Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min.


General methods
Unless otherwise stated, all commercial reagents were used as received. Merrifield resin (1% DVB, f = 0.53 mmol of Cl g -1 resin) was obtained from Novabiochem. Flash chromatography was carried out with 60 mesh silica gel and dry-packed columns. NMR spectra were registered in a Bruker Advance 400 Ultrashield spectrometer in CDCl 3 at room temperature, operating at 400.13 MHz ( 1 H) and 100.63 MHz ( 13 C{1H}). TMS was used as internal standard for 1

Synthesis of O-tert-butyl-N,N'-diisopropylisourea [4]
CuCl (259 mg, 3.63 mmol, 1 mol %) was added to a solution of N,N'-diisopropylcarbodiimide (56.8 mL, 45.8 g, 363 mmol) in dry t-BuOH (39.7 mL, 417 mmol). The reaction mixture was stirred for 14 h at rt. A 1 H NMR spectrum was recorded to check that the reaction was completed. After filtration most of the t-BuOH was removed from the filtrate under reduced pressure. The product (58.9 g, 294 mmol, 81%) was used directly in the next reaction without any further purification.
All spectroscopic data of the product were identical to those reported in the literature [4].
The so-obtained mixture was stirred under nitrogen atmosphere for 1 h at −20 °C, after which propargyl bromide (0.46 mL propargyl bromide 80% in toluene, 4.1 mmol) was added dropwise.
The reaction mixture was allowed to slowly reach rt and stirred under nitrogen atmosphere for 16 h. The reaction was then quenched with methanol (5 mL) and subsequently with water (50 mL). After that, the mixture was extracted with ethyl acetate (3 x 50 mL), the organic layers were combined, treated with brine (25 mL) and dried over anhydrous Na 2 SO 4 . The crude product, obtained after filtration and evaporation of the solvents under reduced pressure, was purified by flash column chromatography on silica gel (hexanes/EtOAc 8:2) to afford 0.74 g (65% yield) of the title compound as a yellow oil.

S4
All spectroscopic data of the product were in agreement with those reported in the literature [6].

Synthesis of azidomethyl resins (4a,b)
Resins 4a,b were prepared by reported procedures [6]. A slightly cross-linked (1% 1,4divinylbenzene) Merrifield resin with a functionalization of 0.53 mmol Cl g −1 and a home-made Merrifield resin (8% 1,4-divinylbenzene, 0.80-1.00 mmol Cl g −1 ) were used as starting materials for 4a and 4b, respectively. In each case, the extent of the resin functionalization with azide groups was calculated by using the %N determined by elemental analysis. and dichloromethane (100 mL). The resulting resin was dried in vacuo at 40 °C for 24 h, before being submitted to the next step.
2) General procedure for N-Boc and tert-butylester deprotection The resin resulting from the previous step was swollen with 5 mL of CH 2 Cl 2 . After 10 min, 10 mL of trifluoroacetic acid was added and the evolution of the deprotection was followed by ATR-