Sonogashira reaction pyridines

Halopyridines, like simple carbocyclic aryl halides, are viable substrates for Pd-catalyzed crosscoupling reactions with terminal acetylenes in the presence of Pd/Cu catalyst. The Sonogashira reaction of 2,6-dibromopyridine with trimethylsilylacetylene afforded 2,6-bis(trimethylsilyl-ethynyl)pyridine (130), which was subsequently hydrolyzed with dilute alkali to provide an efficient access to 2,6-diethynylpyridine (131) [106]. Extensions of the reactions to 2-chloropyridine, 2-bromopyridine, and 3-bromopyridine were also successful albeit at elevated temperatures [107]. 

Additional examples of the Sonogashira reactions of pyridine triflates include coupling of 2-pyridyltriflate and 3-hydroxy-3-methylbut-l-yne to afford alkyne 141 [114], The carbinol adduct could be readily unmasked to give 2-ethynylpyridine via a basic-catalyzed retro-Favorsky elimination of acetone. Due to the volatility of 2-ethynylpyridine, use of a high boiling liquid such as paraffin oil for the basic hydrolysis made the distillation more convenient [115]. 

In conclusion, the Pd chemistry of pyrimidines has its own characteristics when compared to carbocyclic arenes and other nitrogen-containing heterocycles such as pyridine and imidazole. One salient feature of halopyrimidines is that the C(4) and C(6) positions are more activated than C(2). As a result, 2-, 4- and 6-chloropyrimidines are viable substrates for Pd-catalyzed reactions and 4- and 6-chloropyrimidines react more readily than 2-chloropyrimidines. For the Sonogashira reaction, though, there is little difference in the reactivity among 2-, 4- and 5-positions of substituted halopyrimidines. Not only is the Sonogashira reaction a reliable method... 

The synthesis of derivatized, concave pyridines could be accomplished in a straightforward manner [118]. Thus, 335 could be transformed to 336 upon cross-coupling with phenylacetylene. Furthermore, the Sonogashira reaction was also able to generate dimerized variations 338 of these compounds by reacting 337 with 325. 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

In the synthesis of Vemurafenib (Scheme 26) the 5-bromo-7-azaindole part of 113 is made by a Sonogashira reaction (Scheme 42) [73]. Thus, reaction between pyridine 161 and 2-methyl-but-3-yne-2-ol 162 catalysed by PdCl2(PPh3)2, Cul and Et3N yielded the protected pyridine-acetylene 163 in 93% yield. This was deprotected under basic conditions to yield 164, which was cyclised to 165 using tBuOK in NMP for an overall 62% yield. 

The findings of an extensive study on NHC-based Hgands with semilabile pendant functionalities were reported by CaveU [61]. Here, better conversions were achieved in Sonogashira reactions if the complex took advantage of the donor capability of one NHC Ugand, and an additional stabihzation was induced by the presence of an N-donor pyridine. Despite long reaction times, a maximum TON of 540 was achieved (Scheme 6.12). 

The post-synthetic methodology has also been used to incorporate catalytic centres. The incorporation of chiral l,l -bi-2-naphthols (BINOLs) into CMPs has been used to perform catalytic reactions using the alcohol groups to bind to catalytically active centres such as phosphoric acids for asymmetric transfer hydrogenations or titanium for diethyl-zinc additions. Other metal-containing functionalities have also been incorporated into CMP networks. The coordination of metals to pyridine or phenylpyridine via Sonogashira reactions has also been reported for catal5Aic transformations such as reductive amination or aza-Henry reactions, a-atylations and oxyaminations. ... 

Compounds like tribenzocyclotriyne 47 are of interest because they have the ability to form conducting complexes with low-valent nickel by virtue of their planar, anti-aromatic character and cavity size. Youngs et al. published a synthesis of 47 where cyclotrimerization of precursor 48 is accomplished by S3mthesizing and then purifying the copper acetylide of the latter iodo alkyne and then refluxing said material in pyridine for 24 hours. In this way, the desired cyclotrimer 47 is obtained in an impressive 80% yield. The palladium-based Sonogashira reaction was attempted for this same substrate (48) and was much less effective (5% yield of 47). There are several examples where the Castro-Stephens approach was superior to other methods for creating cyclic arene/yne macrocycles. ... 

The [4+2] cycloaddition reactions of some triazole substituted 3,5-dichloro-2(lH)-pyrazinones have been studied by Kaval et al. (2006). They developed the required intermediates from the corresponding 3,5-dichloropyrazinones, following either a nucleophilic substitution or a Sonogashira reaction to install the alkyne handle on the scaffold. The various triazole derivatives linked to the pyrazinones were synthesized through a microwave-assisted CuAAC reaction. Then [4+2] cycloaddition reactions were carried out under microwave irradiations with dimethyl acetylenedicaiboxylate (DMAD) at 180-200 °C for 10-20 min, and the corresponding highly decorated pyridine and pyridine scaffolds were isolated in good yields. 

Aryl hydrazide-based linker 79 was developed as a traceless handle that released products under mild oxidative conditions (Scheme 42) [91]. Polymeric bound p-iodophenylhydrazide was subjected to a variety of Pd°-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille). Oxidation with Cu(OAc)2 in MeOH and pyridine released the final products in 50-96% yield. 

Several Sonogashira adducts of heteroaromatics including some pyridines (see Section 4.3) and pyrimidines underwent an unexpected isomerization [69]. This observed isomerization appeared to be idiosyncratic, and substrate-dependent. The normal Sonogashira adduct 100 was obtained when 2-methylthio-5-iodo-6-methylpyrimidine (99) was reacted with but-3-yn-ol, whereas chalcone 101, derived from isomerization of the normal Sonogashira adduct, was the major product when the reaction was carried out with l-phenylprop-2-yn-l-ol. 

Scope of this synthetic strategy is not limited to benzofiirans. The reaction of 2-iodo-3-hydroxypyridine and 1,1 -diethoxy-2-propync under Sonogashira coupling conditions (palladium-copper catalyst system) leads to the formation of the substituted furo[3,2-6]pyridine shown in 3.56.72... 

Palladium-catalyzed coupling reactions of 2-(5-iodoisoxazol-3-yl)pyridine 274 with a variety of organometallic compounds led to derivatives 275-278 through Sonogashira, Suzuki, Negishi, and Stille reactions, respectively (Scheme 64) <20010L4185>. 

The pyridyl group has also been immobilized on the resin and was able to survive lithiation conditions necessary to prepare the halopyridine [62]. This approach has also been applied to the Sonogashira, Stille, and Negishi reactions vide infra). In the Suzuki example, the resin-bound pyridine 177 can be converted to the haloderivative 178 using standard lithiation chemistry. With 178 in-hand, cross-coupling and cleavage from the resin afforded 179. 

Figure 4.8 graphically illustrates the result of a simple keyword search of SciFinder using the name reactions and pyridine. The pubhcation frequency shows the dramatic increase in use of these cross-coupling reactions over the past 10 years. In particular, the Sonogashira and the Suzuki reactions have experienced a geometric increase in use. 

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