Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

We recently reported a novel hybrid batch–flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow conditions using sodium dithionite. We now report the expansion of this method to include the reduction of aldehydes. The method developed affords yields which are comparable to those under batch conditions, has a reduced reaction time and improved space-time productivity. Furthermore, the approach allows the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process.


General methods
All solvents, chemicals, and reagents were obtained commercially and used without further purification. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded on Bruker AVANCE-III-300 instrument using CDCl 3 or DMSO-d 6 as solvent. CDCl 3 contained tetramethylsilane as an internal standard. Chemical shifts, δ, are reported in parts per million (ppm), and splitting patterns are given as singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Coupling constants, J, are expressed in hertz (Hz). In noted cases conversions were determined from NMR by comparison of integral areas of starting materials and products. Infrared spectra were run on a Bruker ALPHA Platinum ATR spectrometer. The absorptions are reported on the wavenumber (cm −1 ) scale, in the range 400-4000 cm −1 . The retention factor (R f ) values quoted are for thin-layer chromatography (TLC) on aluminium-backed Macherey-Nagel ALUGRAM Sil G/UV254 plates pre-coated with 0.25 mm silica gel 60, spots were visualised with UV light and basic KMnO 4 spray reagent. Chromatographic separations were performed on Macherey-Nagel Silica gel 60 (particle size 0.063-0.200 mm). Yields refer to isolated pure products unless stated otherwise.
General method for the reduction of aldehydes and ketones under traditional batch conditions Benzaldehyde (1 g, 9.5 mmol, 1 equiv) was dissolved in 38 mL (1:1 IPA/ H 2 O), (0.25 M). Sodium dithionite (7.5 g, 43 mmol, 4.5 equiv) and NaHCO 3 (1.6 g, 19 mmol, 2 equiv) was dissolved in water (43 mL, [1 M]) and added to the aldehyde. The mixture was refluxed for 12 hours under argon. The solution was allowed to cool to room temperature and the products were extracted using EtOAc (3 × 50 mL). This was dried using Na 2 SO 4 , filtered and dried under vacuum with a yield of 0.95 g (92%).
For entry 1.15 the compound was neutralized with 1 M HCl and extracted with EtOAc (3 × 50 mL) and washed with water (3 × 50 mL) the organic extracts were combined and dried using Na 2 SO 4 . The solvent was evaporated in vacuo and the resulting residue purified using column chromatography.
Unless specified a 3:1 EtOAc/hexane eluent was used for chromatographic purification [1][2][3]. were primed with the two stock solutions respectively. The solutions were then pumped continuously through a 2 mL mixing chip at ambient temperature followed by a 14 mL HT Teflon coil at 110 °C (aldehydes and ketones). Unless otherwise stated the flow rate was set to 0.25 mL·min −1 (64 min residence) for aldehydes and 0.20 mL·min −1 (80 min residence) for ketones. Product work-up and isolation was achieved using the approach described for the batch reductions.

Reduction of benzaldehyde in a sealed tube
General method for the selective reduction of aldehydes in the presence of ketones The solutions were pumped continuously through a T-piece at ambient temperature followed by a 29 mL coil (14 mL HT Teflon coil and 15 mL stainless steel coil) at 110 °C. The reaction was halted after 55 hours and 18 minutes. Thereafter, the flow reactor was washed with 1 M NaOH to remove any precipitate. The reaction mixture was extracted with EtOAc (5 × 100 mL). The organic extracts were combined and dried using Na 2 SO 4 . The solvent was evaporated, and the crude material obtained was purified by column chromatography 3:1 EtOAc/hexane eluent was used for chromatographic purification. to afford 6.99 g phenylmethanol in 79% yield.   (4-Methylphenyl)methanol Figure S3: 1 H NMR spectrum of (4-methylphenyl)methanol. Figure S4: 13 C NMR spectrum of (4-methylphenyl)methanol.