enaminones 1 could be readily prepared from the Michael addition of the aliphatic amines 3 to ynones 4 [46], we employed a straightforward one-pot strategy to synthesize the desired 3,4-dihydroquinazoline products 2 directly from the 2-(aminomethyl)anilines 3 and ynones 4, without isolating the enaminone intermediates 1. To our delight, from the one-pot strategy, 2-phenyl-3,4-dihydroquinazoline 2aa was afforded at a comparable yield to that from enaminone 1aa (94% vs. 96%). Then, the scope of ynones 4 was explored. As illustrated in Scheme 2, When R2 was an aryl substituent, steric effects exert a pronounced influence on the reaction. Substrates with ortho-substituents, such as methoxy, fluorine, or chlorine, experience significant steric hindrance, which interferes with the nucleophilic attack of the amino group on the C=C double bond. Consequently, these substrates require longer reaction times, and the yields are generally lower compared to substrates with para- or meta-substituents (2ab–2ad, 53–68%). In contrast, substrates with meta- or para-substituents undergo the reaction smoothly, yielding the target 3,4-dihydroquinazoline products with good to excellent yields (2ae–2ap, 86–95%). The electronic effects of substituents on the phenyl ring play a lesser role in determining the reaction outcome. Both electron-donating groups (e.g., Me-, Et-, tBu-, and MeO-) and electron-withdrawing groups (e.g., F-, CF3-) at the para-position do not significantly alter the reactivity, allowing the reaction to proceed efficiently. As a result, high yields of the desired products are consistently achieved (2ai–2ap, 86–95%). Furthermore, the reaction demonstrates notable tolerance to a variety of halogen substituents, enabling the synthesis of halogenated 3,4-dihydroquinazoline derivatives (2ac–2ad, 2af–2ag, 2am–2ao). This tolerance is particularly advantageous for subsequent structural modifications, such as palladium-catalyzed coupling reactions, which could facilitate the further functionalization of the products.
In addition to phenyl rings, ynones substituted with other fused or heterocyclic aromatic groups (R2) also serve as excellent substrates for this reaction. Ynones substituted with a 2-naphthyl, 3-pyridyl, 2-thienyl, or 3-thienyl group undergo the reaction smoothly, yielding the target products at good to excellent yields (2aq–2at, 82–89%). Ynones bearing alkyl-substituted R2 groups, such as hexyl and tert-butyl, are also viable substrates in this reaction, albeit with relatively lower yields of 62% and 56%, respectively (2au–2av). This may be attributed to the absence of conjugation disruption in the corresponding products. When R2 was H (1-phenyl-prop-2-yn-1-one 4w as substrate), the reaction failed to yield the targeted product 2aw.
For 2-(aminomethyl)anilines, various functional groups are compatible, including electron-withdrawing groups, such as fluorine (3b) and chlorine (3c), as well as electron-donating groups, like methyl (3d) and tert-butyl (3e). The reaction with these substrates proceeded successfully, yielding the desired products at 84–92% yields (2ba–2ea). Additionally, we obtained single crystals of product 2ba, and the structure of the target compound was further confirmed via single-crystal X-ray diffraction analysis (Figure 2). Based on the X-ray crystallographic data (see Supplementary Materials), the double bond is fixed rather than undergoing facile tautomerization.
To validate the practicality of this acid-catalyzed cascade transformation, a gram-scale one-pot synthesis of 2-phenyl-3,4-dihydroquinazoline 2aa was carried out. Starting from 1.22 g of 3a (10 mmol) and 2.06 g of 4a (10 mmol), the reaction afforded 1.79 g of 2aa with an overall yield of 86% (Scheme 3, Equation (1)). Notably, the reaction also produced acetophenone 5a as a byproduct, which was isolated at an 81% yield. To further demonstrate the synthetic versatility of the obtained product, we explored its application in the preparation of quinazoline and acylated 3,4-dihydroquinazoline derivatives. The oxidation of 2aa using DDQ as an oxidant at room temperature resulted in the efficient formation of 2-phenylquinazoline 6a with a yield of 88% (Equation (2)). Additionally, 2aa underwent smooth acylation using acetyl chloride and benzoyl chloride as acylating agents to furnish the corresponding acylated products, 7a and 7b, with yields of 83% and 87%, respectively (Equation (3)).
Based on our study and the previous literature [39,40,41,42,43], a plausible reaction mechanism was proposed (Scheme 4). With the help of HOAc, the Michael addition of 2-(aminomethyl)anilines 3 to ynones 4 would generate the enaminone intermediates 1. Iminoketone intermediates A may exist though the tautomerization of enaminones 1 in the presence of HOAc. Then, the intramolecular nucleophilic addition of 1 produced the intermediates B. After that, the C–C bond cleavage reaction occurred to generate the 3,4-dihydroquinazoline products 2 and byproduct 5.

