Regioselective synthesis and biological evaluation ofN-substituted 2-aminoquinazolin-4-ones

Abstract

The reaction of methyl anthranilates with N-arylcyanamides in the presence of p-TsOH in t-BuOH under reflux afforded predominantly 3-arylquinazolin-4-ones. In contrast, the reaction of the same reactants with TMSCl in t-BuOH at 60 °C followed by the Dimroth rearrangement in aqueous ethanolic sodium hydroxide gave exclusively the regioisomers, 2-(N-arylamino)quinazolin-4-ones. The regioselective synthesis of N-aryl-substituted 2-aminoquinazolin-4-ones can be further applied to the synthesis of benzimidazo[2,1-b]quinazolin-12-ones.

Carbonylation Chemistry Applied to the Synthesis of Benzimidazo[2,1‐b]quinazolin‐12‐ones

“…t, J =7.7 Hz, 2H [C‐8 and C‐9 isomer]), 7.60–7.40 (m, 3H [C‐8 and C‐9 isomer]), 7.40–7.27 (m, 4H [C‐8 and C‐9 isomer]), 7.17–7.05 (m, 1H [C‐8 isomer]); 13 C NMR (101 MHz, DMSO‐ d 6 ) δ=160.79 (d, 1 J CF =238.4 Hz), 159.21, 159.01, 157.56 (d, 1 J CF =236.2 Hz), 148.29, 147.74, 143.64 (br), 135.58, 135.44, 128.04, 127.91, 127.46, 127.42, 124.87, 122.95, 122.85, 119.99, 119.78, 116.01 (d, J =10.3 Hz), 115.33, 115.26, 114.45, 114.29, 113.25 (d, J =24.2 Hz), 108.53 (d, J =24.9 Hz), 102.68 (d, J =29.3 Hz), 101.95 (d, J =27.1 Hz); IR (neat) (cm −1 ): 2952 (aromatic C−H stretching), 1698 (C=O), 1653–1461 (ring breathing, C=N, aryl N−H deformations), 1249 (C−N stretch), 1148 (aryl‐F), 742 (aromatic C−H bending); HRMS (ESI) m/z calcd for C 14 H 9 FN 3 O [M+H]+ 254.0724, found 254.0715. These data are in agreement with literature data [2b] …”

“…; 13 C NMR (151 MHz, MeOH‐ d 4 +1 drop DCl) δ=158.49 (C‐12 [C‐8 or C‐9 isomer], 158.32 (C‐12 [C‐8 or C‐9 isomer]), 145.59 (C‐5a [C‐8 or C‐9 isomer]), 145.56 (C‐5a [C‐8 or C‐9 isomer]), 139.80 (C‐8 [C‐8 isomer]), 138.92 (C‐12a [C‐8 or C‐9 isomer]), 138.90 (C‐12a [C‐8 or C‐9 isomer]), 137.72 (C‐2 [C‐8 or C‐9 isomer]), 137.67 (C‐2 [C‐8 or C‐9 isomer]), 136.82 (C‐9 [C‐9 isomer]), 130.89 (C‐6a [C‐8 isomer]), 129.74 (C‐8 [C‐9 isomer]), 129.02 (C‐4 [C‐8 or C‐9 isomer]), 128.97 (C‐4 [C‐8 or C‐9 isomer]), 128.55 (C‐6a [C‐9 isomer]), 127.68 (C‐10a [C‐9 isomer]), 127.11 (C‐9 [C‐8 isomer]), 126.98 (C‐3 [C‐8 or C‐9 isomer]), 126.94 (C‐3 [C‐8 or C‐9 isomer]), 125.41 (C‐10a [C‐8 isomer]), 118.74 (C‐1 [C‐8 or C‐9 isomer]), 118.70 (C‐1 [C‐8 or C‐9 isomer]), 117.19 (C‐10 [C‐9 isomer]), 116.73 (C‐10 [C‐8 isomer]), 116.35 (C‐4a [C‐8 or C‐9 isomer]), 116.33 (C‐4a [C‐8 or C‐9 isomer]), 113.63 (C‐7 [C‐8 isomer]), 113.23 (C‐7 [C‐9 isomer]), 21.78 (methyl [C‐9 isomer]), 21.74 (methyl [C‐8 isomer]); IR (neat) (cm −1 ): 2987 (aromatic C−H stretching), 2918 (symmetric C−H stretch), 1671 (C=O), 1633–1445 (ring breathing, C=N, aryl N−H deformations), 1237 (C−N stretch), 758 & 742 (aromatic C−H bending); HRMS (ESI) m/z calcd for C 15 H 12 N 3 O [M+H]+ 250.0972, found 250.0964. The data of the C‐8 isomer are in agreement with literature data [2b,8a] …”

Optimization of 2-Aminoquinazolin-4-(3H)-one Derivatives as Potent Inhibitors of SARS-CoV-2: Improved Synthesis and Pharmacokinetic Properties

“…The second step, which used an excess of POCl 3 , made the synthesis difficult because the product was unstable and easily returned to the starting material. For efficient and bulk synthesis, we used the one-pot reaction method of Tun-Cheng Chien’s group to synthesize intermediate 1 with an overall yield of 76% ( Scheme 1 ) [ 23 ]. Anthranilic acid 3 was treated with phenylcyanamide 4 and chlorotrimethylsilane to yield a mixture of 2-( N -substituted-amino)quinazolin-4-one 1 and 3-substituted 2-aminoquinazolin-4-one.…”

One-Pot Three-Component Reaction for the Synthesis of 3,4-Dihydroquinazolines and Quinazolin-4(3H)-ones

“…The realization of this proposal would provide a potentially powerful route for the expedient access to a diverse range of 3,4-dihydroquinazolines and quinazolin-4­(3 H )-ones via one-pot reaction, overcoming the aforementioned drawbacks of the precedents. Previously, Liu and co-workers successfully demonstrated one-pot synthesis of quinazolin-4­(3 H )-imines and N -arylquinazolinium salts from 2-cyano- and 2-keto-substituted anilines, respectively, involving the in situ generation of the N -arylnitrilium intermediate and its cascade reaction (Scheme c, upper) …”