Stille coupling pyridines

Pyridine 117 undergoes a Stille coupling with l-methyl-2-trimethylstannylpyrrole to give 118 in 36% yield [83], and the same stannane has been joined with bromopyrimidines [84]. 

Intriguingly, the Stille coupling of quaternary pyridylstannane 12 with 2-chloropyrazine (13) proceeded to afford adduct 14 [12]. A-Methylated 3-(tributylstannyl)pyridine 12 was easily prepared by refluxing 3-(tributylstannyl)pyridine (11) with methyl tosylate in EtOAc. By contrast, only 29% yield of the coupling adduct was isolated from the Stille reaction of 3-(tributylstannyl)pyridine A-oxide and 13. 

Stille coupling of 54 with 1-ethoxy-1-tributylstannylethene constructed 4-(l-ethoxyethenyl)pyridine 55, which was then annulated to 1-fluoroellipticine (56) upon treatment with acid. 

The arylation of support-bound arenes has mainly been performed using the Suzuki and Stille coupling reactions. Both reactions proceed smoothly with arenes and het-eroarenes such as furans, thiophenes, or pyridines. Examples of the arylation of het-eroarenes are presented in Chapter 15. 

Hexamethylditin is a suitable reagent for Pd-catalyzed metallation of aryl-halides to furnish aryltin compounds that in turn can react in Stille couplings with aryl halides to form biaryl derivatives. Hitchcock and coworkers [ 126] have shown that 2-pyridyl triflate and (hetero)aryl bromides can be coupled to 2-(hetero)aryl pyridines 174 in moderate to good yields (Scheme 66). The underlying principle of this heterocoupling of two aryl (pseudo)hahdes is the selective stannylation of the triflate that is undergoing a faster oxidative addition to the Pd(0) complex than the bromide. 

Boron-substituted pyridine reagents can be used to construct the bipyridine ring system by coupling them with halopyridines in the presence of a Pd° catalyst and a base (Suzuki method). Various ligands have been made in this manner in moderate to high yields, including 2,3-bipyridine (85%)41 and 3,5-dimethyl bipyridine (60%) 42 One valuable feature of the Suzuki method is that it is compatible with stannanes. A pyridyl diethylborane has been coupled to a tributyl tin-functionalized pyridyl bromide.43 This compatibility is useful for polypyridine syntheses because subsequent Stille coupling of the bipyridyl stannane is possible. 

Bipyridines have also been synthesized by a number of cycloaddition methods. For example, stannylated bipyridines, (12), which can serve as Stille coupling partners for the synthesis of terpyridines and higher oligopyridines, have been generated in 77% and 83% yield by a thermally induced [4 + 2], regioselective cycloaddition between 1,2,4-triazines (11) and tributyl(ethynyl)tin derivatives (Scheme 6).51 Because of the steric interaction of the bulky tributyl tin group with the pyridine ring, less than 5% of the final product was the 3-substituted isomer. 

Stille coupling has been used to prepare tpy using two complementary routes which work with equal efficiency. Either 2-trimethylstannylpyridine may be coupled with 2,6-dibromopyridine, or 2,6-di-(trimethylstannyl)pyridine may be coupled with 2-bromopyridine, to afford tpy in yields of 74% and 72%, respectively.7 If an efficient method could be developed for the direct oxidative coupling of pyridine to form tpy, this ligand might become more available and its subsequent coordination chemistry would benefit commensurably. 

A variety of 4 -substituted tpys have been prepared, either by condensation to form the central ring or by Stille coupling of the pyridine components. The former approach, starting with ethyl 2-pyridinecarboxylate and acetone, leads to (25a) in three steps with an overall yield of 40%.25 This chloro-derivative can, in turn, be converted to a variety of other 4 -substituted tpys, such as (26a-g).26 The nucleosides 2 -deoxyadenosine and 2"-o-methyladenosine were similarly coupled with (25a) to afford the tpys (27), whose Cu11 complexes effected efficient site-specific cleavage of RNA.27... 

Double Stille couplings which employ 2,6-di-(tri- -butylstannyl)pyridine (45) and two equivalents of a 5-substituted-2-bromopyridine lead efficiently to 5,5"-disubstituted tpys. Thus 5-methyl-2-bromopyridine (44) reacts with (45) to provide (46a) (Scheme 7).44... 

An air and moisture stable, low-coordinate phosphine ligand has been found to be effective in the Stille coupling of pyridine derivatives. This was exemplified in the transformation of 136 to 169 [85]. 

The Stille coupling reaction is the most versatile method among all Pd-catalyzed crosscoupling reactions with organometallic reagents. By lithiation of 4-methyloxazole with H-BuLi and subsequent quenching with trimethyltin chloride, Dondoni et al. prepared 2-trimethylstannyl-4-methyloxazole [39], which was then coupled with aryl- and heteroaryl-halides to provide the expected 2-aryloxazole. Thus, 2-trimethylstannyl-4-methyloxazole was coupled with 3-bromo-pyridine to afford oxazolylpyridine 35. 

Using the Stille reaction similar to the one described immediately above, a new synthetic route to imidazo[4,5-c]pyridines has been delineated [46]. Following the coupling reaction to provide alkenyl imidazole 79b, an electrocyclic reaction was employed to provide 80 after aromaticity was attained by the elimination of methanol. The flexibility of this process is demonstrated by the fact that nearly identical yields are possible regardless of whether the Stille coupling reaction is done on compound 79a or the aldehyde compound that immediately precedes it in the synthetic sequence. 

A convenient synthetic method was described to introduce reactive functionalities as well as heterocyclic moieties at the C(2) position of 4-(A,2V-dimethylamino)pyridine (4-DMAP) via an unprecedented direct lithiation with BuLi-LiDMAE reagent [23]. Stille coupling of 2-chloropyrazine with 2-tributyltin-4-(2V,2V-dimethylamino)pyridine in the presence of PdCl2(PPh3)4 afforded 2-pyrazinyl-(4-A,2V-dimethylamino)pyridine (30) [23]. New useful 4-DMAP-containing synthons as polyhetero-cycles have been efficiently prepared. 

Moreover, the group explored Sonogashira, Suzuki and Stille couplings of 25, where the reactivity of the C-Cl and C-Br bonds was shown to be similar. Scheme 8 illustrates an example of the Stille reaction accomplished with compound 25 yielding 2,5-diphenyl pyridine 28. 

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