Pd(0)-Catalyzed Carboiodination: Early Developments and Recent Advances - New Trends in Cross-Coupling: Theory and Applications - page 288

(a)

Br

1. Ar 1 B(OH) 2 (1.2 equiv), Pd(PPh 3 ) 4 , Na 2 CO 3
90 °C, 12 h
2. Ar 2 B(OH) 2 (1.2 equiv)
90 °C, 12 h

Ar 2

C2-Br bond more
electron-deficient

N Br

Ar 1 N

(b)

1. Ar 1 B(OH) 2 (1.2 equiv), Pd(PPh 3 ) 4 , Na 2 CO 3
90 °C, 12 h
2. Ar 2 B(OH) 2 (1.2 equiv)
90 °C, 12 h

Ar 1 I

C3-I bond weaker
than C2-Br bond

Ar 2 N

N Br

Scheme 7.10 Switch in regioselectivity based on differences in electronic effects and

bond dissociation energies.

developed a one-pot procedure towards disubstituted pyridine derivatives
starting from dihalogenated pyridines via two sequential Suzuki cross-
couplings. 66 In one example (Scheme 7.10a), the more electron-deficient
C-Br bond undergoes selective monocoupling, whereas in another
(Scheme 7.10b), the reverse regioselectivity is observed, as the more reactive
(i.e., weaker) C-I bond couples first. Selective and sequential cross-couplings
of polyhalogenated aromatics are perhaps the most direct and e cient route
to highly substituted aromatics. Therefore, studying the factors that govern
regioselectivity in oxidative addition is a worthwhile and ongoing pursuit.
Handy and Zhang also developed a predictive guide for the order and site
of coupling in polyhalogenated aromatics based on the 1 H NMR chemical
shifts of the unsubstituted parent compounds, since chemical shifts are
sensitive to electronic effects. 67 They observed that the order of reactivity can
be paralleled to the chemical shift values, which are related to the intrinsic
electron deficiency of each bond. In a more theoretically rigorous report,
Merlic and co-workers performed extensive computational studies on the
factors that govern regioselectivity in oxidative additions by Pd into poly-
halogenated aromatics. 68 They proposed that distortion energies, which are
related to the bond dissociation energies of the respective C-X bonds, and
interaction energies, which involve the d xy (Pd)

p*(C-X) frontier molecular
orbital interactions, are both responsible for the observed regioselectivities
in cross-couplings of polyhalogenated heterocycles (Figure 7.1). These
studies provide a more fundamental understanding of how electronic effects
can govern site-selective oxidative additions.

-

7.5.1.2 Neighboring Substituents: Steric Effects and Directing
Groups
Neighboring substituents or heteroatoms about the C-X bond can also affect
the rate of oxidative addition due to either steric effects and/or the ability to
act as directing groups. In the total synthesis of (-)-FR182877 by Evans and
Starr highlighted in Section 7.5, the synthetic route took advantage of the
inherent reactivity of the gem-dibromoolefin 7.20 (Scheme 7.9). The authors