Abstract
A transition-metal-free synthesis of quinazolin-4-ones by Cs2CO3-promoted SNAr reaction of ortho-fluorobenzamides with amides followed by cyclization in dimethyl sulfoxide has been developed. The present procedure can provide efficient synthetic methods for the formation of both 2-substituted and 2,3-disubstituted quinazolin-4-one rings depending on the use of easily available starting materials and an efficient, one-pot protocol for the synthesis of the marketed drug product of methaqualone.
Introduction
Quinazolin-4-ones are an important class of heterocyclic structural scaffolds that have been found in many natural products1 and bioactive compounds.2 For example, the natural alkaloids of luotonin A and luotonin F and the marketing drugs of piriqualone and methapualone are the derivatives of quinazolin-4-one (Scheme 1). In addition, quinazolin-4-ones are also the important intermediates for the synthesis of other nitrogen heterocyclic compounds having physiological and biological activity.3
Scheme 1. Selected Naturally Found Alkaloids and Drugs with the Quinazolinone Skeleton.
Therefore, the chemistry and the synthetic strategies for constructing the quinazolin-4-one ring have been well investigated.4 Among them, the most common and practical synthetic methods are intermolecular annulation using ortho-aminobenzamides or ortho-halobenzamides as starting materials.5,6 For example, quinazolin-4-one derivatives can be obtained from the cyclocondensation of ortho-aminobenzamides with aldehydes catalyzed either by copper salts in dimethylacetamide5b or by bis-sulfonated ionic liquids via aerobic oxidative reaction in water or ethanol5j or by aerobic oxidative reaction in wet dimethyl sulfoxide (DMSO).5d The reactions of ortho-aminobenzamide with primary alcohols in dimethyl carbonate catalyzed by iodine with the use of DMSO as the oxidant5c or with 1,3-diketones in aqueous ethyl lactate catalyzed by camphorsulfonic acid5h or with isocyanides and arylboronic acids in dimethylformamide (DMF) catalyzed by PdCl2(PPh3)2 with the use of Cu(OAc)2 as the oxidant5k can also afford quinazolin-4-ones. In addition, the syntheses of quinazolin-4-ones from the intermolecular annulation of ortho-halobenzamides are shown in Scheme 2. It involves the reaction of ortho-halobenzamides with benzylamines6a or amino acids6b in DMSO catalyzed by CuBr using air as the oxidant, the reaction of N-substituted ortho-bromobenzamides with formamide in DMF catalyzed by CuI/4-hydroxy-l-proline,6cortho-bromobenzamides with aldehydes and aqueous ammonia in DMSO catalyzed by CuBr/l-proline using Cs2CO3 as the base and air as the oxidant6d or with the use of Cu–Mn spinel oxide as a heterogeneous catalyst,6fortho-iodobenzamides with benzylamines or cinnamylamines in DMSO catalyzed by copper salts with the use of K2CO3 as the base and air as the oxidant,6eortho-bromobenzamides with aldehydes or alcohols, or methyl arenes catalyzed by CuI in DMSO in the presence of the oxidant and using TMSN3 as a nitrogen source,6gortho-bromobenzamides with benzylic alcohols and sodium azide catalyzed by CuO/l-proline in DMF with the use of 2,2,6,6-tetramethylpiperidine-1-oxyl as the oxidant and TsOH·H2O as the additive,6h and ortho-halobenzamides with nitriles catalyzed by Cu(OAc)2 in the presence of tBuOK as the base.6i On the basis of the above-described procedures for the construction of the quinazolin-4-one ring from ortho-halobenzamides as starting materials, it is readily apparent and interesting to find that, besides the requirement of copper catalysts, in most cases, DMSO is used as the solvent, and inorganic bases are employed as additives.
Scheme 2. Synthesis of Quinazolin-4-ones from ortho-Halobenzamides.
On the other hand, inorganic base/DMSO medium have been well applied to promote the nucleophilic haloarenes substitution of the C–X bond for the formation of the C–N bond and the synthesis of nitrogen heterocyclic compounds.7 In the continuation of our interest in developing the efficient methods for the synthesis of nitrogen heterocyclic compounds8 and the application of base/DMSO-promoted SNAr reaction for the formation of the C–N bond,7g we herein would like to report a new approach to the construction of the quinazolin-4-one ring under transition-metal-free conditions, which involves the base-promoted SNAr reaction of ortho-fluorobenzamides with amides followed by cyclization (Scheme 2).
