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Synlett 2025; 36(11): 1441-1446
DOI: 10.1055/s-0043-1775466
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Enantioselective 1,4-Borylamination Enabled by Copper Catalysis

Yu-shen Zhu
,
Bo Su  ∗

We thank the National Natural Science Foundation of China (22271161, 22188101), the Science Fund for Distinguished Young Scholars of Tianjin Municipality (23JCJQJC00180), the Fundamental Research Funds for the Central Universities (63223065 and 63243134), and Nankai University, for financial support.
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Abstract

Compounds bearing both boryl and amino groups are highly valuable synthons in organic synthesis. However, while enantioselective 1,1- and 1,2-borylamination reactions have been developed, processes enabling distal borylamination have rarely been investigated. Here, we present an enantioselective 1,4-borylamination reaction, achieved through a copper-catalyzed cascade hydroborylation and hydroamination of arylidenecyclopropanes. This four-component reaction provides direct access to enantioenriched 4-aminoalkylboronate products with high chemo-, site-, and enantioselectivity. The versatility of these products was demonstrated through their broad transformations and extensive applications in the synthesis of various drug core structures. Additionally, preliminary mechanistic studies were conducted to investigate the reaction pathway, intermediates, and high chemo- and site-selectivity.


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Key words

arylidenecyclopropane - 1,4-borylamination, borylative functionalization - copper catalysis - copper hydride - asymmetric synthesis

Chiral amines play a crucial role in pharmaceuticals and natural products, with approximately 30% of the top 200 small-molecule drugs by retail sales in 2023 containing chiral amine motifs (Scheme [1a]).[1] [2] Similarly, alkyl borons are important intermediates in organic synthesis, facilitating the formation of key chemical bonds such as C–C, C–O, and C–N bonds.[3] Given the significance of both chiral amines and alkyl borons, considerable effort has been dedicated to developing efficient methods for their synthesis.[4] [5] Among these approaches, enantioselective borylamination reactions stand out as particularly valuable. These reactions enable the simultaneous incorporation of both boryl and amino groups, providing a powerful strategy for generating structurally diverse chiral amines and offering a robust platform for the construction of more complex chiral amine-containing compounds.

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Bo Su (left) received his BSc in chemistry from Zhengzhou University in 2008 and his Ph.D. in synthetic chemistry from Nankai University in 2013. After graduation, he worked as a postdoc first with Zhang-Jie Shi at Peking University and then with John Hartwig at UC Berkeley, during which his research mainly focused on transition-metal-catalyzed functionalization of C–H bonds. In May 2020, Bo joined the faculty of the State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy at Nankai University to start his independent research career. His current research interests mainly focus on transition-metal-catalyzed carbon–heteroatom bond-forming reactions, asymmetric catalysis, and total synthesis of biologically active natural products and drug candidates. Yu-Shen Zhu (right) obtained his BSc and MSc in chemistry from Zhengzhou University in 2021. In the same year, he joined the Su research group at Nankai University. His research focuses on transition-metal-catalyzed asymmetric synthesis.

In recent years, significant progress has been made in the development of enantioselective 1,2- and 1,1-borylamination reactions (Scheme [1b], left).[6] [7] For instance, in 2013, Miura and Hirano reported the first copper-catalyzed enantioselective 1,2-borylamination of alkenes. More recently, in 2020, Engle and Liu introduced the enantioselective 1,1-borylamination of terminal alkynes. Despite these advancements, the development of enantioselective distal borylamination reactions,[7e] such as 1,3- or 1,4-borylaminations remains a challenge (Scheme [1b], right). The primary obstacles are achieving the necessary reactivity and controlling the chemo-, site-, and enantioselectivity.

