METAL-CATALYZED C–HETEROATOM CROSS-COUPLING REACTIONS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 104

for building C-C and C-heteroatom bonds [108]. However, despite the valuable
catalytic potential, their application is less widespread compared to Pd and Cu in the
total synthesis of biologically interesting compounds. We therefore decided not to
present them in this chapter.

3.5. CONCLUSION

The selected examples presented in this chapter show that from the development of
highly active catalytic systems via transition metal complexes, the cross-coupling
reactions have become a valuable addition to the repertoire of efficient C-heteroatom
bond-forming reactions. Furthermore, in most cases, the choice of an appropriate
ligand revealed beneficial effects, allowing the use of less harsh reaction conditions
and an increase in the substrates and functional groups tolerance. Such methods have
inspired new creative reaction designs, consequently allowing new retrosynthetic
disconnections. Since then, these transformations have rapidly proved to be suc-
cessful in the field of synthetic organic chemistry, being efficiently applied to the
construction of very complex targets. Here, we have shown that palladium- and
copper-mediated cross-coupling reactions are frequently chosen for carrying out such
reactions. In most cases, the optimization of the reaction conditions is essential since
the nature of the substrate governs the operational conditions that render palladium
and copper catalysis extremely complementary. Even though palladium and copper
(as well as iron, gold, nickel, iridium, platinum, and so on not addressed here) were
successfully used for accomplishing the total syntheses of natural and unnatural
products, drawbacks still remain for some reactions and few points need to be well
established. In some cases, copper salts are used in stoichiometric amounts in order to
give rise to the required products in satisfactory yields and less expensive aryl
chlorides are scarcely used as substrates. High temperatures are commonly required
for copper-mediated cross-coupling reactions that are not always compatible with
sensitive compounds. In addition, little is known about the mechanism of the copper-
mediated transformations. Another point, which is a real problem specially for
industrial purposes, is how to get rid of traces of the metal used for the cross-
couplings from the final products. Nevertheless, since the last decade, impressive
progress have been made in this field and outstanding studies have recently been
published that paved the way to the preparation of a great deal of natural products.
Undoubtedly, increasing improvements on the utilization of transition metal catalysts
will be made in the future, placing such methods among the most challenging and
exciting current research fields.

REFERENCES

1. (a) T. Kohei, N. Miyaura, Top. Curr. Chem. 2002 , 219 , 1-9; (b) E. I. Negishi, Acc. Chem. Res. 1982 ,

15 , 340-348; (c) S. L. Buchwald (Ed.), Acc. Chem. Res. 2008 , 41 , 1439-1564 (special issue on cross-

coupling reactions).
2. A. Suzuki, J. Organomet. Chem. 1999 , 576 , 147-168.