Preparation of Functionalized Aryl- and Heteroarylpyridazines by Nickel-Catalyzed Electrochemical Cross-Coupling Reactions Ste´phane Sengmany,† Eric Le´onel,*,† Frantz Polissaint,† Jean-Yves Ne´de´lec,† Muriel Pipelier,‡ Christine Thobie-Gautier,§ and Didier Dubreuil‡ Electrochimie et Synthe` se Organique, Institut de Chimie et des Mate´ riaux Paris-Est UMR 7182-CNRS, UniVersite´ Paris 12, 2 rue Henri-Dunant, F-94320 Thiais, France, Laboratoire de Synthe` se Organique, UMR 6513-CNRS, UniVersite´ de Nantes, 2 rue de la Houssinie` re, BP 92208, F-44322 Nantes Cedex 3, France, and Laboratoire d’Analyse Isotopique et Electrochimique de Me´ tabolismes, UMR 6006-CNRS, UniVersite´ de Nantes, 2 rue de la Houssinie` re, BP 92208, F-44322 Nantes Cedex 3, France
[email protected] ReceiVed March 13, 2007
A general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6-methylpyridazine with a range of functionalized aryl or heteroaryl halides is reported.
Introduction Substituted arylpyridazines have given rise to considerable interest because of their diverse pharmacological properties ranging from antibacterial and antifungal to anti-inflammatory, antidepressant, and cardiovascular drugs (Figure 1).1 Pyridazine rings can also be used as precursors of pyrroles by ring contraction2 by either chemical3 or electrochemical * Author to whom correspondence should be addressed. Phone: +33-1-4978-11-36. Fax: +33-1-49-78-11-48. † Universite ´ Paris 12. ‡ Laboratoire de Synthe ` se Organique, Universite´ de Nantes. § Laboratoire d’Analyse Isotopique et Electrochimique de Me ´ tabolisme, Universite´ de Nantes.
(1) (a) Heinisch, G.; Kopelent-Frank, H. Progress in Medicinal Chemistry: Pharmacologically ActiVe Pyridazine DeriVatiVes, Part 2; Ellis G.P., Luscombe D.K., Eds; Elsevier Science B.V.; Amsterdam, The Netherlands, 1992; Vol. 29, pp 141-183. (b) So¨nmez, M.; Berber, I.; Akbas, E. Eur J. Med. Chem. 2006, 41, 101-105. (c) Rohet, F.; Rubat, C.; Coudert, P.; Couquelet, J. Bioorg. Med. Chem. 1997, 5, 655-659. (d) Dolle, R. E.; Hoyer, D.; Rinker, J. M.; Ross, T. M.; Schmidt, S. J.; Helaszek, C. T.; Ator, M. A. Bioorg. Med. Chem. Lett. 1997, 7, 1003-1006. (e) Steiner, G.; Gries, J.; Lenke, D. J. Med. Chem. 1981, 24, 59-68. (f) Sotelo, E.; Fraiz, N.; Yanez, M.; Terrades, V.; Laguna, R.; Cano, E.; Ravina, E. Bioorg. Med. Chem. 2002, 10, 2873-2882. (2) Joshi, U.; Pipelier, M.; Naud, S.; Dubreuil, D. Curr. Org. Chem. 2005, 9, 261-288. (3) Boger, D. L.; Coleman, R. S.; Ponek, J. S.; Yohannes, D. J. Org. Chem. 1984, 49, 4405-4409.
methods.4 Pyrrole components are widely found in natural products and in many pharmaceuticals.5 In addition to the many biological applications reported in the literature, pyridazine moiety also plays an important role as chelating agent or metal complexing ligand. Indeed, associated with heteroaryl rings, e.g., pyridines, the pyridazine ring can be employed for constructing grid-like architectures through self-assembly processes with metal ions like Cu(I) and Ag(I).6,7 Numerous publications have dealt with the preparation of substituted pyridazines by conventional chemical routes. Basically, the approach involves a transition metal mediated carboncarbon bond forming cross-coupling, mainly through palladium or nickel complex catalysis, and usually referred to as Kumada,8 (4) Manh, G. T.; Hazard, R.; Tallec, A.; Prade`re, J. P.; Dubreuil, D.; Thiam, M.; Toupet, L. Electrochim. Acta 2002, 47, 2833-2841. (5) (a) Joshi, U.; Josse, S.; Pipelier, M.; Chevallier, F.; Prade`re, J. P.; Hazard, R.; Legoupy, S.; Huet, F.; Dubreuil, D. Tetrahedron Lett. 2004, 45, 1031-1033. (b) Sternberg, E. D.; Dolphin, D.; Bru¨ckner, C. Tetrahedron 1998, 54, 4151-4202. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603. (6) Hoogenboom, R.; Kickelbick, G.; Schubert, U. S. Eur. J. Org. Chem. 2003, 4887-4896. (7) Baxter, P. N. W.; Lehn, J.-M.; Baum, G.; Fenske, D. Chem. Eur. J. 2000, 6, 4510-4517. (8) Corbet, J.-P.; Magnani, G. Chem. ReV. 2006, 106, 2651-2710.
