Pyridyl triflate coupling reactions

Overman and co-workers [75] prepared alkenyltins via a vinyl triflate/ditin coupling. Mitchell and Kwetkat developed a simple route to acyltrimethylstannanes [187], whereas Hitchcock et al. [ 188] carried out a three-component tandem coupling reaction by reacting a 2-pyridyl triflate, aryl or heteroaryl bromides, and hexamethylditin with Pd(PPh3)4 the presence of LiCl to give azabiai yls (Scheme 4-48). 

The triflate leaving group was introduced to coupling reactions as an alterative to halogens. They are particularly useful when there is no simple way to prepare the required halide partner. Aryl triflates can be prepared from phenols and pyridyl triflates can be prepared from pyridones. This transformation is usually achieved using triflic anhydride and an amine base. The coupling of a triflate 2.191, derived from quinolone 2.190, with stannane 2.192 was used in a short synthesis of dubamine 2.193 (Scheme 2.66). 

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]. 

Both vinyl- and aryl triflates have been cross-coupled with 2-furylzinc chloride [26-28]. Since vinyl triflates are easily obtained from the corresponding ketones, they are useful substrates in Pd-catalyzed reactions. In the following example, a Negishi coupling of 2-furylzinc chloride and indol-5-yl triflate (22) provided an expeditious entry to 2-(5 -indolyl)furan (23). Protection of the NH in the indole ring was not required. A similar reaction was successful with pyridyl- and quinolinyl triflates. 

Finally, a recently reported copper catalyzed carbon-nitrogen bond forming process utilises reagents with polarity opposite to the common disconnection protocols. An electrophilic nitrogen, in most cases an (9-acyl hydroxylamine derivative, was successfully coupled with diarylzinc reagents in the presence of copper triflate or copper chloride. Di(2 -pyridyl)zinc and TV-benzoyloxy-morpholine were reacted at ambient temperature in the presence of 1% copper(I) triflate to give 2-morpholinopyridine in 71% yield (7.81.), Under these mild conditions the reaction was over in less than one hour.103... 

However, aryl triflates have been coupled with arylstannanes in even less polar solvents in the absence of LiCl. The reactions of arylstannane 192 with pyridyl-2-sulfonates 193a-c furnish the corresponding 2,2 -bipyridines 194 and 195 in moderate to good yields, whereas the amount of the homo-coupling products derived from the parent arylstannane decreases in order Ar-OMs > Ar-OTs > ArOTf [83], Table 8. 

Abiraterone acetate 117 is an androgen biosynthesis inhibitor, which was developed by the Institute of Cancer Research in the UK and further developed by Janssen for the oral treatment of patients with metastatic castration-resistant prostate cancer [75]. Its synthesis is relatively easy through a Suzuki coupling between the 17-enol triflate derived from the 3-acetate of dehydro-epiandrosterone (115) and 3-pyridyl-diethylborane (116) (Scheme 27) [76]. The reaction is catalysed by PdCl2(PPh3)2 and proceeds in good yield (84%). A similar Suzuki-based route in which the ketone starting material was converted into an alkenyliodide has also been published [77]. 

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