Synthesis, NMR and crystallographic studies of 2-substituted dihydroquinazolinones derived from (S)-phenylethylamine.

Jaime Escalante,Jaime M Priego,Cirilo García-Martínez,Patricia Flores,Claudia Ortíz-Nava

doi:10.3390/12020173

Abstract

2,3-Dihydro-3-[(S)-1-phenethyl]quinazolinone and some new 2-substituted derivatives bearing isopropyl, o-nitrophenyl and p-nitrophenyl groups were prepared in 40-90% yield by amidation of isatoic anhydride with (S)-phenylethylamine, followed by condensation with triethyl orthoformate, isopropylaldehyde, o-nitro- and p-nitro-benzaldehyde, respectively. The two 2-subtituted dihydroquinazolinones obtained either by using isopropylaldehyde, o-nitro- or p-nitrobenzaldehyde, were separated and purified before their NMR spectra in CDCl3 solutions were recorded. The detection of the low energy conformation of O=C-N-phenethyl segment in solution allowed the correlation of the NMR data with the configuration of newly stereogenic carbon C-2; thus, one diastereomer was labeled SS while the other was RS. Configurations determined by the NMR method were corroborated by X-ray diffraction analysis. X-ray structures of each diastereomeric series showed characteristic conformational types: a propeller-like for the SS and a hairpin for the RS series. Interatomic distances of the hairpin conformation suggest the existence of intramolecular face-to-face interactions between two aromatic rings.

Highlights

Amidation of chiral primary amines with single enantiomers of methoxytrifluoromethylphenylacetyl chloride and related derivatizing agents is commonly used to determine the configuration of new stereogenic centers by 1H-NMR spectrocopy [1]
Studies carried out with chiral four- and five-membered cyclic amides prepared from a single enantiomer of either arylethylisocyanates [4] or phenylethylamine [5], showed that interaction between the methine hydrogen of the 1-phenethyl group and the carbonyl-oxygen favors the low-energy conformer 3
The configuration of new stereogenic centers located in the neighborhood of the 1-phenethyl group, were readily determined from the chemical shifts and the orientation of phenyl ring [4,5]

Summary

Introduction

Amidation of chiral primary amines with single enantiomers of methoxytrifluoromethylphenylacetyl chloride and related derivatizing agents is commonly used to determine the configuration of new stereogenic centers by 1H-NMR spectrocopy [1]. The detection of the low energy conformation 1 of the resulting amides is fundamental to establish the correlation between the chemical shifts (δ) of the hydrogen nuclei of the amine moiety and the configuration of the chiral derivatizing agent [2]. This strategy can be used to study the configuration of cyclic secondary amines, inherent ring conformations and slow rotation about amide bonds (see 2) make it difficult to interpret the NMR spectra [3]. We report the synthesis and configurational analysis of some new 2,3-dihydro-3-[(S)-1-phenethyl]quinazolinones 8-11

Results and Discussion

H CH3 Ph

Conclusions