METAL-CATALYZED C–HETEROATOM CROSS-COUPLING REACTIONS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 87

3.3. ULLMANN-TYPE REACTIONS

3.3.1. Introduction
Pioneering work on copper-mediated and catalyzed reactions dates from the begin-
ning of last century with the work on aryl aminations and diaryl ether synthesis by
Ullmann [44], as well as aryl aminations and amidations by Goldberg [45]
(Scheme 3.20). Although these methods are known for more than a century, it is
only in the past 10 years that major improvements with respect to the experimental
conditions have been disclosed. Since then, their utilization in the total synthesis of
natural compounds has found widespread applications. A lesser sensitivity toward
reaction conditions and, generally, a larger choice of catalyst precursors (Cu(I) and
Cu(II) salts or oxides and even copper powder) are among the advantages of copper
over palladium. In contrast, copper-mediated transformations strongly depend on the
reaction conditions. Indeed, the choice of the solvent (commonly with high boiling
point as toluene, N -methylpyrrolidone (NMP), and dimethylformamide (DMF)), base
(K 2 CO 3 , MeONa, Cs 2 CO 3 , t- BuONa), and ligand (neutral bidentate chelators,
carbenes, phosphines) is crucial and needs a good deal of experimentation.

3.3.2. Mechanism
In this section, it is not intended to give a full explanation on each step of the
mechanistic pathway of these reactions. While many mechanistic studies have been
conducted for Pd-catalyzed cross-couplings (in which transmetalation takes place
after the oxidative addition step), little is known for Cu-catalyzed reactions and the
mechanistic rationales are still speculative [46]. Basically, two general pathways
can be proposed for the Cu-driven arylation of nucleophiles (Scheme 3.21). In path A,
the oxidative addition of the aryl or vinyl halide (R-X) takes place prior to the
nucleophilic substitution and affords complex

that in turn gives the coupling
compound and regenerates the catalytic species. In path B, the nucleophilic substi-
tution of NuH precedes the oxidative addition of R-X. In both cases, it is believed
that this copper cross-coupling transformation takes place over Cu(I) and Cu(III)
intermediates.

49

Ullmann (1905)

R 1 R 2 R 1 R 2

Cu

X YH Y

X = I, Br, Cl YH = NH, O

Goldberg (1906)

R 1 R 1

H
N

Cu

O

R 2

R

R 2 X N

O

R

X = I, Br, Cl

SCHEME 3.20 Ullmann and Goldberg condensation reaction.