Flow synthesis of cyclobutanones via [2 + 2] cycloaddition of keteneiminium salts and ethylene gas

Abstract

A robust and safe flow method for the synthesis of mono-substituted cyclobutanones.

Synthesis of 2‐Substituted Cyclobutanones by a Suzuki Reaction and Dephosphorylation Sequence

“…GP1 starting from 1 a (146 mg, 0.5 mmol), 3‐thienylboronic acid (83 mg, 0.65 mmol), Pd(OAc) 2 (1.2 mg, 0.005 mmol), RuPhos (4.7 mg, 0.01 mmol), K 3 PO 4 (0.75 mL, 1.5 mmol), CF 3 CH 2 ONa (183 mg, 1.5 mmol), (Hexane/AcOEt 20 : 1, R f =0.30), 59 mg (75 %) yellowish oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.33–7.30 (m, 1H), 7.13–7.11 (m 1H), 7.01–6.99 (m, 1H), 4.58–4.52 (m, 1H), 3.29–3.16 (m, 1H), 3.12–3.00 (m, 1H), 2.61–2.48 (m, 1H), 2.23–2.10 (m, 1H), in accordance with literature [22a] …”

“…GP1 starting from 1 a (288 mg, 1.0 mmol), 4‐methoxyphenylboronic acid (197 mg, 1.3 mmol), Pd(OAc) 2 (2.3 mg, 0.01 mmol), RuPhos (9.3 mg, 0.02 mmol), K 3 PO 4 (1.5 mL, 3.0 mmol), CF 3 CH 2 ONa (367 mg, 3.0 mmol) gave (Hexane/AcOEt 20 : 1, R f =0.26), 136 mg (76 %) yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.16 (d, J =8.9 Hz, 2H), 6.87 (d, J =8.9 Hz, 2H), 4.48 (tt, J =8.2, 2.7 Hz, 1H), 3.79 (s, 3H), 3.22 (dddd, J =17.6, 10.6, 8.3, 2.4 Hz, 1H), 3.01 (dddd, J =17.7, 9.7, 4.9, 2.6 Hz, 1H), 2.52 (dtd, J =11.2, 10.5, 4.9 Hz, 1H), 2.18 (ddt, J =11.2, 9.7, 8.3 Hz, 1H), in accordance with literature [22a] …”

“…1 H NMR (300 MHz, CDCl 3 ) δ 3.32–3.22 (m, 1H), 3.06–2.86 (m, 2H), 2.21–2.12 (m, 1H), 1.72–1.59 (m, 2H), 1.52–1.42 (m, 1H), 1.38–1.20 (m, 8H), 0.89–0.85 (m, 3H). 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 212.8, 60.8, 44.5, 31.8, 29.7, 29.3, 27.1, 22.7, 17.0, 14.2, in accordance with literature [22a] …”

An automated colorimetric inline titration of CO2 concentrations in solvent flow streams using a Teflon AF-2400 tube-in-tube device

“…Whilst remaining impermeable to the liquid phase, Teflon AF-2400 allows gasses to rapidly permeate through its amorphous microporous structure. [21,22] Initially used in synthetic applications with ozone, [23] these devices have since been used with a diverse array of gasses including hydrogen, [24,25] ammonia, [26][27][28] oxygen, [29][30][31][32][33][34] ethene, [35][36][37] carbon monoxide, [38,39] syngas [40] and diazomethane [41,42]. Jensen and co-workers have also used this material to remove an ethene byproduct in a continuous flow application.…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…Other continuous-flow systems in which a ketene was generated in situ and then directed into a [2 + 2] cycloaddition have been reported, many of these reactions present improved results compared to their batch modes with higher throughputs [ 522 – 523 ].…”