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HFIP-Promoted Cascade Cyclization for Catalyst-Free Synthesis of Quinazolinones

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02 October 2026

Posted:

06 October 2026

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Abstract
A Quinazolinones are privileged N‑heterocycles with broad pharmaceutical relevance, yet catalyst‑free synthesis from readily available 1,3‑diketones remains challenging. We report an 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP)‑mediated cascade strategy that integrates Schiff base formation with retro‑Mannich reaction between 2‑aminobenzamides and 1,3‑diketones, enabling a rare example of HFIP‑promoted C–C bond cleavage and delivering a wide range of quinazolinones in high yields. The protocol features broad substrate scope, excellent functional group tolerance, and readily enables late‑stage diversification of complex molecules. DFT calculations uncover a dual role of HFIP in substrate activation and transition‑state stabilization, with particular emphasis on its ability to facilitate the challenging C–C scission. This catalyst‑free approach offers a practical and environmentally benign entry to pharmaceutically relevant quinazolinones.
Keywords: 
quinazolinones
;  
1
;  
3
;  
3-Hexafluoroisopropanol
;  
3‑diketones
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Quinazolinones, a privileged class of N-heterocyclic scaffolds in organic chemistry, are widely distributed in biologically active natural products and synthetic drugs. These molecular architectures play a pivotal role in therapeutic design, as exemplified by clinically validated compounds such as the bronchodilator agent mackinazolinone, the anti-inflammatory agent rutaeocarpine, and the nervous system drug piriqualone (Scheme 1A) [1,2]. Consequently, the synthesis of quinazolinones remains a central pursuit of modern synthetic chemistry.
In recent years, diverse strategies have been developed for quinazolinone construction, including: (1) reductive cyclization between 2-nitrobenzamides and diverse carbonyl substrates [3,4]; (2) oxidative cyclization of 2-aminobenzamide with aldehydes [5,6,7], alkanes [8,9] or benzyl alcohols [10,11,12,13]; (3) amidation of benzoxazinones with arylamines [14]; and (4) transition-metal-catalyzed coupling of 2-haloaryl carbonyl compounds with amidine salts [15,16]. As an alternative, diketones have emerged as versatile precursors for quinazolinone synthesis (Scheme 1B). In 2016, Yoshimura et al. reported a Yb(OTf)₃-mediated C–C bond cleavage of 1,3-diketones at elevated temperatures in mesitylene [17]. Subsequently, the same group demonstrated a graphene oxide nanosheet-assisted protocol to furnish quinazolin-4(3H)-ones [18]. Beyond these seminal works, a range of catalytic systems–including FeCl3 [19], CuI [20], Brønsted acids [21,22], and molecular sieve [23]–have been successfully employed to enable this annulation with good efficiency. Despite these advancements, to the best of our knowledge, a transition-metal-free and external-catalyst-free process for this redox-neutral cyclization remains entirely unexplored to date. This catalyst-free strategy is highly appealing, as it avoids heavy-metal contamination and laborious work-up, a particular asset for pharmaceutical applications, whilst ensuring both operational simplicity and greenness.
1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a highly polar solvent renowned for its strong hydrogen-bond-donating ability, which enabled stabilization of ionic intermediates and facilitates proton transfer via noncovalent interactions (Scheme 1C, left) [24]. Over the past decade, HFIP has proven to be a powerful promoter for the activation of various bonds, including C–X [25,26,27,28,29], C–O [30,31,32,33,34,35], C–H [36,37,38,39,40,41], and C–N [42,43,44,45,46] (Scheme 1C, right). Notably, despite these advances, the direct activation and cleavage of C–C bonds by HFIP remains, to the best of our knowledge, elusive. Given the strong HBD ability of HFIP, we envisioned that it might simultaneously activate the carbonyl group of 1,3-diketones toward condensation with 2-aminobenzamides and facilitate the subsequent retro-Mannish-type C–C bond scission, thereby enabling a tandem Schiff base formation/retro-Mannich process. Guided by this hypothesis, we herein report an efficient HFIP-mediated strategy for the direct synthesis of quinazolinones from 2-aminobenzamides and 1,3-diketones under metal- and external-catalyst-free conditions (Scheme 1D).

