1 Introduction
Compared to the wealth of catalytic methods which have been developed for the
functionalization of C(sp
2 )–H bonds of arenes and heteroarenes, relatively little
work has focused on the functionalization of unactivated, nonacidic C(sp
3 )–H
bonds of alkyl fragments. Most transition-metal-catalyzed C(sp
2 )–H functionalization methods involve a C–H activation step in which a C–H bond is cleaved
and a carbon–metal bond is formed, a process which has been termed “organometallic” or “inner-sphere” C–H activation [1]. But the organometallic activation of C
(sp
3 )–H bonds is generally more difficult to achieve, because these bonds are less
acidic and lack proximal empty low-energy or filled high-energy orbitals that
interact with filled or empty orbitals of the metal, respectively. Despite this intrinsic
difficulty, considerable progress has been made in the past decade, and catalytic
organometallic C(sp
3 )–H bond activation has now become a straightforward and
practical tool to build C¼C and C(sp
3 )–X bonds (X¼C or heteroatom) in a complex
molecule setting [2–5].
This chapter highlights recent remarkable examples of the fast-growing literature on the application of catalytic organometallic C(sp
3 )–H bond functionalization
to the synthesis of natural products and active ingredients, of interest for medicine
and agrochemistry [6–8]. Reactions involving the cleavage of activated C–H bonds,
in α position to heteroatoms or electron-withdrawing groups, or which do not
involve organometallic intermediates are not covered herein.
2 Heteroatom-Directed C–H Activation
2.1 Pioneering Stoichiometric Studies
Pioneering applications of heteroatom-directed C(sp
3
)–H activation using stoichiometric amounts of metal salts were described by Sames and co-workers in the early
2000s. These studies paved the way for the development of subsequent catalytic
methods. In 2000, the total synthesis of the antimitotic natural product (Æ)rhazinilam was achieved using a platinum-mediated dehydrogenative C–H bond
activation as key step [9]. Several seminal reports had shown that platinum complexes containing nitrogenous bidentate ancillary ligands were prone to undergo C–
H activation [10–13]. Exploiting this property, Johnson and Sames employed
optimized Schiff base 1 as a bidentate ligand to form the pivotal platinum complex
2 by reaction with a dimethylplatinum reagent [Me 2 Pt(μ-SMe 2 )] 2 (Scheme 1).
Treatment of 2 with triflic acid afforded a cationic platinum complex 3, which
upon heating in CF 3 CH 2 OH provided the hydridoplatinum (II) complex 4, resulting
from the selective dehydrogenation of one ethyl group, with excellent yield (90%,
NMR yield). Subsequent platinum decomplexation with aqueous KCN followed by
cleavage of the imine afforded racemic alkene 5 in 60% overall yield from 1.
134
D. Dailler et al.
Compared to the wealth of catalytic methods which have been developed for the
functionalization of C(sp
2 )–H bonds of arenes and heteroarenes, relatively little
work has focused on the functionalization of unactivated, nonacidic C(sp
3 )–H
bonds of alkyl fragments. Most transition-metal-catalyzed C(sp
2 )–H functionalization methods involve a C–H activation step in which a C–H bond is cleaved
and a carbon–metal bond is formed, a process which has been termed “organometallic” or “inner-sphere” C–H activation [1]. But the organometallic activation of C
(sp
3 )–H bonds is generally more difficult to achieve, because these bonds are less
acidic and lack proximal empty low-energy or filled high-energy orbitals that
interact with filled or empty orbitals of the metal, respectively. Despite this intrinsic
difficulty, considerable progress has been made in the past decade, and catalytic
organometallic C(sp
3 )–H bond activation has now become a straightforward and
practical tool to build C¼C and C(sp
3 )–X bonds (X¼C or heteroatom) in a complex
molecule setting [2–5].
This chapter highlights recent remarkable examples of the fast-growing literature on the application of catalytic organometallic C(sp
3 )–H bond functionalization
to the synthesis of natural products and active ingredients, of interest for medicine
and agrochemistry [6–8]. Reactions involving the cleavage of activated C–H bonds,
in α position to heteroatoms or electron-withdrawing groups, or which do not
involve organometallic intermediates are not covered herein.
2 Heteroatom-Directed C–H Activation
2.1 Pioneering Stoichiometric Studies
Pioneering applications of heteroatom-directed C(sp
3
)–H activation using stoichiometric amounts of metal salts were described by Sames and co-workers in the early
2000s. These studies paved the way for the development of subsequent catalytic
methods. In 2000, the total synthesis of the antimitotic natural product (Æ)rhazinilam was achieved using a platinum-mediated dehydrogenative C–H bond
activation as key step [9]. Several seminal reports had shown that platinum complexes containing nitrogenous bidentate ancillary ligands were prone to undergo C–
H activation [10–13]. Exploiting this property, Johnson and Sames employed
optimized Schiff base 1 as a bidentate ligand to form the pivotal platinum complex
2 by reaction with a dimethylplatinum reagent [Me 2 Pt(μ-SMe 2 )] 2 (Scheme 1).
Treatment of 2 with triflic acid afforded a cationic platinum complex 3, which
upon heating in CF 3 CH 2 OH provided the hydridoplatinum (II) complex 4, resulting
from the selective dehydrogenation of one ethyl group, with excellent yield (90%,
NMR yield). Subsequent platinum decomplexation with aqueous KCN followed by
cleavage of the imine afforded racemic alkene 5 in 60% overall yield from 1.
134
D. Dailler et al.