Heteroarenes intermolecular alkylations

Contrary to heteroarenes, only few examples of intermolecular alkylations of the less reactive arenes have been reported. In a seminal example, perylene bisimides have been meta-alkylated with various alkyl halides under palladium catalysis and using CS2CO3 as the base (Scheme 19.25) [39]. The C-H activation step was again proposed to occur through the base-induced CMD mechanism (Scheme 19.18), and the exclusive functionaU2ation at the meta position can be correlated to the higher acidity of the meta C-H bond, as already shown in the related C-H arylation of electron-deficient arenes [29b,c]. 

The scope of the intermolecular alkylation of heteroarenes has been expanded to include pharmaceutically important pyridines and quinoHnes (Scheme 19.89) [131]. The reactions were performed at high concentration (0.8 M) with catalyst loadings as low as 1 mol%. Substitution ortho to the heterocyclic nitrogen was required for efficient alkylation at the other ortho position. In addition, increasing the bulk of this ortho substituent from methyl to isopropyl led to an increase in both the alkylation rate and the isolated yield of the alkylated product In that prospect silyl groups were found to be suitable temporary blocking groups. 

An intermolecular asymmetric addition of heteroarenes (indoles, thiophenes, pyrroles, and furans) to bicycloalkenes has been developed (with <99% ee). The reaction is catalysed by the complex generated from [(COD)lrCl]2 (1.5mol%) and (5)-TDBM-SEGPHOS (3 mol%) and proceeds in THF at 100 °C over 24 h via the initial activation of the C-H bond vicinal to the heteroatom (even with unprotected indoles, which typically undergo alkylation at the C(3) position), followed by a iy -addition across the C=C bond.128... 

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