Bromopyridine Suzuki coupling

Due to the abundance of halopyridines, Suzuki reactions in which they serve as electrophiles have been used to synthesize a plethora of arylpyridines and heteroarylpyridines [39, 40]. 6-Phenyl-2-nitro-3-methylpyridine (55) was obtained via the reaction of 6-bromo-2-nitro-3-methylpyridine (54) and phenylboronic acid [39]. Not surprisingly, 3-chloropyridine was virtually inert under such conditions in contrast to 2-chloro- and 4-chloropyridine. The Suzuki coupling of 2-hydroxy-6-bromopyridine failed as well, possibly because 2-hydoxypyridines exist almost entirely in the keto form. 

In Baldwin s formal total synthesis of haliclamines A and B, a Suzuki coupling of 3-bromopyridine was the central operation [52], Chemoselective hydroboration of diene 66 employing 9-BBN occurred at the less hindered terminal olefin. Suzuki coupling of the resulting alkylborane with 3-bromopyridine then furnished alkylpyridine 67 as a common intermediate for the synthesis of haliclamines A and B. 

Chloropyrimidine was coupled with diethyl (3-pyridyl)borane in the presence of Pd(Ph3P)4, Bt NBr, and KOH to afford 3-(2 -pyrimidinyl)pyridine [23]. Likewise, the Suzuki coupling of 2-bromopyrimidine with diethyl (4-pyridyl)borane (47) led to 4-(2 -pyrimidinyl)pyridine (48) in 50% yield, whereas 2-chloropyrimidine produced 48 in only 20% yield under the same conditions [24], Diethyl (4-pyridyl)borane (47), on the other hand, was readily accessible from sequential treatment of 4-bromopyridine with n-BuLi and diethylmethoxyborane. 

An alternative Stille approach was not considered due to concerns about the toxicity of tin, and an attempted Kumada coupling between 2-pyridylmagnesium bromide and 5-iodo-2-chloropyrimidine 991 in the presence of Ni(Cl2)DPPF failed to give the desired product. An attempted Suzuki coupling with 2-bromopyridine 992 also failed, due to the deboronation of 2-chlotopyrimidine-5-boronic acid 993, which gave 2-chloropyrimidine 994 as the... 

Suzuki coupling reaction of phenylboronic acids such as 74 with 4-bromopyridine [34]. Inada and Miyuara [35] have extended the method to 2-chloroquinoline 25. Therefore, the coupling between 25 and phenylboronic acid 74 led to 2-tolylquinoline 75 in 91% yield. The catalyst was recovered with ease and used in further coupling reactions. Not surprisingly, the couplings of phenylboronic acids with electron-rich chloroarenes were ineffective due to their slow oxidative addition to the palladium(O) complex. This reaction is an example where even quinolinyl chloride is a good substrate for the oxidative addition of Pd(0) if the chlorine atom is at the activated position (a or 8). 

Suzuki and co-workers found that aryl triflates react with arylboronic acids [ArB(OH)2], in the presence of a palladium catalyst, to give biaryls in a reaction that is now known as Suzuki coupling.269 Even hindered boronic acids give good yields of the coupled product.2 0 Organoboranes, react with aryl triflates under these conditions as well. In a simple example, boronic acid 426 reacted with 3-bromopyridine in the presence of Pd(PPh3)4 to give a 90% yield of the biaryl 427.2 2... 

The discovery route varied little from the industrial synthesis. From bromopyridine 24, the boronic acid 30 was prepared in 88% yield via metal-halogen exchange and quenching the corresponding anion with BfOCHsls. Suzuki coupling with 2-bromopyridine 31 afforded the common intermediate 25. 

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

In continuation of his extraordinarily versatile and efficient directed-metalation technology, Snieckus employed indole 87 to selectively lithiate C-4 and to effect a Negishi coupling with 3-bromopyridine to give 88 in 90% yield [110]. In contrast, a Suzuki protocol gave 88 in only 19% yield (with loss of the TBS group). 

The palladium catalyzed cross-coupling of organosilicon compounds and aryl halides found only limited application with azines compared to the Suzuki or Negishi coupling. In a recent paper DeShong reported the efficient coupling of bromopyridine derivatives with aryl siloxanes (7.44.) 62 The transmetalating ability of the siloxane was enhanced by the addition of tetrabutylammonium fluoride. 

As with the Negishi and Suzuki reactions, the same solid-support (vide supra) could be adapted to the Sonogashira reaction [62]. The solid-supported bromopyridine 178 could undergo cross-coupling reactions with a variety of alkynes and be released from the solid-support to allow isolation of 331. 

For Suzuki reactions using haloboronic acids and another halide, the obviously best course is to have a more reactive halide in the substrate than in the boronate, so there are quite a few examples of chloro-heteroaryl-boronic acids coupling efficiently with aryl bromides. This difference is clearly shown by the coupling reactions of 2-chloro- and 2-bromopyridine-5-boronic acids with bromo-heterocycles. ... 

Several intermediates in the Suzuki-Miyaura coupUng of bromopyridines with arylboronic adds have been identified by in situ analysis of the reaction by electrospray ionization mass spectrometry (ESI-MS) [268]. Interestingly, monitoring the coupling by ESI-MS demonstrates that, at the end of the reaction, there is an accumulation of binuclear Pd(0)-Pd(II) halide clusters, which are stiU catalytically active [269]. 

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