Org Prep Daily

October 13, 2006


Filed under: procedures — milkshake @ 3:39 pm


37% aq. formaldehyde 81.2g (1.00 mol, Fisher, methanol-stabilized grade) was cooled on ice bath and morpholine 175.0mL (2.00 mol) was added in 20 mL portions over 20 min with vigorous stirring on ice bath (exothermic!).The reaction was continued at 0-5C for additional 1 hour and then at RT for 2 hours. The reaction mixture was concentrated on rotavap (50 to 5 Torr, RT to 50C) and the remaining liquid was distilled at reduced pressure, b.p. 102-105C/5 Torr. Y=167.44g (90%) of a slightly oily colorless liquid. 1H(CDCl3, 400MHz): 3.690(app t, 4.7Hz, 8H), 2.902(s, 2H), 2.495(app br t, 4.5Hz, 8H); 13C(CDCl3, 100MHz): 81.94, 67.33(4C), 52.35(4C)


Using the above procedure on half the scale, bis(1-pyrrolidino)-methane was obtained from 37% HCHO 40.6g (500mmol) and pyrrolidine 83.5mL (1.00mol) in 77% yield (59.33g) as a colorless liquid, bp 65-67C/6Torr. 1H(CDCl3, 400MHz): 3.213(s, 2H), 2.581(m, 8H), 1.772(m, 8H); 13C(CDCl3, 100MHz): 77.76, 52.98(4C), 23.75(4C)

These preparations are modified (simplified workup) from a procedure published in Tetrahedron 53/8 2941-58 (1997)

Bis-morpholinomethane and bis-pyrrolidinomethane are useful reagents for aminomethylating electron-rich heterocycles (pyrroles, indoles) and active-methylene compounds in presence of TFA. Even more electrophilic reagent, [CH2=NR2+]Cl- can be generated from these bis-aminomethanes in quantitative yield with 1 eq. of acetyl chloride (anh. Et2O, 0C to RT, the iminium salt precipitates in a nearly quantitative yield. Very hygroscopic.).

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