9708
via
H
N
NBn2
H
N
(25)
Br
Bn2N
Br
N
H
OH
H2N
OH
Bn2N
27
CsOH·H2O, 4 Å MS
24
26
DMF, 23 °C, 36 h, 46%
Scheme 4.
In conclusion, we have developed a convenient and efficient protocol for the chemoselective
mono-N-alkylation of diamines and polyamines using a wide variety of halides. Our protocols
offered moderate to high yields, and the use of protecting groups proved to be unnecessary.
Furthermore, our technology was applicable to the efficient synthesis of peptidomimetic
compounds.
Acknowledgements
We gratefully acknowledge financial supports from the H. Lee Moffitt Cancer Center &
Research Institute and the American Cancer Society (Institutional Research Grant c032).
References
1. For recent reviews on polyamines and their derivatives, see: (a) Advances in Polyamine Research 1 and 2;
Campbell, R. A.; Morris D. R.; Bartos, D.; Davies, G. D.; Bartos F., Eds.; Raven Press: New York, 1978. (b)
Ganem, B. Acc. Chem. Res. 1982, 15, 290 and references cited therein.
2. For a comprehensive review on the neuropharmacology of polyamines, see: The Neuropharmacology of
Polyamines; Carter, C., Ed.; Academic Press: San Diego, 1994.
3. Ojima, I. Catalytic Asymmetric Synthesis; VCH Verlag: Weinheim, 1993.
4. Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org. Lett. 1999, 1, 1893.
5. McClure, M. R.; Jung, K. W.; Worrell, J. H. Coord. Chem. Rev. 1998, 174, 33.
6. Teumac, F. U. S. Patent 3,362,996, 1968; Chem. Abstr. 1968, 68, 77738.
7. Weiss, A. L.; Chen, S.-F.; Reddy, P. S.; Mittakanti, M.; Dexter, D. L.; Woynarowski, J. M. U. S. Patent
5,561,042, 1996.
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,
9. Representative experimental procedure: To activated powdered dry 4 A molecular sieves (5.0 g) in anhydrous
N,N-dimethylformamide (45 mL), were added cesium hydroxide monohydrate (3.7 g, 22 mmol) and 1,5-diamino-
3-thiopentane 9 (1.1 g, 8.8 mmol). With vigorous stirring, 2-bromoethylamine hydrobromide 8 (2.7 g, 13 mmol)
was added and the mixture was stirred at room temperature for 12 h, at which time the reaction was quenched
with 100 mL of 1 N NaOH. Following filtration to remove solids, the solution was concentrated by blowing air.
The resulting solid was then taken up in a small amount of methanol, triturated with Et2O, subsequently filtered,
and reduced to dryness in vacuo. Trituration was repeated two more times to ensure the removal of the inorganic
salts. The resulting thick yellow oil was then subjected to silica gel chromatography using 5% NH4OH–MeOH,
followed by 15% NH4OH–MeOH, which gave 3 (1.04 g, 73% yield).
10. Product 23 was converted back to the starting diamine 22 by hydrogenolysis, followed by salt formation using
dry HCl gas. The optical rotation of the resultant salt was 16.5°, whereas the reported value is 15.6° (c=1.3;
H2O). See: J. Org. Chem. 1963, 2898.
11. Nagle, A. S.; Salvatore, R. N.; Chong, B. D.; Jung, K. W. Tetrahedron Lett. 2000, 41, 3011.
12. 1H, 13C and 2-D NMR indicated the product as a single diastereomer.