Modern Heck Reactions - New Trends in Cross-Coupling: Theory and Applications - page 426

CF 3 CF 3

CO 2 Et

Pd(O Ac) 2 (10 mol%)
L, Ac 2 O, O 2
excess arene or EtOAc
90 °C, 36 h

CF 3 EtO 2 C CF 3

62%

Bu Bu

Et N Et

L

Scheme 9.107 Oxidative arylation by electron-deficient arenes in the presence of
2,6-dialkylpyridine.

Pyridine derivatives used as ligands allow the alkenylation of common
electron-deficient substrates containing one or two electron-withdrawing
groups, such as CF 3 ,NO 2 ,CO 2 R and COMe, as in the system described by Yu
and co-workers (Scheme 9.107). 324 Such substituents direct the reaction
mainly at meta-positions, thus supporting the electrophilic nature of the
mechanism of Pd(II) attack.
A very fine balance of steric bulk is required for the system to work well.
Less bulky pyridines (pyridine itself, 2,6-lutidine, ethyl nicotinate) were un-
reactive, similarly to the much bulkier 2,6-di-tert-butyl- and 2,6-dineo-
pentylpyridines. Good yields were obtained with moderately bulky primary n-
pentyl and 2-ethylhexyl 2,6-disubstituted pyridines. Such a requirement for a
fine balance of steric bulk and, probably, ligand nucleophilicity indicates
that stable monoligation of the Pd centre by a pyridine ligand is what is
needed. Probably, indeed, such ligands favour the formation of LPd(OAc) 2
complexes, but why such complexes may exhibit high electrophilicity suf-
ficient for attacking strongly deactivated arenes remains a question. Sanford
and co-workers further showed that pyridine ligands, such as that shown in
Scheme 9.107 taken in a 1 : 1 Pd:L ratio are highly effective in increasing the
activity and selectivity of catalytic systems, thus making the intermolecular
Fujiwara-Moritani reaction much closer to practical application. 325
On the other hand, although competitive experiments were not per-
formed, from the data on yields and reaction times it is evident that the
differences between electron-rich benzenes, benzene itself and electron-
deficient arenes were minimal, which is hardly compatible with true
electrophilic metallation. The ability to attack nitrobenzene and 1,3-bis-
(trifluoromethyl)benzene at the meta position indicates high electrophilicity,
whereas the substrate selectivity does not, being more common for directed
palladation (see below). Moreover, if we take electrophilic mercuration as an
archetypal metallation reaction with a highly reactive metal electrophile, the
positional selectivity of mercuration is different to be highly typical for
common electrophilic reactions. 326 The palladation involved in the reaction
under consideration is less positionally selective than mercuration. The
other analogy to be drawn is with palladium-catalysed oxidative homo-
coupling of arenes, described by Labinger and co-workers to involve the