Org Prep Daily

October 6, 2006

4-(3′-azetidino)-2,6-cis-dimethylmorpholine and 4-(3′-azetidino)-morpholine

Filed under: procedures — milkshake @ 10:59 am

azet.gif 

Allyl amine 15.00mL (200mmol) solution in non-denaturated ethanol 300mL was acidified with 48% aq. HBr 22.5mL (200mmol) with cooling on ice bath. Neat bromine 10.80mL (210mmol) was added over 2 min with vigorous stirring and the stirring was continued at 0C for 15 min, the ice bath was replaced with ambient water bath and the bromination was continued at RT for 1 hour. The reaction mixture was evaporated to dryness and the obtained orange solid residue was suspended in THF 40mL. The slurry was heated to reflux until the solid become white (bromine color was extracted to supernatants). The mixture was cooled, the product was collected by filtration, washed with THF and carefully dried on higvac. Y=57.82g(97%) of a white heavy crystalline solid.

1H(d4-MeOH, 400MHz): 4.540(m, 1H), 4.018(dd, 10.9Hz, 4.7Hz, 1H), 3.875(dd, 10.9Hz, 9.0Hz, 1H), 3.715(dd, 14.0Hz, 3.9Hz, 1H), 3.353(dd, 13.3Hz, 9.0Hz, 1H) 

[The original procedure (Tet Lett, 40 (1999), 3761-64) did not use HBr but doubled the amount of Br2 instead – HBr was generated in situ by bromination of ethanol.]

2,3-dibromopropyl amine hydrobromide 35.0g (117.5 mmol) slurry in anh THF 350mL was cooled to -78C and 10M BuLi 35.0 mL (350mmol) was added dropwise over 20 min. The mixture was stirred at -78C for 1 hour, then an ice-cooled solution of 85% KOH pellets, 50g in water 50mL was added dropwise at -78C. The cooling bath was removed, the mixture was stirred at RT for 30 min. The reaction flask was equipped with a distillation head and the mixture was distilled at atmospheric pressure (The receiver flask was cooled with ice). Approximately 250mL of distillate was collected (bp 35-65C). The distillate containing the unstable aziridine (a sharp lacrymatory fishy odor) was divided to two equal halfs.

One half of the aziridine solution was added to ice-cooled solution of 2,6-cis-dimethylmorpholine 20.7g (180mmol, Lancaster) and conc. sulfuric acid 3.3g (95%) in ethanol 250mL. The mixture was stirred at 0C for 30 min, then at RT for 8 hours (overnight). Calcium hydroxide powder 5.50g was added, the mixture was diluted with water 100mL and stirred for 1 hour. The reaction mixture was filtered through Celite (the solids were washed with ethanol). The filtrates were concentrated and the residue was distilled on Kugelrohr apparatus on highvac (0.5Torr) to obtain the pure product. Y= 3.358g (33.5%) of a colorless oil.

1H(CDCl3, 400MHz): 3.673(m, 2H), 3.607(t, 7Hz, 2H), 3.533(t, 7Hz, 2H), 3.172(m, 1H), 2.613(br d, 7Hz, 2H), 1.850(br s, 1H), 1.590(br t, 10Hz, 2H), 1.162(d, 6.3Hz, 6H), 71.51(2C), 59.28, 55.77(2C), 51.71(2C), 19.29(2C)

Using an identical procedure, the second half of the aziridine solution with morpholine 15.7mL (180mmol) provided 4-(3′-azetidino)-morpholine, 2.759g (33%) of a colorless oil. 1H(CDCl3, 400MHz): 3.727(t, 4.4Hz, 4H), 3.619(t, 8Hz, 2H), 3.566(t, 8Hz, 2H), 3.227(m, 7Hz, 1H), 2.895(br s, 1H), 2.329(br s, 4H); 13C(CDCl3, 100MHz): 66.71(2C), 59.37, 51.46(2C), 49.95(2C)

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