Results and Discussion
Fu’s group developed a CuBr-catalyzed synthesis of quinazolinones via the reaction of 2-iodo/bromobenzamides with benzylamines in DMSO using K2CO3 as the base;6a thus, we first carried out the reaction of 2-fluoro-N-methylbenzamide (1a) with benzamide (2a, 2.5 equiv) in the presence of K2CO3 (4.0 equiv) in DMSO. After 24 h at 135 °C, on the basis of the analysis of the reaction mixture by gas chromatography–mass spectrometry (GC–MS), only a trace amount of 3-methyl-2-phenylquinazolin-4-one (3aa) was formed (Table 1, entry 1). The reaction was then repeated in the presence of KOH (4.0 equiv) because Bolm’s group established intramolecular N-arylations of N-(2-haloaryl)ureas to form benzimidazol-2-ones under the conditions of KOH (2.0 equiv)/DMSO;93aa can be isolated from the reaction mixture in 10% yield (Table 1, entry 2), and in this case, the considerable amount of 2-hydroxy-N-methylbenzamide formed via the SNAr reaction of 1a with KOH. The use of KOtBu resulted in the similar yield of 3aa as KOH employed (Table 1, entry 3). Fortunately, when Cs2CO3 was used in DMSO, 3aa could be obtained in 72% isolated yield (Table 1, entry 4),10 although the yields of 3aa were not satisfactory in other solvents, such as tetrahydrofuran (THF), 1,4-dioxane, and DMF (Table 1, entries 5–7). The decrease of either 2a (2.5 equiv to 1.5–1.0 equiv) or Cs2CO3 (4.0 equiv to 1.0–0.5 equiv) resulted in the considerable decrease of yields (Table 1, entries 8–11). In addition, it was found that 2.5 equiv of Cs2CO3 was suitable for the present transformation as a similar and good yield of 3aa was achieved (70%, entry 12 vs entry 4). As expected, Cs2CO3 is found to be the essential promoter for the formation of 3aa in DMSO because its absence led to no 3aa formation at all (Table 1, entry 13).
Table 1. Optimization of Reaction Conditions for Quinazolin-4-one Synthesisa.
| entry | 2a (equiv) | base (equiv) | solvent | yield (%)b |
|---|---|---|---|---|
| 1 | 2.5 | K2CO3 (4) | DMSO | trace |
| 2 | 2.5 | KOH (4) | DMSO | 10 |
| 3 | 2.5 | KOtBu (4) | DMSO | 12 |
| 4 | 2.5 | Cs2CO3 (4) | DMSO | 72 |
| 5 | 2.5 | Cs2CO3 (4) | THF | 15 |
| 7 | 2.5 | Cs2CO3 (4) | dioxane | 19 |
| 6 | 2.5 | Cs2CO3 (4) | DMF | 25 |
| 8 | 1.0 | Cs2CO3 (4) | DMSO | 61 |
| 9 | 1.5 | Cs2CO3 (4) | DMSO | 65 |
| 10 | 2.5 | Cs2CO3 (0.5) | DMSO | 33 |
| 11 | 2.5 | Cs2CO3 (1.0) | DMSO | 55 |
| 12 | 2.5 | Cs2CO3 (2.5) | DMSO | 70 |
| 13 | 2.5 | DMSO | 0 |
Reactions were carried out using 1a (1.0 mmol) and 2a, base in 4.0 mL of solvent in a sealed tube at 135 °C for 24 h.
Yields of 3aa are isolated.
To evaluate the scope and limitations of the present procedure, the reactions of several ortho-fluorobenzamides with a wide variety of amides were examined under the reaction conditions indicated in entry 12 of Table 1.
