D. Norris et al. / Tetrahedron Letters 42 (2001) 4297–4299
4299
carbonyl–imidazole dimer 6) under similar conditions
yielded compound 11 (Ar=2,4-dimethoxyphenyl) in
86% isolated yield (Scheme 2).
3. Colltta, V.; Cecchi, L.; Catarzi, D.; Filacchioni, G.; Mar-
tini, C.; Tacchi, P.; Lucacchini, A. Eur. J. Med. Chem.
1995, 30, 133.
4. Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.;
Sakamoto, S. J. Med. Chem. 1997, 40, 2053.
Typical reaction conditions:
5. TenBrink, R. E.; Jacobsen, E. J.; Gammill, R. B., US
Patent 5541324, July 30, 1996; Chem. Abstr. 1996, 125,
195687.
6. Hansen, H. C.; Watjen, F., EP 344943 A1, December 6,
1989; Chem. Abstr. 1990, 112, 216962.
Compound 7d: To a cold (−10°C) solution of 3-amino-
2-chloropyridine (2.87 g, 22.3 mmol) in dry THF (13
mL) purged with argon was added NaHMDS (51 mL,
51 mmol, 1.0 M solution in THF). After 1 h, a suspen-
sion of imidazole carbonyl dimer 6 (2 g, 10.6 mmol) in
dry THF (20 mL) was added and the reaction mixture
was stirred at room temperature for 2 h (or until the
reaction was complete as indicated by HPLC). After
cooling to 0°C, sufficient acetic acid was added to
adjust the pH to ꢀ7 and the mixture was concentrated
in vacuo. Water was added, followed by satd NaHCO3.
The solid product was collected by filtration, washed
with water and hexane, and dried under vacuum to give
compound 7d as a light beige solid.
7. Lee, T. D.; Brown, R. E., US 4440929, April 3, 1984;
Chem. Abstr. 1984, 101, 7202.
8. Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini,
S.; Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.;
Goegan, M.; Cervo, L.; Valle, D. F.; Fracasso, C.; Cac-
cia, S.; Mennini, T. J. Med. Chem. 1999, 42, 4362.
9. Kasina, S.; Nematollahi, J. Synthesis 1975, 162; Gode-
froi, E. F.; van der Eycken, C. A.; van de Westerngh, C.
J. Org. Chem. 1964, 29, 3707. Compound 6 was prepared
according to the following modified procedure: A mixture
of 4-imidazolecarboxylic acid (25 g, 0.22 mol) and thionyl
chloride (50 mL) in 500 mL of toluene containing 3.5 mL
of dry DMF was heated to reflux for 3 h. After cooling
to room temperature, the solid was collected by filtration,
rinsed with toluene and resuspended in 250 mL of chloro-
form. To this suspension was added 60 mL of triethyl-
amine and the mixture was stirred for 2 h at room
temperature. The solid was then collected by filtration,
rinsed with a large volume of chloroform. After drying
under high vacuum overnight, 16.2 g of compound 6 was
obtained as an off-white solid. In our hands, this material
Compound 8d: A mixture of compound 7d (1.89 g, 8.49
mmol) and potassium carbonate (3.5 g, 25.5 mmol) in
40 mL of N,N-dimethyl acetamide was heated to reflux
for 6 h (or until the completion of the reaction as
indicated by HPLC or TLC). After cooling to room
temperature, the solvent was removed under reduced
pressure and water was added, followed by satd NH4Cl
solution. The white precipitate was collected by filtra-
tion, rinsed with water and ether, dried under vacuum
to give the desired compound 8d with >95% purity by
HPLC. Alternatively, soluble base DBU in DMF can
be used in place of potassium carbonate in DMA for
the preparation of compound 8 (entry 6, Table 1). In
this case, the reaction was completed within 1 h at
160°C (3.0 equiv. DBU).
1
usually has a purity of >98% by HPLC and H NMR.
10. Spectroscopic and analytical data of all new compounds
were consistent with their assigned structures. Represen-
1
tative H NMR (400 MHz) data: 8a: (DMSO-d6): 9.06 (s,
1H), 8.19 (d, J=7.62, 1H), 7.87 (s, 1H), 7.15–7.50 (m,
3H); 8b: (DMSO-d6): 11.5 (bs, 1H), 9.10 (s, 1H), 8.50 (d,
J=2.13, 1H), 7.87 (d, J=0.86 Hz, 1H), 7.54 (dd, J=2.13,
J=8.55, 1H), 7.25 (d, J=8.55, 1H); 8c: (DMSO-d6): 9.00
(s, 1H), 8.37 (d, J=9.23, 1H), 7.83 (s, 1H), 7.54 (d,
J=6.59, 1H); 8d: (DMSO-d6): 11.77 (bs, 1H), 9.35 (s,
1H), 8.30 (dd, J=1.32, J=4.83, 1H), 8.18 (s, 1H), 7.77
(dd, J=1.32, J=7.91, 1H), 7.55 (dd, J=4.83, J=7.91,
1H); 8e: (DMSO-d6): 8.87 (s, 1H), 7.93 (s, 1H), 7.71 (d,
J=8.34, 1H), 7.56 (d, J=8.34, 1H); 8f: (CD3OD): 9.02 (s,
1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H); 10: (CDCl3):
7.88 (s, 1H), 7.50 (dd, J=8.44, J=2.20, 1H), 7.24 (d,
J=8.44, 1H), 7.19 (d, J=8.25, 1H), 6.71 (d, J=2.20, 1H),
6.48, dd, J=8.25, J=2.20, 1H), 6.37 (d, J=2.20, 1H),
4.05–4.25 (m, 2H), 3.85 (s, 3H), 3.58 (s, 3H); 11: (DMSO-
d6): 8.58 (t, J=5.16, 1H), 8.49 (s, 1H), 7.83 (s, 1H), 7.74
(dd, J=8.49, J=1.68, 1H), 7.66 (dd, J=8.49, J=1.68,
1H), 7.65 (s, 1H), 4.14 (d, J=5.16, 2H).
In summary, we have developed a novel and efficient
approach for the construction of imidazo-[1,5-a]-
quinoxalin-4(5H)-one templet. This newly developed
method is general and provides products in good to
excellent yields. Because the formation of the hetero-
cyclic core via this route is regiospecific, this method
serves as a complementary approach to our recently
described method using TosMIC reagent that gives
both possible regioisomers.11
References
1. Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter, D.
B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Von Voigt-
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2. Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg,
S. S.; Ingebretsen, W. R.; Wiggins, J. J. Med. Chem.
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11. Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.; Bednarz,
M. S.; Chen, B.-C. Tetrahedron Lett. 2001, 42, 4293.
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