Synthesis of 3‐imidazolylazole derivatives from a new nitrile oxide

Abstract

The synthesis of a series of 3-Imidazolylazole derivatives using cycloaddition reactions of a useful new nitrile oxide is described.J. Heterocyclic Chem., 38, 539 (2001).Imidazole chemistry continues to be an intense investigative area since a large number of natural and synthetic compounds are associated with this class of heterocycle. For example, many naturally occurring imidazoles have remarkable biological activity, and a large number of synthesised compounds are widely used as antibacterial drugs and in cancer therapy [2].The idea of employing an isoxazole or an oxazole substrate, which are widely used by pharmaceutical and agricultural industries, combined with an imidazole ring to obtain more complex heterocycle compounds, led us to design and synthesise the N-methyl-2-imidazolyl nitrile oxide 4. The new nitrile oxide allowed us to prepare, via a 1,3 dipolar cycloaddition with selected substrates, 3-imidazolyl, 5-membered N,O-heterocycles.The 1,3-dipole was synthesised starting from the aldehyde 1 [3] using a three-step procedure (70% overall yield): oxime 2 formation followed by chlorination to 3 and subsequent in situ generation of 4 by dehydrohalogenation with triethylamine.Cycloaddition reactions were performed on selected electron-rich or electron-poor dipolarophiles using diethyl ether as solvent. As expected, the cycloaddition with monosubstituted dipolarophiles showed high regioselectivity, giving only the 5-substituted derivatives 5 and 6 where the oxygen atom is bound to the more hindered terminus of the dipolarophilic site [4]. The relative yields, which are not optimized are in the range of 30-57%.Attempted cycloaddition of the nitrile oxide with nonconjugated nitriles such as acetonitrile and phenylacetonitrile was unsuccessful. However, reaction with benzonitrile in the presence of the appropriate catalyst [5] afforded oxadiazolyl-imidazole 7 in moderate yield.Attempts to oxidise the isoxazoline rings to the isoxazole derivatives, using literature methods employing MnO 2 and NiO 2 [6], were unsuccessful and the required products were not isolated. EXPERIMENTALMelting points were determined with Reichert-Kofler hot stage apparatus and are uncorrected. IR spectra were obtained on Nicolet FT-IR Impact 400D spectrometer, mass spectra were acquired using a Finnigan Mat 90 spectrometer and the microanalyses for C, H, and N on a Carlo Erba 1102. 1 H NMR spectra were recorded on a Bruker ARX 300 spectrometer, in the solvent indicated. Chemical shifts (δ) are relative to TMS, which was used as an internal reference. Column chromatography was performed on Merck silica gel 70-270 mesh. All solvents and reagents were obtained from commercial sources and purified before use if necessary. Preparation of 2-Imidazolyloxime (2).A solution of 20.85 g of NH 2 OH . HCl in 30 ml of water and 60 ml of a 20% NaOH were added to 5.5 g, 0.05 mol of N-methyl-2-formylimidazole in 150 ml of ethanol. The mixture was heated to boiling for a few minutes, and subsequently the alcohol was evaporated under reduced pressure. T...

Synthesis and Ocular Effects of Imidazole Nitrolic Acids

“…Yield 80%. 1 H NMR (DMSO- d 6 ): δ = 3.80 (s, 3H), 6.98 (s, 1H), 7.26 (s, 1H), 8.05 (s, 1H), 11.53 (s, 1H) 1 H NMR shifts are in agreement with the literature . MS (ESI): Calcd for C 5 H 8 N 3 O 1 [M + H] + = 126.06619.…”

“…Unless otherwise indicated, all common reagents and solvents together with the compounds 1c, 1g, and 1h were obtained from commercial suppliers and were used without further purification. 1-Benzylimidazole-5-carbaldehyde (1a), 25 1-methylimidazole-5-carbaldehyde (1b), 25 1(H)imidazole-4(5)-carbaldehyde oxime (2c), 26 1-benzylimidazole-2-carbaldehyde (1f), 27 and 1-benzylimidazole-2-carbaldehyde oxime (2f) 27 were prepared according to literature procedures and oximes 2b 28 and 2g 29 according to slightly modified ones. 1 H and 13 C NMR spectra were recorded on a Bruker Avance 250 NMR spectrometer.…”

“…1 H NMR (DMSO-d6): δ ) 3.80 (s, 3H), 6.98 (s, 1H), 7.26 (s, 1H), 8.05 (s, 1H), 11.53 (s, 1H) 1 H NMR shifts are in agreement with the literature. 29 General Method for Preparation of Nitrolic Acids. The solution of the oxime in glacial acetic acid was cooled in an ice bath.…”

1,3-Dipolar Cycloaddition of Nitrones to a Nitrile Functionality in closo-Decaborate Clusters: A Novel Reactivity Mode for the Borylated C≡N Group

“…nitrones, to the nitrile functionality. Note that several boron-catalyzed DCAs to nitrile species were reported and all these examples (viz., F 3 B-catalyzed CAs of N 3 – , organic azides, or nitrile oxides to RCN species − ) are restricted exclusively to CA of propargyl–allenyl type dipoles .…”

“…Thus, in the case of the propargyl−allenyl type dipoles, CA of sodium azide or organic azides to substituted arylacetonitriles 64,65 and to perfluoro-or perchloroalkylnitriles 65 takes place only with prolonged heating at 100−150 °C. Furthermore, CAs of the nitrile oxides ArCN + O − to RCN were conducted under reflux conditions for 0.5−2 h in the case R = alkyl, 59,60 aryl 60,61 or at room temperature for much more reactive malononitrile derivatives. 59,62,63 In contrast to all these examples, the nitrile functionality in the closo-decaborate clusters exhibits enhanced reactivity in the DCA of nitrones (CAs were completed over 16−18 h at 20−25 °C) similar to that found earlier for CA of nitrones to nitrile ligands bound to such exceptionally powerful activators as Pt IV centers.…”