Convenient Synthesis of Pyrazolo[4',3':5,6]pyrano[4,3- c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition

Abstract

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4',3':5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of ¹J_CH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed ¹H, ¹³C and ¹⁵N NMR spectroscopic experiments and HRMS measurements.

Keywords: 4-pyrazolaldoximes 1JCH; fused ring systems; intramolecular nitrile oxide cycloaddition; isoxazole 15N NMR; isoxazoline 15N NMR; isoxazoline/isoxazole; pyrazole.

Scheme 1

Synthetic route for the 3a,4-dihydro-3H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring system. Reagents and conditions: (i) NaH, DMF, 0 °C, 15 min, allylbromide, 60 °C, 1 h; (ii) DMF, POCl₃, −10 °C, 15 min, 70 °C, 1 h; (iii) NH₂OH·HCl, NaOAc, EtOH, reflux, 15 min; (iv) aq. NaOCl, DCM, rt, 1 h; (v) MnO₂, toluene, reflux, 4 h.

Figure 1

Relevant ¹H-¹³C HMBC, ¹H-¹³C J-HMBC, ¹H-¹⁵N HMBC, ¹H-¹H NOESY and 1,1-ADEQUATE correlations and ¹H NMR (italics), ¹³C NMR and ¹⁵N NMR (bold) chemical shifts of compounds 5a (a) and 6 (b).

Scheme 2

Synthetic route for the 3a,4-dihydro-3H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole 10. Reagents and conditions: (i) in accordance to ref. [35]; (ii) NaH, DMF, 0 °C, 15 min, cinnamyl chloride, 60 °C, 15 min; (iii) NH₂OH·HCl, NaOAc, EtOH, reflux, 15 min; (iv) NaOCl, DCM, rt, 1 h.

Scheme 3

Synthetic route for the 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring system. Reagents and conditions: (i) in accordance to ref. [26]; (ii) NH₂OH·HCl, NaOAc, EtOH, reflux, 15 min; (iii) NaOCl, DCM, rt, 1 h; (iv) RX, Pd(PPh₃)₂Cl₂, TEA, DMF, 60 °C, 15 min.