E. Sotelo et al. / Tetrahedron Letters 42 (2001) 8633–8636
Table 2. Deprotection of 2-MOM-pyridazinones using Lewis acids
8635
Compound
R
Reagenta
Yield (%)
Compound
R
Reagenta
Yield (%)
5a
5b
5cb
5d
5e
5f
CHꢀCH2
COCH3
CꢁC–CH2OH
CꢁC–TMS
CꢁC–Ph
Ph
A
B
A
A
A
A
93
95
76
97
98
98
5gc
5h
5i
5j
5k
5l
CꢁCH
A
A
A
A
A
A
90
94
97
98
97
95
CHꢀCHPh
CHꢀCHCOPh
2-Thienyl
CHꢀCHCOOEt
CHꢀCHCN
a Although both reagents were effective in all cases (except 5c), the best yields were obtained with the listed method.
b Only obtained using method A.
c Obtained in low yield using BBr3.
BBr3 (deprotection of compound 5c using BBr3 gave
the corresponding bromopropargyl derivative in 76%
yield).
5. Greene, T.; Wust, G. P. M. Protective Groups in Organic
Synthesis, 3rd ed; Wiley: New York, 1999; p. 632.
6. Laguna, R.; Rodriguez-Lin˜ares, B.; Cano, E.; Este´vez, I.;
Ravin˜a, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45,
1151–1156.
7. Montero-Lastres, A.; Fraiz, N.; Cano, E.; Laguna, R.;
Este´vez, I.; Ravin˜a, E. Biol. Pharm. Bull. 1999, 22, 1376–
1379.
8. Ravin˜a, E.; Tera´n, C.; Santana, L.; Garc´ıa Dom´ınguez,
N.; Este´vez, I. Heterocycles 1990, 31, 1967–1974.
9. Sotelo, E.; Ravin˜a, E.; Este´vez, I. J. Heterocyclic Chem.
1999, 36, 985–990.
10. Este´vez, I.; Coelho, A.; Ravin˜a, E. Synthesis 1999, 9,
1666–11670.
In order to test the scope of this approach (in addition
to the synthesis of 3a–h) we applied it to the preparation
of the 2-MOM-deprotected pyridazinones 5a–l (Scheme
3, Table 2). These experiments also afforded the expected
deprotected pyridazinones in high yields.14,16
The effects of the compounds obtained on platelet
aggregation were assayed by the turbidimetric method.15
Most compounds showed antiaggregation activity in the
micromolar or submicromolar range; the most active
compounds were 5i and 5k. Preliminary results of phar-
macological studies concerning the mechanisms of action
of these compounds suggest that they inhibit platelet
function due to their ability to stimulate the phosphoryl-
ation of certain amino acids on the platelet surface.
Further studies are in progress in our laboratory to
determine in greater detail the structural requirements for
antiplatelet agents aimed at this new target.
11. Coelho, A.; Sotelo, E.; Este´vez, I.; Ravin˜a, E. Synthesis
2001, 6, 871–876.
12. Meyers, A. I.; Durandetta, J. L.; Munavu, R. J. Org.
Chem. 1975, 40, 2025–2029.
13. Selected physical and spectral data for compounds 4a and
4b. Compound 4a: Yield: 90%, mp 146–147°C (dec.),
iso-PrOH. IR (KBr): 3808–3065, 1663, 1590 cm−1 1H
.
NMR (DMSO-d6, 300 MHz): 4.02 (s, 1H, CH), 6.58 (s,
1H, CH), 7.06 (s, 1H, CH), 7.42 (m, 5H, arom.), 13.26
(brs, 1H, NH). HRMS, m/z: calcd. for C13H11ClN2O2
(M+) 262.0509, found 262.0521. Compound 4b: Yield:
90%, mp 175–176°C (dec.), iso-PrOH. IR (KBr): 3903–
In conclusion, we have developed a practical palladium-
assisted procedure for the synthesis of MOM-protected
pyridazinones and combined this with a convenient
selective protocol to perform the MOM-deprotection of
such systems bearing acid-sensitive alkenyl or alkynyl
substituents. The deprotection method employs Lewis
acids under very mild conditions. These procedures have
allowed us to prepare a series of novel 3(2H)-pyridazi-
nones that inhibit platelet function by what appears to
be a previously undescribed mechanism.
1
3648, 1661, 1589 cm−1. H NMR (DMSO-d6, 300 MHz):
6.31 (dd, 1H, J=8.3 Hz, 1H, CH), 6.53 (dd, 1H, J=8.3
Hz, CH), 7.42 (m, 5H, arom.), 7.47 (s, 1H, CH), 13.04
(brs, 1H, NH). HRMS, m/z: calcd. for C13H9ClN2O2
(M+) 232.0403, found 232.0410.
14. Selected physical and spectral data for representative
compounds. Compound 5a: Yield: 97%, mp 169–170°C.
IR (KBr): 1669, 1092 cm−1. 1H NMR (CDCl3, 300 MHz):
5.50 (d, 1H, J=10.9 Hz, CHꢀCH2), 5.87 (d, 1H, J=17.2
Hz, CHꢀCH2), 6.45 (dd, 1H, J=10.9, 17.2 Hz, CHꢀCH2),
7.11 (s, 1H, CH), 7.43 (m, 5H, arom.), 12.68 (brs, 1H,
NH). Compound 5b: Yield: 95%, mp 191–192°C, iso-
PrOH. IR (KBr): 1702, 1668 cm−1. 1H NMR (CDCl3, 300
MHz): 2.14 (s, 3H, CH3), 7.02 (s, 1H, CH), 7.43–7.46 (s,
5H, arom.), 12.64 (brs, 1H, NH). Compound 5c: Yield:
References
1. Sotelo, E., Ravin˜a, E., Synth. Commun., accepted for
publication.
2. Frank, H.; Heinisch, G. In Progress in Medicinal Chem-
istry; Ellis, G. P.; West, G. B., Eds. Pharmacologically
active pyridazines; Elsevier: Amsterdam, 1990; pp. 1–49.
3. Moos, W. H.; Humblet, C. C.; Sircar, I.; Rithner, C.;
Weishar, R. E.; Bristol, J. A.; McPhail, A. J. J. Med.
Chem. 1987, 30, 1963–1972.
4. Coates, W. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds. Pyridazines and their
benzo derivatives; Pergamon Press, 1996; pp. 1–1183.
1
76%, mp 200°C, AcOEt. IR (KBr): 3100, 1680 cm−1. H
NMR (MeOD, 300 MHz): 3.34 (t, 1H, J=1.6 Hz, OH),
4.35 (s, 2H, CH2), 7.16 (s, 1H, CH), 7.47 (m, 3H, arom.),
7.75 (m, 2H, arom.), 13.18 (brs, 1H, NH). Compound 5e:
Yield: 90%, mp 292–293.4°C, iso-PrOH. IR (KBr): 3854,
1
3672, 1647 cm−1. H NMR (DMSO-d6, 300 MHz): 4.79
(s, 1H, CH), 7.18 (s, 1H, CH), 7.44 (m, 3H, arom.), 7.62
(m, 2H, arom.), 13.35 (brs, 1H, NH). Compound 5g: