Nucleoside analogues. Part 12. The anomalous 19F NMR spectrum of B.3996, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea and synthesis of its N′-nitroso isomer and related compounds

Abstract

In an attempt to explain the two signals in the ¹⁹F NMR spectrum of the 5-fluorouracil (5-FU)/N(2-chloroethyl)-N-nitrosourea (CNU) molecular combination B.3996, we synthesised the isomeric N(2-Chloroethyl)-N′-nitrosourea (isoCNU) by an unequivocal route involving N-nitrosation of an aryl carbamate bearing the appropriate pyrimidine-containing N-substituent. In the event, this isoCNU was not responsible for the second peak in the ¹⁹F NMR spectrum, but itself showed two peaks. The ¹H NMR spectra at 300 MHz of these sulphides and the two corresponding N′-isomers and the two methoxy CNU analogues confirmed that a combination of methylthio/N³-substitution is necessary for the duplication pattern. In the compounds which show this behaviour, it is suggested that the Z and E isomers (around the N–NO system) equilibrate at a rate slower than the NMR time scale. This may have implications for the mechanism of biological action of 8.3996.