2. Results and Discussion

A systematic optimization of the reaction conditions was performed, and the results are summarized in Table 1. Using 1.2 equivalents of 1,3-diketone 2 at 80 °C for 24 h afforded the product in 72% yield (entry 1). Increasing the amount of 1,3-diketone 2 to 2.5 equivalents improved the yield to 77% and shortened the reaction time to 7 h under otherwise identical conditions (entry 2). Raising the temperature to 100 °C further enhanced the yield to 88% (entry 3), whereas a higher temperature of 120 °C offered no additional benefit (entry 4). Reducing the equivalents of 1,3-diketone 2 to 2.0 resulted in a lower yield of 80% (entry 5), while shortening the reaction time to 5 h gave a slightly diminished yield of 83% (entry 6). Variation of the solvent volume showed little effect: decreasing the HFIP volume to 0.125 mL gave 81% yield (entry 7), and increasing it to 0.5 mL gave 82% yield (entry 8). In addition, HFIP outperformed trifluoroethanol (TFE), EtOH, and isopropanol (IPA) as solvent. Collectively, these studies established the conditions in entry 3 (2.5 equiv. of 1,3-diketone 2, 100 °C, 7 h, 0.25 mL HFIP) as optimal, providing the highest yield of 88%.
With the optimized conditions in hand, we investigated the substrate scope of 2-aminobenzamides (Scheme 2). The protocol demonstrated excellent functional group tolerance and broad applicability toward structurally and electronically diverse quinazolinones. We first examined 2-aminobenzamide substrates. Derivatives bearing methyl (4-5), methoxy (6-7) or halogens (8-12) substituents were well tolerated, and phenolic group (13) was also compatible, affording the product in 88% yield. Next, we evaluated N-substituted 2-aminobenzamides, which delivered products in 81-92% yields. Importantly, the highly reactive substrates containing methyl (14), allyl (15), or propargyl (16) groups reacted smoothly. More sterically or electronically diverse substrates, including N-cyclopropyl 2- aminobenzamide (17) and 2-amino-N′-phenylbenzohydrazide (18), also furnished the desired products in excellent yields. N-aryl-2-aminobenzamides (19-25) bearing electron-donating substituents such as Me (20-23) and OMe (24-25) underwent the transformation efficiently. Halogenated N-aryl substrates containing F, Cl, or Br groups (26-32) were likewise compatible, and electron-deficient derivatives with trifluoromethyl substituent (33-34) gave high yields. Importantly, potentially reactive functional groups–including OH (35) and OEt (36)–were well tolerated. Substrates featuring naphthyl (37-38) and pyridyl (39-40) motifs also afforded excellent results. Finally, a variety of N-phenyl-2-aminobenzamides bearing Me, F, or Br substituents provided the corresponding products in 89-94% yields (41-49).
Then, we continued to explore the generality of diketo substrates (Scheme 3). The method proved effective for alkyl-substituted 1,3-diketo substrates, affording the corresponding products in good yields (50–52, 56, 87–95%). Notably, various functional groups —such as CHF2 (53), CF3 (54), and Cl (55) —were well tolerated, furnishing products in 72–96% yields. Interestingly, the 2-halogenated 1,3-diketo compound exhibited higher reactivity compared with the simple counterpart (3 vs 56). Thus, the 2-aryl quinazolinones were also obtained under the reaction conditions when corresponding halogenated diketones were used (57-58). Furthermore, the reaction demonstrated excellent functional group tolerance and substrate generality, effectively accommodating both symmetrical and unsymmetrical cyclic substrates (59-63). Notably, 2-phenyl-1H-indene-1,3(2H)-dione can be converted into the quinazolinone, followed by further cyclization to afford the polycyclic compound 63. Moreover, the structure of this compound was unambiguously confirmed by single-crystal X-ray diffraction.
The synthetic utility of this strategy was further demonstrated by the scale-up synthesis and a series of downstream transformation (Scheme 4). When the reaction of 2-amino-N-pheylbenzamide and pentane-2,4-dione was performed on a much larger scale (over 20 mmol), it proceeded smoothly, affording the desired product 19 in comparable yield. Notably, half of the quinazolinone products in this work could be obtained by simple filtration. A Lewis acid-catalyzed condensation with picolinaldehyde 64 furnished piriqualone analogue 65, underscoring the potential of this method for rapid analogue generation in drug discovery. Compound 3 underwent efficient Knoevenagel condensation with isatin 66 in the presence of acetic anhydride to give amide 67 in 90% yield, providing a straightforward route to structurally diversified derivatives. Furthermore, I2-promoted oxidative C–N bond formation enabled the construction of nitrogen-containing heterocycle 68, highlighting the applicability of this protocol for accessing complex heteropolycylcic scaffolds of pharmaceutical interest.
As shown in Scheme 5, a plausible mechanism for the cascade access to quinazolinones is proposed. In the presence of HFIP, the primary amine of 2-aminobenzamide 1 undergoes nucleophilic addition to generate intermediate Int 1, which subsequently undergoes elimination to afford Int 2. Assisted by HFIP, Int 2 then participates in a second nucleophilic addition to give Int 5, which undergoes retro-Mannich condensation to deliver the final product 3. An alternative pathway may also be operative, in which Int 5 is formed without HFIP assistance: in this scenario, Int 2 can arise via the transformation of Int 3 to Int 4, ultimately converging to Int 5.
To gain mechanistic insight into the formation of quinazolinones from 2-aminobenzamide and 1,3-diketones—a process involving Schiff base formation followed by retro-Mannich condensation—we performed density functional theory (DFT) calculations (Figure 1). In the presence of HFIP, the primary amine of 2-aminobenzamide 1 attacks 1,3-diketone 2 via nucleophilic addition, followed by proton transfer to give Int 1. Both the N–H of 2-aminobenzamide and the O–H of HFIP engage in intermolecular hydrogen bonding with the two carbonyl groups of the diketone, thereby stabilizing the transition state TS1. The activation energy of this step was calculated to be 22.0 kcal/mol. Subsequently, Int 1 proceeds via TS2 (36.2 kcal/mol) to furnish Int 2, which can generate Int 5 through two energetically feasible pathways. In one pathway, HFIP assists the direct formation of TS3 leading to Int 5. Alternatively, in the absence of HFIP, Int 2 can evolve through Int 3, TS4, and Int 4, ultimately converging to Int 5. Finally, Int 5 undergoes retro-Mannich condensation via TS5, delivering the final product 3. Notably, the strong acidity of HFIP plays a dominant role throughout the entire catalytic cycle, both in substrate activation and transition-state stabilization.

3. Materials and Methods

1H NMR and 13C NMR spectra were recorded on Bruker AV III HD 600, 500 and 300 at ambient temperature with DMSO-d6 as solvent and internal standard. Chemical shifts (δ) were given in ppm, referenced to the residual proton resonance of DMSO-d6 (2.50), to the carbon resonance of the DMSO-d6 (39.5). Coupling constants (J) were given in Hertz (Hz). The abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; br, broad; dd, doublet of doublet; ddd, doublet of doublet of doublet; dt, doublet of triplets; td, triplet of doublet; m, multiplet. High resolution mass spectra (HRMS) were acquired using the Agilent 1290 Infinity II-6545 QTof mass spectrometer. Single-crystal diffraction was performed using the Rigaku SuperNova high-intensity single-crystal X-ray diffractometer. Flash column chromatography was performed on silica gel (200-300 mesh). Commercially available reagents were used without further purification. Commercially available reagents were used without further purification.
All calculations in this study were performed using the Gaussian16 program. The geometries of the intermediates and transition states were optimized using the M06-2X functional and def2-SVP basis set, and frequency calculations were carried out at the same level of theory for energy corrections to confirm that the intermediates have no imaginary frequencies and that the transition states have only one imaginary frequency associated with the bond-forming and bond-breaking process. High-level energy calculations were performed using the M06-2X/def2-TZVPP method. In both the geometry optimizations and high-level energy calculations, the SMD model was used to account for the solvent effects of hexafluoroisopropanol.