10.1021/jo070429+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/20/2007
J. Org. Chem. 2007, 72, 5631-5636
5631
Sengmany et al.
FIGURE 1. Examples of arylpyridazine derivatives and their properties.
or Negishi,9 Stille,10 or Suzuki11 reaction. For instance, Rival et al.12 have synthesized a series of substituted arylpyridazines in 50% to 90% yields by a Suzuki reaction from 3-chloro-6methoxypyridazine and substituted phenylboronic acids in toluene/ethanol medium at 110 °C in the presence of tetrakis(triphenylphosphine)palladium and sodium carbonate. Another example reported by Bailey et al.13 is the coupling of iodopyridazine with heteroarylstannanes according to the Stille procedure. The drawback of these two methods is the need of preparing reagents like phenylboronic acids or heteroarylstannanes, which can hardly be obtainable if the aryl ring bears sensitive functional groups. Alternative approaches have also been reported. Thus, Krische and co-workers14 have described the rhodium-catalyzed aldolization of enals with glyoxal followed by treatment with hydrazine to afford 3-arylpyridazines in moderate yields. Sauer et al.15 have prepared 3-aryl and 3-heteroaryl-5-stannylated pyridazines by a [4+2] cycloaddition of 3-aryl or 3-heteroaryl-1,2,4,5-tetrazines with ethynyltributyltin in high yields. To our knowledge, there has been no reports concerning the use of an electrochemical approach to perform of such crosscoupling. In our laboratory, Gosmini16 has previously described the preparation in good yields of several arylpyridines, arylpyrimidines, and arylpyrazines by nickel bromide 2,2′-bipyridine complex (NiBr2bpy) catalysis combined with an electroreductive process.17 In this paper we report the application of this simple and smooth one-pot nickel-catalyzed electrochemical method to access a library of various functionalized aryl- or heteroarylpyridazines. We particularly turned our attention to the crosscoupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro6-methylpyridazine, with a range of aryl or heteroaryl halides variously substituted by electron-withdrawing and electrondonating functional groups. We have an interest to these two (9) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 18211823. (10) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524. (11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (12) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 7, 11631168. (13) Draper, T. L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748-750. (14) Marriner, G. A.; Garner, S. A.; Jang, H-Y.; Krische, M. J. J. Org. Chem. 2004, 69, 1380-1382. (15) Sauer, J.; Heldmann, D. K. Tetrahedron 1998, 54, 4297-4312. (16) (a) Gosmini, C.; Lasry, S.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron 1998, 54, 1289-1298. (b) Gosmini, C.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron Lett. 2000, 41, 201-203. (17) Chaussard, J.; Folest, J.-C.; Ne´de´lec, J.-Y.; Pe´richon, J.; Sibille, S.; Troupel, M. Synthesis 1990, 5, 369-381.
