Key words
C–H bond functionalization - remote - cyclic amines - transition metals - catalysis
- synthesis
Cyclic amines are ubiquitous structures in natural products and pharmaceuticals, many
of which contain one or multiple substituents on the ring at the α-position as well
as at positions remote from the nitrogen atom. The development of new synthetic methods
to access these substituted cyclic amines is thus of great importance. For this purpose,
C–H bond functionalization of parent aza-heterocycles arguably represents the most
direct and facile strategy among others, being particularly suitable for the late-stage
modification of existing cyclic amine structures in complex molecules. Research in
this field, however, has largely focused on the functionalization of α-C–H bonds,
while functionalization of more remote C–H bonds, such as β- and γ-C–H bonds, is much
less studied. This is due to challenges associated with remote C–H bond functionalization
of cyclic amines. Firstly, a handful of such reactions are initiated via the lone
pair of electrons on the amine nitrogen atom, which is further away from remote C–H
bonds compared to the α-C–H bond. Secondly, reactions for the remote C–H bond functionalization
of cyclic amines often involve labile endocyclic iminium ion and enamine intermediates,
which are electrophiles and nucleophiles respectively in nature. This dramatically
enhances the complexity of reaction pathways, and significantly increases the difficulty
in controlling the selectivity of the target reaction. Thirdly, the conformations
of cyclic compounds are not as flexible as those of acyclic compounds. As a result,
strategies that are not uncommon for the remote C–H bond functionalization of acyclic
amines are sometimes not feasible for cyclic amines. Despite the above challenges,
significant progress has still been made in recent years toward the remote C–H bond
functionalization of cyclic amines, with the majority of methods relying on transition-metal
catalysis.
This graphical review summarizes the transition-metal-catalyzed methods developed
to date for the purpose of C–H bond functionalization at remote positions of the rings
of saturated cyclic amines, some of which involve concurrent α-C–H bond functionalization
as well. Reactions are grouped according to the mechanistic pathway that initiates
the reaction of the cyclic amine substrate, and full references are grouped by Figure
number. Transition-metal-catalyzed reactions using prefunctionalized substrates, such
as cross-coupling with halogenated cyclic amines and hydrofunctionalization of partially
unsaturated aza-heterocycles, are outside the scope of this review, and are thus not
discussed.
Figure 1 Oxidation with metal tetroxides[1]
Figure 2 Hydride abstraction from cyclic amines, part I[2]
Figure 3 Hydride abstraction from cyclic amines, part II[3]
Figure 4 Hydride abstraction from cyclic amines, part III[4]
Figure 5 Single-electron transfer (SET) from cyclic amines, part I[5]
Figure 6 Single-electron transfer (SET) from cyclic amines, part II[6]
Figure 7 Single-electron transfer (SET) from cyclic amines, part III[7]
Figure 8 Hydrogen atom transfer (HAT) from cyclic amines, part I[8]
Figure 9 Hydrogen atom transfer (HAT) from cyclic amines, part II[9]
Figure 10 Hydrogen atom transfer (HAT) from cyclic amines, part III[10]
Figure 11 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination,
part I[11]
Figure 12 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination,
part II[12]
Figure 13 Directed β-C–H bond activation of cyclic amines[13]
Figure 14 Directed γ- and more remote C–H bond activation of cyclic amines, part I[14]
Figure 15 Directed γ- and more remote C–H bond activation of cyclic amines, part II[15]
Figure 16 Undirected remote C–H bond activation of cyclic amines[16]