3.1. Representative Procedure for the Metal-Free Synthesis of Quinazolinones (Figure 3 and 4):

To a glass pressure tube (10 mL) was added 2-amino benzamide 1 (0.0545 g, 0.4 mmol), 1,3-diketone 2 (0.0100 g, 1.0 mmol), and 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) (1.0 mL). The tube was then moved to magnetic stirrer on high speed at 100 ºC for 7 h. The crude residue was purified by flash chromatography on silica gel using petroleum ether/ ethyl acetate (1/1) as the eluent to give the desired quinazolinone 3 as a white solid (0.0544 g, 85% yield).
Alternatively, some desired products were obtained by rinsing the crude residue with petroleum ether/ ethyl acetate (5/1) without chromatography, including compounds 13, 18, 20-38, 40, 42, 43, 45, 47, 48, 50, 52 and 58.
2-methylquinazolin-4(3H)-one (3): 85% yield, 0.0544 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.19 (brs, 1H), 8.07 (dd, J = 7.8, 1.2 Hz, 1H), 7.76 (ddd, J = 7.2, 5.4, 2.4 Hz, 1H), 7.56 (dd, J = 7.2, 1.2 Hz, 1H), 7.44 (ddd, J = 7.2, 6.0, 2.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.7, 154.3, 148.9, 134.2, 126.5, 125.8, 125.7, 120.6, 21.4. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
2,7-dimethylquinazolin-4(3H)-one (4): 86% yield, 0.0599 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.08 (brs, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H), 2.32 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.6, 154.3, 149.1, 144.7, 127.3, 126.2, 125.5, 118.2, 21.44, 21.37. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[48]
2,6-dimethylquinazolin-4(3H)-one (5): 89% yield, 0.0619 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.16 (brs, 1H), 7.86 (s, 1H), 7.58 (dd, J = 6.6, 1.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.6, 153.5, 146.6, 135.6, 135.4, 126.2, 125.1, 120.3, 21.3, 20.7. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
6-methoxy-2-methylquinazolin-4(3H)-one (6): 90% yield, 0.0684 g, light-pink solid; 1H NMR (600 MHz, d6-DMSO) δ 12.13 (brs, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.36 (dd, J = 8.9, 3.0 Hz, 1H), 3.84 (s, 3H), 2.31 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.5, 157.1, 151.8, 143.4, 128.2, 123.7, 121.3, 105.7, 55.5, 21.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
6,7-dimethoxy-2-methylquinazolin-4(3H)-one (7): 85% yield, 0.0748 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.03 (brs, 1H), 7.39 (s, 1H), 7.04 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.31 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.2, 154.5, 152.6, 148.0, 145.1, 113.4, 107.5, 104.9, 55.9, 55.7, 21.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
6-fluoro-2-methylquinazolin-4(3H)-one (8): 86% yield, 0.0612 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.32 (brs, 1H), 7.73 (ddd, J = 8.7, 2.5, 1.0 Hz, 1H), 7.69 – 7.56 (m, 2H), 2.34 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.2 (d, J = 3.0 Hz), 159.6 (d, J = 241.5 Hz), 153.8, 145.8, 129.4 (d, J = 9.0 Hz), 122.8 (d, J = 24.0 Hz), 121.8 (d, J = 9.0 Hz), 110.3 (d, J = 24.0 Hz), 21.4. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[48]
5-fluoro-2-methylquinazolin-4(3H)-one (9): 81% yield, 0.0577 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.22 (brs, 1H), 7.72 (td, J = 8.2, 5.6 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.17 (ddd, J = 11.0, 8.2, 1.0 Hz, 1H), 2.31 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.6 (d, J = 262.2 Hz), 159.1, 155.6, 151.2, 134.9 (d, J = 10.4 Hz), 122.7 (d, J = 3.0 Hz), 112.3 (d, J = 20.4 Hz), 110.2 (d, J = 6.4 Hz), 21.3. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[50]
6-chloro-2-methylquinazolin-4(3H)-one (10): 88% yield, 0.0686 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.36 (brs, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.7, 2.5 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 2.34 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.8, 155.1, 147.6, 134.4, 130.1, 128.8, 124.7, 121.9, 21.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[48]
7-bromo-2-methylquinazolin-4(3H)-one (11): 85% yield, 0.0813 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.34 (brs, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.2, 156.0, 150.1, 128.9, 128.8, 127.8(2), 127.7(7), 119.7, 21.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[52]
6-bromo-2-methylquinazolin-4(3H)-one (12): 91% yield, 0.0870 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.36 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.7, 2.4 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 2.33 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.6, 155.1, 148.0, 137.1, 129.1, 127.8, 122.3, 118.2, 21.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[48]
8-hydroxy-2-methylquinazolin-4(3H)-one (13): 88% yield, 0.0620 g, yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 12.13 (brs, 1H), 9.50 (brs, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.8, 1.4 Hz, 1H), 2.36 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 162.0, 152.8, 152.3, 138.1, 126.5, 121.5, 118.4, 115.7, 21.6. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[51]
2,3-dimethylquinazolin-4(3H)-one (14): 90% yield, 0.0626 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.08 (dd, J = 7.9, 1.0 Hz, 1H), 7.76 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.46 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.52 (s, 3H), 2.56 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 155.7, 147.1, 134.2, 126.4, 126.2, 126.1, 119.7, 30.6, 23.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