3. Experimental Sections

3.1. General Information

Unless otherwise stated, all commercial materials and solvents were used directly without further purification. 1H NMR spectra were recorded on 400 MHz spectrometers (Bruker, Karlsruhe, Germany) and 13C NMR spectra were recorded on a 100 MHz spectrometer. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard at room temperature. 13C NMR spectra were obtained by using the same NMR spectrometers and were calibrated with CDCl3 (δ = 77.00 ppm). High-resolution mass spectra (HRMS) were equipped with an ESI source and a TOF detector (Agilent, Santa Clara, CA, USA). Column chromatography was performed on a silica gel (70–230 mesh ASTM, Adamas-beta, Shanghai, China) using the reported eluents. Thin-layer chromatography (TLC) was carried out on 4 × 15 cm plates with a layer thickness of 0.2 mm (silica gel 60 F254). The ynone substrates were prepared according to the literature [47]. Enaminone 1aa was prepared according to the literature [46].

3.2. General Procedure for the Synthesis of 3,4-Dihydroquinazolines 2

A mixture of ynones 4 (0.3 mmol), 2-(aminomethyl)anilines 3 (0.3 mmol, 1.0 equiv.), and HOAc (0.06 mmol, 20 mol%) in EtOH (1.5 mL) was stirred at 100 °C in a sealed tube for 4 h. After completion of the reaction (monitored by TLC), the reaction was quenched by 10 mL of water and made alkaline with 10% NaOH. The mixture was extracted with dichloromethane (3 × 10 mL). The organic layer was washed with water (20 mL), dried over sodium sulfate, and filtered. The solvent was removed in vacuo, and the crude products was purified via chromatography (silica gel, EtOAc/PE: 1/1 to MeOH/ EtOAc: 1/4) to give 2 (copies of 1H, 13C and 19F NMR spectra see Supplementary Materials).
2-Phenyl-3,4-dihydroquinazoline 2aa. 58.7 mg, 94% yield (one-pot operation). White solid, mp 134–136 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.0 Hz, 2H), 7.40 (dq, J = 14.4, 7.1 Hz, 3H), 7.22–7.09 (m, 2H), 7.05 (td, J = 7.4, 1.0 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.89 (s, 1H), 4.74 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 155.3, 139.9, 134.0, 131.0, 128.6, 128.2, 126.8, 125.6, 124.9, 121.1, 119.7, 44.4. HRMS (ESI) m/z calcd for C14H13N2 (MH+) 209.1073, found 209.1077. The NMR data are in accordance with those reported in the literature [48].
2-(2-Methoxyphenyl)-3,4-dihydroquinazoline 2ab. 48.6 mg, 68% yield. White solid, mp 128–130 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.00 (dt, J = 15.3, 7.6 Hz, 3H), 6.95–6.84 (m, 2H), 6.26 (s, 1H), 4.71 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.2, 154.9, 140.0, 131.9, 130.8, 127.9, 125.5, 124.3, 121.8, 121.1, 120.2, 119.8, 111.4, 55.8, 44.5. HRMS (ESI) m/z calcd for C15H15N2O (MH+) 239.1179, found 239.1180.
