Stille coupling nitrogen nucleophiles

A number of nitrogen nucleophiles can be arylated by triflates, and this methodology has found application, for example, in the synthesis of nonsteroidal selective glucocorticoid modulators [91]. However, triflates are not always practical due to their sensitivity toward moisture and strong nucleophiles such as NaOtBu, which is still the most often utilized base in aminations. Buchwald et al. [92] reported the efficient coupling of nonaflates as an appealing alternative to triflates (Scheme 13.30). 

Compared with aUylic C-H bond, benzylic C-H bond has similar BDE. Under the oxidative conditions, it is still susceptible to undergo SET to form a benzyl radical or carbocation, which would like to be trapped by a series of C(sp )-H nucleophiles or electron-rich aromatic rings (Scheme 2.30). For example, active methylenic 1,3-dicarbonyl compounds [148-153], nitrogen nucleophiles (amines or amides or almidine), [154—158] IV-hydroxyamides [159], ketones [160, 161], aldehydes [162], electron-rich alkenes [163], aromatic rings [164, 165], and terminal alkynes [166] are good coupling partners in the oxidative benzylic C-H bond... 

As seen with the previous example, activation of the organostannane to promote the transmetalation step has a dramatic and positive influence on the outcome of the reaction. In 1992, Vedejs et al. showed that intramolecular coordination of tin by a nucleophilic center like a nitrogen can considerably increase the rate of the transmetalation step in the Stille coupling . Derivatives like 22 proved to be more reactive than their analogue trialkyl tin... 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

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