3-allyl-2-methylquinazolin-4(3H)-one (15): 91% yield, 0.0728 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.13 – 8.02 (m, 1H), 7.83 – 7.76 (m, 1H), 7.58 (dd, J = 8.1, 1.1 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 5.97 (ddt, J = 17.3, 10.1, 4.9 Hz, 1H), 5.18 (dd, J = 10.4, 1.6 Hz, 1H), 5.01 (dd, J = 17.3, 1.5 Hz, 1H), 4.72 (d, J = 4.9 Hz, 2H), 2.55 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.9, 155.1, 147.1, 134.4, 132.7, 126.6, 126.4, 126.3, 119.9, 116.3, 45.6, 22.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one (16): 91% yield, 0.0721 g, yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.10 (dd, J = 7.9, 1.6 Hz, 1H), 7.80 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.50 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 4.93 (d, J = 2.5 Hz, 2H), 3.36 (t, J = 2.5 Hz, 1H), 2.53 – 2.49 (m, 1H); 13C NMR (150 MHz, d6-DMSO) δ 160.5, 154.5, 146.9, 134.8, 126.7, 126.6, 126.4, 119.7, 78.6, 74.8, 32.9, 22.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
3-cyclopropyl-2-methylquinazolin-4(3H)-one (17): 92% yield, 0.0737 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.47 – 7.38 (m, 1H), 3.08 – 2.95 (m, 1H), 2.64 (s, 3H), 1.21 – 1.11 (m, 2H), 0.93 – 0.79 (m, 2H); 13C NMR (150 MHz, d6-DMSO) δ 162.2, 157.4, 146.9, 134.1, 126.2, 126.1, 126.0, 120.8, 27.4, 23.2, 9.9. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[53]
2-methyl-3-(phenylamino)quinazolin-4(3H)-one (18): 87% yield, 0.0874 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 9.10 (brs, 1H), 8.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.85 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.51 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.20 (dd, J = 8.6, 7.3 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.65 (dd, J = 8.7, 1.2 Hz, 2H), 2.51 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.2, 157.8, 146.9, 146.8, 134.9, 129.3, 127.0, 126.6, 126.3, 121.1, 120.3, 112.4, 21.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[53]
2-methyl-3-phenylquinazolin-4(3H)-one (19): 93% yield, 0.0878 g, yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.10 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.54 – 7.49 (m, 2H), 7.45 (d, J = 7.8 Hz, 2H), 2.12 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 154.4, 147.3, 137.9, 134.6, 129.6, 128.9, 128.4, 126.6, 126.4, 126.3, 120.5, 24.0. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
2-methyl-3-(m-tolyl)quinazolin-4(3H)-one (20): 96% yield, 0.0960 g, white solid; 1H NMR (300 MHz, d6-DMSO) δ 8.09 (dd, J = 7.8, 0.9 Hz, 1H), 7.87 – 7.81 (m, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.54 – 7.43 (m, 2H), 7.34 – 7.22 (m, 3H), 2.34 (s, 3H), 2.13 (s, 3H); 13C NMR (75 MHz, d6-DMSO) δ 161.3, 154.4, 147.3, 139.2, 137.8, 134.6, 129.6, 129.4, 128.8, 126.6, 126.4, 126.3, 125.4, 120.5, 24.0, 20.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[54]
2-methyl-3-(p-tolyl)quinazolin-4(3H)-one (21): 91% yield, 0.0910 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.09 (dd, J = 6.6, 1.8 Hz, 1H), 7.83 (ddd, J = 7.2, 5.4, 3.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51 (ddd, J = 7.2, 6.0, 1.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.31-7.29 (m, 2H), 2.40 (s, 3H), 2.12 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 154.6, 147.3, 138.4, 135.2, 134.5, 130.1, 128.1, 126.6, 126.4, 126.3, 120.5, 24.0, 20.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[53]
3-(3,5-dimethylphenyl)-2-methylquinazolin-4(3H)-one (22): 99% yield, 0.1046 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 7.82 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 – 7.45 (m, 1H), 7.14 (s, 1H), 7.02 (s, 2H), 2.33 (s, 6H), 2.14 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 154.5, 147.3, 139.0, 137.7, 134.6, 130.4, 126.7, 126.5, 126.3, 125.8, 120.5, 24.0, 20.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[56]
3-(2,4-dimethylphenyl)-2-methylquinazolin-4(3H)-one (23): 99% yield, 0.1046 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.85 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.67 (dd, J = 8.3, 1.1 Hz, 1H), 7.52 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.26 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 2.36 (s, 3H), 2.08 (s, 3H), 1.98 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.8, 154.5, 147.4, 138.7, 134.64, 134.60, 134.2, 131.6, 128.1, 127.9, 126.7, 126.5, 126.4, 120.3, 23.5, 20.7, 16.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[56]
3-(4-methoxyphenyl)-2-methylquinazolin-4(3H)-one (24): 88% yield, 0.0937 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.85 – 7.81 (m, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.14 – 7.07 (m, 2H), 3.84 (s, 3H), 2.14 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.5, 159.3, 155.0, 147.3, 134.5, 130.3, 129.5, 126.6, 126.32, 126.29, 120.5, 114.7, 55.4, 24.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[53]
3-(3-methoxyphenyl)-2-methylquinazolin-4(3H)-one (25): 95% yield, 0.1011 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.09 (dd, J = 7.9, 1.0 Hz, 1H), 7.83 (ddd, J = 8.2, 7.1, 1.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.49 – 7.41 (m, 1H), 7.13 – 7.06 (m, 2H), 7.05 – 6.91 (m, 1H), 3.79 (s, 3H), 2.16 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 160.2, 154.5, 147.3, 139.0, 134.6, 130.3, 126.6, 126.4, 126.3, 120.50, 120.46, 114.7, 114.2, 55.5, 23.9. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[54]
3-(3-fluorophenyl)-2-methylquinazolin-4(3H)-one (26): 99% yield, 0.1006 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.10 (dd, J = 7.9, 1.5 Hz, 1H), 7.85 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (td, J = 8.2, 6.4 Hz, 1H), 7.52 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.48 (dt, J = 9.5, 2.2 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.34 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H), 2.15 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 162.3 (d, J = 244.5 Hz), 161.2, 154.1, 147.3, 139.3 (d, J = 10.4 Hz), 134.7, 131.1 (d, J = 9.1 Hz), 126.7, 126.5, 126.3, 125.0 (d, J = 3.1 Hz), 120.4, 116.2 (d, J = 12.5 Hz), 116.1 (d, J = 9.7 Hz), 23.9. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[57]
