T.J. Donohoe et al. / Tetrahedron 65 (2009) 8969–8980
8979
7. (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179; (b) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett.
2000, 41, 9973–9976.
8. Zhan, Z.-Y. J. U.S. Patent 20,070,043,180, 2007. This catalyst is sold under license
from Zannan by Strem Chemicals, Inc.
9. For recent reviews on olefin metathesis: (a) Special issue dedicated to olefin
metathesis, see:Adv. Synth. Catal. 2007, 349, 1–265; (b) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243–251; (c) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527; (d) Fu¨ rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (e) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371–388.
10. Reviews: (a) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem.dEur. J. 2008,
14, 5716–5726; (b) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed.
2006, 45, 2664–2670.
11. For selected recent work from other groups on the construction of hetero-
aromatic systems by RCM, see: (a) Nun˜ez, A.; Abarca, B.; Cuadro, A. M.; Alvarez-
Builla, J.; Vaquero, J. J. J. Org. Chem. 2009, 74, 4166–4176; (b) Chen, Y.; Dias, H. V. R.;
Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379–1382; (c) Declerck, V.; Ribie`re, P.;
Martinez, J.; Lamaty, F. J. Org. Chem. 2004, 69, 8372–8381.
12. For selected recent references on the construction of carbocyclic aromatic
systems by RCM, see: (a) Yoshida, K.; Narui, R.; Imamoto, T. Chem.dEur. J. 2008,
14, 9706–9713; (b) Yoshida, K.; Takahashi, H.; Imamoto, T. Chem.dEur. J. 2008,
14, 8246–8261; (c) Yoshida, K.; Toyoshima, T.; Imamoto, T. Bull. Chem. Soc. Jpn.
2008, 81, 1512–1517; (d) Grandbois, A.; Collins, S. K. Chem.dEur. J. 2008, 14,
9323–9329; (e) Yoshida, K.; Shishikura, Y.; Takahashi, H.; Imamoto, T. Org. Lett.
2008, 10, 2777–2780; (f) Yoshida, K.; Toyoshima, T.; Imamoto, T. Chem. Com-
mun. 2007, 3774–3776; (g) Yoshida, K.; Horiuchi, S.; Iwadate, N.; Kawagoe, F.;
Imamoto, T. Synlett 2007, 1561–1564; (h) Chen, P.-Y.; Chen, H.-M.; Chen, L.-Y.;
Tzeng, J.-Y.; Tsai, J.-C.; Chi, P.-C.; Li, S.-R.; Wang, E.-C. Tetrahedron 2007, 63,
2824–2828; (i) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.; Imamoto, T.
Chem. Asian J. 2006, 1, 611–613.
afforded the title compound 57a (12 mg, 74%) as a pale yellow oil; dH
(400 MHz, CDCl3) 8.83 (1H, dd, J¼4.5, 1.0 Hz), 7.35 (1H, dd, J¼9.5,
4.5 Hz), 6.97 (1H, dd, J¼9.5, 1.0 Hz), 4.13 (3H, s); dC (100 MHz, CDCl3)
165.1, 147.3, 128.8, 117.2, 54.7. The spectroscopic properties of this
compound were consistent with the data available in the literature.36
4.2.32. 3-Ethoxypyridazine (57b). Imidate 55b (102 mg, 0.33
mmol) was subjected to General Procedure F. The metathesis step
was conducted for 32 h. Purification by FCC (1:1 to 2:1 EtOAc/
petrol) afforded the title compound 57b (34 mg, 83%) as colourless
needles; mp 34–35 ꢀC (CH2Cl2/petrol) [lit. 34 ꢀC (no recrystalli-
sation solvent quoted)]45
;
dH (400 MHz, CDCl3) 8.79 (1H, dd, J¼4.5,
1.5 Hz), 7.33 (1H, dd, J¼9.0, 4.5 Hz), 6.92 (1H, dd, J¼9.0, 1.5 Hz),
4.56 (2H, q, J¼7.0 Hz), 1.42 (3H, t, J¼7.0 Hz); dC (100 MHz, CDCl3)
165.0, 147.0, 128.8, 117.2, 63.1, 14.5. The spectroscopic properties of
this compound were consistent with the data available in the
literature.37
4.2.33. 3-Ethoxy-4-methylpyridazine (57c). Imidate 55c (88 mg,
0.27 mmol) was subjected to General Procedure F. The metathesis
step was conducted for 65 h. Purification by FCC (2:1 to 1:2 petrol/
EtOAc) afforded the title compound 57c (33 mg, 88%) as a pale
yellow oil; nmax/cmꢁ1 2981, 1596, 1561, 1448, 1376, 1346, 1296, 1214,
1033; dH (400 MHz, CDCl3) 8.63 (1H, d, J¼4.5 Hz), 7.14 (1H, dq,
J¼4.5, 1.0 Hz), 4.56 (2H, q, J¼7.0 Hz), 2.20 (3H, d, J¼1.0 Hz), 1.44 (3H,
t, J¼7.0 Hz); dC (100 MHz, CDCl3) 164.5, 146.9, 128.6, 128.2, 63.0,
15.4, 14.6; HRMS (ESIþ) calcd for C7H10N2NaO [MþNa]þ: 161.0685,
found: 161.0682.
