8700
M. Sendzik, H. C. Hui / Tetrahedron Letters 44 (2003) 8697–8700
and cooling to room temperature. The precipitate was
filtered and the dissolving–precipitation process
repeated. The solid was dried in vacuo to afford the
hydrochloride salt of 1 (4.46 g, 9.23 mmol, 92%)17 as a
white solid with a purity of >99%. The iron content was
determined to be 33 ppm (Robertson Microlit Labora-
tories, Inc.). Alternatively, the aqueous layer was
lyophilized, dissolved in a small amount of acetonitrile/
1 M HCl, filtered through a short plug of C18 to remove
iron salts and re-lyophilized to provide pure amidine
hydrochloride salt.
Lepore, S. D.; Schacht, A. L.; Wiley, M. R. Tetrahedron
Lett. 2002, 43, 8777–8779.
8. Eloy, F. Fortschr. Chem. Forsch Bd. 1965, 4, 807–876.
9. Unpublished results.
10. (a) Katz, B. A.; Sprengeler, P. A.; Luong, C.; Verner, E.;
Elrod, K.; Kirtley, M.; Janc, J.; Spencer, J. R.; Breiten-
bucher, J. G.; Hui, H. C.; McGee, D.; Allen, D.; Martelli,
A.; Mackman, R. L. Chem. Biol. 2001, 8, 1107–1121; (b)
Mackman, R. L.; Katz, B. A.; Breitenbucher, J. G.; Hui,
H. C.; Verner, E.; Luong, C.; Sprengeler, P. A. J. Med.
Chem. 2001, 44, 3856–3871.
11. Examples for reduction of the NꢁO bond in NO2 using
iron: (a) Desai, D. G.; Swami, S. S.; Hapase, S. B. Synth.
Comm. 1999, 29, 1033–1036; (b) Koch, V.; Schnatterer, S.
Synthesis 1990, 499–501.
12. Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42,
1441–1443.
13. (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
New York, 1998; Chapter 5; (b) Yasuhara, A.;
Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo, Y.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529–
534.
In conclusion, we have described a new synthetic
method for the chemoselective reduction of 5-aryl-
1,2,4-oxadiazoles to benzamidines employing iron pow-
der in acidic aqueous solution. The conditions are
sufficiently mild to be compatible with functional
groups such as chlorine, benzyl ether, and alkynes. The
method was successfully applied in the synthesis of the
potent and selective uPA-inhibitor 1.
Acknowledgements
14. (a) The alkyne, which is required for the synthesis of 11,
with R1=OMem, R2=Ph, R3=CH2CONMe2 was pre-
pared from methyl p-hydroxyphenyl acetate in 7 steps;
(b) See also: Young. W. B.; Kolesnikov, A.; Rai, R.;
Sprengeler, P. A.; Leahy, E. M.; Shrader, W. D.;
Sanalang, J.; Burgess-Henry, J.; Spencer, J. R.; Elrod, K.;
Cregar, L. Bioorg. Med. Chem. Lett. 2001, 11, 2253–2256.
15. Iron, powder, −325 mesh, 97%; commercially available
from Acros Organics.
We would like to thank Dr R. L. Mackman for helpful
discussions and Dr. K. E. Wesson for the review of this
manuscript.
References
16. Heating the reaction mixture for 3 days at 50–55°C does
not initiate the formation of byproducts.
17. 12: H NMR (270 MHz, DMSO-d6) l 8.09 (s, 1H), 7.68
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1
(s, 1H), 7.57–7.33 (m, 7H), 7.11 (d, 1H, J=2.0 Hz), 7.04
(d, 1H, J=0.7 Hz), 3.71 (s, 2H), 3.06 (s, 3H), 2.84 (s,
3H), 2.68 (s, 3H). 13C NMR (68 MHz, DMSO-d6) l
176.2, 170.4, 149.2, 138.3, 138.1, 137.6, 131.6, 131.3,
129.3, 128.3, 127.1, 127.0, 124.1, 123.2, 121.5, 116.4,
113.0, 101.8, 37.2, 35.0, 11.9; MS ESI (m/z) 487 (MH+).
HPLC (Polaris 5m 50×2.0 mm; 2–95% in 5 min with 1
mL/min, MeCN/H2O, 0.05% TFA), retention time: 3.97
1
min, purity >99%. 1: H NMR (270 MHz, DMSO-d6) l
11.83 (s, 1H), 9.34 (s, 2H), 9.21 (s, 2H), 8.94 (s, 1H), 7.84
(s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.53–7.32 (m, 5H), 7.07
(s, 2H), 3.68 (s, 2H), 3.04 (s, 3H), 2.81 (s, 3H). 13C NMR
(68 MHz, DMSO-d6) l 185.0, 153.6, 136.9, 126.2, 125.9,
125.5, 119.4, 119.1, 116.9, 116.1, 116.0, 114.8, 114.1,
109.8, 109.4, 108.9, 107.8, 100.0, 89.39, 24.87, 22.69. MS
ESI (m/z) 447 (MH+). HPLC (Polaris 5m 50×2.0 mm;
2–95% in 5 min with 1 mL/min, MeCN/H2O, 0.05%
TFA), retention time: 3.02 min, purity >99%. Anal.
(C25H23ClN4O2–HCl), C, H, N, Cl. Fe detection (Robert-
son Microlit Laboratories, Inc.)=33 ppm.