5580
L. Revesz et al. / Tetrahedron Letters 46 (2005) 5577–5580
6. Cignarella, G.; Occelli, E.; Maffii, G.; Testa, E. J. Med.
Chem. 1969, 12, 836–839.
7. Liu, H.; Cheng, T.; Zhang, H.; Li, R. Arch. Pharm. Med.
Chem. 2003, 336, 510–513.
8. Villa, S.; Barlocco, D.; Cignarella, G.; Papp, G. J.; Balati,
B.; Takacs, J.; Varro, A.; Borosy, A.; Keseru, K.; Matyus,
P. Eur. J. Med. Chem. 2001, 36, 495–506.
both generated from an aziridinium intermediate when
heating 10 or cis-23 with benzylamine. Compound 20
was finally obtained by selective debenzylation of 24.
Modification of the synthetic sequence in Scheme 5 by
reacting 22 first with benzylamine followed by p-fluoro-
benzylamine resulted in isomer 19.
9. Testa, E.; Occelli, E. Gazz. Chim. Ital. 1968, 98, 861–865.
10. McGuirk, P. R.; Jefson, M. R.; Mann, D. D.; Elliott, N.
C.; Chang, P.; Cisek, E. P.; Cornell, C. P.; Gootz, T. D.;
Haskell, S. L., et al. J. Med. Chem. 1992, 35, 611–620.
11. Pinna, G. A.; Murineddu, G.; Curzu, M. M.; Villa, S.;
Vianello, P.; Borea, P. A.; Gessi, S.; Toma, L.; Colombo,
D.; Cignarella, G. Il Farmaco 2000, 55, 553–562.
12. Culpepper, W.C. Ph.D. Thesis, University of Georgia,
Athens, GA, USA, 1972.
In summary, we have developed methods for the prepa-
ration of four novel bridged piperazine based building
blocks15—3,7,9-triazabicyclo[3.3.1]nonane 1, 3-oxa-7,9-
diazabicyclo[3.3.1]nonane 2, 3,6,8-triazabicyclo[3.2.2]-
nonane 3 and 3-oxa-6,8-diazabicyclo[3.2.2]nonane 4—
which may find useful application in target-oriented
and diversity-oriented organic synthesis directed to drug
discovery.
13. Terauchi, H.; Yamasaki, A.; Takemura, S. Chem. Pharm.
Bull. 1975, 23, 3162–3169.
14. Takahata, H.; Takahashi, S.; Kouno, S.; Momose, T.
J. Org. Chem. 1998, 63, 2224–2231.
Acknowledgements
15. All new compounds gave satisfactory elemental analysis
and spectral data. Selected data for compounds 12, 15, 16,
19 and 20 are shown below. Compound 12: 1H NMR
(400 MHz; DMSO-d6), d (ppm): 2.71 (d, 2H); 2.98 (dd,
2H); 3.08 (m, 2H); 3.21 (dd, 2H); 3.43 (dd, 2H); 3.72 (dd,
4H); 7.17–7.30 (m, 10H); 7.53 (t, 2H); 7.71 (m, 1H); 7.28
The authors express their appreciation to the Analytical
Department of Novartis Pharma AG for NMR, MS and
IR spectra including their interpretation. The Kilolab is
gratefully acknowledged for the preparation of ample
quantities of compounds 13, 18 and 19.
1
(d, 2H). MS (m/z) ES+: 448.2 (MH+). Compound 15: H
NMR (400 MHz; DMSO-d6), d (ppm): 2.17 (s, 3H); 2.25–
2.35 (m, 4H); 2.58–2.65 (br d, 4H); 2.91 (br s, 2H); 3.39 (s,
2H); 4.35 (br s, 1H); 7.10 (t, 2H); 7.35 (dd, 2H). MS (m/z)
References and notes
1
ES+: 250.1 (MH+). Compound 16: H NMR (400 MHz;
DMSO-d6), d (ppm): 2.10 (s, 3H); 2.40 (br s, 2H); 2.53 (br
d, 3H); 2.69 (br d, 2H); 2.75 (br d, 2H); 3.03 (br d, 2H);
3.83 (s, 2H); 7.10 (t, 2H); 7.36 (dd, 2H). MS (m/z) ES+:
250 (MH+). Compound 19: 1H NMR (400 MHz; DMSO-
d6), d (ppm): 2.33 (br d, 2H); 2.72 (br s, 2H); 2.80 (d, 2H);
3.47 (s, 2H); 3.63–3.74 (m, 4H); 7.13 (t, 2H); 7.38 (dd, 2H).
The ROESY spectrum is in agreement with the structure.
MS (m/z) ES+: 237.2 (MH+, 100). Compound 20: 1H
NMR (400 MHz; DMSO-d6), d (ppm): 2.27 (s, 2H); 2.84
(d, 2H); 3.16 (br d, 2H); 3.79 (d, 2H); 3.98 (s, 2H); 4.03 (d,
2H); 7.13–7.40 (m, 5H). MS (m/z) ES+: 219.1 (MH+, 100).
1. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.;
Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P.
A. J. Med. Chem. 2004, 47, 224–232.
2. Salonia, A.; Rigatti, P.; Montorsi, F. Curr. Med. Res.
Opin. 2003, 19, 241–262.
3. Campoli-Richards, D. M.; Monk, J. P.; Price, A.;
Benfield, P.; Todd, P. A.; Ward, A. Drugs 1988, 35, 373–
447.
4. Guilhot, F. The Oncologist 2004, 9, 271–281.
5. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.
2003, 43, 46–58.