Building on our interest in developing novel borylative functionalization reactions,[8] [9] we initiated a study to establish an enantioselective distal borylamination reaction. After several unsuccessful attempts to achieve 1,4-borylamination of 1,3-diene substrates, we shifted our focus to arylidenecyclopropanes (ACPs), a distinct class of C4-synthons. While transition-metal-catalyzed ring-opening and functionalization strategies have shown promise for incorporating functionalities at distal positions,[10,11] enantioselective reactions remain relatively rare,[12] primarily limited to allylic mono-functionalization, as well as diamination[12c] and diboration[13] at the 1,3- or 1,4-positions (Scheme [1c]). Here, we report our recent achievement in enantioselective 1,4-borylamination through a copper-catalyzed four-component cascade hydroborylation and hydroamination of ACPs (Scheme [1d]). This reaction proceeded in good yields with excellent chemo-, site-, and enantioselectivity. The synthetic utility of the obtained 1,4-borylaminated products was demonstrated through the synthesis of a diverse range of enantioenriched cyclic amine scaffolds, which serve as core structures in numerous pharmaceuticals.

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Scheme 1 Catalytic enantioselective borylamination reactions

We selected ACP 1a as the model substrate to explore suitable conditions for enantioselective 1,4-aminoboration (Table [1]). After extensive screening, we found that the desired ring-opened 1,4-borylaminated product 3a could be obtained in good yield and with high enantiomeric excess (93% yield and 99% ee) when the reaction was conducted with Cu(OAc)2 as the catalyst, in combination with the bidentate ligand DTBM-Segphos, HBpin as the boron source, and O-benzoyl-N,N-dibenzylhydroxylamine as the amine reagent in THF at room temperature (entry 1). In comparison, other bidentate phosphine ligands, such as L2–5, did not promote the reaction, resulting in only the ring-opened borylated alkene intermediate mono-B (entry 2). When the substituted aryl group of the amine reagent 2a was replaced with a less sterically hindered phenyl group, the yield dropped to 51%, while maintaining high enantioselectivity (entry 3). Decreasing the number of equivalents of 1a and HBpin or changing the concentration also resulted in lower conversion (entries 4 and 5). Silane was found to be crucial for the reaction: in the absence of silane, only the intermediate mono-B and the diborylated by-product di-B were formed (entry 6) (for details of the role of silane, see below).

Table 1 Conditions Optimizationa

a Reaction was conducted with 1a (0.13 mmol), 2a (0.1 mmol), HBpin (0.13 mmol), Cu(OAc)2 (5 mol%), L (6 mol%), (MeO)2MeSiH (2.0 equiv), KO t Bu (5 mol%), THF (1.0 mL), rt, 48 h. The yield was determined by 1H NMR analysis with 1,3,5-(MeO)3C6H3 as internal standard, and the ee was determined by chiral HPLC analysis.

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Scheme 2 Scope of the copper-catalyzed enantioselective 1,4-borylamination reaction. a Reaction was conducted with 1 (0.13 mmol), 2 (0.1 mmol), HBpin (0.13 mmol), (MeO)2MeSiH (0.2 mmol), yields refer to isolated yields, yields in parenthesis refer to NMR yields (with CH2Br2 as internal standard) of 3, and ee was determined by HPLC analysis.

With the optimal conditions in hand, we explored the scope of both the ACP and amine components (Scheme [2]). A wide range of ACPs, bearing aryl groups with varied electronic properties, underwent ring-opening borylative amination with excellent site-selectivity, consistently yielding the corresponding 1,4-borylaminated products with high yields and enantioselectivity. However, due to the instability of some of the 1,4-borylaminated products 3 during column purification, isolated yields were occasionally lower than those determined by 1H NMR analysis of the crude reaction mixtures. In these cases, the products were isolated and characterized after in-situ oxidation of the boryl group. The reaction exhibited broad functional group tolerance, accommodating alkyloxy (1e, 1l, 1q, and 1u), alkylthio (1f), trifluoromethylthio (1g), trifluoromethyl (1i and 1n), halide (1k and 1p), and ester (1o) groups. ACPs with both electron-rich and electron-poor aryl groups produced products with exceptionally high enantiomeric excess values. Furthermore, methylenecyclopropanes featuring heteroaryl groups, including quinoline, pyridine, and thiophene (1v–x), were also compatible with the reaction. However, for reasons that remain unclear, the pyridine-containing substrate led to the borylaminated product with a moderate enantioselectivity of 61% ee. Notably, although alkyl-substituted methylenecyclopropane easily underwent ring-opening borylation, the resulting borylated alkene intermediate did not proceed with the subsequent hydroamination due to the low reactivity of the internal alkene. We then investigated the effect of substituents on the electrophilic amine component. Besides the N,N-dibenzyl-based hydroxylamine ester 2, those with substituted benzyl groups (e.g., Br, Cl, Me, iPr) were also compatible, yielding the desired 1,4-borylaminated products 3y–zc in good yields and with high enantioselectivity (96–99% ee). Additionally, a cyclic (morpholine) and a dialkyl-substituted amine reagents were tested, resulting in efficient and enantioselective formation of products 4zd and 4ze. The absolute configurations of the 1,4-borylaminated products 3 were determined by analogy to compound 4b, the configuration of which was unequivocally determined through X-ray crystal structure analysis (4b: CCDC 2374499).[14]

To demonstrate the synthetic utility of the enantioenriched 1,4-borylaminated products 3, we conducted a series of transformations of the newly introduced distal boryl and amino groups (Scheme [3]). These transformations highlight the value of the products as highly versatile chiral synthons for constructing structurally diverse scaffolds, commonly found in top-selling pharmaceuticals and biologically active drug candidates.[1] [15] [16] For example, oxidation of the boryl group in 3b, followed by palladium-catalyzed debenzylation and in-situ protection of the amine with Boc2O, led to the formation of enantiopure 4-aminoalcohol derivative 5. Conversion of the hydroxyl group in 5 into a methylsulfonate allows for intramolecular SN2-substitution under basic conditions, yielding the 2-phenyl pyrrolidine derivative 6.[17] This core structure is found in several top-selling drugs approved by the US FDA, including Larotrectinib (used for treating TRK fusion cancer) and Ombitasvir.[2] Compound 5 can also be transformed into the enantiopure 4-phenyl pyrrolidone unit 7 under oxidative conditions.[18] Homologation of 3b, followed by oxidation, yielded the 5-aminoalcohol 8,[9b] [19] which serves as a precursor to the core skeletons of valuable 6-arylpiperidine drugs, such as lptacopan, Avacopan, and Valbenazine.[2] [16] In addition, oxidizing the boryl group in 3p to a hydroxyl group, followed by intramolecular SNAr substitution, resulted in the formation of the tetrahydrobenzoxepine motif 9. Furthermore, Zweifel-vinylation gave the 6-amino alkene 10,[19] which is a valuable precursor for synthesizing 2,6-disubstituted piperidine and 2-phenyl seven-membered N-heterocycles.[20]

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Scheme 3 Transformations of the products to synthesize common pharmaceutical scaffolds

To understand the operative reaction pathway, key intermediates, and the origins of the high chemo- and site-selectivity, we carried out a series of mechanistic experiments (Scheme [4]). Monitoring the full reaction profile showed that the reaction proceeds through two distinct processes: a rapid ring-opening hydroborylation reaction and a slower hydroamination reaction (Scheme [4a]). ACP 1b was fully converted into the ring-opened intermediate mono-B (E/Z = 1.4:1) within one hour, after which both isomers of mono-B slowly underwent regioselective and enantioconvergent hydroamination to produce the 1,4-borylaminated product 3b.[12c] [21]

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Scheme 4 Preliminary mechanistic studies

To probe the origins of the observed high chemo- and site-selectivity, we measured the initial rates of the individual steps involved in the cascade reaction (Scheme [4b] and 4c). The results showed that the ring-opening hydroborylation of ACP 1b occurred approximately 12 times faster than the corresponding hydroamination, implying that the ring-opened primary alkyl-Cu species reacts with the boron reagent (HBpin) more rapidly than with the electrophilic amine reagent. This explains the chemoselectivity observed during the initial ring-opening hydrofunctionalization step. The subsequent hydroamination of mono-B proceeded about 88 times faster than the competing hydroborylation process, indicating the secondary alkyl-Cu species generated during the hydrocupration of mono-B preferentially undergoes amination rather than borylation, thus clarifying the chemoselectivity in the hydrofunctionalization of the ring-opened intermediate mono-B. The remarkably high reactivity of the primary alkyl-Cu towards borylation and the secondary alkyl-Cu towards amination together account for the high site-selectivity observed in the cascade 1,4-borylamination reaction.