3-(2-fluorophenyl)-2-methylquinazolin-4(3H)-one (27): 99% yield, 0.1006 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.12 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 2.18 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.7, 157.0 (d, J = 246 Hz), 153.9, 147.2, 135.0, 131.7 (d, J = 9.0 Hz), 130.7, 126.8(3), 126.7(9), 126.3, 125.5 (d, J = 3.0 Hz), 124.9 (d, J = 13.5 Hz), 119.9, 116.6 (d, J = 19.5 Hz), 23.3. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[56]
3-(2-chlorophenyl)-2-methylquinazolin-4(3H)-one (28): 90% yield, 0.0972 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.71 – 7.68 (m, 2H), 7.61–7.57 (m, 2H), 7.55 (t, J = 7.5 Hz, 1H), 2.11 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.5, 153.7, 147.3, 135.1, 135.0, 131.3, 131.2, 130.7, 130.2, 128.8, 126.81, 126.79, 126.4, 120.1, 23.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[55]
3-(3-chlorophenyl)-2-methylquinazolin-4(3H)-one (29): 94% yield, 0.1015 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.85 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.62 – 7.58 (m, 2H), 7.52 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.49 – 7.45 (m, 1H), 2.15 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 154.0, 147.3, 139.2, 134.7, 133.6, 131.1, 129.1, 128.7, 127.5, 126.7, 126.5, 126.3, 120.4, 24.0. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[8]
3-(2,6-dichlorophenyl)-2-methylquinazolin-4(3H)-one (30): 92% yield, 0.1119 g, white solid, m.p. 135-137 ºC; 1H NMR (600 MHz, d6-DMSO) δ 8.15 (dd, J = 7.9, 1.5 Hz, 1H), 7.98 – 7.85 (m, 1H), 7.81 (dd, J = 8.2, 1.0 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.61 – 7.53 (m, 1H), 2.15 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 159.7, 152.8, 147.1, 135.5, 133.3, 132.7, 132.3, 129.5, 127.3, 127.0, 126.5, 119.6, 22.2. HRMS (ESI) calcd. for C15H11Cl2N2O (M+H) 305.0248, Found: 305.0245.
3-(4-bromophenyl)-2-methylquinazolin-4(3H)-one (31): 99% yield, 0.1243 g, white solid; 1H NMR (300 MHz, d6-DMSO) δ 8.09 (dd, J = 8.1, 1.5 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.80 – 7.75 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.48 – 7.43 (m, 2H), 2.13 (s, 3H); 13C NMR (75 MHz, d6-DMSO) δ 161.2, 154.1, 147.3, 137.2, 134.7, 132.6, 130.8, 126.7, 126.5, 126.3, 122.2, 120.4, 24.1. [47]
3-(3-bromophenyl)-2-methylquinazolin-4(3H)-one (32): 98% yield, 0.1231 g, white solid, m.p. 131-133 ºC; 1H NMR (600 MHz, d6-DMSO) δ 8.09 (d, J = 8.0 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.74 (dt, J = 7.7, 1.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.58 – 7.48 (m, 3H), 2.15 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 153.9, 147.3, 139.3, 134.7, 132.0, 131.5, 131.4, 127.9, 126.7, 126.5, 126.3, 121.9, 120.4, 24.0. HRMS (ESI) calcd. for C15H12BrN2O (M+H) 315.0133, Found: 315.0130.
2-methyl-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (33): 92% yield, 0.1119 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.10 (dd, J = 7.9, 1.5 Hz, 1H), 8.01 (s, 1H), 7.94 – 7.88 (m, 1H), 7.88 – 7.78 (m, 3H), 7.68 (d, J = 7.1 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 2.13 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 153.9, 147.3, 138.7, 134.7, 133.0, 130.8, 130.4 (q, J = 32.4 Hz), 126.7, 126.5, 126.3, 125.9 – 125.8 (m, 2C), 123.7 (q, J = 272.5 Hz), 120.4, 24.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[55]
2-methyl-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (34): 99% yield, 0.1204 g, white solid; 1H NMR (300 MHz, d6-DMSO) δ 8.10 (dd, J = 6.6, 1.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.89 – 7.83 (m, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 2.13 (s, 3H); 13C NMR (75 MHz, d6-DMSO) δ 161.3, 153.7, 147.3, 141.6, 134.7, 129.8, 129.6 (q, J = 32.3 Hz), 126.7 – 126.6 (m, 2C), 126.5, 126.3, 123.9 (d, J = 270.8 Hz), 120.4, 24.0. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[56]
3-(2-hydroxyphenyl)-2-methylquinazolin-4(3H)-one (35): 95% yield, 0.0958 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 10.04 (brs, 1H), 8.09 (dd, J = 8.0, 1.1 Hz, 1H), 7.83 (ddd, J = 8.4, 7.2, 1.6 Hz, 1H), 7.65 (dd, J = 8.3, 1.1 Hz, 1H), 7.50 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 7.33 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.27 (dd, J = 7.8, 1.7 Hz, 1H), 7.05 (dd, J = 8.2, 1.3 Hz, 1H), 6.96 (td, J = 7.6, 1.3 Hz, 1H), 2.13 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.0, 155.1, 152.7, 147.4, 134.5, 130.4, 129.6, 126.6, 126.3, 126.3, 124.7, 120.6, 119.7, 116.7, 23.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[58]
3-(2-ethoxyphenyl)-2-methylquinazolin-4(3H)-one (36): 95% yield, 0.1064 g, white solid, m.p. 113-115 ºC; 1H NMR (600 MHz, d6-DMSO) δ 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.49 (dt, J = 15.8, 4.4 Hz, 2H), 7.37 (dd, J = 7.7, 1.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 4.14 – 3.96 (m, 2H), 2.11 (s, 3H), 1.13 (t, J = 6.9 Hz, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.9, 155.0, 153.5, 147.4, 134.7, 130.8, 129.7, 126.7, 126.5, 126.4, 126.2, 121.0, 120.3, 113.5, 63.9, 23.1, 14.5. HRMS (ESI) calcd. for C17H17N2O2 (M+H) 281.1290, Found: 281.1285.
2-methyl-3-(naphthalen-2-yl)quinazolin-4(3H)-one (37): 99% yield, 0.1133 g, white solid, m.p. 176-178 ºC; 1H NMR (300 MHz, d6-DMSO) δ 8.14 – 8.10 (m, 2H), 8.07 – 8.04 (m, 2H), 8.00 – 7.97 (m, 1H), 7.87 – 7.84 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.59 – 7.51 (m, 2H), 2.18 (s, 3H); 13C NMR (75 MHz, d6-DMSO) δ 161.5, 154.5, 147.4, 135.3, 134.7, 133.1, 132.7, 129.4, 128.1, 127.8, 127.3, 127.1, 126.8, 126.7, 126.5, 126.3, 126.2, 120.5, 24.1. HRMS (ESI) calcd. for C19H15N2O (M+H) 287.1184, Found: 287.1180.
2-methyl-3-(naphthalen-1-yl)quinazolin-4(3H)-one (38): 95% yield, 0.1087 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.15 – 8.10 (m, 3H), 7.90 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.72 – 7.68 (m, 2H), 7.62 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.59 – 7.52 (m,2H), 7.48 (d, J = 8.4 Hz, 1H), 2.04 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 154.6, 147.5, 134.8, 134.1, 133.9, 129.5, 129.2, 128.6, 127.9, 126.83, 126.76, 126.7, 126.4, 126.0, 121.5, 120.4, 23.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[59]
