METAL-CATALYZED C–HETEROATOM CROSS-COUPLING REACTIONS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 77

Pd or Cu

Het

X Base Het

O
-H

X = I, Br, Cl, OTf ...
Het = R 2 N-H, RO-H, RS-H, R 2 P

SCHEME 3.1 Cross-coupling reactions considered in this text.

transformations in which an oxidative addition, a transmetalation followed by a
reductive elimination, guides the mechanistic pathway [10].
This chapter describes the combination of aryl and vinyl halides (or pseudo-
halides) with heteroatomic nucleophiles for the preparation of complex molecular
scaffolds for the total synthesis of natural (and nonnatural) products with medicinal
properties. Special emphasis will be placed on palladium coupling-type reaction
(Buchwald-Hartwig) and copper coupling-type reaction (Ullmann-Goldberg)
(Scheme 3.1). In a first part, we intend to give a general overview of each reaction
concept with a short introduction, followed by a brief survey on mechanistic
insights, scope, and limitations. Finally, some representative examples of copper-
and palladium-catalyzed cross-coupling reactions for the synthesis of complex
bioactive molecules will be presented. Since the chapter concerns the cross-coupling
reactions for the C-heteroatom bond formation, Tsuji-Trost [11] mediated C-N,
C-O, and C-S bond formation as well as the gold catalysis [12] will not be discussed
here as those subjects are beyond the scope of this text.

3.2. BUCHWALD-HARTWIG-TYPE REACTIONS

3.2.1. Introduction
Pd-catalyzed reactions of aryl and vinyl halides (or pseudohalides) with “hard”
organometallic nucleophiles have been a straightforward procedure for the
C-C bond creation and have been known for several decades. In contrast “soft”
nonorganometallic nucleophiles (amines, amides, imines, hydrazines, alcohols,
thiols, malonates, etc.) involved in this kind of coupling reaction emerged only
starting from the mid-1990s with the seminal work by Buchwald and Hartwig [13].
They have independently and simultaneously described the Pd-catalyzed cross-
coupling reactionwith nitrogen- and oxygen-based substrates affording anilines and
aryl ethers, respectively [14]. Since then, the method has rapidly proved to be
successful in the field of synthetic organic chemistry, being efficiently applied to
excel over unsolved long-standing synthetic problems and allowing the construction
of very complex targets. Thus, several research groups have embarked on inves-
tigating new catalytic Pd-mediated systems that broaden the applicability of the
transformation [15].
The Pd-catalyzed Buchwald-Hartwig-type reaction takes place under mild
reaction conditions that consequently widen the substrate scope. Commonly, the
transformation takes place in the presence of catalytic amounts of a palladium source
(usually palladium acetate (Pd(OAc) 2 ), tris(dibenzylideneacetone)dipalladium