Acidity and N-methylation of N-aryl-N ′-cyanoguanidines †

Abstract

Acid dissociation constants in water have been determined for proton loss from a series of N-aryl-N ′-cyanoguanidines 1. Treatment of the same compounds with a strong base, butyllithium, followed by excess methyl iodide leads to successive N-methylation to yield mono-, di- and tri-methylated N-aryl-N ′-cyanoguanidines. The mechanism of the methylation is discussed.

References

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11. Other forms such as 5 where resonance involves the cyano group are much less likely to be involved given the known propensity of the cyano group to behave as a π-inductive group in cyanoguanidines; see ref. 4 and G. R. Bedford, P. J. Taylor and G. A. Webb, Magn. Reson. Chem., 1995, 33, 383.
12. Structures such as 8′ and 9′ can be dismissed since it is well established that prototropic tautomerism favours the imino double bond towards the more electron-withdrawing cyano group (as in 9) or if the cyano-substituted nitrogen is methylated towards the aryl group (as in 8).
13. N-Cyano-N′-methyl-N′-phenylguanidine 1j from N-methylaniline and dicyanamide, mp 139–141 °C (lit. 135–136 °C, see ref. 10).
14. In addition to the above arguments, structure 9 can almost certainly be excluded since two NH signals would be expected (as is seen for the parent cyanoguanidines 1) and furthermore, the methyl signals from the CH₃NH group would appear as a doublet.
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17. This compound shows unusual crystallisation behaviour and will be the subject of a separate paper. The X-ray crystallographic data (excluding structure factors) for the structure have been deposited with the Cambridge Crystallographic Data Centre. For details of the deposition scheme, see ‘Instructions for Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web page (http://www.rsc.org/authors). Any request to the CCDC for this material should quote the full literature citation and the reference number 188/162.
18. The pK_a for 1c(R = Ph, R′= H) is 12. 0 in water while that for the N-methylated 1j(R = Ph, R′= Me) is > 14; this suggests a difference in stability in the anions 3vs. 17 of at least 2 log units.
19. Several of the products 6 are known literature compounds. The low mp values quoted (see Supplementary material for refs.) and the fact that some were obtained here in only trace amounts makes identification by mp comparison difficult. However, NMR spectra, where published, are in good agreement with those here (see Supplementary material)(see A. Alemagna, P. Del Buttero, E. Licandro and A. Papagni, Gazz. Chim. Ital., 1988, 118, 249 and R. Radeglia, W. Storek, G. Engelhardt, F. Ritschi, E. Lipmaa, T. Pehk, M. Magi and D. Martin, Org. Magn. Reson., 1973, 5, 419).
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