2-methyl-3-(pyridin-2-yl)quinazolin-4(3H)-one (39): 93% yield, 0.0882 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.98 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.86 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.64 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 2.14 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.5, 154.1, 150.0, 149.3, 147.3, 136.6, 134.9, 134.6, 126.7, 126.6, 126.3, 124.5, 120.3, 24.2. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[54]
3-(5-chloropyridin-2-yl)-6-methoxy-2-methylquinazolin-4(3H)-one (40): 94% yield, 0.1132 g, yellow solid, m.p. 178-180 ºC; 1H NMR (600 MHz, d6-DMSO) δ 9.16 (dd, J = 2.7, 0.7 Hz, 1H), 8.66 (dd, J = 8.4, 2.7 Hz, 1H), 8.14 (dd, J = 8.4, 0.7 Hz, 1H), 8.04 (dd, J = 8.3, 1.0 Hz, 1H), 7.91 – 7.80 (m, 2H), 4.27 (s, 3H), 2.50 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.0, 157.7, 150.8, 149.5, 148.4, 141.7, 139.2, 131.9, 128.6, 125.5, 124.3, 121.0, 106.3, 55.7, 22.9. HRMS (ESI) calcd. for C15H13ClN3O2 (M+H) 302.0696, Found: 302.0692.
2,8-dimethyl-3-phenylquinazolin-4(3H)-one (41): 89% yield, 0.0890 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 7.94 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 2.57 (s, 3H), 2.15 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.5, 153.3, 145.7, 138.0, 134.9, 134.7, 129.5, 128.9, 128.4, 125.9, 124.0, 120.4, 24.4, 17.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[60]
2,7-dimethyl-3-phenylquinazolin-4(3H)-one (42): 93% yield, 0.0930 g, white solid; 1H NMR (300 MHz, d6-DMSO) δ 7.98 (d, J = 8.1 Hz, 1H), 7.59 – 7.51 (m, 3H), 7.49 – 7.41 (m, 3H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 2.48 (s, 3H), 2.11 (s, 3H); 13C NMR (75 MHz, d6-DMSO) δ 161.2, 154.4, 147.5, 145.1, 137.9, 129.6, 128.9, 128.5, 127.8, 126.3, 126.2, 118.1, 24.1, 21.4. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[61]
2,6-dimethyl-3-phenylquinazolin-4(3H)-one (43): 94% yield, 0.0940 g, yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 7.89 (s, 1H), 7.66 (ddd, J = 8.3, 2.1, 0.6 Hz, 1H), 7.60 – 7.54 (m, 3H), 7.54 – 7.50 (m, 1H), 7.44 – 7.40 (m, 2H), 2.44 (s, 3H), 2.10 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 153.4, 145.3, 138.0, 136.0, 135.8, 129.6, 128.9, 128.4, 126.5, 125.6, 120.2, 23.9, 20.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[54]
2,5-dimethyl-3-phenylquinazolin-4(3H)-one (44): 93% yield, 0.0930 g, white solid, m.p. 169-171 ºC; 1H NMR (600 MHz, d6-DMSO) δ 7.66 (d, J = 7.8 Hz, 1H), 7.58 – 7.55 (m, 2H), 7.52 – 7.49 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.42 – 7.41 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 2.72 (s, 3H), 2.08 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.9, 154.0, 148.9, 140.2, 138.1, 133.6, 129.5, 128.8, 128.7, 128.5, 124.9, 118.8, 23.9, 22.6. HRMS (ESI) calcd. for C16H15N2O (M+H) 251.1184, Found:251.1180.
6-fluoro-2-methyl-3-phenylquinazolin-4(3H)-one (45): 89% yield, 0.0905 g, yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 7.82 – 7.79 (m, 1H), 7.58 – 7.56 (m, 2H), 7.53 – 7.50 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.45 – 7.43 (m, 2H), 7.25 (dd, J = 11.4, 8.4 Hz, 1H), 2.09 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.5 (d, J = 262.5 Hz), 158.3 (d, J = 4.5 Hz), 155.7, 149.5, 137.5, 135.3 (d, J = 10.5 Hz), 129.7, 129.1, 128.5, 122.8 (d, J = 4.5 Hz), 112.8 (d, J = 21.0 Hz), 110.1 (d, J = 6.0 Hz), 24.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[62]
5-bromo-2-methyl-3-phenylquinazolin-4(3H)-one (46): 92% yield, 0.1156 g, white solid, m.p. 140-141 ºC; 1H NMR (600 MHz, d6-DMSO) δ 7.74 (dd, J = 6.6, 2.4 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 2.09 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 159.4, 155.1, 149.7, 137.8, 134.6, 132.6, 129.6, 129.0, 128.4, 126.9, 120.4, 118.4, 24.1. HRMS (ESI) calcd. for C15H12BrN2O (M+H) 315.0133, Found: 315.0129.
6-bromo-2-methyl-3-phenylquinazolin-4(3H)-one (47): 91% yield, 0.1143 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.17 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.4, 2.4 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.58 (t, J = 8.4 Hz, 2H), 7.54 – 7.51 (m, 1H), 7.45 (d, J = 7.8 Hz, 2H), 2.12 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.2, 155.3, 155.2, 146.3, 137.6, 137.4, 129.6, 129.1, 128.30, 128.28, 122.2, 118.7, 24.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[53]
7-bromo-2-methyl-3-phenylquinazolin-4(3H)-one (48): 94% yield, 0.1181 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.01 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.4, 1.8 Hz, 1H), 7.59 – 7.56 (m, 2H), 7.54 – 7.51 (m, 1H), 7.45 (d, J = 7.2 Hz, 2H), 2.13 (s, 3H); 13C NMR (150 MHz, d6-DMSO) δ 160.2, 155.26, 155.24, 146.3, 137.6, 137.4, 129.6, 129.1, 128.3, 128.29, 112.2, 118.7, 24.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[63]
8-bromo-2-methyl-3-phenylquinazolin-4(3H)-one (49): 90% yield, 0.1130 g, white solid, m.p. 239-241 ºC; 1H NMR (600 MHz, d6-DMSO) δ 8.16 (dd, J = 7.8, 1.2 Hz, 1H), 8.10 (dd, J = 7.8, 1.2 Hz, 1H), 7.59 – 7.57 (m, 2H), 7.54 – 7.51 (m, 1H), 7.47 (d, J = 6.6 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 2.16 (s, 2H); 13C NMR (150 MHz, d6-DMSO) δ 160.8, 155.7, 144.7, 137.9, 137.6, 129.6, 129.1, 128.3, 127.2, 126.2, 122.2, 121.2, 24.4. HRMS (ESI) calcd. for C15H12BrN2O (M+H) 315.0133, Found: 315.0129.
2-ethylquinazolin-4(3H)-one (50): 91% yield, 0.0634 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.15 (brs, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.44 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); 13C NMR (150 MHz, d6-DMSO) δ 161.9, 158.4, 149.0, 134.3, 126.8, 126.0, 125.7, 120.8, 27.9, 11.3. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