To understand the indispensable role of silane in this cascade reaction, we compared the initial rates of hydroamination of mono-B with and without silane (Scheme [4c]) and found that hydroamination of mono-B occurred about 300 times faster with silane than without it. Although the exact rate-accelerating role of silane remains unclear at this stage, it probably activates the electrophilic amine or facilitates the regeneration of the Cu-H species, ultimately enhancing the overall efficiency of the cascade reaction.[22] [23]

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Scheme 5 Proposed catalytic cycle

Based on reported studies[12c] [13a] [24] [25] and our preliminary mechanistic studies, we propose a mechanism that involves two interconnected catalytic cycles (Scheme [5]). The [Cu*]-H species,[22,26,27] generated in the presence of copper salt, chiral ligand, and hydride reagents, initiates the ring-opening hydroborylation cycle through regioselective hydrocupration of APC 1,[12c] [13a] resulting in the formation of alkyl-Cu intermediate I. This intermediate then undergoes β-carbon elimination to produce the primary alkyl-Cu species II, which selectively reacts with HBpin via σ-bond metathesis to yield the borylated intermediate mono-B and regenerate the [Cu*]-H species.[10c] [28] In the subsequent hydroamination cycle, mono-B undergoes regio- and enantioselective hydrocupration,[24] forming the chiral secondary alkyl-Cu species III. This species preferentially reacts with the hydroxylamine ester 2, leading to the formation of the final 1,4-borylaminated product 3 and the copper intermediate ArCO2[Cu*]. Finally, this copper intermediate reacts with silane reagents to regenerate the [Cu*]-H catalyst.

In summary, we have developed an enantioselective 1,4-borylamination through an unprecedented copper-catalyzed four-component cascade hydroborylation and hydroamination reaction. The distal boryl and amino groups provide a versatile platform for the rapid construction of structurally diverse chiral amine-containing scaffolds, which are prevalent in natural products, pharmaceuticals, and drug candidates. Mechanistic studies showed that the high chemo- and site-selectivity observed in the 1,4-borylamination stems from the distinct reactivity of primary alkyl-Cu towards borylation and secondary alkyl-Cu towards amination.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Bo Su
State Key Laboratory of Medical Chemical Biology and College of Pharmacy, Nankai University
38 Tongyan Road, Jinnan District, Tianjin, 300350
P. R. of China   

Publication History

Received: 05 February 2025

Accepted after revision: 06 March 2025

Article published online:
09 April 2025

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   Permissions and Reprints All articles of this category
Zoom Image
Bo Su (left) received his BSc in chemistry from Zhengzhou University in 2008 and his Ph.D. in synthetic chemistry from Nankai University in 2013. After graduation, he worked as a postdoc first with Zhang-Jie Shi at Peking University and then with John Hartwig at UC Berkeley, during which his research mainly focused on transition-metal-catalyzed functionalization of C–H bonds. In May 2020, Bo joined the faculty of the State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy at Nankai University to start his independent research career. His current research interests mainly focus on transition-metal-catalyzed carbon–heteroatom bond-forming reactions, asymmetric catalysis, and total synthesis of biologically active natural products and drug candidates. Yu-Shen Zhu (right) obtained his BSc and MSc in chemistry from Zhengzhou University in 2021. In the same year, he joined the Su research group at Nankai University. His research focuses on transition-metal-catalyzed asymmetric synthesis.
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Scheme 1 Catalytic enantioselective borylamination reactions
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Scheme 2 Scope of the copper-catalyzed enantioselective 1,4-borylamination reaction. a Reaction was conducted with 1 (0.13 mmol), 2 (0.1 mmol), HBpin (0.13 mmol), (MeO)2MeSiH (0.2 mmol), yields refer to isolated yields, yields in parenthesis refer to NMR yields (with CH2Br2 as internal standard) of 3, and ee was determined by HPLC analysis.
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Scheme 3 Transformations of the products to synthesize common pharmaceutical scaffolds
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Scheme 4 Preliminary mechanistic studies
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Scheme 5 Proposed catalytic cycle