In situgeneration of nitrile oxides from copper carbene andtert-butyl nitrite: synthesis of fully substituted isoxazoles

Abstract

Herein, we present a novel [3 + 2] cycloaddition reaction of β-keto esters with nitrile oxides, which were generated in situ from copper carbene and tert-butyl nitrite. This three-component reaction provides new methodology for the direct synthesis of fully substituted isoxazole derivatives, featuring mild reaction conditions, readily accessible starting materials and simple operation. The experimental studies and DFT calculations suggest that the reaction starts with the generation of the key intermediate nitrile oxides, followed by a [3 + 2] cycloaddition reaction of β-keto esters to give the final isoxazole products.

tert‐Butyl Nitrite (TBN), a Multitasking Reagent in Organic Synthesis

“…In 2018, Bao and Wan group disclosed a multi‐component reaction for the synthesis of highly substituted isoxazoles from the in situ generated nitrile oxides using copper carbene and TBN. The proposed mechanism was supported by experimental studies and DFT calculations which suggest that this conversion goes via in situ generated nitrile oxides from copper carbene and TBN, followed by a dipolar cycloaddition with the β‐keto esters …”

“…The proposed mechanism was supported by experimental studies andD FT calculations whichs uggest that this conversion goes via in situ generated nitrile oxidesf rom copper carbene and TBN, followedb yadipolar cycloaddition with the b-keto esters. [64] Our group in 2017, demonstrated an efficient method for the synthesis of isoxazolines (52)a nd isoxazoles (52')f rom terminal alkenes (51)a nd alkynes (51')u sing TBN. Most of the hetero-aromatic olefins were well tolerated in this method and no significant change in the yields of the products was observed for substrates bearing either electron-withdrawing or electron-donating substituents (Scheme 38).…”

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

“…The formation of 3a,4-dihydro-3H,7H-and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3c] [1,2]oxazole ring systems was easily deduced after an in-depth analysis of NMR spectral data, which were obtained through a combination of standard and advanced NMR spectroscopy techniques, such as 1 H- 13 C HMBC, 1 H-13 C J-HMBC, 1 H- 15 N HMBC, 1 H- 13 C HSQC, 1 H- 13 C H2BC, 1 H-1 H COSY, 1 H-1 H NOESY and 1,1-ADEQUATE experiments (Figure 1). In the case of compound 5a, the multiplicity-edited 1 H- 13 C HSQC spectrum allowed us to identify the pairs of geminally coupled methylene protons, since both protons displayed cross-peaks with the same carbon. For instance, it showed two pairs of negative signals at δ H 4.66, 3.79 and 4.78, 4.17 ppm, which have one-bond connectivities with the methylene carbons C-3 (δ 69.7 ppm) and C-4 (δ 70.9 ppm), respectively.…”

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

“…In a 2018 work by the Wan group, diazo esters 85 were used for in situ preparation of nitrile oxides, which underwent highly regioselective [3+2] cycloaddition with enols generated from β -ketoesters 86 [ 50 ] . The reaction tolerated a broad range of substituents in the aromatic ring and furnished 3,4,5-substituted isoxazoles 87 in moderate to good yields.…”