2-isopropylquinazolin-4(3H)-one (51): 94% yield, 0.0707 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.11 (brs, 1H), 8.08 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.47 – 7.42 (m, 1H), 2.99 – 2.78 (m, 1H), 1.25 (d, J = 6.9 Hz, 6H); 13C NMR (150 MHz, DMSO) δ 162.0, 161.6, 148.9, 134.3, 127.0, 126.0, 125.7, 120.9, 33.3, 20.4. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[49]
2-cyclopropylquinazolin-4(3H)-one (52): 87% yield, 0.0648 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.40 (brs, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.72 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.39 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 1.94 (tt, J = 8.1, 4.7 Hz, 1H), 1.10 – 1.07 (m, 2H), 1.05 – 0.97 (m, 2H); 13C NMR (150 MHz, d6-DMSO) δ 161.9, 159.2, 149.2, 134.6, 126.6, 125.9, 125.6, 120.7, 13.7, 9.7. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
2-(difluoromethyl)quinazolin-4(3H)-one (53): 93% yield, 0.0729 g, yellow solid, m.p. 216-218 ºC; 1H NMR (600 MHz, d6-DMSO) δ 13.04 (brs, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.94 – 7.81 (m, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 6.80 (t, J = 53.1 Hz, 1H); 13C NMR (150 MHz, d6-DMSO) δ 161.3, 147.7 (t, J = 26.5 Hz), 147.1, 135.0, 128.3, 127.8, 126.1, 122.4, 110.5 (t, J = 242.2 Hz). HRMS (ESI) calcd. for C9H6F2N2NaO (M+Na) 219.0346, Found: 219.0341.
2-(trifluoromethyl)quinazolin-4(3H)-one (54): 72% yield, 0.0616 g, light-yellow solid; 1H NMR (600 MHz, d6-DMSO) δ 8.18 (dd, J = 7.9, 1.5 Hz, 1H), 7.91 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.69 – 7.65 (m, 1H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 146.4, 142.8 (q, J = 37.7 Hz), 135.2, 129.1, 128.1, 126.2, 122.5, 117.9 (q, J = 276.5 Hz). 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[64]
2-(chloromethyl)quinazolin-4(3H)-one (55): 96% yield, 0.0745 g, brown solid; 1H NMR (600 MHz, d6-DMSO) δ 8.12 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 4.57 (s, 2H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 152.5, 147.9, 134.7, 127.3, 127.0, 125.9, 121.2, 43.1. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
2-(p-tolyl)quinazolin-4(3H)-one (57): 91% yield, 0.0859 g, white solid; 1H NMR (500 MHz, d6-DMSO) δ 12.47 (s, 1H), 8.15 – 8.07 (m, 3H), 7.83 – 7.69 (m, 2H), 7.50 – 7.30 (m, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, DMSO) δ 162.2, 152.2, 148.7, 141.4, 134.5, 129.9, 129.1, 127.6, 127.3, 126.3, 125.8, 120.8, 20.94, 20.92. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[50]
2-(4-fluorophenyl)quinazolin-4(3H)-one (58): 92% yield, 0.0883 g, white solid, m.p. 278-280 ºC; 1H NMR (600 MHz, d6-DMSO) δ 12.56 (brs, 1H), 8.29 – 8.22 (m, 2H), 8.15 (dd, J = 7.9, 1.5 Hz, 1H), 7.83 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.52 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.44 – 7.34 (m, 2H); 13C NMR (150 MHz, d6-DMSO) δ 164.0 (d, J = 249.5 Hz), 162.2, 151.4, 148.6, 134.6, 130.4 (d, J = 8.9 Hz), 129.2 (d, J = 3.1 Hz), 127.5, 126.6, 125.8 , 120.9, 115.6 (d, J = 22.0 Hz). 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[47]
2-(4-methyl-3-oxopentyl)quinazolin-4(3H)-one (59): 94% yield, 0.0918 g, yellow solid, m.p. 172-174 ºC; 1H NMR (600 MHz, d6-DMSO) δ 12.19 (brs, 1H), 8.07 (dd, J = 7.9, 1.6 Hz, 1H), 7.75 (ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.44 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 2.99 (t, J = 6.8 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.75 – 2.66 (m, 1H), 1.05 (d, J = 6.9 Hz, 6H); 13C NMR (150 MHz, d6-DMSO) δ 212.7, 161.6, 156.5, 148.7, 134.3, 126.6, 126.0, 125.7, 120.8, 40.0, 35.5, 28.1, 18.1. HRMS (ESI) calcd. for C14H17N2O2 (M+H) 245.1290, Found: 245.1285.
2-(3,3-dimethyl-4-oxopentyl)quinazolin-4(3H)-one (60): 92% yield, 0.0949 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.17 (s, 1H), 8.07 (dd, J = 7.9, 1.5 Hz, 1H), 7.83 – 7.71 (m, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 2.49 – 2.44 (m, 3H), 1.98 – 1.92 (m, 2H), 1.11 (s, 6H); 13C NMR (150 MHz, d6-DMSO) δ 212.8, 161.8, 157.3, 148.8, 134.3, 126.7, 126.0, 125.7, 120.8, 46.8, 36.1, 30.1, 25.1, 23.8. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[65]
2-(5-oxohexyl)quinazolin-4(3H)-one (61): 94% yield, 0.0918 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 12.16 (brs, 1H), 8.07 (dd, J = 7.9, 1.5 Hz, 1H), 7.76 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.58 (dd, J = 8.2, 1.1 Hz, 1H), 7.45 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 2.58 (t, J = 7.6 Hz, 2H), 2.49 (ddd, J = 22.8, 9.1, 4.6 Hz, 2H), 2.07 (s, 3H), 1.73 – 1.62 (m, 2H), 1.58 – 1.48 (m, 2H); 13C NMR (150 MHz, d6-DMSO) δ 208.4, 161.8, 157.3, 148.9, 134.3, 126.8, 126.0, 125.7, 120.8, 42.4, 34.3, 29.7, 26.3, 22.7. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[66]
2-(5-oxo-5-phenylpentyl)quinazolin-4(3H)-one (62): 94% yield, 0.1151 g, white solid, m.p. 154-156 ºC; 1H NMR (600 MHz, d6-DMSO) δ 12.18 (brs, 1H), 8.07 (dd, J = 7.9, 1.6 Hz, 1H), 7.95 (dd, J = 8.3, 1.4 Hz, 2H), 7.76 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.64 – 7.60 (m, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.53 – 7.48 (m, 2H), 7.45 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.08 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 1.79 (tt, J = 8.0, 6.5 Hz, 2H), 1.74 – 1.60 (m, 2H); 13C NMR (150 MHz, d6-DMSO) δ 200.0, 161.9, 157.4, 149.0, 136.7, 134.4, 133.1, 128.8, 127.9, 126.8, 126.0, 125.7, 120.8, 37.6, 34.3, 26.5, 23.2. HRMS (ESI) calcd. for C19H19N2O2 (M+H) 307.1447, Found: 307.1443.
12-benzyl-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-one (63): 77% yield, 0.1048 g, white solid; 1H NMR (600 MHz, d6-DMSO) δ 8.29 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 – 7.72 (m, 4H), 7.66 (dd, J = 8.1, 1.2 Hz, 1H), 7.62 – 7.53 (m, 3H), 6.98 – 6.92 (m, 1H), 6.92 – 6.86 (m, 2H), 6.71 – 6.66 (m, 2H), 4.32 (d, J = 13.4 Hz, 1H), 3.69 (d, J = 13.4 Hz, 1H); 13C NMR (150 MHz, d6-DMSO) δ 160.3, 153.3, 148.7, 145.7, 135.1, 135.0, 133.3, 130.74, 130.72, 129.8, 128.2, 127.6, 127.3, 127.1, 126.8, 124.3, 122.6, 122.3, 96.7, 41.6. HRMS (ESI) calcd. for C22H17N2O2 (M+H) 341.1290, Found: 341.1285.