13. For syntheses of quinolines using a sequential RCM-oxidation strategy: (a)
´
´
Bennasar, M. L.; Roca, T.; Monerris, M.; Garcıa-Dıaz, D. Tetrahedron Lett. 2005,
46, 4035–4038; (b) Arisawa, M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2001, 42, 8029–8033.
14. For syntheses of pyridones using a sequential RCM-oxidation strategy: (a)
Stead, D.; O’Brien, P.; Sanderson, A. J. Org. Lett. 2005, 7, 4459–4462; (b) Chen, Y.;
Zhang, H.; Nan., F. J. Comb. Chem. 2004, 6, 684–687.
15. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288.
16. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Synthesis 2008, 2665–2667.
17. Donohoe, T. J.; Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopiou, P. A.;
Thompson, A. L. Chem. Commun. 2009, 3008–3010.
18. For the synthesis of pyridines using a strategy related to reference 17 and to
that depicted in Route B (Scheme 1), see: Yoshida, K.; Kawagoe, F.; Hayashi, K.;
Horiuchi, S.; Imamoto, T.; Yanagisawa, A. Org. Lett. 2009, 11, 515–518.
19. Yamago, S.; Nakamura, M.; Wang, X. Q.; Yanagawa, M.; Tokumitsu, S.; Nakamura,
E. J. Org. Chem. 1998, 63, 1694–1703.
20. (a) Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem. 2004, 2, 1921–1933; (b)
Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37, 5273–5276.
21. For examples of metathesis of N-alkoxyacrylamides, see: (a) Choi, T.; Chatterjee,
A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277–1279; (b) Martin, S. F.;
Follows, B. C.; Hergenrother, P. J.; Franklin, C. L. J. Org. Chem. 2000, 65, 4509–4514.
22. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
23. Yoo, K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384–16393. The
use of a base-free Heck protocol was essential in preventing complications
arising from premature elimination of benzyl alcohol from 10a.
24. For related examples involving Pd-catalysed cross-coupling of 2-pyridyl tri-
flates, see: (a) Takaaki, O.; Minoru, I. Synlett 1994, 589–590; (b) Ciattini, P. G.;
Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 4815–4818; (c) Meyers, A. I.;
Robichaud, A. J.; McKennon, M. J. Tetrahedron Lett. 1992, 33, 1181–1184;
(d) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1988, 110,
3296–3298; (e) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–
5486; (f) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27,
3931–3934.
Acknowledgements
We are grateful to Dr. Amber L. Thompson (compounds 34 and
37) (University of Oxford) for X-ray crystallographic analysis. We
also thank the Oxford Chemical Crystallography Service for use of
instrumentation. We would like to thank the ESPRC and Glax-
oSmithKline for funding this project and the Clarendon Fund
(University of Oxford) for a studentship (to J.A.B.). AstraZeneca,
Merck, Novartis and Pfizer are also thanked for support.
