2702
C. del Pozo et al.
PAPER
(7) For 1,4-benzodiazepines as potent and selective oxytocin
antagonist, see: (a) Evans, B.; Pipe, A.; Clark, L.; Banks, M.
Bioorg. Med. Chem. Lett. 2001, 11, 1297. (b) Wyatt, P. G.;
Allen, M. J.; Chilcott, J.; Hickin, G.; Miller, N. D.;
Woollard, P. M. Bioorg. Med. Chem. Lett. 2001, 11, 1301.
(8) For 1,4-benzodiazepines as antagonists of the GPllb/llla
receptor, see: (a) Hayes, J. F. Synlett 1999, 865.
8-Chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-3-(4-tolu-
enesulfonyl)-4H-imidazo[1,5-a][1,4]benzodiazepine (8)
To a vigorously stirred suspension of powdered activated Zn (2.1 g,
6.45 mmol) in THF (30 mL), sat. aq NH4Cl (40 mL), and a solution
of 7a (0.24 g, 0.5 mmol) in THF (20 mL) were sequentially added.
The mixture immediately turned to an intense blue color and it was
stirred for 2 h until the color disappeared. The reaction mixture was
filtered through a pad of Celite, which was washed with CH2Cl2.
The combined solvents were evaporated and the residue was puri-
fied by flash chromatography (33% hexanes–EtOAc) to afford 8.
(b) Andrews, I. P.; Atkins, R. J.; Badham, R. F.; Bellingham,
R. K.; Breen, G. F.; Carey, J. S.; Etridge, S. K.; Hayes, J. F.;
Hussain, N.; Morgan, D. O.; Share, A. C.; Smith, S. A. C.;
Walsgrove, T. C.; Wells, A. S. Tetrahedron Lett. 2001, 42,
4915.
Yield: 0.23 g (0.48 mmol, 96%); white solid.
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H), 2.50 (s, 3 H), 3.38
(d, J = 15.4 Hz, 1 H), 4.94 (d, J = 15.4 Hz, 1 H), 5.06 (br s, 1 H),
6.78 (br s, 1 H), 7.00–7.06 (m, 1 H), 7.20–7.44 (m, 7 H), 7.96 (d,
J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2, 21.6, 38.8, 52.0, 115.3, 115.6,
124.5, 125.1, 126.3, 127.7, 129.0, 129.3, 129.8, 133.2, 134.7, 135.2,
136.5, 138.5, 144.1, 145.1, 158.3, 161.6.
(9) For 1,4-benzodiazepines as cholecystokinin (CCK-A)
receptor antagonists, see: Sherrill, R. G.; Berman, J. M.;
Birkemo, L.; Croom, D. K.; Dezube, L.; Ervin, G. N.;
Grizzle, M. K.; James, M. K.; Johnson, M. F.; Queen, K. L.;
Rimele, T. J.; Vanmiddlesworth, F.; Sugg, E. E. Bioorg.
Med. Chem. Lett. 2001, 11, 1145.
(10) For 1,4-benzodiazepines as herbicides, see: (a) Karp, G. M.;
Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C. L.; Marc, P.;
Szamosi, I. T. J. Agric. Food Chem. 1997, 45, 493.
(b) Karp, G. M. J. Org. Chem. 1999, 64, 8156. .
(11) (a) Vida, J. A. In Medicinal Chemistry; Wolf, M. W.;
Burger, A., Eds.; Wiley: New York, 1981, 787. (b) Fryer,
R. I. In Comprehensive Heterocyclic Chemistry, Vol 3;
Hansch, C., Ed.; Pergamon Press: New York, 1990, 539.
(12) (a) Hester, J. B.; Rudzik, A. B.; Kamdar, B. V. J. Med.
Chem. 1971, 14, 1078. (b) Schulte, E. Dtsch. Apoth.-Ztg.
1975, 115, 1243. (c) Gilman, N. W.; Holland, B. C.; Fryer,
R. I. J. Heterocycl. Chem. 19 77, 14, 1163. (d) Walser, A.;
Benjamin, L. E.; Flynn, T.; Mason, C.; Schwartz, R.; Fryer,
R. I. J. Org. Chem. 1978, 43, 936.
ESI-MS: m/z = 482 (M + H)+, 504 (M + Na)+, 520 (M + K)+.
Anal. Calcd for C25H21ClFN3O2S: C, 62.30; H, 4.39; N, 8.72.
Found: C, 62.44; H, 4.29; N, 8.77.
Acknowledgment
This research was supported by the European Community (Feder
Project 1FD97-0869).
References.
(1) (a) Benzodiazepines Divided: A Multidisciplinary Review;
Wiley: New York, 1983. (b) Bock, M. G.; DiPardo, R. M.;
Evans, B. E.; Rittle, K. E.; Whitter, W. L.; Veber, D. F.;
Anderson, P. S.; Freidinger, R. M. J. Med. Chem. 1989, 32,
13.
(2) Sneader, W. In Comprehensive Medicinal Chemistry, Vol.
1; Hansch, C.; Sammes, P. G.; Taylor, J. B., Eds.; Pergamon:
London, 1990, 65.