As concluded in Table 2, except for benzamide (2a), the annulation of 1a with other arylamides (2b–2g) and heteroaryl amides (2h) occurs smoothly to give the corresponding quinazolin-4-one products (3ab–3ah) in good isolated yields. ortho-Fluorobenzamides bearing either the electron-rich group (OMe, 1b) or electron-poor group (CF3, 1c) undergoes the annulation reaction affording 3ba, 3ca, and 3cc in acceptable yields. ortho-Fluoro-N-(n-propyl)benzamides (1d and 1e) show good reactivity to undergo the annulation with electron-rich arylamides. In addition, both electron-rich and electron-poor arylamides, as well as heteroaryl amides (2h and 2i) are efficiently annulated with ortho-fluorobenzamide (1f) to give the corresponding quinazolin-4-one products in good isolated yields (3fa, 3fb, 3fd, 3fe, 3fh, 3fi, and 3fk). Note that the annulation reactions of 1a and 1d with ortho-iodobenzamide (2f) or ortho-bromobenzamide (2g) proceed with high chemoselectivity to give the corresponding quinazolin-4-ones [3af, 3ag, 3df (X-ray, see the Supporting Information), and 3dg] via the SNAr reaction of the C–F bond in 1a and 1d, while the C–I and C–Br bonds in 2f and 2g are untouched. The products having the C–I or C–Br bond are very useful for their further functionalization through carbon–halide bond activation. Moreover, except for (hetero)aryl amides, acetamide (2j) was also subjected for annulation reaction with 1a to give 3aj in high yields (78%). More importantly, the reaction of 2-fluoro-N-(o-tolyl)benzamide (1g) with 2j produces 3gf (methaqualone) in 67% yield, providing an efficient and simple, one-pot protocol for the synthesis of the marketed drug product of methaqualone. In addition, we are also interested in the homocyclodimerization of 1f under the same reaction conditions, as expected, the reaction occurs smoothly to give 3f in 92% yield.
Table 2. Substrate Scope of Quinazolin-4-one Synthesisa.
Reactions were carried out using 1 (1.0 mmol), 2 (2.5 mmol), and Cs2CO3 (2.5 mmol) in 4.0 mL of DMSO in a sealed tube at 135 °C for 24 h.
A plausible mechanism for the formation of 3aa is shown in Scheme 3. It involves the SNAr reaction of 1a with 2a giving the intermediate of diamide 4aa, which undergoes the intramolecular nucleophilic addition promoted by the base, and the final dehydration to afford 3aa. 4aa can be isolated from a reaction mixture of 1a and 2a under the similar reaction conditions as for the formation of 3aa but after a short reaction time (12h, 4aa 41%). As expected, 4aa can be converted into 3aa in high yields (eq 1).
 |
1 |
Scheme 3. Plausible Mechanism for the Formation of Quinazolin-4-one.
Conclusions
In conclusion, we have established a Cs2CO3-promoted synthesis of quinazolin-4-ones in DMSO through SNAr reaction of ortho-fluorobenzamides with amides followed by intramolecular cyclization, providing an alternative protocol for the construction of the quinazolin-4-one ring. The significant advantages of the present procedure include the formation of C–N under transition-metal-free conditions and the direct application in the synthesis of marketed drug of methaqualone.
Experimental Section
General Information
All commercial reagents are analytically pure and used without further purification. Nuclear magnetic resonance (NMR) spectra were recorded using CDCl3 and DMSO-d6 at 298 K. 1H NMR (400 MHz) chemical shifts (δ) were referenced to internal standard tetramethylsilane (for 1H, δ = 0.00 ppm). 13C NMR (100 MHz) chemical shifts were referenced to internal solvent CDCl3 (for 13C, δ = 77.16 ppm) and DMSO-d6 (for 13C, δ = 39.52 ppm). Mass spectra were obtained on a low-resolution GC–MS spectrometer, and high-resolution mass spectrometry (HRMS) spectra were recorded on a high-resolution magnetic sector mass spectrometer with an electrospray ionization (ESI) source. The melting points are uncorrected.
Typical Experimental Procedure for the Synthesis of 3-Methyl-2-phenylquinazolin-4(3H)-one (3aa)
To a 25 mL tube equipped with a magnetic stirrer were added 2-fluoro-N-methylbenzamide (1a) (153.1 mg, 1.0 mmol), benzamide (2a) (302.8 mg, 2.5 mmol), Cs2CO3 (815.1 mg, 2.5 mmol), and the freshly distilled DMSO (4.0 mL) under nitrogen. The tube was sealed and stirred at 135 °C for 24 h in an oil bath. After the reaction mixture was cooled to room temperature, it was poured into a solvent mixture of water (50.0 mL) and ethyl acetate (20.0 mL), and the two phases were then separated. The aqueous layer was extracted with ethyl acetate (3 × 20.0 mL). The combined organic extracts were dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (gradient mixture ratio from 100:0 to 70:30) as the eluent to afford 3aa as a white solid (165.3 mg, 70%).
