Efficient Synthesis of Pharmaceutically Relevant Prochiral Heterocyclic Aminoketones

General All chemicals were purchased from Acros Organics (Queluz, Portugal), Aldrich (St. Louis, Missouri, United States), Alfa Aesar (Haverhill, Massachusetts, United States), Merck (Darmstadt, Germany) and Eurisotop (Saint-Aubin, France) and were used as received. All reactions were monitored by TLC and the precoated TLC plates ( Silica gel 60 F254 ) were visualized by exposure to ultraviolet light and/or ninhydrin stain.

Piperazine (1000 mg, 11.6 mmol) was dissolved in MTBE (10 mL) at reflux temperature, then chloroacetone (0.5 equiv.) was added and the reaction was refluxed until completion (followed by TLC DCM:MeOH 9:1+0.1 % NH 4 OH).The precipitation was filtered off, and the solvent evaporated to yield a yellow oil that was treated with MTBE. After filtration the solvent was evaporated to yield the crude mixture of 6j and 4j (Scheme S4).
Piperazine (1000 mg, 11.6 mmol) was dissolved in MTBE (10 mL) at reflux temperature, then potassium carbonate (3 equiv.) and chloroacetone (2.1 equiv.) was added and the reaction was refluxed until completion (followed by TLC DCM:MeOH 9:1+0.1 % NH 4 OH). The mixture was filtered and Scheme S1 Alkylation of morpholine (4a) at room temperature Scheme S2 General procedure for alkylation of amine heterocycles (4a-i) with external base K 2 CO 3 Scheme S3 General procedure for alkylation of amine heterocycles (4a-i) without external base Scheme S4 Monoalkylation of piperazine (4j) the solvent and excess chloroacetone removed under reduced pressure (10 mbar) by keeping the water bath at 70 °C to yield 6k (Scheme S5).
The solution of 6a-g in MTBE was treated with 4N HCl in dioxane (1.05 equiv.) under nitrogen atmosphere. The forming crystals were triturated and filtered under N 2 atm. to afford 7a-g. If the hydrochloride was not forming properly, the MTBE was evaporated and the residue was taken up in EtOH, then the hydrochloride was recrystallized by addition of MTBE (Scheme S6).
The solution of 6h,i,k in MTBE was treated with 4N HCl in dioxane (2.05 equiv.) under nitrogen atmosphere. The forming crystals were triturated and filtered under N 2 atm to afford 7h,i,k (Scheme S7).
The solution of 6j in MTBE was treated with 4N HCl in dioxane (1.05 equiv.) under nitrogen atmosphere. The forming crystals were triturated and filtered under N 2 atm. to afford 7j (Scheme S8).

Regeneration of 4i
The filter cake of the respective preparation of 6i with external base was dissolved in aqueous 1N NaOH solution (20 mL, pH > 10) and extracted with ethyl acetate. The organic phases were combined and dried on sodium sulfate. The solvent was evaporated to yield 4i as a colorless liquid.

Characterization of compounds
All melting points (mp) were determined on TA Instruments DSC250 calorimeter and are uncorrected. NMR spectra (Fig. S1-Fig. S36) were obtained with a Bruker Fourier 300 spectrometer, or a Magritec Spinsolve Benchtop NMR spectrometer at room temperature. Proton NMR spectra were recorded at 43 or 300 MHz, 13 C NMR spectra were recorded at 75 MHz. Chemical shifts are given in ppm units, ( 1 H NMR in DMSO-d 6 : δ 2.50 ppm, or D 2 O: δ = 4.79; 13 C NMR in DMSO-d 6 : δ = 39.5). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Spin-spin coupling constants (J) were given in Hz units. Infrared spectra (IR) of solid samples were recorded on a Nicolet Avatar 360 Fourier Transform Infrared spectrometer, of oils spectra were recorded on a Shimadzu IRAffinity-1 FTIR spectrometer. High-resolution mass spectra (HRMS) were recorded on an AB Sciex TripleTOF® 6600 System mass spectrometer.