References and notes
1. Pyridines: (a) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Rams-
den, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: 2008; Vol. 7, Chapters 1–
6, pp 1–336; Pyridazines: (b) Maes, B. U. W.; Lemiere, G. L. F. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Eds.; Elsevier: 2008; Vol. 8, pp 1–116.
`
2. For a review on the de novo synthesis of pyridines: Henry, G. D. Tetrahedron
2004, 60, 6043–6061.
3. Selected recent de novo approaches to pyridines: (a) Lu, J.-Y.; Keith, J. A.; Shen,
W.-Z.; Schu¨ rmann, M.; Preut, H.; Jacob, T.; Arndt, H.-D. J. Am. Chem. Soc. 2008,
130, 13219–13221; (b) Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130,
8602–8603; (c) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918–6919;
(d) Barluenga, J.; Ferna´ndez-Rodriguez, M. A.; Garcia-Garcia, P.; Aguilar, E. J. Am.
Chem. Soc. 2008, 130, 2764–2765; (e) Parthasarathy, K.; Jeganmohan, M.; Cheng,
C.-H. Org. Lett. 2008, 10, 325–328; (f) Movassaghi, M.; Hill, M. D.; Ahmad, O. K.
J. Am. Chem. Soc. 2007, 129, 10096–10097; (g) Trost, B. M.; Gutierrez, A. C. Org.
Lett. 2007, 9, 1473–1476.
4. Selected recent de novo approaches to pyridazines: (a) Attanasi, O. A.; Favi, G.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Org. Lett. 2009, 11, 309–312; (b)
Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2005,
44, 3889–3892.
5. Selected reviews on metal-catalysed cross-couplings of aza-heteroaromatics:
Pyridines and pyridazines: (a) Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245–2267; Pyridazines and pyridazinones: (b) Nara, S.; Martinez, J.; Wermuth,
C. G.; Parrot, I. Synlett 2006, 3185–3204; (c) Maes, B. U. W.; Tapolcsanyi, P.;
Meyers, C.; Matyus, P. Curr. Org. Chem. 2006, 10, 377–417.
6. (a) Donohoe, T. J.; Kershaw, N. M.; Orr, A. J.; Wheelhouse, K. M. P.; Fishlock, L. P.;
Lacy, A. R.; Bingham, M.; Procopiou, P. A. Tetrahedron 2008, 64, 809–820; (b)
Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M. Angew. Chem., Int. Ed. 2008, 47,
7314–7316; (c) Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou, P. A. Org.
Lett. 2007, 9, 953–956; (d) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J.
Org. Chem. 2005, 1969–1971.
25. Weinreb, S. M.; Nahm, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
26. De Kowalewski, D. G.; De Los Santos, C. J. Mol. Struct. 1990, 221, 299–308.
27. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210–10211.
28. Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761–
6762.
29. Krafft, M. E.; Song, E. H.; Davoile, R. J. Tetrahedron Lett. 2005, 46, 6359–
6362.
30. Sato, T.; Homma, I. Bull. Chem. Soc. Jpn. 1971, 44, 1885–1891.
31. Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492–4493.
32. Toussaint, D.; Suffert, J.; Wermuth, C. G. Heterocycles 1994, 38, 1273–1286.
33. Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444–2457.
34. (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt. Chem. 1937,
147, 257–285; (b) Meerwein, H.; Battenberg, E.; Gold, H.; Pfeil, E.; Willfang, G.
J. Prakt. Chem. 1939, 154, 83–156.
35. Sato, K.; Miyamoto, O.; Inoue, S.; Ota, T. Synthesis 1982, 137–138.
36. Tori, K.; Ogata, M.; Kano, H. Chem. Pharm. Bull. 1963, 11, 235–242.
37. Tavares, F. X.; Boucheron, J. A.; Dickerson, S. H.; Griffin, R. J.; Preugschat, F.;
Thomson, S. A.; Wang, T. Y.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 4716–4730.
38. Pluempanupat, W.; Chantarasriwong, O.; Taboonpong, P.; Jang, D. O.; Chavasiri,
W. Tetrahedron Lett. 2007, 48, 223–226.
39. Erkkila¨, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.