pleasant surprise, excellent chemoselectivity (C4 over C2-
Cl) was achieved in the reaction with 6-chloropyrimidin-
4(3H)-one (entry 9, Table 4), clearly demonstrating an
advantage over conventional C-N bond formation from an
aryl halide. Regioselectivity was also achieved with uracil
systems (entry 7, Table 4) due to higher reactivity of the C4
position.12 It was also discovered that guanidinylation of
cyclic ureas proceeded smoothly to produce the desired cyclic
guanidines 5l and 5m, in good yields (entry 10, Table 4).
The success of these direct aminations turned our attention
to the syntheses of kinetin and olomoucine. Kinetin, a well-
known plant growth factor that was first isolated from plant
DNA13 and recently from human urine,14 has a wide variety
of biological effects, including those on gene expression,
inhibition of auxin action, stimulation of calcium flux, and
human DNA-repair reactions.15 Olomoucine has been shown
to be a potent and selective cyclin dependent kinase
inhibitor.16 In our hands, kinetin 6 was synthesized in just
one step from hypoxanthine 4a in 90% yield (eq 1, Scheme
4). Meanwhile, direct amination of 1-methylguanine 7,
followed by one-pot reductive amination and desilylation,
provided olomoucine 8 in 80% overall yield in just 2 steps
(eq 2, Scheme 4).
Scheme 4
In summary, an efficient one-step amination of cyclic
amides and cyclic ureas has been developed. This mild,
metal-free amination of cyclic amides and cyclic ureas has
demonstrated a clear advantage over existing procedures. It
facilitated efficient and concise syntheses of biologically
intriguing kinetin and olomoucine in just one and two steps,
respectively. Direct amidinylation and guanidinylation of
more challenging acyclic systems as well as the application
to the syntheses of important heterocyclic products are
underway. The results will be reported in future publications.
(12) Peng, Z.-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8, 395.
(13) Isolation: (a) Miller, C. O.; Skoog, F.; Von Saltza, M. H.; Strong,
F. M. J. Am. Chem. Soc. 1955, 77, 1392. (b) Miller, C. O.; Skoog, F.;
Okumura, F. S.; Von Saltza, M. H.; Strong, F. M. J. Am. Chem. Soc. 1956,
78, 1375. For syntheses see ref 13b and: (c) Villar, J. D. F.; Motta, M. A.
Nucleosides, Nucleotides & Nucleic Acids 2000, 19, 1005.
(14) Barciszewski, J.; Mielcarek, M.; Stobiecki, M.; Siboska, G.; Clark,
B. F. C. Biochem. Biophys. Res. Commun. 2000, 279, 69.
(15) For a recent review on kinetin see: Barciszewski, J.; Rattan, S. I.
S.; Siboska, G.; Clark, B. F. C. Plant Sci. 1999, 148, 37.
(16) For representative biological activities see: (a) Vesely, J.; Havlicek,
L.; Strnad, M.; Blow, J.; Donella-Deana, A.; Pinna, L.; Letham, D.; Kato,
J.; Detivaud, L.; Leclerc, S.; Meijer, L. Eur. J. Biochem. 1994, 224, 771.
(b) Mistelli, T.; Warren, G. J. Cell Sci. 1995, 108, 2715. (c) Hartwell, L.
H.; Kastan, M. B. Science 1994, 266, 1821. For recent 6-9 step syntheses
see: (d) Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J. W. J. Org. Chem.
1997, 62, 201. (e) Dorff, P. H.; Garigipati, R. S. Tetrahedron Lett. 2001,
42, 2771. (f) Hammarstro¨m, L. G. J.; Smith, D. B.; Talama´s, F. X.; Labadie,
S. S.; Krauss, N. E. Tetrahedron Lett. 2002, 43, 8071.
Acknowledgment. The authors wish to thank Drs. Steve
Tam, Eddine Saiah, and Pawel Nowak of Wyeth Research
for helpful discussions, Drs. Nelson Huang and Xidong Feng
for obtaining HRMS data, Dr. Melissa Lin for measuring
31P NMR, and Mr. Douglas Willson and Ms. Jill Nunez for
technical support.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
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Org. Lett., Vol. 8, No. 11, 2006