2-(2-Fluorophenyl)-3,4-dihydroquinazoline 2ac. 42.7 mg, 63% yield. Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.01 (td, J = 7.9, 1.8 Hz, 1H), 7.42–7.35 (m, 1H), 7.22–7.14 (m, 2H), 7.12–6.98 (m, 3H), 6.93 (d, J = 7.2 Hz, 1H), 5.57 (s, 1H), 4.75 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 160.5 (d, J = 248.0 Hz), 151.9, 140.7, 131.9 (d, J = 9.0 Hz), 130.9 (d, J = 2.6 Hz), 128.0, 125.5, 124.6 (d, J = 3.0 Hz), 124.6, 122.3 (d, J = 10.4 Hz), 121.1, 120.0, 116.0 (d, J = 23.4 Hz), 44.8; 19F NMR (376 MHz, CDCl3) δ −116.06 (s). The characterization data are in accordance with that reported in the literature [49].
2-(2-Chlorophenyl)-3,4-dihydroquinazoline 2ad. 38.5 mg, 53% yield. Pale yellow solid, mp 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.3, 1.7 Hz, 1H), 7.41–7.26 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.95 (dd, J = 14.1, 7.6 Hz, 2H), 5.03 (s, 1H), 4.72 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 154.5, 140.6, 135.1, 131.7, 130.8, 130.7, 129.9, 128.0, 127.1, 125.6, 124.6, 120.9, 119.9, 45.0; HRMS (ESI) m/z calcd for C14H12ClN2 (MH+) 243.0684, found 243.0684.
2-(m-Tolyl)-3,4-dihydroquinazoline 2ae. 58.6 mg, 88% yield. White solid, mp 117–118 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.28 (dd, J = 11.7, 6.1 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 5.26 (dd, J = 304.8, 230.4 Hz, 1H), 4.77 (s, 2H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.4, 155.0, 138.4, 135.4, 131.3, 128.6, 128.4, 128.0, 127.2, 125.5, 124.6, 123.3, 120.2, 44.4, 21.4. HRMS (ESI) m/z calcd for C15H15N2 (MH+) 223.1230, found 223.1235.
2-(3-Fluorophenyl)-3,4-dihydroquinazoline 2af. 62.4 mg, 92% yield. White solid, mp 124–125 °C. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.38 (dd, J = 13.9, 7.8 Hz, 1H), 7.16 (ddd, J = 11.7, 9.8, 4.5 Hz, 2H), 7.05 (dd, J = 12.6, 5.3 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 4.78 (s, 2H), 4.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.8 (d, J = 246.9 Hz), 153.6, 140.9, 137.6 (d, J = 7.5 Hz), 130.2 (d, J = 8.1 Hz), 128.2, 125.5, 124.8, 122.1, 121.9 (d, J = 2.9 Hz), 120.1, 117.5 (d, J = 21.2 Hz), 113.8 (d, J = 23.2 Hz), 44.7; 19F NMR (376 MHz, CDCl3) δ −112.11 (s). HRMS (ESI) m/z calcd for C14H12FN2 (MH+) 227.0979, found 227.0978.
2-(3-Bromophenyl)-3,4-dihydroquinazoline 2ag. 76.4 mg, 89% yield. White solid, mp 132–133 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 8.3 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 4.94 (s, 1H), 4.77 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.4, 140.9, 137.3, 133.5, 130.1, 129.7, 128.2, 125.6, 125.0, 124.9, 122.7, 121.8, 120.1, 44.7. HRMS (ESI) m/z calcd for C14H12BrN2 (MH+) 287.0178, found 287.0178.
2-([1,1′-Biphenyl]-4-yl)-3,4-dihydroquinazoline 2ah. 73.3 mg, 86% yield. Grey solid, mp 193–195 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.1 Hz, 2H), 7.61 (dd, J = 18.2, 7.7 Hz, 4H), 7.44 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 4.78 (s, 2H), 4.24 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.5, 143.4, 140.1, 133.8, 128.9, 128.1, 127.8, 127.2, 127.1, 127.0, 127.0, 125.5, 124.6, 121.6, 120.2, 44.67. HRMS (ESI) m/z calcd for C20H17N2 (MH+) 285.1386, found 285.1389.