3-Methyl-2-phenylquinazolin-4(3H)-one (3aa)5k
It is obtained as a white solid (165.3 mg, 70%); 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.9 Hz, 1H), 7.81–7.70 (m, 2H), 7.61–7.45 (m, 6H), 3.49 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.8, 156.2, 147.4, 135.5, 134.4, 130.1, 129.0, 128.1, 127.16, 127.6, 126.8, 120.6, 34.3; GC–MS m/z: 236 (M+).
3-Methyl-2-(o-tolyl)quinazolin-4(3H)-one (3ab)5j
It is obtained as a white solid (182.7 mg, 73%); 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.9 Hz, 1H), 7.79–7.26 (m, 2H), 7.49 (t, J = 6.4 Hz, 1H), 7.42–7.27 (m, 4H), 3.32 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.4, 156.0, 147.3, 135.2, 135.1, 134.3, 130.7, 129.8, 127.5 (2C), 127.0, 126.7, 126.5, 120.7, 32.7, 19.1; GC–MS m/z: 250 (M+).
3-Methyl-2-(p-tolyl)quinazolin-4(3H)-one (3ac)5k
It is obtained as a white solid (187.7 mg, 75%); 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.0 Hz, 1H), 7.76–7.67 (m, 2H), 7.51–7.42 (m, 3H), 7.31 (d, J = 7.9 Hz, 2H), 3.49 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.8, 156.3, 147.4, 140.3, 134.2, 132.6, 129.5, 128.0, 127.5, 126.8, 126.7, 120.5, 34.3, 21.5; GC–MS m/z: 250 (M+).
2-(4-Methoxyphenyl)-3-methylquinazolin-4(3H)-one (3ad)6e
It is obtained as a white solid (154.4 mg, 58%); 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 7.9 Hz, 1H), 7.80–7.69 (m, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.49 (t, J = 6.9 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.53 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.1, 161.1, 156.1, 147.5, 134.3, 129.9, 127.9, 127.5, 126.9, 126.8, 120.5, 114.3, 55.6, 34.5; GC–MS m/z: 266 (M+).
3-Methyl-2-(naphthalen-2-yl)quinazolin-4(3H)-one (3ae)5k
It is obtained as a white solid (174.6 mg, 61%); 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 8.03–7.88 (m, 3H), 7.77 (d, J = 3.8 Hz, 2H), 7.65–7.48 (m, 4H), 3.54 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.9, 156.2, 147.5, 134.4, 133.8, 133.0, 132.8, 128.8, 128.6, 128.2, 127.9, 127.67, 127.62, 127.1 (2C), 126.8, 124.8, 120.7, 34.4; GC–MS m/z: 286 (M+).
2-(2-Iodophenyl)-3-methylquinazolin-4(3H)-one (3af)
It is obtained as a white solid (246.2 mg, 68%); mp 112–114 °C; 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81–7.70 (m, 2H), 7.57–7.47 (m, 2H), 7.41 (d, J = 6.3 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.3, 156.3, 147.3, 140.7, 139.5, 134.4, 131.1, 128.9, 128.8, 127.7, 127.4, 126.8, 121.0, 95.7, 32.7; HRMS (ESI) m/z: [M + H]+ calcd for C15H11IN2O, 362.9989; found, 362.9993.
2-(2-Bromophenyl)-3-methylquinazolin-4(3H)-one (3ag)
It is obtained as a white solid (201.7 mg, 64%); mp 139–141 °C; 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.1 Hz, 1H), 7.78–7.72 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.53–7.44 (m, 3H), 7.37 (t, J = 7.4 Hz, 1H), 3.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.2, 154.6, 147.3, 136.7, 134.4, 133.1, 131.3, 129.5, 128.2, 127.6, 127.4, 126.8, 121.6, 121.0, 32.5; HRMS (ESI) m/z: [M + H]+ calcd for C15H11BrN2O, 315.0128; found, 315.0135.
7-Methoxy-3-methyl-2-phenylquinazolin-4(3H)-one (3ba)5k
It is obtained as a white solid (135.8 mg, 51%); 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.8 Hz, 1H), 7.58–7.48 (m, 5H), 7.11 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.6, 162.3, 156.9, 149.6, 135.6, 130.1, 128.9, 128.3, 128.0, 117.4, 114.1, 107.9, 55.7, 34.1; GC–MS m/z: 266 (M+).
