Study of the factors that control the ratio of the products between 5-fluorouracil, uracil, and tetrahydrobenzoxazepine O,O-acetals bearing electron-withdrawing groups on the nitrogen atom.
(RS)-1-(2-Nitrobenzenesulfonyl)- and (RS)-1-(4-nitrobenzenesulfonyl)-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepines are better substrates than 1-acyl-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives for the Lewis acid mediated condensation reaction with pyrimidine bases to give O,N-acetals. Acetonitrile, stannic chloride, 50 degrees C, and a reaction time higher than 48 h are the optimum conditions for such condensation reactions. Under these conditions, 5-fluorouracil preferably links to the aminalic carbon through its N-1" position, while the attachment of the uracil fragment is through N-3" or N-1" of the cyclic or acyclic products, respectively. The causes that influence the course of the reactions are analyzed and discussed. Examination of the (1)H NMR spectra revealed the presence of a single form for the secondary amine 11 and of two conformers for the tertiary sulfonamides 7a,b, 9a,b, and 10b and for the amides 7d and 13, with the following distribution: 7a, 59/41; 7b, 53/47; 9a, 52/48; 9b, 59/41; 10b, 56/44; 7d, 50/50; 13, 80/20. On increasing the temperature, the (1)H NMR spectrum (DMSO-d(6)) of 7b showed coalescence at 110 degrees C. The torsional barrier determined [DeltaG(c)++ value of 19.0 +/- 0.2 kcal.mol(-1) (79.1 +/- 1.0 kJ.mol(-1))] proved to be the highest ever observed for sulfonamide moieties.
Díaz-Gavilán
Mónica
M
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain.
Gómez-Vidal
José A
JA
Entrena
Antonio
A
Gallo
Miguel A
MA
Espinosa
Antonio
A
Campos
Joaquín M
JM
D000080:Acetals / Q000737:chemistry*; D004583:Electrons; D005461:Fluorine / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D014498:Uracil / Q000737:chemistry*
D000080:Acetals; D011743:Pyrimidines; D005461:Fluorine; D014498:Uracil; D006859:Hydrogen; C030986:pyrimidine; D009584:Nitrogen