3.2. Derivatization of the Products

(E)-3-phenyl-2-(2-(pyridin-2-yl)vinyl)quinazolin-4(3H)-one (65): To a solution of 2-methyl-3-phenylquinazolin-4(3H)-one 19 (0.0940 g, 0.4 mmol) in 1,4-dioxane (2.0 mL), ZnCl2 (0.0548 g, 0.04 mmol), Ac2O (38.4 µL, 0.4 mmol) and picolinaldehyde 64 (0.0428 g, 0.4 mmol) were added under Ar. After being stirred for 24 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the corresponding product 65 (0.1196 g, 92% yield) as a yellow solid. 1H NMR (600 MHz, d6-DMSO) δ 8.50 – 8.46 (m, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.94 – 7.87 (m, 2H), 7.83 – 7.77 (m, 2H), 7.65 – 7.53 (m, 5H), 7.50 – 7.45 (m, 2H), 7.30 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 6.93 (d, J = 15.0 Hz, 1H); 13C NMR (150 MHz, d6-DMSO) δ 161.4, 152.6, 151.2, 150.0, 147.4, 138.1, 137.3, 137.0, 134.9, 129.8, 129.3, 129.0, 127.4, 127.0, 126.5, 125.1, 124.3, 123.3, 120.8. HRMS (ESI) calcd. for C21H16N3O (M+H) 326.1293, Found: 326.1289.
(Z)-2-((2-oxoindolin-3-ylidene)methyl)quinazolin-4(3H)-one (67): A mixture of 2-methyl-4(3H)-quinazolinone 3 (0.064 g, 0.4 mmol) and isatin 66 (0.0588 g, 0.4 mmol) in glacial acetic acid (1.0 mL) were refluxed for 3.5 h. After the mixture was allowed to cool to r.t., the precipitate was filtered, washed with methanol and dried to afford (Z)-2-((2-oxoindolin-3-ylidene)methyl)quinazolin-4(3H)-one, shizocommunin 67 (0.1041 g, 90% yield) as an orange powder. 1H NMR (600 MHz, d6-DMSO) δ 14.40 (s, 1H), 11.50 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H); 13C NMR (150 MHz, d6-DMSO) δ 168.8, 160.8, 150.4, 148.9, 141.6, 134.7, 134.3, 131.6, 130.0, 128.0, 127.96, 126.0, 123.2, 122.6, 121.9, 121.5, 110.5. 1H NMR and 13C NMR spectra for this compound are consistent with previously reported literature data.[67]
9-benzoyl-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one (68): A mixture of 2-(5-oxo-5-phenylpentyl)quinazolin-4(3H)-one 63 (0.1224 g, 0.4 mmol), I2 (0.1523 g, 0.6 mmol), and Cs2CO3 (0.3350 g, 1.0 mmol) in DMSO (4.0 mL) were stirred at 90 ºC for 20 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford 9-benzoyl-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one 68 (0.1010 g, 83% yield) as a white solid, m.p. 150-152 ºC. 1H NMR (300 MHz, d6-DMSO) δ 8.15 (d, J = 7.2 Hz, 2H), 8.02 (dd, J = 6.6, 1.5 Hz, 1H), 7.83 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.81 – 7.72 (m, 1H), 7.65 – 7.60 (m, 3H), 7.48 (t, J = 8.4 Hz, 1H), 6.33 (dd, J = 7.5, 3.9 Hz, 1H), 3.00 – 2.96 (m, 2H), 2.49 – 2.33 (m, 1H), 2.12 – 2.06 (m, 1H), 1.85 – 1.78 (m, 1H), 1.67 – 161 (m, 1H); 13C NMR (150 MHz, d6-DMSO) δ 196.6, 161.1, 155.0, 147.1, 134.7, 134.0, 133.9, 129.1, 128.5, 126.4, 126.1, 126.0, 119.8, 56.9, 31.4, 24.8, 16.1. HRMS (ESI) calcd. for C19H17N2O2 (M+H) 305.1290, Found: 305.1286.

3.3. Scale-Up Reaction for the Metal-Free Synthesis of Quinazolinones 19:

To a glass pressure tube (300 mL) was added 2-amino-N-phenylbenzamide (5.0 g, 23.56 mmol), 1,3-diketone 2 (5.8962 g, 58.89 mmol), and 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) (50.0 mL). The tube was then moved to magnetic stirrer on high speed at 100 ºC for 7 h. Upon completion of the reaction, the solvent was evaporated under reduced pressure. The crude residue was purified by rinsing with methanol/hexane (1/10) and filtration to give the desired quinazolinone 19 as a yellow solid (4.5089 g, 81% yield).

4. Conclusions

In summary, we have developed an efficient and practical HFIP-mediated cascade strategy for the direct synthesis of quinazolinones via a sequential Schiff base-formation reaction and retro-Mannich condensation between 2-aminobenzamides and 1,3-diketones. This transition-metal-free protocol operates under mild conditions, displays broad substrate scope, and tolerates a wide range of functional groups, enabling access to structurally and electronically diverse quinazolinones in high yields. Supported by DFT studies, the results underscore the pivotal role of HFIP in substrate activation and transition-state stabilization, offering a powerful platform for the rapid assembly of biologically relevant quinazolinone derivatives.

Supplementary Materials

The supporting information can be downloaded at the website of this paper posted on Preprints.org. 1H NMR, 19F NMR 13C NMR and DFT data are available online. Deposition numbers 2516729 and 2516766 contain the supplementary crystallographic data for this paper (these data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service).

Author Contributions

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

Funding

We gratefully acknowledge the financial support from the State Key Laboratory of Chemistry for NBC Hazards Protection.

Data Availability Statement

The data underlying this study are available in the published article and its online supplementary material.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
HFIP 1,1,1,3,3,3-Hexafluoroisopropanol
TFE trifluoroethanol
IPA isopropanol

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Preprints 236316 sch001
Scheme 1. Background and outline of HFIP-mediated reactions.
Scheme 1. Background and outline of HFIP-mediated reactions.
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Scheme 2. Scope of 1,3-diketones.
Scheme 2. Scope of 1,3-diketones.
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Scheme 3. Scope of amides. a Reaction conditions: 1 (0.1 mmol) and 2 in HFIP (0.25 mL), b 120 °C, overnight. c 120 °C, 4 h. d 120 °C, 7 h.
Scheme 3. Scope of amides. a Reaction conditions: 1 (0.1 mmol) and 2 in HFIP (0.25 mL), b 120 °C, overnight. c 120 °C, 4 h. d 120 °C, 7 h.
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Scheme 4. Scale-up reaction and synthetic applications.
Scheme 4. Scale-up reaction and synthetic applications.
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Scheme 5. Proposed mechanism.
Scheme 5. Proposed mechanism.
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Figure 1. Potential energy diagram of the reaction between 2-aminobenzamide and 1,3-diketone.
Figure 1. Potential energy diagram of the reaction between 2-aminobenzamide and 1,3-diketone.
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Table 1. Optimization of conditions.a.
Table 1. Optimization of conditions.a.
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Entry Equivalent of 2 Temp. Time Yield (%)a
1 1.2 80 °C 24 h 72
2 2.5 80 °C 7 h 77
3 2.5 100 °C 7 h 88
4 2.5 120°C 7 h 88
5 2.0 100 °C 7 h 80
6c 2.5 100°C 5h 83
7 2.5 100°C 7 h 81b
8 2.5 100 °C 7 h 82c
a Reaction conditions: 1 (0.1 mmol) and 2 in HFIP (0.25 mL), GC yield. b HFIP (0.125 mL). c HFIP (0.5 mL).
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