Regioselective Suzuki coupling on pyridinium N-(3,5-dibromoheteroar-2-yl)aminides

A regioselective Suzuki–Miyaura cross-coupling reaction on 3 0,5 0-dibromo pyridinium N-(2 0-azinyl)aminides is reported. A series of 3 0-aryl(or heteroaryl)-5 0-bromo-pyridinium N-(2 0-pirazinyl)aminides were obtained in good yields. Two isomeric 3 0,5 0diaryl pyridinium N-(2 0-azinyl)aminides were also prepared. 2006 Elsevier Ltd. All rights reserved. Functionalization of heterocycles through Suzuki– Miyaura palladium-catalyzed cross-coupling has been established as a standard method for the synthesis of biaryl and heterobiaryl systems. Substituted pyridines and pyrazines are valuable intermediates in the pharmaceutical and flavour fields, so development of regioselective processes over both systems has an indubitable interest. In the past years, our research programme has been related with the synthetic utility of pyridinium N-(2 0-azinyl)aminides 1 (Fig. 1) as building blocks in the synthesis of azine derivatives, and we recently reported preliminary results obtained in the crosscoupling reaction between arylboronic acids and pyridinium N-(5 0-bromoheteroar-2 0-yl)aminides 1a–c (Fig. 1). The promising results obtained from ylides 1a,b justified broadening of the process over other aminides, such as N-(3 0,5 0-dibromopyrid-2 0-yl)pyridinium aminide 1c. On this substrate, a double Suzuki reaction was performed, and different 3,5-disubstituted azines were obtained. 0040-4039/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.06.097 * Corresponding author. Fax: +34 91 885 46 86; e-mail: julio. [email protected] N N N N N N Br X W 1 + Het 1a W=CH, X=H 1b W=N, X=H 1c W=CH, X=Br 1d W=N, X=Br + Figure 1. The same double coupling methodology on 1c, employing 3-pyridylboronic acid (Scheme 1), produced a low yield (18%) of the expected bis-heteroaryl aminide 2a, while the monosubstituted ylide 3a appeared as the main reaction product (48%), in addition to 28% of starting material 1c that was recovered. Neither the use of a large excess of 3-pyridylboronic acid and/or palladium catalyst, nor longer reaction times, improved the yields of compound 2a. The structure elucidation of 3a was solved by comparison of its H NMR spectra with those of related compounds. H6 0 of the 2-aminopyridine ring appears more shielded when a bromine atom is in position 5 0-, than when an arene is placed in the same position. The following data were obtained for dH6 0 (CD3OD) in compounds 1c, 2a and 3a: 7.74 ppm, 8.03 ppm and 7.71 ppm, respectively. This result pointed out a considerable degree of regioselectivity in the Suzuki process, when N-(3 0,5 0-dibromo-2 0-pyridin-2 0-yl)pyridinium aminide 1c was reacted with pyridyl-3-boronic acid. Regioselectivity in palladium cross-coupling reactions of di-haloazines, having two identical halogen atoms in different positions of the ring, has not been often described in the literature. On uncharged systems, 2,5-dibromopyridine undergoes a regioselective palladium-catalyzed coupling with terminal acetylenes and arylzinc halides, and 2,5-dichloropyridine selectively reacts at 2-position with phenylboronic acid. Moreover, the synthesis of 2-aryl-6-chloronicotinamides via Suzuki coupling of 2,6-dichloronicotinamide with aryl boronic acids has also been described, and in this case, regioselectivity