5632 J. Org. Chem., Vol. 72, No. 15, 2007
6-methoxy- and 6-methyl-substituted chloropyridazines not only because of their cost and their limited commercially availability, but especially because of their possible further synthetic transformations. For instance, the methoxy group of resulting cross-coupled product, once hydrolyzed, can be halogenated and then subjected to a second cross-coupling reaction. On the other hand, the methyl group can be used to introduce a functional group like a carboxylic acid after oxidation. Results and Discussion We started by investigating the cross-coupling reaction between 3-chloro-6-methoxypyridazine and methyl 4-bromobenzoate (Scheme 1). This latter substrate has been taken as a model because of its efficient nickel-catalyzed homocoupling. After having tuned the key reaction parameters such as the nature of the catalyst (NiBr2 or CoCl2 in DMF/pyridine, NiBr2(PPh3)2 or NiBr2bpy in DMF), anode (Fe/Ni: 64/36, Fe, Mg, Zn), and current density (0.05, 0.1, 0.2 A), we found the following as the most convenient and general set of reaction conditions: the reaction is conducted in DMF, at a constant current of 0.2 A, and with an iron rod as the anode, 10% of NiBr2bpy as the catalyst, and a stoichiometric amount of the two reagents. The reactions went to completion in 3 to 4 h. The other conditions afforded no more than 20% GC of the cross-coupled product, homocoupled or reduction products were the major products. Under the optimized working reaction conditions, methyl 4-(6methoxypyridazin-3-yl)-benzoate (3a) was obtained in 57% yield. This satisfactory first result opened the way for a screening of cross-coupling between a broad range of aromatic and heteroaromatic halides and 3-chloro-6-methoxypyridazine or 3-chloro-6-methylpyridazine. The reaction conditions were similar those used for the model reaction above. The results are given in Tables 1-3. Table 1 deals with the results obtained with electronwithdrawing (EWG) substituted phenyl halides. The influence of both the position of the EWG and the nature of the halogen atom (X) on the yield of the cross-coupling products (compounds 1-13 in Table 1) is noticeable. In the absence of a substituent on the phenyl ring, iodine is required for the cross-coupling reaction, while bromine is suitable for EWG-substituted phenyl halides, as long as the substituent is not ortho to the halogen in the case of 3-chloro6-methoxypyridazine. Indeed, only traces of cross-coupled products 1-12 were formed from 2-substituted bromobenzenes with either 3-chloro-6-methoxypyridazine or 3-chloro-6-meth-
Preparation of Aryl- and Heteroarylpyridazines SCHEME 1.
Preparation of Methyl 4-(6-Methoxypyridazin-3-yl)benzoate (3a)
ylpyridazine (entries 1, 4, 7, and 10, Table 1); the reactions led instead exclusively to the reduction of the phenyl halide and formation of a small amount of pyridazine dimer. EWG-4substituted bromobenzenes gave the cross-coupling products in satisfactory average 60% yield (entries 3, 6, 9, and 12, Table 1). Iodine instead of bromine seems to impede somehow the cross-coupling reaction as illustrated with 4-haloacetophenone (entries 12 and 14, Table 1), while chloro derivatives are not reactive at all. In the case of EWG-3-substituted bromobenzenes, yields of the cross-coupled products with 3-chloro-6-methoxypyridazine were surprisingly lower (18-50%, entries 2, 5, 8, and 11, Table 1) than those with the para-substituted derivatives; the identified side products were the two dimers. Since 3-substituted phenyl halides gave low to moderate yields, we tried to improve them by doubling the amount of the phenyl halides (10 mmol) relative to 3-chloro-6-methoxypyridazine (5 mmol). In all cases, yields are significantly increased, ranging from 57% to 99% (entries 2, 5, 8, and 11, numbers in parentheses, Table 1). Applying this modified procedure with a 4-substituted phenyl halide (4-bromobenzonitrile) showed also a slight improvement of the yield, from 58% to 68% (entry 6, Table 1). However, this procedure could not allow cross-coupling of EWG-ortho-substituted phenyl halides with pyridazine halides (entry 1, Table 1). The behavior of 3-chloro-6-methylpyridazine in the coupling with EWG-substituted phenyl halides was surprisingly found to be rather different from that observed with the 6-methoxylated derivative. Indeed, only 4-substituted bromobenzenes underwent the cross-coupling reaction (entries 3, 6, 9, and 12, Table 1) in TABLE 1. Cross-Coupling Reaction between 3-Chloro-6-methoxypyridazine or 3-Chloro-6-methylpyridazine and EWG-Substituted Phenyl Halides
entry
FG
X
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
2-CO2CH3 3-CO2CH3 4-CO2CH3 2-CN 3-CN 4-CN 2-CF3 3-CF3 4-CF3 2-COCH3 3-COCH3 4-COCH3 4-COCH3 4-COCH3 H H H
Br Br Br Br Br Br Br Br Br Br Br Br Cl I Cl Br I
R ) OCH3 isolated R ) CH3 isolated products a yields (%) products b yields (%) 1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a 12a 12a 12a 13a 13a 13a
-a (-a)b 45 (86)b 57 -a 27 (99)b 58 (68)b -a 50 (67)b 62 -a 18 (57)b 50 -a 18 -a -a 60
1b 2b 3b 4b 5b 6b 7b 8b 9b 10b 11b 12b 12b 12b 13b 13b 13b
-a -a 59 -a 12 (31)b 46 -a -a 18 -a -a 30 -a 21 -a -a 53
a The reaction led either exclusively to the reduction products or to the mixture of the reduction, dimers and cross-coupled products (