3-Methyl-2-phenyl-7-(trifluoromethyl)quinazolin-4(3H)-one (3ca)
It is obtained as waxy oil (145.9 mg, 48%); 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.60–7.52 (m, 5H), 3.52 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.1, 157.6, 147.3, 136.0 (q, J = 33.0 Hz), 135.0, 130.5, 129.1, 128.1, 120.0, 125.2 (q, J = 4.0 Hz), 123.5 (q, J = 271.0 Hz), 123.0 (q, J = 3.0 Hz), 122.8, 34.6; HRMS (ESI) m/z: [M + H]+ calcd for C16H11F3N2O, 305.0896; found, 305.0895.
3-Methyl-2-(p-tolyl)-7-(trifluoromethyl)quinazolin-4(3H)-one (3cc)
It is obtained as waxy oil (174.3 mg, 55%); 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.54 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.2, 157.8, 147.6, 140.9, 135.9 (q, J = 32.7 Hz), 132.2, 129.7, 128.1, 128.0, 125.2 (q, J = 4.0 Hz), 123.6 (q, J = 272.0 Hz), 122.9 (q, J = 3.0 Hz), 122.8, 34.7, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for C17H13F3N2O, 319.1053; found, 319.1058.
2-Phenyl-3-propylquinazolin-4(3H)-one (3da)11
It is obtained as a white solid (163.8 mg, 62%); 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.7 Hz, 1H), 7.78–7.70 (m, 2H), 7.54–7.46 (m, 6H), 3.93 (t, J = 7.6 Hz, 2H), 1.69–1.57 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.2, 156.3, 147.2, 135.7, 134.4, 129.9, 128.8, 127.8, 127.5, 127.0, 126.8, 121.0, 47.5, 22.2, 11.2; GC–MS m/z: 264 (M+).
3-Propyl-2-(o-tolyl)quinazolin-4(3H)-one (3db)
It is obtained as a white solid (180.9 mg, 65%); mp 89–91 °C; 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.1 Hz, 1H), 7.80–7.69 (m, 2H), 7.50 (t, J = 8.1 Hz, 1H), 7.44–7.28 (m, 4H), 4.18–4.06 (m, 1H), 3.51–3.39 (m, 1H), 2.23 (s, 3H), 1.74–1.42 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.1, 155.9, 147.4, 135.4, 135.0, 134.3, 130.7, 129.8, 127.8, 127.5, 127.0, 126.8, 126.2, 121.1, 47.0, 21.9, 19.3, 11.3; HRMS (ESI) m/z: [M + H]+ calcd for C18H18N2O, 279.1492; found, 279.1495.
3-Propyl-2-(p-tolyl)quinazolin-4(3H)-one (3dc)11
It is obtained as a white solid (197.6 mg, 71%); 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 7.9 Hz, 1H), 7.79–7.67 (m, 2H), 7.49 (t, J = 7.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 3.95 (t, J = 8.0 Hz, 2H), 2.44 (s, 3H), 1.71–1.58 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.4, 156.6, 147.3, 140.0, 134.3, 132.9, 129.5, 127.8, 127.5, 126.9, 126.8, 121.0, 47.6, 22.2, 21.5, 11.3; GC–MS m/z: 278 (M+).
2-(4-Methoxyphenyl)-3-propylquinazolin-4(3H)-one (3dd)
It is obtained as a white solid (182.4 mg, 62%); mp 65–67 °C; 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 7.9 Hz, 1H), 7.77–7.68 (m, 2H), 7.52–7.44 (m, 3H), 7.02 (d, J = 8.7 Hz, 2H), 3.98 (t, J = 7.6 Hz, 2H), 3.88 (s, 3H), 1.70–1.56 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.5, 160.7, 156.3, 147.3, 134.3, 129.5, 128.2, 127.5, 126.95, 126.90, 120.9, 114.2, 55.6, 47.6, 22.2, 11.3; HRMS (ESI) m/z [M + H]+ calcd for C18H18N2O2, 295.1441; found, 295.1446.
2-(2-Iodophenyl)-3-propylquinazolin-4(3H)-one (3df)
It is obtained as a white solid (269.2 mg, 69%); mp 110–112 °C; 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81–7.70 (m, 2H), 7.55–7.47 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 4.26–5.15 (m, 1H), 3.42–3.31 (m, 1H), 1.83–1.67 (m, 1H), 1.56–1.43 (m, 1H), 0.76 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 162.0, 156.2, 147.2, 140.3, 139.4, 134.4, 131.1, 129.2, 128.5, 127.6, 127.3, 126.9, 121.3, 96.4, 47.4, 22.0, 11.4; HRMS (ESI) m/z: [M + H]+ calcd for C17H15IN2O, 391.0302; found, 391.0308.