2-(p-Tolyl)-3,4-dihydroquinazoline 2ai. 62.6 mg, 94% yield. White solid, mp 159–161 °C. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.23–7.08 (m, 4H), 7.03 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 5.07 (s, 1H), 4.70 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1, 141.5, 139.8, 130.9, 129.3, 128.2, 126.7, 125.5, 124.7, 120.9, 119.8, 44.3, 21.4. HRMS (ESI) m/z calcd for C15H15N2 (MH+) 223.1230, found 223.1235.
2-(4-Ethylphenyl)-3,4-dihydroquinazoline 2aj. 65.8 mg, 93% yield. White solid, mp 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 2H), 7.24 (t, J = 6.5 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.11–6.97 (m, 2H), 6.92 (d, J = 7.2 Hz, 1H), 4.82 (s, 1H), 4.74 (s, 2H), 2.67 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 154.9, 147.1, 141.4, 132.7, 128.0, 128.0, 126.4, 125.5, 124.3, 121.6, 120.3, 44.7, 28.7, 15.4. HRMS (ESI) m/z calcd for C26H17N2 (MH+) 237.1386, found 237.1389.
2-(4-(tert-Butyl)phenyl)-3,4-dihydroquinazoline 2ak. 76.8 mg, 87% yield. White solid, mp 148–150 °C. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.12–6.98 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 4.89 (d, J = 37.4 Hz, 1H), 4.76 (s, 2H), 1.33 (s, 9H); 13C NMR (10 MHz, CDCl3) δ 154.7, 153.9, 141.5, 132.6, 128.0, 126.1, 125.5, 125.5, 124.3, 120.3, 44.8, 34.8, 31.2. HRMS (ESI) m/z calcd for C18H21N2 (MH+) 265.1699, found 265.1703.
2-(4-Methoxyphenyl)-3,4-dihydroquinazoline 2al. 61.4 mg, 86% yield. White solid, mp 151–153 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.7 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.91 (t, J = 8.4 Hz, 3H), 4.72 (s, 2H), 4.48 (s, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 154.6, 141.2, 128.1, 128.0, 127.3, 125.5, 124.3, 121.5, 120.2, 113.8, 55.4, 44.5. HRMS (ESI) m/z calcd for C15H15N2O (MH+) 239.1179, found 239.1179.
2-(4-Fluorophenyl)-3,4-dihydroquinazoline 2am. 61.7 mg, 91% yield. White solid, mp 162–163 °C. 1H NMR (400 MHz, CDCl3) δ 7.85–7.77 (m, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.09 (dt, J = 13.5, 8.0 Hz, 4H), 6.97 (d, J = 7.3 Hz, 1H), 4.80 (s, 2H), 3.99 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 164.2 (d, J = 250.6 Hz), 153.8, 141.2, 131.5 (d, J = 3.1 Hz), 128.6 (d, J = 8.6 Hz), 128.1, 125.5, 124.6, 121.8, 120.1, 115.6 (d, J = 21.8 Hz), 44.7; 19F NMR (376 MHz, CDCl3) δ −109.73 (s). HRMS (ESI) m/z calcd for C14H12FN2 (MH+) 227.0979, found 227.0979.
2-(4-Chlorophenyl)-3,4-dihydroquinazoline 2an. 66.8 mg, 92% yield. White solid, mp 168–170 °C. 1H NMR (400 MHz, CDCl3) δ 7.77–7.69 (m, 2H), 7.43–7.34 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 11.5, 4.1 Hz, 2H), 6.94 (d, J = 7.4 Hz, 1H), 4.77 (s, 2H), 3.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.7, 141.2, 136.6, 133.8, 128.8, 128.1, 127.8, 125.5, 124.7, 121.9, 120.1, 44.7. HRMS (ESI) m/z calcd for C14H12ClN2 (MH+) 243.0684, found 243.0683.
