CC BY-NC-ND 4.0 · SynOpen 2022; 06(04): 286-305
DOI: 10.1055/a-1929-9789
Graphical Review

Transition-Metal-Catalyzed Remote C–H Bond Functionalization of Cyclic Amines

Weijie Chen
a   School of Chemical Science and Engineering, Tongji University, 1239 Siping Rd, Shanghai 200092, P. R. of China
b   Institute for Advanced Studies, Tongji University, 1239 Siping Rd, Shanghai 200092, P. R. of China
,
Xiaoyu Yang
a   School of Chemical Science and Engineering, Tongji University, 1239 Siping Rd, Shanghai 200092, P. R. of China
,
Xi Cao
a   School of Chemical Science and Engineering, Tongji University, 1239 Siping Rd, Shanghai 200092, P. R. of China
› Author Affiliations
Financial support from the National Natural Science Foundation of China (NSFC) (Grant no. 22101206) and the Fundamental Research Funds for the Central Universities (Grant no. 22120220087) is gratefully acknowledged.
 


Abstract

C–H bond functionalization is one of the most effective strategies for the rapid synthesis of cyclic amines containing substituents on the ring, which are core structures of many bioactive molecules. However, it is much more challenging to perform this strategy on remote C–H bonds compared to the α-C–H bonds of cyclic amines. This graphical review aims to provide a concise overview on transition-metal-catalyzed methods for the remote C–H bond functionalization of cyclic amines. Examples are categorized and demonstrated according to mechanistic pathways that initiate the reactions of cyclic amine substrates. Where relevant, selected substrate scope and detailed reaction mechanisms are given.


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Biographical Sketches

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Weijie Chen studied chemistry at the University of Science­ and Technology of China (USTC) (B.S. 2010), and conducted undergraduate research in the group of Prof. Liu-Zhu Gong. He then undertook his graduate studies in the lab of Prof. Daniel Seidel at Rutgers University (USA), obtaining his Ph.D. in 2016. He subsequently worked as a postdoctoral fellow in the group of Prof. Michael Krische at the University of Texas at Austin (USA) from 2016 to 2017. He then moved to the University of Florida (USA) with the group of Prof. Daniel Seidel in the summer of 2017, and continued his postdoctoral research until 2020. He started his independent career at Tongji University (China) in 2021.

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Xiaoyu Yang studied chemistry at the University of Shanghai for Science and Technology (USST) (B.S. 2021). He then moved to Tongji University for his M.Sc. degree, working with Dr. Weijie Chen. His research focuses on the development of new synthetic methods toward nitrogen-containing compounds.

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Xi Cao studied chemistry at Hunan Normal University (B.S. 2021). She then moved to Tongji University for her Ph.D. studies, working with Dr. Weijie Chen. Her research focuses on the development of new synthetic methods toward nitrogen-containing compounds.

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.

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Figure 1 Oxidation with metal tetroxides[1]
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Figure 2 Hydride abstraction from cyclic amines, part I[2]
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Figure 3 Hydride abstraction from cyclic amines, part II[3]
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Figure 4 Hydride abstraction from cyclic amines, part III[4]
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Figure 5 Single-electron transfer (SET) from cyclic amines, part I[5]
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Figure 6 Single-electron transfer (SET) from cyclic amines, part II[6]
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Figure 7 Single-electron transfer (SET) from cyclic amines, part III[7]
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Figure 8 Hydrogen atom transfer (HAT) from cyclic amines, part I[8]
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Figure 9 Hydrogen atom transfer (HAT) from cyclic amines, part II[9]
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Figure 10 Hydrogen atom transfer (HAT) from cyclic amines, part III[10]
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Figure 11 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination, part I[11]
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Figure 12 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination, part II[12]
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Figure 13 Directed β-C–H bond activation of cyclic amines[13]
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Figure 14 Directed γ- and more remote C–H bond activation of cyclic amines, part I[14]
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Figure 15 Directed γ- and more remote C–H bond activation of cyclic amines, part II[15]
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Figure 16 Undirected remote C–H bond activation of cyclic amines[16]

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Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Author

Weijie Chen
Institute for Advanced Studies, Tongji University
1239 Siping Rd, Shanghai 200092
P. R. of China   

Publication History

Received: 09 August 2022

Accepted after revision: 23 August 2022

Accepted Manuscript online:
24 August 2022

Article published online:
24 October 2022

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  • References

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Figure 1 Oxidation with metal tetroxides[1]
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Figure 2 Hydride abstraction from cyclic amines, part I[2]
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Figure 3 Hydride abstraction from cyclic amines, part II[3]
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Figure 4 Hydride abstraction from cyclic amines, part III[4]
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Figure 5 Single-electron transfer (SET) from cyclic amines, part I[5]
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Figure 6 Single-electron transfer (SET) from cyclic amines, part II[6]
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Figure 7 Single-electron transfer (SET) from cyclic amines, part III[7]
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Figure 8 Hydrogen atom transfer (HAT) from cyclic amines, part I[8]
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Figure 9 Hydrogen atom transfer (HAT) from cyclic amines, part II[9]
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Figure 10 Hydrogen atom transfer (HAT) from cyclic amines, part III[10]
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Figure 11 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination, part I[11]
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Figure 12 Directed α-C–H bond activation of cyclic amines, followed by β-hydride elimination, part II[12]
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Figure 13 Directed β-C–H bond activation of cyclic amines[13]
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Figure 14 Directed γ- and more remote C–H bond activation of cyclic amines, part I[14]
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Figure 15 Directed γ- and more remote C–H bond activation of cyclic amines, part II[15]
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Figure 16 Undirected remote C–H bond activation of cyclic amines[16]