2-(2-Bromophenyl)-3-propylquinazolin-4(3H)-one (3dg)
It is obtained as a white solid (253.9 mg, 74%); mp 83–85 °C; 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 8.1 Hz, 1H), 7.80–7.72 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 4.4 Hz, 2H), 7.42–7.35 (m, 1H), 4.28–4.17 (m, 1H), 3.49–3.36 (m, 1H), 1.81–1.65 (m, 1H), 1.57–1.41 (m, 1H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.9, 154.5, 147.2, 136.5, 134.4, 133.1, 131.3, 129.9, 127.8, 127.6, 127.3, 126.9, 121.9, 121.3, 47.2, 22.0, 11.4; HRMS (ESI) m/z: [M + H]+ calcd for C17H15BrN2O, 343.0441; found, 343.0450.
8-Methyl-3-propyl-2-(o-tolyl)quinazolin-4(3H)-one (3eb)
It is obtained as a white liquid (222.2 mg, 76%); 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.43–7.29 (m, 5H), 4.16–4.04 (m, 1H), 3.57–3.34 (m, 1H), 2.57 (s, 3H), 2.25 (s, 3H), 1.74–1.40 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.6, 154.3, 146.1, 136.2, 135.7, 135.5, 134.8, 130.6, 129.6, 128.1, 126.5, 126.0, 124.4, 121.1, 47.0, 21.9, 19.5, 17.5, 11.3; HRMS (ESI) m/z: [M + H]+ calcd for C19H20N2O, 293.1648; found, 293.1650.
8-Methyl-3-propyl-2-(p-tolyl)quinazolin-4(3H)-one (3ec)
It is obtained as a white solid (236.8 mg, 81%); mp 91–93 °C 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 3.98 (t, J = 8 Hz, 2H), 2.58 (s, 3H), 2.45 (s, 3H), 1.68–1.57 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.9, 155.0, 146.1, 139.8, 136.1, 134.8, 133.4, 129.3, 128.2, 126.4, 124.4, 120.9, 47.5, 22.2, 21.5, 17.4, 11.2.; HRMS (ESI) m/z: [M + H]+ for C19H20N2O 293.1648, found, 293.1652.
2-Phenylquinazolin-4(3H)-one (3fa)5j
It is obtained as a white solid (140.0 mg, 63%); 1H NMR (400 MHz, CDCl3): δ 11.50 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.28–8.20 (m, 2H), 7.88–7.77 (m, 2H), 7.64–7.56 (m, 3H), 7.51 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 163.9, 151.8, 149.6, 135.0, 132.9, 131.8, 129.2, 128.1, 127.5, 126.9, 126.5, 121.0; GC–MS m/z: 222 (M+).
2-(o-Tolyl)quinazolin-4(3H)-one (3fb)5j
It is obtained as a white solid (153.5mg, 65%); 1H NMR (400 MHz, CDCl3): δ 10.42 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 3.8 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.53–7.48 (m, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.38–3.31 (m, 2H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.9, 153.5, 149.1, 136.9, 135.0, 133.7, 131.6, 130.7, 128.7, 128.0, 127.1, 126.5, 126.4, 120.9, 20.2; GC–MS m/z: 236 (M+).
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3fd)6i
It is obtained as a white solid (151.3 mg, 60%); 1H NMR (400 MHz, CDCl3): δ 11.47 (br s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.23 (d, J = 8.8 Hz, 2H), 7.83–7.73 (m, 2H), 7.52–7.42 (m, 1H), 7.07 (d, J = 8.7 Hz, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.0, 162.5, 151.5, 149.8, 143.1, 134.9, 129.2, 127.9, 126.4, 125.2, 120.7, 114.5, 55.6; GC–MS m/z: 252 (M+).
2-(Naphthalen-2-yl)quinazolin-4(3H)-one (3fe)
It is obtained as a white solid (185.1 mg, 68%); mp 211–213 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.83 (s, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.10–7.98 (m, 3H), 7.87 (t, J = 7.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69–7.59 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 162.3, 152.3, 148.7, 134.6, 134.1, 132.2, 129.9, 128.9, 128.2, 128.1, 127.9, 127.6, 127.4, 126.9, 126.6, 125.9, 124.5, 121.0; HRMS (ESI) m/z: [M + H]+ calcd for C18H12N2O, 273.1022; found, 273.1028.
