Rh(II)-Catalyzed Ring Expansion of Cyclopropyl N-Tosylhydrazones to 1-Substituted Cyclobutenes

We dedicate this paper to Prof. Masahiro Murakami for his outstanding contribution to organic chemistry.

Abstract

Cyclobutenes are highly useful synthetic intermediates as well as important motifs in functional molecules. Herein, we report a straightforward access toward monosubstituted cyclobutenes from cyclopropyl N-tosylhydrazone. 1,2-Aryl or -alkyl shift of the Rh(II) carbene intermediate plays the key role in this transformation.

Key words

Rh(II) catalysis - N-tosylhydrazone - 1,2-shift - metal carbene - cyclobutene - cyclopropane

Publication History

Received: 30 October 2022

Accepted after revision: 09 December 2022

Accepted Manuscript online:
09 December 2022

Article published online:
03 January 2023

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• 19 All the reactions of rhodium-catalyzed ring expansion of cyclopropanes to cyclobutenes were performed under nitrogen atmosphere in a flame-dried reaction tube. All solvents were distilled under nitrogen atmosphere prior to use. Toluene, dioxane, and THF were dried over Na with benzophenone-ketyl intermediate as indicator, DCE and MeCN were dried over CaH₂. ¹H NMR (400 MHz) and ¹³C NMR spectra (100 MHz) were recorded with Bruker ARX 400 spectrometer. ¹⁹F NMR spectra were recorded with Bruker ARX 500 (160 MHz). The data for NMR spectra were reported as following: chemical shifts (δ) were reported in ppm using tetramethylsilane as internal standard when using CDCl₃ as solvent, and coupling constants (J) are in Hertz (Hz). Infrared spectra were recorded on a Nicolet Avatar 330 Fourier transform spectrometer (FT-IR) and are reported in terms of frequency of absorption (cm^–1). HRMS were obtained with Bruker APEX IV FTMS. All the cyclopropanes N-tosylhydrazones were prepared according to the literature procedures.^15a,²⁰,²¹ Rh₂(OAc)₄ was purchased from Adamas and used directly without further purification. Other starting materials were obtained from commercial suppliers and were used without further purification. Typical Procedure for Rh(II)-Catalyzed Ring Expansion of N-Tosylhydrazones to Cyclobutenes Under a nitrogen atmosphere, Rh₂(OAc)₄ (2.2 mg, 0.005 mmol, 2.5 mol%), N-tosylhydrazones 1a–ab (0.2 mmol, 1 equiv) and NaOt-Bu (38.4 mg, 0.4 mmol, 2.0 equiv) were successively added to a flame-dried 10 mL Schlenk reaction tube. The reaction flask was degassed three times with nitrogen, and dry DCE (0.5 mL) was added using a syringe. The resulting solution was then stirred at the 70 °C for 20 h. After completion of the reaction, the reaction mixture was filtered through a short plug of silica gel with Et₂O as eluent. The solvent was removed with rotary evaporator under reduced pressure to leave a crude mixture. The residue was purified by flash column chromatography on silica gel using pentane/Et₂O mixtures as eluent to afford the corresponding in analytically pure form product 2a–ab. Procedure for Scale-up Synthesis of 2a Under a nitrogen atmosphere, Rh₂(OAc)₄ (44 mg, 0.10 mmol, 2.5 mol), N-tosylhydrazones 1a (1.56 g, 4.0 mmol, 1 equiv), and NaOt-Bu (0.786 g, 8.0 mmol, 2.0 equiv) were successively added to a flame-dried 25 mL Schlenk reaction tube. The reaction flask was degassed three times with nitrogen, and dry DCE (8 mL) was added using a syringe. The resulting solution was then stirred at the 70 °C for 20 h. After completion of the reaction, the reaction mixture was filtered through a short plug of silica gel with Et₂O as eluent. The solvent was removed with rotary evaporator under reduced pressure to leave a crude mixture. which was purified by silica gel column chromatography (PE–Et₂O = 100:1) to afford pure product 2a (0.695 g, 84% yield). Hydroboration–Oxidation of 2a Under a nitrogen atmosphere, 1 M solution of borane–THF complex in THF (0.9 mL, 0.9 mmol, 4.5 equiv) was added to 2a (41.2 mg, 0.2 mmol, 1.0 equiv), and the reaction mixture was stirred for 5 h. 3 M aqueous solution of sodium hydroxide (0.2 mL, 0.4 mmol, 2.0 equiv) and 30% (w/w) aqueous solution of hydrogen peroxide (0.6 mL, 4 mmol, 20 equiv) were added dropwise to the reaction at 0 °C, and the reaction mixture was allowed to stir for another 3 h. The aqueous phase was extracted with Et₂O, the combined organic phases were washed with water and brine, and then dried over Na₂SO₄. After evaporation of the solvent, the remaining material was purified by flash chromatography on silica gel (PE–EtOAc = 4:1) to give alcohol 3a as a white solid (24 mg, 53% yield). Hydrogenation of 2a Compound 2a (41.2 mg, 0.2 mmol, 1.0 equiv) was dissolved in EOAc (2 mL) in a 10 mL reaction flask, and Pd/C (5%; 11 mg, 0.02 mmol, 10 mol%) was added to the flask. The mixture was degassed by ‘pump-freeze-thaw’ cycles (3×) and flushed with H₂ (1 atm). Then the reaction system was stirred at room temperature, under 1 atm of H₂ atmosphere for 24 h, and the reaction was monitored by TLC. After the crude material reaction is complete, the resulting mixture was filtered through a short column of silica gel and washed with EtOAc. The solution was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE–Et₂O = 100:1) to give 4a as a white solid (39.4 mg, 95% yield). Olefin Metathesis of 2a (a) Under nitrogen atmosphere, compound 2a (20.6 mg, 0.1 mmol, 1.0 equiv) and a solution of precatalyst (H₂IMes)(PCy₃)₂Cl₂Ru=CHPh (2.1 mg, 0.01 mmol, 10 mol%) in toluene (1 mL) was added to a flame-dried 10 mL Schlenk reaction tube. After complete mixing of the solution, the styrene (110 μL, 1 mmol, 10 equiv) was added to the solution. The resulting solution was then stirred at the 80 ^oC for 12 h. The resulting mixture was filtered through a short column of silica gel and washed with EtOAc. The solution was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE–EtOAc = 100:1) to give 5a as a white solid (19.7 mg, 64% yield, Z/E = 1:4.1). (b) Under a nitrogen atmosphere, compound 2a (20.6 mg, 0.1 mmol, 1.0 equiv) and a solution of precatalyst (H₂IMes)(PCy₃)₂Cl₂Ru=CHPh (2.1 mg, 0.01 mmol, 10 mol%) in toluene (1 mL) was added to a flame-dried 10 mL Schlenk reaction tube. After complete mixing of the solution, the ethyl vinyl ether (100 μL, 1 mmol, 10 equiv) was added to the solution. The resulting solution was then stirred at 80 °C for 12 h. The resulting mixture was filtered through a short column of silica gel and washed with EtOAc. The solution was then concentrated in vacuo and the residue was purified by silica gel column chromatography (PE–EtOAc = 100:1) to give 5b as a white solid (24.5 mg, 88% yield, Z/E = 1:1).
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