2-(4-Bromophenyl)-3,4-dihydroquinazoline 2ao. 81.5 mg 95% yield. White solid, mp 173–175 °C. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 7.3 Hz, 2H), 6.95 (d, J = 7.2 Hz, 1H), 5.27 (s, 1H), 4.79 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.7, 141.2, 134.3, 131.7, 128.1, 128.0, 125.5, 124.9, 124.7, 120.1, 44.7. HRMS (ESI) m/z calcd for C14H12BrN2 (MH+) 287.0178, found 287.0178.
2-(4-(Trifluoromethyl)phenyl)-3,4-dihydroquinazoline 2ap. 71.2 mg, 86% yield. White solid, mp 181–183 °C. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.3 Hz, 2H), 6.96 (d, J = 7.4 Hz, 1H), 5.40 (s, 1H), 4.81 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.4, 138.8, 132.3 (q, J = 32.6 Hz), 128.2, 126.8, 125.6, 125.6, 125.5, 125.2, 125.0, 122.4, 120.0, 44.7; 19F NMR (376 MHz, CDCl3) δ −62.78 (s). HRMS (ESI) m/z calcd for C15H12F3N2 (MH+) 277.0947, found 277.0946.
2-(Naphthalen-2-yl)-3,4-dihydroquinazoline 2aq. 68.9 mg, 89% yield. Pale yellow solid, mp 156–158 °C. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (dt, J = 17.8, 8.9 Hz, 4H), 7.52 (p, J = 7.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 4.83 (s, 2H), 4.82–4.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.8, 134.3, 132.8, 132.7, 128.6, 128.4, 128.1, 127.7, 127.1, 126.6, 126.0, 125.5, 124.5, 123.8, 120.3, 44.7. HRMS (ESI) m/z calcd for C18H15N2 (MH+) 259.1230, found 259.1228.
2-(Pyridin-3-yl)-3,4-dihydroquinazoline 2ar. 53.9 mg, 86% yield. Pale yellow solid, mp 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 1.7 Hz, 1H), 8.57 (dd, J = 4.8, 1.3 Hz, 1H), 8.15 (dt, J = 8.0, 1.8 Hz, 1H), 7.27 (dd, J = 7.3, 5.4 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 7.06 (ddd, J = 10.1, 8.4, 4.1 Hz, 2H), 6.91 (d, J = 7.4 Hz, 1H), 6.18 (s, 1H), 4.74 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.2, 151.4, 147.6, 139.5, 135.0, 130.0, 128.2, 125.6, 125.2, 123.4, 121.1, 119.5, 44.2. HRMS (ESI) m/z calcd for C13H12N3 (MH+) 210.1026, found 210.1028.
2-(Thiophen-2-yl)-3,4-dihydroquinazoline 2as. 52.6 mg, 82% yield. White solid, mp 98–99 °C. 1H NMR (400 MHz, CDCl3) δ 7.44–7.37 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (dt, J = 14.7, 5.8 Hz, 3H), 6.94 (d, J = 7.4 Hz, 1H), 4.74 (s, 2H), 4.13 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 149.8, 139.8, 128.8, 128.4, 128.1, 127.3, 126.4, 125.5, 125.3, 124.5, 120.5, 44.7. HRMS (ESI) m/z calcd for C12H11N2S (MH+) 215.0637, found 215.0638.
2-(Thiophen-3-yl)-3,4-dihydroquinazoline 2at. 55.2 mg, 86% yield. White solid, mp 139–141 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.8, 1.1 Hz, 1H), 7.50 (dd, J = 5.1, 1.0 Hz, 1H), 7.33 (dd, J = 5.0, 3.0 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.03 (dd, J = 15.2, 7.7 Hz, 2H), 6.93 (d, J = 7.4 Hz, 1H), 4.74 (s, 2H), 4.25 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 150.9, 141.0, 137.6, 128.1, 126.4, 126.1, 125.6, 125.2, 124.5, 121.5, 120.2, 44.5. HRMS (ESI) m/z calcd for C12H11N2S (MH+) 215.0637, found 215.0638.