(3) (a) Archer, G. A.; Sternbach, L. H. Chem. Rev. 1968, 68,
747. (b) Sharp, J. T. In Comprehensive Heterocyclic
Chemistry II, Vol 7; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Amsterdam, 1984, 593. (c) Tucker, H.; Le
Count, D. J. In Comprehensive Heterocyclic Chemistry II,
Vol 9; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Amsterdam, 1996, 151.
(4) For 1,4-benzodizazepines as inhibitors of reverse
transcriptase, see: (a) Robl, J. A.; Cimarusti, M. P.;
Simpkins, L. M.; Brown, B.; Ryono, D. E.; Bird, J. E.;
Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med.
Chem. 1996, 39, 494. (b) Merluzzi, V. J.; Hargrave, K. D.;
Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih, C.-
K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.;
Faanes, R.; Eckner, R. J.; Koup, R. A.; Sullivan, J. L.
Science 1990, 250, 1411.
(5) For 1,4-benzodiazepines as antitumor and gene targeted
drugs, see: (a) Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org.
Lett. 1999, 1, 1835. (b) Novelli, F.; Sparatore, A.; Tasso, B.;
Sparatore, F. Bioorg. Med. Chem. Lett. 1999, 9, 3031.
(c) Wilson, S. C.; Howard, P. W.; Forrow, S. M.; Hartley, J.
A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston, D.
E. J. Med. Chem. 1999, 42, 4028.
(6) For 1,4-benzodiazepines as inhibitors of phosphodiesterases
PDE4, see: Pascal, Y.; Andrianjara, C. R.; Auclair, E.;
Avenel, N.; Bertin, B.; Calvet, A.; Féru, F.; Lardon, S.;
Moodley, I.; Ouagued, M.; Payne, A.; Pruniaux, M.-P.;
Szilagyi, C. Bioorg. Med. Chem. Lett. 2000, 10, 35.
(13) (a) Hester, J. B. Jr.; Duchamp, D.; Chidester, C. G.
Tetrahedron Lett. 1971, 1609. (b) Coffen, D. L.; DeNoble,
J. P.; Evans, E. L.; Field, G. F.; Fryer, R. I.; Katonak, D. A.;
Mandel, B. J.; Sternbach, L. H.; Zally, W. J. J. Org. Chem.
1974, 39, 167. (c) Gall, M.; Hester, J. B. Jr.; Rudzik, A. D.;
Lahti, R. A. J. Med. Chem. 1976, 19, 1057. (d) Hester, J. B.
Jr. J. Heterocycl. Chem. 1980, 17, 575. (e) Hester, J. B. Jr.;
Rudzik, A. D.; Voigtlander, P. F. V. J. Med. Chem. 1980, 23,
392. (f) Hester, J. B. Jr.; Rudzik, A. D.; Voigtlander, P. F. V.
J. Med. Chem. 1980, 23, 402. (g) Hester, H. B. Jr.; Rudzik,
A. D.; Voigtlander, P. F. V. J. Med. Chem. 1980, 23, 643.
(h) Gall, M.; Kamdar, B. V. J. Med. Chem. 1981, 24, 1575.
(i) Walser, A.; Fryer, R. I. J. Heterocycl. Chem. 1983, 20,
551. (j) Gall, M.; Kamdar, B. V. J. Heterocycl. Chem. 1988,
25, 1649. (k) Banks, W. L.; Digenis, G. A. Tetrahedron Lett.
1989, 6473. (l) Hester, J. B.; Ludens, J. H.; Emmert, D. E.;
West, B. E. J. Med. Chem. 1989, 32, 1157. (m) Walser, A.;
Flynn, T.; Mason, C.; Crowley, H.; Maresca, C.; Yaremko,
B.; O’Donnel, M. J. Med. Chem. 1991, 34, 1209.
(14) Ning, R. Y.; Fryer, R. I.; Madan, P. B.; Sluboski, B. C. J.
Org. Chem. 1976, 41, 2724.
(15) Walser, A.; Fryer, R. I. J. Org. Chem. 1975, 40, 153.
(16) van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S–111.
(17) (a) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M.
Tetrahedron Lett. 1980, 3723. (b) Massa, S.; Di Santo, R.;
Costi, R.; Mai, A.; Artico, M. Med. Chem. Res. 1993, 3,
192. (c) Di Santo, R.; Massa, S.; Artico, M. Il Farmaco
1993, 48, 209. (d) Sisko J.; J. Org. Chem.; 1998, 63: 4529.
(e) Mendiola, J.; Minguez, J. M.; Alvarez-Buylla, J.;
Vaquero, J. J. Org. Lett. 2000, 2, 3253. (f) Sisko, J.;
Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen,
M. A. J. Org. Chem. 2000, 65, 1516. (g) Chen, P.; Barrish,
J. C.; Iwanowicz, E.; Lin, J.; Bernarz, M. S.; Chen, B.-C.
Tetrahedron Lett. 2001, 4293. (h) Barret, A. G. M.; Cramp,
S. M.; Hennessy, A.; Procopiou, P. A.; Roberts, R. S. Org.
Synthesis 2004, No. 16, 2697–2703 © Thieme Stuttgart · New York