Elsevier

Tetrahedron

Volume 76, Issue 24, 12 June 2020, 131255
Tetrahedron

Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates

https://doi.org/10.1016/j.tet.2020.131255Get rights and content

Highlight.

• One-pot multi-operation.

• C(sp2)-C(sp2) construction.

• Cascade reaction.

Abstract

Treatment of electron-rich arenes with Tf2O and DMF, followed by the reaction with NH2OH·HCl and then with Oxone® in the presence of diethyl acetylenedicarboxylate generated diethyl 3-arylisoxazole-4,5-dicarboxylates in good to moderate yields. Other alkynes could be also used for the present one-pot transformation of arenes into 3-arylisoxazole derivatives. Click here and insert your abstract text. © 2020 Elsevier Science. All rights reserved.

Introduction

Isoxazoles are one of the most important nitrogen-containing heteroaromatics, because there are many biologically active compounds and natural products containing isoxazole unit [1]. For example, Valdecoxib and Oxacillin, both of which are 3-arylisoxazole derivatives, are anti-inflammatory and antibiotic drugs, respectively, as shown in Fig. 1 [1]. Therefore, extensive synthetic studies have been carried out [2].

The most common method for the preparation of isoxazoles is the 1,3-dipolar cycloaddition of nitrile oxides onto alkynes [2]. Recent reports for the preparation of isoxazoles with nitrile oxides are as follows: the preparation of 3,5-disubstituted isoxazoles with O-silylated hydroxamic acids, Tf2O, Et3N, and 1-alkynes [3a]; the preparation of 3,5-disubstituted isoxazoles with alkynes, tBuONO, α-diazo esters, and Cu(OAc)2 [3b]; the preparation of 3,5-disubstituted isoxazoles with hydroximoyl fluorides, 1-alkynes, and Ag2CO3 [3c]; the preparation of 3-arylisoxazoles with N-hydroxybenzimidoyl chloride and enamino carbonyl compounds under ball milling conditions [3d]; the preparation of 5-arylisoxazole-4,5-dicarboxylates with α-(aroyl)acetates, ethyl α-diazoacetate, and tBuONO in the presence of Cu(OAc)2 and Mg(OTf)2 [3e]; the preparation of 5-substituted 3-arylisoxazoles with aromatic aldoximes, 1-alkynes, and isoamyl nitrite [3f]; the preparation of 3-arylisoxazoles with aromatic aldoximes, acetylenedicarboxylate esters, and (diacetoxyiodo)benzene (DIB) [3 g]; the preparation of 4,5-disubstituted 3-arylisoxazoles with hydroximoyl chloride and β-ketoamides in the presence of 1,1,3,3-tetramethylguanidine (TMG) [3h]; the preparation of 5-substituted 3-phenylisoxazoles with N-hydroxybenzimidonyl chloride and 1-alkynes in the presence of CuSO4 [3i]; and the preparation of 5-substituted 3-arylisoxazoles with arylnitrile oxide, and allenyl-MgBr in the presence of organo-NHC catalyst [3j].

Other methods for synthesis of isoxazoles have been also developed. Recent reports include the preparation of 3-(qunoline-2′-yl)isoxazoles with 2-methylquinoline, ethynylarenes, and HNO3 [4a], the preparation of 4-substituted 3,5-diarylisoxazoles with alkynone O-methyloximes, ethynylarenes, and [C2O2mim]Cl in the presence of Pd(TFA)2 [4b], the preparation of 3-difluoromethyl- and 3-trifluoromethyl-5-arylisoxazoles with ethynylarenes, XCF2CH2NH2 (X = H, F), and tBuONO in the presence of ZnBr2 and CuI [4c], the preparation of 5-acyl-3-cyanoisoxazoles with nitroisoxazolone and α-chloro-α,β-unsaturated ketones [4d], the preparation of 3,5-diaryl(alkyl)isoxazoles with ynones and trimethylsilylazide [4e], the preparation of 3,5-diarylisoxazoles with enone oximes in the presence of Cu(OAc)2 under O2 atmosphere [4f], the preparation of 4-borylated 3-arylisoxazoles with ynone oximes and HBcat in the presence of IPrAuTFA [4 g], and the preparation of 3-thiomethyl-5-arylisoxazoles with β-oxodithioesters and NH2OH [4h].

Among the above mentioned methods, the preparation of 3-arylisoxazoles with nitrile oxides and alkynes via the 1,3-dipolar cycloaddition reaction is rather useful due to the availability of the starting materials, although it is a common and classic method. Previously, we reported the preparation of 3,5-diarylisoxazoles from the reactions of ethynylarenes with n-BuLi, followed by the reaction with aromatic aldehydes, and then molecular iodine and hydroxylamine [5a], and the preparation of diethyl 3-arylisoxazole-4,5-dicarboxylates from the reactions of aryl bromides with n-BuLi, followed by the reaction with DMF, hydroxylamine, and then diethyl acetylenedicarboxylate and Oxone® (2KHSO5·KHSO4·K2SO4) [5b].

To the best of our knowledge, the one-pot transformation of arenes into 3-arylisoxazoles through the intermolecular C–C bond formation has scarcely been studied. We would like to report herein the preparation of diethyl 3-arylisoxazole-4,5-dicarboxylates by the reaction of electron-rich arenes with DMF and Tf2O using the Vilsmeier-Haack reaction, followed by the reaction with NH2OH·HCl, and then diethyl acetylenedicarboxylate and Oxone® in one-pot under transition-metal-free conditions.

Section snippets

Results and discussion

First, treatment of 1,3-dimethoxybenzene 1A (3.0 mmol) with trifluoromethanesulfonic anhydride (Tf2O, 1.4 equiv.) and DMF (1.4 equiv.) at room temperature for 4 h under stirring and solvent-free conditions (1st step), followed by reaction with NH2OH·HCl (1.2 equiv.) and K2CO3 (0.6 equiv.) in a mixture of acetonitrile and water (5:1, 6.0 mL) (2nd step) gave 2,5-dimethoxybenzaldoxime 2A in 93% yield. Based on this result, after treatment of compound 1A with Tf2O and DMF (1st step), and then with

Conclusion

Electron-rich arenes could be smoothly transformed into diethyl 3-arylisoxazole-4,5-dicarboxylates in good to moderate yields by the successive treatment with Tf2O and DMF, with NH2OH·HCl and K2CO3, and with diethyl acetylenedicarboxylate and Oxone® in the presence of 1-hexene. Other alkynes, such as dimethyl acetylenedicarboxylate, ethyl propiolate, 3-buten-1-ol, ethynylbenzene, and 1-octyne, could also be used instead of diethyl acetylenedicarboxylate to form the corresponding 3-arylisoxazole

General

1H NMR and 13C NMR spectra were obtained with JEOL-JNM-ECX400 and JEOL-JNM-ECS400 spectrometers. Chemical shifts were recorded as follows: chemical shift in ppm from internal tetramethylsilane (TMS) on the δ scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad), coupling constant (Hz), integration, and assignment. High-resolution mass spectra (HRMS) were recorded by a Thermo Fisher Scientific Exactive Orbitrap mass spectrometer. IR spectra were

Acknowledgments

This research was funded by JSPS (KAKENHI) Grant Number JP No. 18K05118 in Japan.

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