2-Hexyl-3,4-dihydroquinazoline 2au. 34.9 mg, 62% yield. Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 6.9 Hz, 1H), 7.00–6.92 (m, 1H), 6.88 (d, J = 6.3 Hz, 2H), 4.95 (s, 1H), 4.62 (d, J = 2.5 Hz, 2H), 2.32–2.13 (m, 2H), 1.63 (dt, J = 15.6, 7.9 Hz, 2H), 1.34 (d, J = 5.2 Hz, 2H), 1.28 (d, J = 3.1 Hz, 4H), 0.86 (d, J = 2.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5, 140.7, 134.0, 127.8, 125.5, 123.7, 119.7, 44.8, 36.4, 31.5, 29.0, 27.2, 22.5, 14.0; HRMS (ESI) m/z calcd for C14H21N2 (MH+) 217.1699, found 217.1703. The characterization data are in accordance with those reported in the literature [50].
2-(tert-Butyl)-3,4-dihydroquinazoline 2av. 36.3 mg, 56% yield. Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 4.75 (s, 2H), 4.21–3.99 (m, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.9, 134.7, 128.5, 125.8, 125.7, 118.2, 117.8, 44.0, 37.2, 27.7; HRMS (ESI) m/z calcd for C12H17N2 (MH+) 189.1386, found 189.1389.
5-Fluoro-2-phenyl-3,4-dihydroquinazoline 2ba. 57.0 mg, 84% yield. White solid, mp 142–144 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 2H), 7.56–7.30 (m, 3H), 7.12 (dd, J = 14.7, 7.5 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.73 (t, J = 8.5 Hz, 1H), 4.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9 (d, J = 245.1 Hz), 155.3, 143.6, 135.2, 130.7, 128.6 (d, J = 9.3 Hz), 128.6, 126.4, 118.2 (d, J = 3.7 Hz), 110.8 (d, J = 21.0 Hz), 107.7 (d, J = 17.7 Hz), 38.9. HRMS (ESI) m/z calcd for C14H12FN2 (MH+) 227.0979, found 227.0979.
6-Chloro-2-phenyl-3,4-dihydroquinazoline 2ca. 58.1 mg, 80% yield. White solid, mp 152–154 °C. 1H NMR (400 MHz, CDCl3) δ 7.80–7.73 (m, 2H), 7.49–7.37 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 4.72 (d, J = 2.6 Hz, 2H), 4.42 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 155.1, 140.6, 135.1, 130.8, 129.2, 128.6, 128.1, 126.4, 125.4, 123.9, 121.9, 44.0. HRMS (ESI) m/z calcd for C18H18NO3 (MH+) 296.1281, found 296.1282.
6-Methyl-2-phenyl-3,4-dihydroquinazoline 2da. 57.9 mg, 87% yield. Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.5 Hz, 2H), 7.37 (dt, J = 14.5, 7.1 Hz, 3H), 7.01 (dd, J = 28.8, 7.9 Hz, 2H), 6.72 (s, 1H), 5.60 (s, 1H), 4.68 (s, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.0, 137.0, 134.8, 133.6, 131.0, 128.8, 128.6, 126.8, 126.1, 121.2, 119.4, 44.1, 21.0. HRMS (ESI) m/z calcd for C15H15N2 (MH+) 223.1230, found 223.1233.
6-(tert-Butyl)-2-phenyl-3,4-dihydroquinazoline 2ea. 72.9 mg, 92% yield. White solid, mp 152–154 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.1 Hz, 2H), 7.39 (dd, J = 15.6, 8.1 Hz, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 4.92 (s, 1H), 4.75 (s, 2H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.8, 147.9, 138.1, 134.8, 130.7, 128.6, 126.6, 125.0, 122.4, 121.2, 119.3, 44.7, 34.4, 31.4. HRMS (ESI) m/z calcd for C18H21N2 (MH+) 265.1699, found 265.1703.

