Org Prep Daily

October 4, 2006

1-Benzyl-4-(4′-morpholinyl)-piperidine-4-carboxylic acid methyl ester

Filed under: procedures — milkshake @ 2:47 pm


1-benzyl-4-(4′-morpholinyl)-piperidine-4-carboxamide 8.133g (26.8 mmol) was dissolved in methanol 50mL and dimethylformamide dimethyl acetal 11.4mL (94%, Aldrich, 80 mmol) and sodium methoxide 3.20g (60mmol) was added. The mixture was stirred in a closed vessel at 60C for 5 days (extended weekend) at which point TLC indicated a near-complete conversion of the acylformamidine. The reaction mixture was cooled and allowed to crystallize at RT overnight (12 hours), the precipitate was collected by filtration, washed with ice-cold methanol and dried on highvac to provide 3.154g of pure product. The filtrates were added to a solution of ammonium carbonate 9.6g (100mmol) in water 250mL, the mixture was stirred for 20 min, the precipitated second crop was collected by filtration, washed with water and dried on highvac. (2.587g of pure product). The combined yield was 5.741g (67%) of a white crystalline solid.

1H(CDCl3, 400MHz): 7.295(d, 4.3Hz, 4H), 7.251(m, 1H), 3.711(s, 3H), 3.658(t, 4.7Hz, 4H), 3.453(s, 2H), 2.690(br m, 2H), 2.533(br t, 4.7Hz, 4H), 2.128(br m, 4H), 1.728(br m, 2H); 13C(CDCl3, 100MHz): 171.76, 138.67, 129.03(2C), 128.22(2C), 126.99, 67.99(2C), 63.84(br), 51.18(br), 50.46(br, 2C), 47.07(2C), 31.66(br, 2C)

Direct hydrolysis of alpha-tert-aminosubstituted amides obtained from Strecker tert-aminonitriles is notoriously sluggish and often accompanied by partial decomposition (isolating the produced aminoacid is no fun either). With this particular substrate, a variety of usual hydrolytic methods failed (heating with acid, heating with concentrated hydroxides, nitrosation, etc). The Me2NCH(OMe)2 /MeOH method is a mild alternative for transforming primary amides to Me-esters. Simple unhindered amides proceed to Me-esters typicaly without methoxide, at RT overnight. For this morpholinoamide, extended heating with excess of methoxide was necessary to provide a good conversion of the acyl formamidine intermediate. (Another good altenative would be to put a Boc- or Tosyl-group on the amide, carefully methylate the NH with diazomethane and then methanolyse.)

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