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]