3-Methyl-2-(thiophen-2-yl)quinazolin-4(3H)-one (3ah)6d
It is obtained as a white solid (133.2 mg, 55%); 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0 Hz, 1H), 7.77–7.67 (m, 2H), 7.55 (d, J = 5.0 Hz, 1H), 7.53–7.44 (m, 2H), 7.16 (t, J = 4.0 Hz, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ.162.8, 150.1, 147.3, 137.2, 134.4, 129.8, 129.5, 127.5, 127.1, 126.8, 120.2, 34.2; GC–MS m/z: 242 (M+).
2-(Thiophen-2-yl)quinazolin-4(3H)-one (3fh)5j
It is obtained as a white solid (141.2 mg, 62%); 1H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 8.23 (d, J = 3.5 Hz, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 4.9 Hz, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 4.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 161.8, 148.6, 147.8, 137.3, 134.6, 132.1, 129.4, 128.5, 126.8, 126.3, 125.9, 120.8; GC–MS m/z: 228 (M+).
2-(Pyridin-2-yl)quinazolin-4(3H)-one (3fi)6i
It is obtained as a white solid (154.0 mg, 69%); 1H NMR (400 MHz, CDCl3): δ 10.96 (s, 1H), 8.68 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 7.9 Hz, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.86–7.76 (m, 2H), 7.56–7.4 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.5, 149.2, 149.0, 148.8, 148.5, 137.6, 134.7, 128.1, 127.4, 126.9, 126.3. 122.6, 122.1; GC–MS m/z: 223 (M+).
2,3-Dimethylquinazolin-4(3H)-one (3aj)5h
It is obtained as a white solid (135.8 mg, 78%); 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 7.9 Hz, 1H), 8.04 (t, J = 8.3 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H), 2.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.4, 154.5, 147.3, 134.2, 126.8, 126.7, 126.4, 120.3, 31.1, 23.7; GC–MS m/z: 174 (M+).
2-Methyl-3-(o-tolyl)quinazolin-4(3H)-one (3gj, Methaqualone)11
It is obtained as a white solid (167.5 mg, 67%); 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.41–7.33 (m, 3H), 7.15 (d, J = 7.3 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.7, 154.4, 147.7, 136.9, 135.4, 134.6, 129.6, 128.0, 127.7, 127.2, 126.8, 126.6, 120.8, 23.9, 17.4; GC–MS m/z: 250 (M+).
2-(2-Fluorophenyl)quinazolin-4(3H)-one (3f)5j
It is obtained as a white solid (110.4 mg, 92%); 1H NMR (400 MHz, CDCl3): δ 10.68 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.20 (t, J = 7.8 Hz, 1H), 7.81–7.71 (m, 2H), 7.54–7.44 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.23–7.14 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 162.3, 160.7 (d, J = 249.0 Hz), 149.0, 148.6 (d, J = 10.0 Hz), 134.8, 133.4 (d, J = 9.0 Hz), 131.3 (d, J = 1.0 Hz), 128.0, 127.2, 126.5, 125.1 (d, J = 3.0 Hz), 121.2, 120.1 (d, J = 10.0 Hz), 116.6 (d, J = 22.0 Hz); GC–MS m/z: 240 (M+).
2-Benzamido-N-methylbenzamide (4aa)
It is obtained as a light yellow solid; mp 163–165 °C; 1H NMR (400 MHz, CDCl3): δ 12.08 (s, 1H), 8.66 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 7.4 Hz, 2H), 7.64–7.37 (m, 5H), 6.95 (t, J = 7.6 Hz, 1H), 6.85 (br s, 1H), 2.99 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 165.9, 139.5, 134.8, 132.3, 132.0, 128.9, 127.4, 126.8, 123.0, 121.6, 120.9, 26.9; HRMS (ESI) m/z: [M + H]+ calcd for C15H14N2O2, 255.1128; found, 255.1125.
Acknowledgments
This project was supported by the National Natural Science Foundation of China (21673124, 21473097). M.A.I., D.M.K., and H.M. thank the China Scholarship Council (CSC) for generous support for their study in Tsinghua University as PhD candidates.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00699.
Copies of 1H and 13C NMR charts of all products and X-ray structural details of 3df (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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