Negishi coupling pyridines

Queguiner used two subsequent Negishi-couplings on a pyridine ring in the total synthesis of the antibiotics Caerulomycin and C. The appropriate... 

The heterocycles may be pyridine, pyridazine, pyrimidine (positional isomers) and the organo-zinc reagents 233 were made from the bromo-compounds. Six compounds such as 234 were made by Negishi coupling.34... 

Negishi couplings on 2-bromo-5- and -6-tri-n-butylstannyl pyridines are possible due to the relatively high reactivity of 2-bromopyridines (the isomeric 5-bromo-2-stannylpyridine gave only low yields under the same conditions) and the low temperature of the reaction. ... 

Completion of the synthesis of caerulomycin C required a crosscoupling with a suitably functionalized pyridine, followed by functional group manipulations to convert the amide to an oxime. We found the best procedure for this cross-coupling to be a Negishi coupling using... 

Other examples of scale-up involved a triphenylphosphine-free one-pot Wittig olefination, a one-step three-component synthesis of imidazo annulated pyridine and a metal-catalyzed Suzuki coupling. Kappe and co-workers also recently transferred conditions for reactions originally performed on a small scale with a mono-modal system, to scale-up by parallel synthesis in a multimodal batch reactor [13]. Typically, the scale-up was 100-fold, from 1 mmol examples included Biginelli condensations, Heck and Negishi couplings, and Diels-Alder cycloadditions with gaseous reactants. 

A series of imidazo[4,5-6]pyridines 89 are high-affinity corticotrophin-releasing factor (CRF) receptor ligands, and they were prepared from intermediates 86 and 88, which were in turn synthesized via either the Suzuki or the Negishi coupling reaction. ... 

Pyridine-containing unnatural amino acids 91 and 94 were prepared by Negishi coupling of alkylzinc species such as 90 or Suzuki coupling of the boron derivative generated by hydroboration of the vinyl-amino-alcohol... 

Zinc Reagents. Negishi coupling of a-zincated vinyltrimethylsilanes with 2-bromopyridine yields 2-vinylpyridine functionalized by a silyl substituent at the a-carbon of the vinyl group 214 (Scheme 81). Similarly, the trifluoroethenyl group has been substituted into the 2-position in pyridine 215 nsing zincated trifluoroethene and 2-iodopyridine. ... 

Fu et al. reported Ni-catalyzed alkyl-alkyl cross-couphng reactions of diverse alkylzinc reagents with unactivated secondary alkyl halides under very mild conditions. Ni(cyclooctadiene)2 and sBu-pyridine-bis(oxazohne) (Pybox) catalyzed the Negishi coupling of various functional alkyl bromides and iodides at room... 

For Negishi reactions in which the pyridines are nucleophiles, the pyridylzinc reagents are usually prepared from the corresponding halopyridines [6, 20, 21]. An excess of 2-chlorozincpyridine /V-oxide (26), arising from 2-bromopyridine N-oxide hydrochloride (25), was coupled with vinyl triflate 27 in the presence of Pd(Ph3p)4 to furnish adduct 28 [20]. Recently, an efficient Pd-catalyzed cyanation of 2-amino-5-bromo-6-methylpyridine (29) using zinc cyanide has been reported to afford pyridyl nitrile 30 [22]. 

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>. 

In order to synthesize unsymmetric as well as symmetric bipyridines, methods involving crosscoupling of a halopyridine with an organometallic pyridine have been developed. Typically, halopyridines are coupled with either pyridylstannanes (Stille), pyridylborates (Suzuki), or pyr-idylzinc reagents (Negishi), where the two pyridines may or may not have the same structure to give symmetric and unsymmetrical products, respectively (Scheme 2). 

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. 

Examples of Negishi cross-couplings by this catalyst system are provided in Table 4. The method tolerates cyanides (entries 3 and 4), pyridines (entry 5), amides (entry 7), imides (entry 8), and esters (entry 10). Furthermore, hindered alkenylzincs (geminally or cfs-substituted entries 6-9) are suitable reaction partners. However, the effectiveness of the catalyst is compromised if the electrophile is hindered (e.g., branching in the a or p positions). 

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