Synthesis of trisubstituted isoxazoles via in situ trapping strategy from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes

doi:10.1016/j.tet.2012.05.055

Tetrahedron

Volume 68, Issue 31, 5 August 2012, Pages 6257-6262

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Abstract

A highly efficient domino method for the synthesis of trisubstituted isoxazoles has been established from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes. Simple and readily available starting materials, mild reaction conditions and very simple operation are significant advantages of the reaction.

Graphical abstract

Introduction

The in situ trapping of unstable intermediates via domino reactions has provided enormous opportunities for the efficient synthesis of complex products from simple substrates.1, 1(a), 1(b), 1(c), 1(d), 1(e) Recently, we have successfully developed several novel domino reactions for the synthesis of 1,4-enediones via in situ trapping of unstable α-ketoaldehyde intermediates.² To further expand this strategy for the synthesis of pharmacologically interesting heterocycles, we report herein a new and efficient domino method for the synthesis of trisubstituted isoxazoles.

Isoxazoles have long been attractive targets for synthetic chemists due to their well known biological activities, such as antibacterial,³ antiviral,³ anticancer,⁴ and antithrombotic activity.⁵ In addition, they also serve as versatile building blocks in organic synthesis6, 6(a), 6(b) and materials science.7, 7(a), 7(b), 7(c) Consequently, a variety of methods have been developed for their synthesis, such as condensation of hydroxylamine with 1,3-dicarbonyl compounds,⁸ cyclization of propargylic oximes,9, 9(a), 9(b) rearrangement of subsituted oxetanes,¹⁰ reaction of nitroacetates with dipolarophiles,11, 11(a), 11(b), 11(c), 11(d) 1,3-dipolar cycloaddition of nitrile oxides with alkynes,12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h) and multicomponent reactions.13, 13(a), 13(b) However, many of these methods suffer from narrow substrate scopes and modest regioselectivities. Thus, a general and regioselective method is still highly needed for chemists to construct isoxazoles from simple and readily available starting materials.

In our previous studies,² methyl ketones or terminal aryl alkenes could be in situ transformed to α-ketoaldehydes via domino iodination–Kornblum oxidation reaction. Correspondingly, we suppose that α-nitro carbonyl compounds with acidic methylenes could in situ trap the unstable α-ketoaldehyde intermediates via Knoevenagel-type condensation to generate 2-nitro-1,4-enediones, which may further react with α-nitro carbonyl compounds to regioselectively afford trisubstituted isoxazoles due to the activating and leaving ability of nitro group (Scheme 1).^11d

Section snippets

Results and discussion

To verify our hypothesis, the initial study started with the reaction between acetophenone 1a and ethyl nitroacetate 3a. Fortunately, treatment of 1a with 3a in the presence of 1.0 equiv of CuO and 1.0 equiv of I₂ in DMSO at 70 °C furnished the desired isoxazole 4aa in 72% yield (Table 1, Entry 1), which was unambiguously confirmed by X-ray diffraction (Fig. 1).¹⁴ Much to our satisfaction, by increasing the CuO and I₂ loading to 2.0 equiv, isoxazole 4aa was obtained in 85% yield after 16 h (

Conclusion

In conclusion, we have developed an efficient route for the synthesis of isoxazoles from easily available α-nitroketones and methyl ketones or terminal aryl alkenes. This method not only represents an interesting domino process but also provides a practical access to trisubstituted isoxazoles with potential applications in the drug discovery.

General methods

All commercially available reagents were used without further purification. α-Nitroketones 3b–3h were prepared according to the literature method.¹⁵ Reactions were carried out under an argon atmosphere unless indicated otherwise. Solvents were dried according to published methods and distilled before use. IR spectra were recorded on an infrared spectrometer as KBr pellets with absorption in cm⁻¹. ¹H spectra were recorded in CDCl₃ on 400/600 MHz NMR spectrometers. Data are reported as follows:

Acknowledgements

We thank the National Natural Science Foundation of China (Grant 20872042 and 21032001).

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Synthesis of trisubstituted isoxazoles via in situ trapping strategy from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General methods

Acknowledgements

Bioorg. Med. Chem.

Org. Lett.

Org. Lett.

J. Am. Chem. Soc.

Tetrahedron Lett.

Synthesis

Eur. J. Org. Chem.

Org. Biomol. Chem.

Tetrahedron Lett.

J. Org. Chem.

J. Org. Chem.

Domino Reactions in Organic Synthesis

Multicomponent Reactions

Chem. Commun.

Tetrahedron

Chem.—Eur. J.

Org. Lett.

J. Org. Chem.

Tetrahedron

Org. Lett.

Org. Lett.

Tetrahedron