Novel Quinazolinone–Isoxazoline Hybrids: Synthesis, Spectroscopic Characterization, and DFT Mechanistic Study

Abstract

Quinazolinone and isoxazoline systems have attracted much attention due to their interesting pharmacological properties. The association of these two pharmacophores in a single hybrid structure can boost the biological activity or bring a new one. Inspired by this new paradigm, in the present work we report the synthesis and spectroscopic characterization of new quinazolinone–isoxazoline hybrids. The target compounds were obtained via 1,3-dipolar cycloaddition reactions of arylnitriloxides and N-allylquinazolinone. The synthesized compounds were characterized using spectroscopic techniques such as IR, 1D NMR (1H and 13C), 2D NMR (COSY and HSQC), and high-resolution mass spectrometry (HRMS). The spectral data show that this reaction leads only to the 3,5-disubstituted isoxazoline regioisomer, and that the observed regiochemistry is not affected by the nature of the substituents in the phenyl ring of the dipole. In addition, a theoretical study was performed using density functional theory (DFT) to support the experimental results in regard to the regiochemistry of the studied reactions. The computational mechanistic study was in good agreement with the experimental data.

Molecular Structure, Thermochemistry, Non-Covalent Interactions Computation Using DFT Studies Of The 1 Amino 2-(3,4- Dihydroxyphenyl) Boronic Acid (AHPEBA) Compound

“…The DFT approach can produce the required output data for a more accurate calculation of the electronic characteristics of complex structures because it takes into consideration the density of electrons. DFT is now the most extensively utilized technique since it produces realistic and reliable findings [11,12].…”

“…m N   (11) In this study, atom-by-atom calculations and molecularlevel simulations were carried out in the gas phase using the software package Gaussian 5.0.9W. In addition to energy, which may be calculated in a variety of methods, it can be used to establish other molecular characteristics, such as vibrational wave numbers [21].…”

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…The same year, 3,5-disubstituted isoxazolines bearing an RPh motif in position 3 and quinazoline–CH 2 motif in position 5 were synthesized via regioselective 1,3-DP cycloaddition by Rhazi and colleagues— Scheme 155 [ 164 ].…”

“…Quinazoline–isoxazoline hybrids obtained via regioselective 1,3-DP cycloaddition of substituted benzonitrile oxide to N -allylquinazolinone by Rhazi and coworkers were once the subject of theoretical assessment [ 164 ] In this work, the analysis of theoretically predicted nucleophilic and electrophilic properties of reagents clearly explains a concerted mechanism for the dipolar cycloaddition reaction. The quantum theory of the atom in the molecule used to characterize the electronic structure of the transition state reveals C–C bond formation between the terminal carbon atom of N -allylquinazolinone and the carbon atom of the CNO group of benzonitrile oxide.…”

“… Syntheses of quinazolinone–isoxazoline hybrids via 1,3-DP cycloaddition of RC 6 H 4 CNO to N -allyl quinazolinones [ 164 ]. R = H, o -Cl, p -Cl, p -Br, p -MeO, p -Me, p -O 2 N; a = CHCl 3 , Et 3 N, rt; up to 96% yield.…”