J. Zhang et al. / Tetrahedron Letters 47 (2006) 8733–8735
8735
Table 1. Results of one-pot process to dibromo- and dichloro-
pyrodazinones
´
2003, 46, 1055–1059; (c) Van der Mey, M.; Bommele, K.
M.; Boss, H.; Hatzelmann, A.; Slingerland, M. V.; Sterk,
G. J.; Timmerman, H. J. Med. Chem. 2003, 46, 2008–2016;
(d) Costantino, L.; Rastelli, G.; Gamberini, C.; Giovan-
noni, M. P.; Piaz, V. D.; Vianello, P.; Barlocco, D. J. Med.
Chem. 1999, 42, 1894–1900; (e) Piaz, V. D.; Giovannoni,
M. P.; Castellana, C. J. Med. Chem. 1997, 40, 1417–1421;
(f) Costantino, L.; Rastelli, G.; Vescovini, K.; Gignarella,
G.; Vianello, P.; Corso, A. D.; Cappiello, M.; Mura,
Umberto.; Barlocco, D. J. Med. Chem. 1996, 39, 4396–
4405.
R2
R1
HX(X=Cl or Br)
NaNO2/water
1. SnCl2
HX/water
H2N
R2
80-90 °C
R1
O
O
X
X
2. Stevenson, T. M.; Crouse, B. A.; Thieu, T. V.; Gebreysus,
C.; Finkelstein, B. L.; Sethuraman, M. R.; Dubas-
Cordery, C. M.; Piotrowski, D. L. J. Heterocycl. Chem.
2005, 42, 427–435.
3. Kerdesky, F. A.; Leanna, M. R.; Zhang, J.; Li, W.;
Lallaman, J. E.; Ji, J.; Morton, H. E. Org. Process Res.
Dev. 2006, 10, 512–517.
N
N
X
X
O
X=Cl or Br
OH
Using HBr with mucobromic acid
Using HCl if mucochloric acid was used
5 X=Br
7 X=Cl
4. Chiou, G. C. Y. Drugs Future 1999, 24, 979–990.
5. (a) Moos, W. H.; Humblet, C. C.; Sircar, I.; Rithner, C.;
Weishaar, R. E.; Bristol, J. A.; McPhail, A. T. J. Med.
Chem. 1987, 30, 1963–1972; (b) Sircar, I.; Duell, B. L.;
Bobowski, G.; Bristol, J. A.; Evans, D. B. J. Med. Chem.
1985, 28, 1405–1413.
6. Gong, Y.; Barbay, J. K.; Byatkin, A. B.; Miskowski, T.
A.; Kimball, E. S.; Prouty, S. M.; Fisher, M. C.; Santulli,
R. J.; Schneider, C. R.; Wallace, N. H.; Ballentine, S. A.;
Hageman, W. E.; Masucci, J. A.; Maryanoff, B. E.;
Damiano, B. P.; Andrade-Gordon, P.; Hlasta, D. J.;
Hornby, P. J.; He, W. J. Med. Chem. 2006, 49, 3402–
3411.
Entry
R1
R2
X
Isolated
yield (%)a
1
2
3
4
5
6
7
8
9
F
H
F
OMe
H
F
H
H
OMe
F
Cl
CF3
F
H
H
F
H
CF3
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
87
74
90
35
88
82
78
85
34
86
10
´
´
7. (a) Matyus, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.;
a The reaction was carried out using 1 (1.0 equiv), NaNO2 (1.05 equiv),
SnCl2 (2.0 equiv) and mucobromic acid or mucochloric acid
(1.0 equiv). HX (X = Cl or Br)/water as solvent.
Lemiere, G. L. F.; Tapolcsanyl, P.; Monsieurs, K.; Elias,
ꢀ
`
´
´
O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 7,
´
´
1123–1139; (b) Tapolcsanyl, P.; Matyus, P.; Maes, B. U.
W. Targets Heterocycl. Syst. 2002, 6, 369–398.
8. (a) R’kyek, O.; Maes, B. U. W.; Jonckers, T. H. M.;
`
Lemiere, G. L. F.; Dommisse, R. A. Tetrahedron 2001, 57,
Acknowledgement
10009–10016; (b) Coelho, A.; Sotelo, E.; Novoa, H.;
Peeters, O. M.; Blaton, N.; Ravinˇa, E. Tetrahedron Lett.
2004, 45, 3459–3463.
We thank Dr. Jeremy Starr for proofreading of this
manuscript.
9. 4,5-Dihalo-3(2H)pyridazinones were normally synthesized
from hydrazine or arylhydrazines and mucohalic acid
(X = Cl or Br) in acetic acid medium.
10. Several issues were considered in our early study: (1) the
stability of diazonium salt and its safety profile; (2) how to
control the ratio of several reagents and how to simplify
the separation; (3) will the process work without removing
excess SnCl2? (4) Is water the best solvent for this one-pot
process?
Supplementary data
Supplementary data associated with this article can be
11. (a) Treating chloropyridazinones with KF in DMSO at
100 °C gave 32–82% fluoropyridazinones, see Gaodeng
Xuexiao Huaxue Xuebao, 1988, 9, 1083–1084; (b) Treat-
ment of, 4,5-dichloro-3(2H)-pyridazinones with 47% HBr
gave a mixture of 4,5-dibromo-3(H)-pyridazinone and
4-bromo-5-chloro-3(2H)-pyridazinone, see Yakugaku Zas-
shi, 1988, 108, 911–915.
12. SnCl2 was still used in the preparation of dibromide since
(1) SnCl2 is much cheaper than SnBr2; (2) the solubility of
SnBr2 in water is much lower; (3) when HBr was used as
solvent, [Br] ꢀ [Cl], therefore it will inhibit the halogen
exchange.
References and notes
1. (a) Colletti, S.; Frie, J. L.; Dixon, E. C.; Singh, S. B.; Choi,
B. K.; Scapin, G.; Fitzgerals, C. E.; Kumar, S.; Nichols, E.
A.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.; Samuel, K.;
Schmatz, D. M.; Schwartz, C. D.; Shoop, W. L.; Thomp-
son, C. M.; Thompson, J. E.; Wang, R.; Woods, A.;
Zaller, D. M.; Doherty, J. B. J. Med. Chem. 2003, 46, 349–
352; (b) Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.;
Galeotti, N.; Bartolini, A.; Piaz, V. D. J. Med. Chem.