M. Dong et al. / Tetrahedron Letters 49 (2008) 4633–4635
4635
OCH3
OCH3
O
N
O
N
O
N
H
HO
N
NH2
NH2
N
N
N
1. HNO2,
aqHOAc
O
O
O
NH2
O
O
NH2
2. Na2S2O4,
NH3/H2O
7
EDC, dioxane/H2O
60%
6
80%
5
BDMS
MeCN, 5h
63%
1N NaOH, reflux
62%
O
N
O
N
N
9
8
H
N
N
1. MeI, K2CO3, DMF
2. BBr3, CH2Cl2
N
OH
O
OCH3
O
N
N
90%
Scheme 3. Synthesis of KW-6002 antagonist.
O
N
O
N
OHC
Br
OHC
OCH3
Br
H
H
N
N
N
N
HO
OCH3
N
BDMS 1.6eq
BDMS 1.6eq
O
N
O
HO
6
MeCN
r.t. 14h
MeCN
r.t. 14h
11
10
80%
74%
Scheme 4. In situ ring closure-tandem bromination sequence.
bromination of the products is an effective adaptation of the pro-
cess, and promises to extend the versatility in the form of heavily
substituted xanthine derivatives.12
Experimental procedure: 8-(4-Bromo-phenyl)-1,3-diethyl-3,4,5,
7-tetrahydro-purine-2,6-dione.
15 min. and then held for 10 min (150 W, 100 psi). The resulting
precipitate was filtered, washed with ethyl acetate (5 ml) and
methanol (2.5 ml), and then recrystallized (EtOAc) to yield the title
compound (0.065 g, 72%) as a yellow solid spectroscopically iden-
tical to an authentic sample.
Conventional thermolysis: (Bromodimethyl) sulfonium bromide
(0.055 g, 0.25 mmol) was added to a mixture of 4-bromobenzalde-
hyde (0.092 g, 0.5 mmol), 1,3-diethyl-5,6-aminouracil (0.1 g,
0.5 mmol), and anhydrous acetonitrile (5 ml) and the mixture
was stirred at room temperature. After 12 h the resulting precipi-
tate was filtered, washed with ethyl acetate (10 ml), methanol
(5 ml), and then recrystallized (EtOAc) to yield the title compound
(0.143 g, 79%) as a yellow solid mp >300 °C; 1H NMR (500 MHz,
DMSO-d6): d 1.13 (t, J = 7 Hz, 3H), 1.26 (t, J = 7 Hz, 3H), 3.94 (q,
J = 7 Hz, 2H), 4.08 (q, J = 7 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H, ArH),
8.05 (d, J = 8.5 Hz, 2H, ArH); HRMS (ESI), m/z (M+H)+: calcd
363.0433, obs. 363.0441.
References and notes
1. Cacciari, B.; Pastorin, G.; Spalluto, G. Curr. Top. Med. Chem. 2003, 3, 403.
2. Jacobson, K. A.; Gallo-Rodriguez, C.; Melman, N.; Fischer, B.; Maillard, M.; van
Bergen, A.; van Galen, P. J. M.; Karton, Y. J. J. Med. Chem. 1993, 36, 1333.
3. Del Giudice, M. R.; Borioni, A.; Mustazza, C.; Gatta, F.; Dionisotti, S.; Zocchi, C.;
Ongini, E. Eur. J. Med. Chem. 1996, 31, 59.
4. Knutsen, L. J.; Weiss, S. M. Curr. Opin. Invest. Drugs 2001, 2, 668.
5. Bara-Jimenez, W.; Sherzai, A.; Dimitrova, T.; Favit, A.; Bibbiani, F.; Gillespie, M.;
Morris, M. J.; Mouradian, M. M.; Chase, T. N. Neurology 2003, 61, 293; Koga, K.;
Kurokawa, M.; Ochi, M.; Nakamura, J.; Kuwana, Y. Eur. J. Pharmacol. 2000, 408,
249.
6. Perumattam J. Synth. Commun. 1989, 19, 3367.
7. de Araujo, A. D.; Bacher, E.; Joachim Demnitz, F. W.; Santos, D. A. Heterocycles
1999, 51, 29.
8. Jerchel, D.; Kracht, M.; Krucker, K. Liebigs Ann. Chem. 1954, 590, 232.
9. Das, B.; Holla, H.; Srinivas, Y. Tetrahedron Lett. 2007, 48, 61; Choudhury, L. H.
Synlett 2006, 1619; Khan, A. T.; Ashif, M.; Goswami, P.; Choudhury, L. H. J. Org.
Chem. 2006, 71, 8961; Das, B.; Ramu, R.; Ravikanth, B.; Reddy, K. R. Synthesis
2006, 1419.
Microwave thermolysis: (Bromodimethyl) sulfonium bromide
(0.010 g, 0.045 mmol) was added to a mixture of 4-bromobenzal-
dehyde (0.0466 g, 0.25 mmol), 1,3-diethyl-5,6-aminouracil
(0.4955 g, 0.25 mmol), and anhydrous acetonitrile (500 ll) in a
14 Â 86 mm (o.d.) glass microwave tube. The tube was capped
with a CEM Corp. PL cap, the atmosphere was flushed with argon
gas, and then the tube was placed in the cavity of a CEM DiscoverÒ
Lab Mate reactor. The solution was subjected to microwave irradi-
ation while stirring, the temperature was brought to 110 °C over
10. All new compounds were fully characterized by appropriate spectroscopic and
analytical techniques.
11. Ma, D.; Sitkovsky, M.; Jones, G. B., in preparation.
12. We acknowledge financial support for this work from the PRF (33920-AC1) and
NIH (RO1GM57123).