A versatile route to 2-alkyl-/aryl-amino-3-formyl- and hetero-annelated-chromones, through a facile nucleophilic substitution at C2 in 2-(N-methylanilino)-3-formylchromones

doi:10.1016/S0040-4020(02)00128-X

Tetrahedron

Volume 58, Issue 12, 18 March 2002, Pages 2471-2480

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Abstract

The N-methylanilino group in 2-(N-methylanilino)-3-formylchromones, obtained in high yield by rearrangement of C(4-oxo-4H[1]-benzopyran-3-yl)-N-phenylnitrones to 2-anilino-3-formyl-chromones followed by N-methylation, undergoes facile nucleophilic substitution by a variety of nitrogen nucleophiles, thereby paving the way for synthesis of a variety of novel 2-substituted-3-formylchromone derivatives as well as hetero-annelated chromones.

Graphic

Introduction

Besides forming the basic nucleus of an entire class of natural products, i.e. flavones,¹ the chromone moiety is also part of a large number of molecules of medicinal significance.² Consequently, considerable attention is being devoted to isolation from natural resources, chemistry and synthesis of chromone derivatives, and evaluation of their biological activity with stress on their potential medicinal applications.2., 3., 4. Some of the biological activities recently ascribed to chromone derivatives include cytotoxic (anticancer),^4a–c P-glycoprotein binding (to overcome multi-drug resistance, anticancer),^4d neuroprotective,^4e HIV-inhibitory,^4f antimicrobial,^4g,h cyclin-dependent kinase inhibitory (anticancer),⁴ⁱ antifungal^4j and antioxidant activity.^4k 3-Formyl-chromone has emerged as a valuable synthon for incorporation of the chromone moiety⁵ and attempts are being made to develop its solid supported synthetic equivalents.^5g However, it has been observed that nucleophilic attack at C2 in 3-formylchromone or its derivatives, results in either pyrone ring opening or loss of the C2–C3– π bond, thereby, limiting its synthetic applications.2., 3., 5. This facile pyrone ring opening has also attracted the attention of theoreticians.⁶ We had earlier observed⁷ that C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenylnitrones (1, R=H, Me, Cl) undergo intramolecular rearrangement to yield 2-anilino-3-formylchromones (2, 70–90%) and 3-phenyliminomethyl-enechromone-2,4-diones (3, 10–25%, Scheme 1).

We report herein that N-methylation of 2 yields 2-(N-methylanilino)-3-formylchromone (4) in high yield (>95%) and the 2-N-methylanilino group in the latter undergoes facile substitution by various nitrogen nucleophiles, paving the way for the preparation of a large number of novel 2-substituted-3-formylchromones and heteroannelated-chromones. To further enhance the synthetic potential of this approach, taking cognizance of a literature report on the acid promoted cyclization of 3-formylchromone-oxime,^3l the yield of 2 has been improved to 96% by refluxing the nitrone 1 in dry benzene in the presence of a catalytic amount of acetic acid (Scheme 1); the product obtained can be directly methylated (without any separation from 3) to 4, which is crystallized out.

Section snippets

Results and discussion

Initially, the reactions of 4b (X=Cl) were carried out with 1 molar equiv. of primary aromatic/aliphatic amines (benzylamine, n-butylamine and p-ansidine) in dry acetonitrile, which afforded, the 2-substituted product (5a–c) in 23–29% yield, along with 2-arylamino-3-(N-aryliminomethyl)chromones (6a–c, 30–36%); the rest of 4 was recovered unreacted. On the other hand, when the reaction was carried out with 2 molar equiv. of the above amines the yields of (6a–c) were more than 90%. However, when

General

NMR spectra ware recorded on Bruker 200, 300 and 400 MHz FT NMR spectrometers, using TMS as internal standard and CDCl₃/DMSO-d₆ as solvents. Chemical shifts are reported in ppm as down field displacements from tetramethylsilane used as internal standard. Mass spectra were recorded on Shimadzu GCMS-QP-2000A spectrometer. The microanalytical data were collected on a Perkin–Elmer 240C elemental analyzer. IR spectra were recorded on a Shimadzu DR 2001 IR spectrophotometer in CHCl₃ solution or as

Acknowledgements

We thank Dr Patrick Perlmutter, Monash University, Clayton, Australia for recording NMR spectra of some samples.

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Citation Excerpt :
Chromones are well known natural and synthetic products that possess diverse biological activities [1], including anticancer [2–4], antitumor [5], antiproliferative [6], neuroprotective [7], HIV-inhibitory [8,9], antimicrobial [10,11], antioxidant [12], anti-inflammatory [13], and antibiotic [14]. Heteroannulated chromones showed significant biological activity including pharmacological [15], antiplatelet [16], antiallergic [17], antiangiogenic [18], antirheumatic [19], antibacterial [20], anti-inflammatory and analgesic [21]. Friedländer condensation of 2-aminochromone-3-carboxaldehydes is a well-known reaction for preparation of chromeno[2,3-b]pyridine derivatives [22–25].
New derivative of heteroannulated chromone identified as 5-methyl-8H-benzo[h]chromeno[2,3-b][1,6]naphthyridine-6(5H),8-dione (5, MBCND) was easily and efficiently synthesized from DBU catalyzed condensation reaction of 2-aminochromone-3-carboxaldehyde (1) with 4-hydroxy-1-methylquinolin-2(1H)-one (2). The same product 5 was isolated from condensation reaction of aldeyde 1 with 3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid (3) or ethyl 4-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2,4-dioxobutanoate (4). Structure of compound (5, MBCND) was deduced based on their elemental analyses and spectral data (IR, ¹H NMR and mass spectra). Density Functional Theory (DFT) calculations at the B3LYP/6-311G (d,p) level of theory have been carried out to investigate the equilibrium geometry of the novel compound (5, MBCND). Moreover, total energy, energy of HOMO and LUMO and Mullikan atomic charges were calculated. In addition, the dipole moment, theoretical study of the electronic structure, nonlinear optical properties (NLO), and natural bonding orbital (NBO) analysis and orientation have been performed and discussed. Also the electronic absorption spectra were measured in polar (methanol) as well as non polar (dioxane) solvents and the assignment of the observed bands has been discussed by TD-DFT calculations. The correspondences between calculated and experimental transitions energies are satisfactory.

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A versatile route to 2-alkyl-/aryl-amino-3-formyl- and hetero-annelated-chromones, through a facile nucleophilic substitution at C2 in 2-(N-methylanilino)-3-formylchromones

Abstract

Introduction

Section snippets

Results and discussion

General

Acknowledgements

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Antimicrob. Agents Chemother.

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