Stereoselective intramolecular cycloadditions of homochiral nitrile imines: synthesis of enantiomerically pure 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones
Introduction
Annulated [1,4]benzodiazepines and their oxo-derivatives constitute valuable synthetic targets due to their well-known pharmacological activity as hypnotics and sedatives.1, 2Among them, pyrazolo[1,5-a][1,4]benzodiazepines have been synthesised in a number of ways,3, 4, 5, 6including the intramolecular nitrile imine cycloaddition route.[7]Even though it would be desirable to obtain such compounds in the enantiomerically pure form, it must be noted that, to date, stereoselective intramolecular cycloadditions of homochiral nitrile imines have been almost entirely neglected, the only report in the field being a paper from our laboratory.[8]This is in contrast to the wide and detailed knowledge about stereoselective cycloadditions of related 1,3-dipolar species, e.g. nitrile oxides[9]and nitrones.[10]The present work is focused on the stereochemical outcome of the intramolecular cycloadditions of nitrile imines 5, which contain the (S)-1-phenylethyl unity.
Section snippets
Results and discussion
First of all, our approach required the synthesis of enantiopure hydrazonoyl chlorides 4, which was achieved recognising N-[(S)-1-phenylethyl]-2-nitrobenzamide 1 as a readily accessible chiral building block (Scheme. 1). Nitrile imines 5 were generated in situ by treating the corresponding hydrazonoyl chlorides 4 with a 2:1 molar ratio of silver carbonate in dry dioxane at room temperature, following a well-established procedure elaborated by us.[11]Products and their isolation yields, as well
Experimental
Melting points were determined with a Büchi apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer 1725 X spectrophotometer. Mass spectra were determined with a VG-70EQ instrument. 1H NMR spectra were taken with a Bruker AC 300 instrument (in CDCl3 solutions). Chemical shifts are given as ppm from tetramethylsilane and coupling constants are given in hertz. Optical rotations, [α]D25, were recorded on a Perkin–Elmer Model 241 polarimeter at the sodium D line.
Acknowledgements
We are grateful to CNR and MURST for financial support. One of us (A.P.) is grateful to Dr. M. Barzaghi (CNR-CSRSRC, Milano) and to Prof. E. Ortoleva (Università di Milano) for their expert help with Gaussian 94.
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Cited by (29)
Diastereoselective nitrilimine cycloaddition to the C=N bond of enantiopure 1,4-benzodiazepinones
2002, Tetrahedron AsymmetryChapter 5.4 Five membered ring systems: With more than one N atom
2000, Progress in Heterocyclic ChemistryCitation Excerpt :The 2-nitrophenylhydrazones of D-arabino-2-hexulopyranosonic acid, D-arabinose, D-galactose, and D-galacturonic acid were used as precursors to form chiral functionalized benzimidazoles by reductive cyclization methods <99JHC589>. Stereoselective syntheses of imidazolidine, imidazoline, and imidazole C-and N-pseudonucleosides were published <99TA3011>. Reactions of 3(,5)-(di)chloro-2H-1,4-(bertz)oxazin-2-ones with a-aminoketones provided new bi-and tricyclic imidazo-fused intermediates via intramolecular cyclization reactions <99T3987>.