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

Abstract

Abstract-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 0 -diaryl pyridinium N-(2 0 -azinyl)aminides were also prepared. Ó 2006 Elsevier Ltd. All rights reserved.Functionalization of heterocycles through SuzukiMiyaura palladium-catalyzed cross-coupling has been established as a standard method for the synthesis of biaryl and heterobiaryl systems. 1 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 2 ( Fig. 1) as building blocks in the synthesis of azine derivatives, 3 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 4 (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. 3c On this substrate, a double Suzuki reaction was performed, and different 3,5-disubstituted azines were obtained. 4 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 1 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. 3b,4 The following data were obtained for dH6 0 (CD 3 OD) 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. 5a On uncharged systems, 2,5-dibromopyridine undergoes a regioselective palladium-catalyzed coupling with terminal acetylenes and arylzinc halides, 5b and 2,5-dichloropyridine selectively reacts at 2-position with phenylboronic acid. 5c,d 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...

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

“…Lastly, to construct central-region-pyrazine arotinoids with a bent overall shape, we selected the position-selective Suzuki reaction of 2-amino-3,5-dibromopyrazine 16 [26,[30][31][32] and boronic acid 3 to prepare 19 (81 %). A subsequent Suzuki coupling with 4-carboxyphenylboronic acid led to 20 in low yield (39 %, Scheme 4); this low yield was due to the compound's instability during the purification step.…”

Efficient Synthesis of Novel Pyridine-Based Derivatives via Suzuki Cross-Coupling Reaction of Commercially Available 5-Bromo-2-methylpyridin-3-amine: Quantum Mechanical Investigations and Biological Activities

“…The Suzuki-Miyaura cross-coupling reaction provides an appropriate and practical approach for the synthesis of biaryl compounds, due to its ability to tolerate a wide range of functional groups and good reaction yields [ 3 ]. In the past, pyridine and its derivatives have been used as starting precursors for several useful compounds due to their availability and stability for direct cross-coupling reactions [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. With this approach, Liu and co-workers have described the Suzuki cross-coupling reactions between 2-aryl-1,2,3-triazole- N -oxides and pyridine- N -oxide with good yield of the final products [ 5 ].…”

Selective Palladium‐Catalyzed Suzuki–Miyaura Reactions of Polyhalogenated Heteroarenes

“…Recently, Reyes et al 117. focused their attention on the palladium‐catalyzed monoarylation of N ‐(3′,5′‐dibromo‐2′‐pyridin‐2′‐yl)pyridinium aminide ( 354 ) with arylboronic acids according to two different protocols ( Procedure A and Procedure B ) (Scheme ) and found that the reaction mixtures of the cross‐couplings contained two monoarylated regioisomers, 355 and 356 , together with the corresponding 3′,5′‐diarylated aminides 357 .…”