Heterocycle–Heterocycle Strategies: (2-Nitrophenyl)isoxazole Precursors to 4-Aminoquinolines, 1H-Indoles, and Quinolin-4(1H)-ones

Abstract

Reductive heterocycle-heterocycle (heterocycle → heterocycle; H–H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis-(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.

Heterocycle‐to‐Heterocycle Route to Quinoline‐4‐amines: Reductive Heterocyclization of 3‐(2‐Nitrophenyl)isoxazoles

“…5,6 In this work, we report that Zn 0 or Fe 0 in HOAc are suitable metal reductants for the conversion of both nitro (→ amine) and isoxazole (→ β-keto imine) moieties with subequent heterocyclization to the targeted quinoline-4-amines. Batra et al 10 reported the reductive heterocyclization of 2-nitrophenyl isoxazoles using H 2 /Pd•C – conditions that do not allow, for example, C=C and C ≡ N functional groups in the substrate.…”

“…Isoxazole 7a (0.826 g, 1.93 mmol) was boc deprotected and N-alkylated following literature procedures 5,14 to yield 7f as a white powder (0.321 g, 39%) over two steps. 1 H NMR (600 MHz, Chloroform -d ) δ 8.25 (d, J = 8.1 Hz, 1H), 7.74-7.72 (m, 1H), 7.70-7.66 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.56 (s, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H); 13 C NMR (150 MHz, Chloroform -d ) δ 173.3, 160.9, 159.0, 149.0, 135.8, 133.4, 132.2, 131.9, 131.1, 129.7, 125.0, 123.2, 121.7, 109.5, 48.4, 45.2, 22.7.…”

“…4 We have also recently shown that substituted isoxazoles undergo reductive heterocyclization in M/HOAc (M = Zn 0 or Fe 0 ) when a 2-nitrophenyl group is appended to the 3-, 4- or 5-position of the isoxazole ring (Figure 1B). 5 In continued exploration of these heterocycle-to-heter-ocycle strategies, 6 we report here on the utility and limitations of 3-(2-nitrophenyl)isoxazole reductive heterocyclizations in obtaining quinoline-4-amines. We also report a brief survey of functional group compatibility with these reductive heterocyclizations conditions.…”

New approaches to the synthesis of canthin-4-one alkaloids and synthetic analogues

“…This is in contrast to the easy formation of quinolin-4(1H)-ones from primary enaminoketones attached to aminophenyl residues. 29,30 Probably, the Z-stereochemistry of the enaminoketones, arising from the pre-organization of the residues in the isoxazole ring, and stabilized by an intramolecular hydrogen bond, prevented nucleophilic attack of the pyrrole nitrogen at the enamine group. We investigated numerous reaction conditions and reagents for promoting the desired cyclization.…”

One-step synthesis of alkyl 2-chloropyrimido[1,2-a]benzimidazole-3-carboxylates under catalyst-free: combined experimental and computational studies

“…To explore the reason for the phenomena observed, underlying reaction mechanisms were calculated in detail and compared employing density functional theory (DFT), a method of choice for the cost-effective treatment of large chemical systems with high accuracy. 21 …”