4-Bromo-2,3-dihydroisoxazoles: synthesis and application in halogen-lithium exchange reactions
Graphical abstract
Introduction
Small metalated heterocycles represent attractive substrates in organic synthesis due to their wide applicability in forming new carbon–carbon bonds.1 Specifically, five-membered aromatic (isoxazol-4-yl)lithium species 1 (Fig. 1) are powerful building blocks in medicinal chemistry and play an important role as promising substrates in the processes of screening for potent pharmacological candidates.2 For instance, Valdecoxib (nonsteroidal antiinflammatory drug) and Oxacillin (β-lactamase-resistant antibiotic) have been recently synthesized from 4-bromo-5-methylisoxazole 2 using bromine-lithium exchange reaction at the 4-position also.2a On the other hand, a method for the successful preparation of nonaromatic lithiated isoxazolines 3 has not been described to date.
Based on our interest in the field of 2,3-dihydroisoxazoles,3 we investigated the synthesis of such novel lithiated heterocycles. In this paper, we report on the preparation of N-benzyl-4-bromo-2,3-dihydroisoxazoles 4 by means of bromination reactions of 4-unsubstituted 2,3-dihydroisoxazoles, and on their utilization in bromine-lithium exchange reactions to afford (2,3-dihydroisoxazol-4-yl)lithium compounds 5 as suitable substrates for carbon–carbon bond formation at C4 (Scheme 1). The presented synthetic route provides the possibility for 4-substituted 2,3-dihydroisoxazoles 6 that could be hard to prepare by other methods.
Section snippets
Synthesis of 2,3-dihydroisoxazoles
In accordance with the literature, the starting N-benzyl-2,3-dihydroizoxazoles 11 and 12 were readily available from the corresponding nitrones (Scheme 2).4 The reactions of nitrones 74b and 85 with phenylacetylene (10) in the presence of Zn(OTf)2 afforded propargylic N-hydroxylamines,4b which upon zinc iodide catalyzed cyclization gave 2,3-dihydroizoxazoles 11 and 12 in very good yields (89% and 92%) nearly consistent with published results.4c 2,3-Dihydroizoxazole 13 was prepared via direct
Conclusions
In conclusion, novel bromination of 2,3-dihydroisoxazoles into the 4-position using pyridinium tribromide in the presence of base is presented. Three representative 4-bromo-2,3-dihydroisoxazoles are prepared and isolated in moderate yields for the first time. Reactivity of the initial substrates and the yields depend on the substituent at C3. To demonstrate a practical scope of the 4-bromo-substituted 2,3-dihydroisoxazoles, representative 2-benzyl-4-bromo-3,5-diphenyl-2,3-dihydroisoxazole is
General
All melting points were measured on a Melting Point B-540 apparatus (Büchi) and are uncorrected. HRMS analyses were performed on Orbittrap Velos Pro spectrometer (Thermo Fisher Scientific). Infrared (IR) spectra were recorded on a Nicolet 5700 FTIR spectrometer with ATR Smart Orbit Diamond adapter (Thermo Electron Corporation) and are reported as wave number (cm−1). NMR spectra were recorded on a Varian VNMRS-600 spectrometer (1H, 600 MHz and 13C, 151 MHz) in CDCl3 using TMS as the internal
Acknowledgements
This work was supported by Slovak Grant Agencies (APVV, Bratislava, project No. APVV-14-0147, VEGA, Bratislava project No. 1/0488/14 and ASFEU, Bratislava, ITMS projects No. 26240120001, 26240120025).
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