4876
Z. Zhao et al. / Tetrahedron Letters 45 (2004) 4873–4876
Table 4. Representative thieno[3,4-b]pyrazines
5. (a) Sakata, G.; Makino, K.; Kurasawa, Y. Heterocycles
1988, 27, 2481; (b) He, W.; Meyers, M. R.; Hanney, B.;
Spada, A.; Bilder, G.; Galzcinski, H.; Amin, D.; Needle,
S.; Page, K.; Jayyosi, Z.; Perrone, H. Bioorg. Med. Chem.
Lett. 2003, 13, 3097; (c) Kim, Y. B.; Kim, Y. H.; Park, J.
Y.; Kim, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 541.
6. (a) Porter, A. E. A. In Comprehensive Heterocyclic
Chemistry; Katritsky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; pp 157–197; (b) Woo, G. H. C.; Snyder, J.
K.; Wan, Z.-K. Prog. Heterocycl. Chem. 2002, 14, 279.
7. Brown, D. J. Quinoxalines: Supplement II. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C.,
Wipf, P., Eds.; John Wiley & Sons: New Jersey, 2004.
8. The single-mode microwave synthesizer employed for this
work was an Emrys Liberatore by Personal Chemistry.
9. Typical experimental (Table 1, entry 4): methyl 2,3-
diphenylquinoxaline-6-carboxylate: To a 5 mL reaction
vial (part# 351521) was added benzil (38 mg, 0.2 mmol)
and methyl 3,4-diaminobenzoate (34 mg, 0.2 mmol), fol-
lowed by 3 mL of 9:1 MeOH–HOAc. The vessel was
heated in Emrys Liberatore reaction cavity for 5 min at
160 °C. After 5 min, the reaction vessel was rapidly cooled
to 40 °C. Upon cooling, a white precipitate formed. The
precipitate was collected and dried to afford 66 mg of the
title compound. 1H NMR (CDCl3, 500 MHz): d (d, J ¼
1:8 Hz, 1H), 8.37 (dd, J ¼ 8:7, 1.8 Hz, 1H), 8.21 (d, J ¼
8:7 Hz, 1H), 7.52–7.56 (m, 4H), 7.33–7.37 (m, 6H), s, 3H);
HRMS: calcd for C22H16N2O2 (M+H); found: 341.1295.
10. (a) Kaye, I. A. J. Med. Chem. 1964, 7, 240; (b) Katritzky,
A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry. 2nd ed.; Pergamon: New York, 2000.
Entry
Product
Yield (%)a
1
74
2
3
77
69
a Yields for analytically pure compounds fully characterized by LCMS,
NMR and HRMS.
observed. Therefore, this MAOS protocol represents the
best method reported to date for the synthesis of thi-
eno[3,4-b]pyrazines 10.
11. Typical experimental (Table 3, entry 3): 2,3-di-2-furylpyr-
ido[2,3-b]pyrazine: To a 5 mL reaction was added 1,2-di-2-
furylethane-1,2-dione (38 mg, 0.2 mmol) and pyrdine-2,3-
diamine (22 mg, 0.2 mmol), followed by 3 mL of 9:1
MeOH–HOAc. The vessel was heated for 5 min at
160 °C. Analysis of the crude reaction mixture by LCMS
indicated a purity of 90%. The product was purified by
preparative LCMS to afford 69 mg (92%, mono-TFA salt)
of the title compound as a brown solid. 1H NMR (CDCl3,
600 MHz): d (ppm): 9.12 (dd, J ¼ 4:2, 1.9 Hz, 1H), 8.47
(dd, J ¼ 8:4, 1.9 Hz, 1H), 7.68 (dd, J ¼ 8:4, 4.2 Hz, 1H),
7.66 (dd, J ¼ 1:8, 0.5 Hz, 1H), 7.60 (dd, J ¼ 1:8, 0.5 Hz,
1H); 7.07 (dd, J ¼ 3:6, 0.5 Hz, 1H); 6.74 (dd, J ¼ 3:5,
0.5 Hz, 1H); 6.61 (dd, J ¼ 3:5, 1.8 Hz, 1H); 6.59 (dd,
J ¼ 3:5, 1.8 Hz, 1H); HRMS: calcd for C15H9N3O2
(M+H); 264.0768, found: 264.0767.
In summary, microwave-assisted protocols for the gen-
eral synthesis of functionalized quinoxalines and het-
erocyclic pyrazines have been developed. In addition to
providing rapid, high-yielding access to a variety of
quinoxalines and heterocyclic pyrazines, microwave
irradiation suppressed undesired polymerization path-
ways, characteristic of conventional thermal heating.
The efficiency of these protocols enables facile library
synthesis and further extends the application of MAOS
as a diversity engine, employing common 1,2-diketone
intermediates, for solution phase parallel synthesis.
Additional examples of microwave technology for
diversity-oriented library synthesis are in progress and
will be reported in due course.
12. Kenning, D. D.; Mitchell, K. A.; Calhoun, T. R.; Funfar,
M. R.; Sattler, D. J.; Rasmussen, S. C. J. Org. Chem. 2002,
67, 9073.
Acknowledgements
13. (a) Garbacia, S.; Desai, B.; Lavastre, O.; Knappe, O. J.
Org. Chem. 2003, 68, 9136; (b) Willis, R. C. Today’s Chem.
Work 2004, 47.
The authors thank Joan S. Murphy for HRMS data.
14. Typical experimental (Table 4, entry 2): 2,3-di-pyridin-2-
ylthieno[3,4-b]pyrazine: To a 5 mL reaction vial was added
1,2-dipyridin-2-ylethane-1,2-dione (42 mg, 0.2 mmol) and
thiophene-3,4-diamine (38 mg, 0.2 mmol), followed by
3 mL of 9:1 MeOH–HOAc. The vessel was heated for
5 min at 60 °C. Analysis of the crude reaction mixture by
LCMS indicated a purity of 93%. Note, no polymer was
observed or detected. The product was purified by
preparative LCMS to afford 79 mg (92%, bis-TFA salt)
of the title compound as a brown solid. 1H NMR (CDCl3,
500 MHz): d (ppm): 8.32 (ddd, J ¼ 6:7, 1.7, 0.9 Hz, 2H),
8.12 (s, 2H), 7.91 (dt, J ¼ 7:9, 1.1 Hz, 2H), 7.80 (ddd,
J ¼ 7:8, 6.7, 1.8 Hz, 2H), 7.21 (ddd, J ¼ 7:8, 6.7, 1.1 Hz,
2H); HRMS: calcd for C16H11N4S (M+H); 291.0626;
found 291.0630.
References and notes
1. For an excellent review of MAOS see: Lidstrom, P.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
2. (a) Furka, A. Drug Discovery Today 2002, 7, 1; (b)
Lindsley, C. W.; Zhao, Z.; Leister, W. H. Tetrahderon
Lett. 2002, 43, 4225; (c) Leister, W.; Struass, K.; Wisniski,
D.; Zhao, Z.; Lindsley, C. J. Comb. Chem. 2003, 5, 322.
3. Zhao, Z.; Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.;
Lindsley, C. W. Tetrahderon Lett. 2003, 44, 1123.
4. Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.;
Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6,
1453.