J. E. Torr et al. / Tetrahedron Letters 47 (2006) 31–34
33
Scheme 3.
´
2. (a) Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
´
´
4059–4090; (b) Turck, A.; Ple, N.; Mongin, F.; Queguiner,
G. Tetrahedron 2001, 57, 4489–4505.
3. Knochel, P.; Dohle, W.; Gommermann, N.; Kniesel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem., Int. Ed. 2003, 42, 4302–4320.
4. Baker, D. C.; Hand, E. S.; Plowman, J.; Rampal, J. B.;
Safavy, A.; Haugwitz, R. D.; Narayanan, V. L. Anticancer
Drug Des. 1987, 2, 297–309.
5. For a recent example, see: Burns, C. J.; Wilks, A. F.; Bu,
X. Worldwide Patent WO2005054230, 2005; Burns, C. J.;
Wilks, A. F.; Bu, X. Chem. Abstr. 2005, 143, 60004.
´
6. Turck, A.; Mojovic, L.; Queguiner, G. Synthesis 1988,
881–884.
7. For a recent review, see: Suwinski, J.; Swierczek, K.
Tetrahedron 2001, 57, 1639–1662.
Scheme 4. Reagents and conditions: (i) 6 equiv morpholine, CH2Cl2,
50 ꢁC, 3 h.
8. Other electrophiles such as N-formylmorpholine and ethyl
formate were employed. THF was distilled from calcium
hydride, or alternatively purchased with water content
60.005% (Acros Organics, UK).
In summary, we have explored a novel route to formyl-
ated chloropyrazines utilising dithiane-derived nucleo-
philes and, in so doing, uncovered an interesting tele-
substitution mechanism. This work represents a useful
and practical alternative to currently existing methodol-
ogy for the preparation of compounds of this type.
9. Allway, P. A.; Sutherland, J. K.; Joule, J. A. Tetrahedron
Lett. 1990, 31, 4781–4782.
10. For a recent review of methodology and applications, see:
Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59,
6147–6212, and references cited therein.
11. Sato, N. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon, 1996; Vol. 6, pp 233–278.
12. Baarschers, W. H.; Loh, T. L. Tetrahedron Lett. 1971, 37,
3483–3484.
Acknowledgements
13. Preparation of 4: nBuLi (9.00 ml, 2.5 M in hexanes,
22.50 mmol) was added dropwise to a cooled (À78 ꢁC),
nitrogen flushed, solution of 1,3-dithiane (2.65 g,
22.04 mmol, 1.1 equiv) in anhydrous THF (10 ml) and
left for 30 min. 2,6-Dichloropyrazine (3.01 g, 20.20 mmol,
1 equiv) in THF (2 ml) was added. TLC indicated the
complete consumption of the starting material after
10 min. The reaction mixture was poured into water
(10 ml) and the organic components were extracted (ethyl
acetate), rinsed (brine) and dried (sodium sulfate) and the
solvent evaporated in vacuo to give an orange solid
(4.49 g). Purification by flash chromatography (silica, 20 g,
hexane–ethyl acetate 20:1) gave the title compound
(3.33 g, 69%) as a white solid; mp 120–122 ꢁC; Rf 0.36
(hexane–ethyl acetate, 5:1); dH (CDCl3, 250 MHz) 8.52
This work was supported by Cancer Research UK
[CUK] programme Grant number C309/A2187. The
provision of a Ph.D. studentship (to J.E.T.) by the Insti-
tute of Cancer Research is gratefully acknowledged. We
also thank Dr. Amin Mirza and Mr. Meirion Richards,
for their assistance with NMR and mass spectrometry.
References and notes
1. Fuhrhop, J. H.; Corey, E. J.; Li, G.; Penzler, G. Organic
Synthesis, Concepts and Methods; John Wiley and Sons,
2003.