3.3. Procedure for Synthesis of 6a

2-Phenyl-3,4-dihydroquinazoline 2aa (0.3 mmol) was dissolved in anhydrous THF (1 mL) and a solution of DDQ (0.3 mmol, 1 equiv.) in anhydrous THF (1 mL) was added. The reaction was stirred at room temperature for 30 min. The reaction was then quenched by the addition of aqueous NaOH solution (1 M, 1 mL). CH2Cl2 (10 mL) and H2O (10 mL) were added to the reaction, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL) and the combined organic phases were dried with MgSO4 and filtered, and all volatiles were removed in vacuo. The residue was purified via flash column chromatography on silica (EtOAc/PE: 1/20) yielding 2-phenylquinazoline 6a.
2-Phenylquinazoline 6a. 54.4 mg, 88% yield. White solid, mp 99–101 °C. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.81–8.50 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.98–7.82 (m, 2H), 7.65–7.44 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 161.0, 160.5, 150.7, 138.0, 134.1, 130.6, 128.6, 128.6, 128.5, 127.2, 127.1, 123.6. The characterization data are in accordance with those reported in the literature [19] (copies of 1H and 13C NMR spectra see Supplementary Materials).

3.4. Procedure for Synthesis of 7

2-Phenyl-3,4-dihydroquinazoline 2aa (0.3 mmol) was dissolved in anhydrous DCM (2 mL). The solution was cooled to 0 °C, and acyl chloride (0.33 mmol, 1.10 equiv.) and Et3N (0.45 mmol, 1.50 equiv.) were added. The mixture was stirred at RT for 2 h. The reaction was then quenched by the addition of H2O (10 mL). CH2Cl2 (10 mL) was added to the reaction, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and the combined organic phases were dried with MgSO4 and filtered, and all volatiles were removed in vacuo. The residue was purified via flash column chromatography on silica (EtOAc/PE: 1/10), yielding 7a and 7b at 83% and 87%, respectively (copies of 1H and 13C NMR spectra see Supplementary Materials).
1-(2-Phenylquinazolin-3(4H)-yl)ethan-1-one 7a. 62.3 mg, 83% yield. White solid, mp 86–88 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 7.8, 1.7 Hz, 2H), 7.55–7.44 (m, 4H), 7.35 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), 4.97 (s, 2H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 154.0, 142.1, 136.5, 131.3, 129.0, 128.5, 128.5, 127.1, 126.5, 125.3, 125.1, 42.9, 25.2; HRMS (ESI) m/z calcd for C16H15N2O (MH+) 251.1179, found 251.1177.
Phenyl(2-phenylquinazolin-3(4H)-yl)methanone 7b. 81.4 mg, 87% yield. White solid, mp 130–132 °C. 1H NMR (400 MHz, CDCl3) δ 7.59–7.54 (m, 3H), 7.46–7.40 (m, 1H), 7.29 (dd, J = 11.8, 7.2 Hz, 4H), 7.20 (tt, J = 13.3, 6.6 Hz, 4H), 7.12 (t, J = 7.6 Hz, 2H), 5.10 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0, 155.0, 142.2, 136.5, 135.6, 131.3, 130.4, 128.6, 128.6, 128.2, 128.0, 127.1, 125.7, 125.3, 125.2, 45.0; HRMS (ESI) m/z calcd for C21H17N2O (MH+) 313.1335, found 313.1336.

