A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

Chloramines are an important class of reagents, providing a convenient source of chlorine or electrophilic nitrogen. However, the instability of these compounds is a problem which makes their isolation and handling difficult. To overcome these hazards, a continuous-flow approach is reported which generates and immediately reacts N-chloramines directly, avoiding purification and isolation steps. 2-Chloramines were produced from the reaction of styrenes with N-alkyl-N-sulfonyl-N-chloramines, whilst N-alkyl or N,N’-dialkyl-N-chloramines reacted with anisaldehyde in the presence of t-BuO2H oxidant to afford amides. Primary and secondary imines were produced under continuous conditions from the reaction of N-chloramines with base, with one example subsequently reduced under asymmetric conditions to produce a chiral amine in 94% ee.


S1. Batch reaction screening for addition of N-chloromorpholine to styrene
Various other non-precious metal catalysts reported in the literature were examined (Cu(OTf) 2 [1] , FeCl 3 [2] ), however, CuI proved most active despite long reaction times and poor conversion.
Increasing temperature (entries [11][12][13][14] or concentration of N-chloromorpholine (entries 3 and 14) did not increase overall conversion. Substitution of N-chloromorpholine with morpholine did not afford any trace of product. The addition of water to the reaction solvent impeded conversion, preventing a one-pot procedure. Interestingly however, addition of further N-chloromorpholine and CuI after 8 hours reaction time led to increased conversion (entry 10, 79%), suggesting catalyst and/or substrate degradation may be taking place.

S2. Differential scanning calorimetry (DSC) of N-chloro-N-methyl-p-
toluenesulfonamide N-Chloro-N-methyl-p-toluenesulfonamide (2.3 mg, 0.01 mmol) was analysed by DSC. The sample was heated from 10 → 250°C at a step-rate of 10 °C min −1 .   (11). Prepared according to the general procedure in reference [3]. 1) Tube reactor with 4 static mixers, a 6 mL reactor volume and a residence time of  General procedure for batch reaction of N-chloramine with styrene (13)   General batch procedures for imine formation with NaOMe base: To a round-bottomed flask was added the required amount of N-chloramine in toluene (1 M). The solution was stirred at room temperature and to it was added an equal volume of MeOH followed by the slow addition of NaOMe (2 equiv). The reaction mixture was stirred, and conversion followed by 1 H NMR spectroscopy or GC analysis. Then MeOH was removed by rotary evaporation. To the residue was added water and EtOAc. The aqueous phase was removed and washed with further EtOAc (3 washes). The organic phases were combined, dried over Na 2 SO 4 , filtered and the solvent removed by rotary evaporation to leave the crude product as a colourless oil, which was analysed by 1 HNMR.

N-Chloro-N-methyl-p-toluenesulfonamide
General batch procedures for imine formation with NaOH base: To a round-bottomed flask was added the required amount of N-chloramine in toluene (1 M). The solution was stirred at room temperature and to it was added an equal volume of aqueous NaOH (25% w/w) and tetrabutylammonium bromide (TBAB, 10 mol % relative to N-chloramine). The reaction mixture was stirred and conversion S12 followed by 1 H NMR spectroscopy or GC analysis. Once complete conversion of starting material was achieved, the organic phase was removed and dried by rotary evaporation to leave the crude product as a colourless oil. The reaction proceeded cleanly and further product purification was not required. The product was analysed by 1 HNMR.
General procedure for continuous imine formation with NaOMe base:

S4.2 Single-stage heated CSTR assembly
A three-necked round-bottomed flask equipped with a condenser was employed as a laboratory scale CSTR and was heated using an aluminium heating block. Reactants were pumped into the CSTR through one neck and out of the opposing neck at equal flow rate to maintain a constant volume, via 1 / 16 " OD PTFE tubing (see Figure S3). Figure S3. Single-stage heated CSTR configuration.

S4.3 Multi-stage CSTR assembly
A laboratory scale cascade CSTR developed within our group (and described elsewhere) [4] was employed to generate and dispense N-chloroamines as described within the manuscript. For clarity, the reactor assembly is reproduced in Figure S4 below.

S4.4 NaOCl titration
Acetic acid (1 mL) and potassium iodide (350 mg) were diluted to 50 mL using DI water. To this solution was added NaOCl solution as obtained from Sigma-Aldrich (1 mL). Na 2 S 2 O 3 (0.1 M) was then titrated into the aqueous solution of potassium iodide, acetic acid and NaOCl until the orange solution became colourless. The concentration of the initial NaOCl solution was determined using the equation supplied below: HOCl + 2I -→ I 2 + Cl -+ OH -