4. Conclusions

In conclusion, we have successfully developed a transition-metal-free method for the synthesis of substituted 3,4-dihydroquinazolines via selective cleavage of the C=C bond of enaminones. This protocol utilizes only 0.2 equiv. of HOAc as an additive and employs ethanol as a green and sustainable solvent, making the process both efficient and environmentally friendly. Given the accessibility of the starting materials, the broad substrate scope, and the high reaction efficiencies, this acid-catalyzed cascade reaction holds significant potential for wide-ranging applications in synthetic organic chemistry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30020350/s1, The crystallographic data of 2ba and copies of the NMR (1H, 13C, 19F) spectra of all products are available in the online Supplementary Materials.

Author Contributions

Conceptualization, J.S.; methodology, T.C. and T.H.; investigation, T.C., T.H., and M.Y.; writing—original draft preparation, T.C. and J.S.; writing—review and editing, J.S.; supervision, J.S.; project administration, J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Natural Science Foundation of Xiamen, China (3502Z20227230), the Natural Science Foundation of Fujian, China (2023J011664, 2023J011674).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We gratefully thank Xiuling Cui group from Huaqiao University for the NMR analysis.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 00350 g001
Figure 1. Biologically active 3,4-dihydroquinazolines.
Figure 1. Biologically active 3,4-dihydroquinazolines.
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Molecules 30 00350 sch001
Scheme 1. Functionalization reactions of enaminones via C=C double bond cleavage.
Scheme 1. Functionalization reactions of enaminones via C=C double bond cleavage.
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Molecules 30 00350 sch002
Scheme 2. Substrate scope. a For 8 h.
Scheme 2. Substrate scope. a For 8 h.
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Molecules 30 00350 g002
Figure 2. X-ray structure of 2ba.
Figure 2. X-ray structure of 2ba.
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Molecules 30 00350 sch003
Scheme 3. Gram-scale reaction and synthetic application.
Scheme 3. Gram-scale reaction and synthetic application.
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Molecules 30 00350 sch004
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 30 00350 sch004
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 30 00350 i001
EntryAdditiveSolventT (°C)R1Yield(%) b
1noEtOH100Ph43
2NaOHEtOH100Ph52
3KOHEtOH100Ph46
4Et3NEtOH100Ph53
5HOAcEtOH100Ph96
6TFAEtOH100Ph88
7TsOH·H2OEtOH100Ph91
8NH4ClEtOH100Ph94
9(NH4)2S2O4EtOH100Ph93
10HOAcMeOH100Ph88
11HOAciPrOH100Ph91
12HOAcDMSO100Ph38
13HOAcDMF100Ph88
14HOAcCH3CN100Ph55
15HOAcPhMe100Ph37
16HOAcdioxane100Ph70
17HOAcEtOH90Ph92
18HOAcEtOH110Ph96
19HOAcEtOH1004–OMeC6H4–89
20HOAcEtOH1004–FC6H4–94
21HOAcEtOH100Me46
a Reaction conditions: 1aa (0.2 mmol), additive (0.04 mmol), in 1 mL of solvent at 100 °C for 4 h. b Isolated yields. TFA = trifluoroacetic acid. TsOH = p-toluenesulfonic acid. DMF = N,N–dimethylformamide. DMSO = dimethylsulfoxide.
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Chen, T.; Huang, T.; Ye, M.; Shen, J. Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines. Molecules 2025, 30, 350. https://doi.org/10.3390/molecules30020350

AMA Style

Chen T, Huang T, Ye M, Shen J. Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines. Molecules. 2025; 30(2):350. https://doi.org/10.3390/molecules30020350

Chicago/Turabian Style

Chen, Ting, Ting Huang, Moudan Ye, and Jinhai Shen. 2025. "Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines" Molecules 30, no. 2: 350. https://doi.org/10.3390/molecules30020350

APA Style

Chen, T., Huang, T., Ye, M., & Shen, J. (2025). Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines. Molecules, 30(2), 350. https://doi.org/10.3390/molecules30020350

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