“Click” Tetradentate Nitrogen Donor Ligands for Nonheme Iron-Catalyzed Asymmetric Epoxidation Reactions

Bo Cao; Xiang Wen; Jie Chen; Bin Wang

doi:10.6023/cjoc202503031

Chinese Journal of Organic Chemistry >

2025 , Vol. 45 >Issue 12: 4490 - 4496

DOI: https://doi.org/10.6023/cjoc202503031

ARTICLES

“Click” Tetradentate Nitrogen Donor Ligands for Nonheme Iron-Catalyzed Asymmetric Epoxidation Reactions

Bo Cao ,
Xiang Wen ,
Jie Chen ^,^* ,
Bin Wang ^,^*

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School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022

^* chm_chenj@ujn.edu.cn;

chm_wangb@ujn.edu.cn

Received date: 2025-03-31

Revised date: 2025-05-08

Online published: 2025-06-06

Supported by

National Natural Science Foundation of China(22372071)

Taishan Scholar Program of Shandong Province(tsqn202408209)

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Abstract

Leveraging the modularity and efficiency of click chemistry, a series of chiral diamine-triazole tetradentate nitrogen donor ligands and their corresponding nonheme iron complexes were synthesized. These iron-based catalysts demonstrated excellent catalytic activity and enantioselectivity in the asymmetric epoxidation of electron-deficient olefins using H₂O₂ as the terminal oxidant.

Key words： biomimetic catalysis; nonheme iron complexes; asymmetric epoxidation; click chemistry

Cite this article

Bo Cao , Xiang Wen , Jie Chen , Bin Wang . “Click” Tetradentate Nitrogen Donor Ligands for Nonheme Iron-Catalyzed Asymmetric Epoxidation Reactions[J]. Chinese Journal of Organic Chemistry, 2025 , 45(12) : 4490 -4496 . DOI: 10.6023/cjoc202503031

1 Introduction

The discovery of efficient and selective catalytic systems for enantioselective epoxidation of olefins is of paramount importance in synthetic chemistry, as epoxides serve as highly versatile intermediates for the synthesis of a wide variety of biologically active molecules and fine chemicals.^[1] Significant advancements have been achieved in the exploration and development of diverse catalytic systems during the past few decades, including transition metal catalysis, photocatalysis, electrocatalysis, and organocatalysis.^[2] Despite these advances, several critical challenges still remain, including the design of highly active catalytic systems capable of achieving efficient and selective conversion of substrate, as well as the utilization of non-noble metals and environmentally friendly oxidants, such as molecular oxygen (O₂) and hydrogen peroxide (H₂O₂).

Nature has evolved a number of remarkable heme and nonheme iron oxygenases, which may hold the key to a solution.^[3-4] For instance, cytochrome P450 and Fe^II/α- ketoglutarate (αKG)-dependent oxygenases are capable of efficiently and selectively oxidizing olefins to epoxides under mild conditions, such as ambient temperature and pressure, through the activation of O₂.^[3-4] Mechanistic studies have revealed that high-valent iron-oxo species, such as iron(IV)-oxo porphyrin π-cation radicals and high- spin (S=2) iron(IV)-oxo complexes, are the reactive intermediates in these catalytic processes.^[3-4] Inspired by the structural features of the active sites of nonheme iron oxygenases and their catalytic reaction mechanisms, a wide range of biomimetic Mn and Fe complexes supported by chiral tetradentate N4 ligands (Figure 1A) with cis-α configuration have been prepared and applied in high-valent metal-oxo (Figure 1B) mediated asymmetric oxidation reactions.^[5-7] The primary coordination sphere, where ligands are covalently bound to the metal center, not only determines the fundamental properties of the catalytic metal center, such as the geometry, Lewis acidity, and electronic structure, but also stabilizes the catalytic metal center and provides a chiral coordination environment.^[8] Consequently, ligand modification has become the most powerful tool for optimizing these biomimetic catalysts, and significant efforts in the communities of bioinorganic chemistry and catalysis have focused on designing and synthesizing new ligands.^[9-11] However, the availability of chiral tetradentate nitrogen donor ligands remains limited, with most of them based on chiral diamine-pyridine,^[9-10] diamine- benzimidazole,^[11] and diamine-oxazoline^[12] frameworks (Figure 1A). The limited methods for modifying these ligand skeletons result in restricted synthetic variations of these chiral tetradentate nitrogen donor ligands. Therefore, it is necessary to develop a new type of readily available and modifiable chiral tetradentate N4 ligand and an efficient method for its construction.

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Figure 1 Selected examples of chiral tetradentate N4 ligands and proposed mechanism for nonheme metal-catalyzed asym- metric epoxidation reaction

“Click chemistry” represents a category of chemical transformations with high efficiency, high selectivity, and modular nature, which proceed with remarkable rapidity under mild conditions to yield stable molecular architectures.^[13] These reactions are characterized by high atom economy and functional group compatibility, making them widely applicable in fields such as chemical synthesis, materials science, and biomedicine. Sharpless and co- workers^[14] coined the term “click chemistry” to describe the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, which generates 1,2,3-triazoles. This reaction has sparked increasing interest in the design of nitrogen-based ligands due to the versatility and stability of the triazole products. Therefore, the click strategy is considered an ideal approach for constructing novel tetradentate nitrogen ligands, as it enables the concise and efficient synthesis of a wide variety of such ligands from commercially available azides and alkynes.

Herein, we report the “click” synthesis of C₂-symmetric chiral diamine-triazole tetradentate nitrogen donor ligands. To demonstrate their application in asymmetric catalysis, nonheme manganese complexes bearing these chiral diamine-triazole ligands have been employed in the epoxidation of α,β-unsaturated ketones and α,β-unsaturated carboxylates using H₂O₂ as the terminal oxidant. Remarkably, the reactions achieved up to 99% yield and 94% enantiomeric excess (ee), demonstrating the high efficiency and enantioselectivity of these catalysts.

2 Results and discussion

Initially, a range of diamine-triazole tetradentate N4 ligands (L5~L10) based on different chiral diamine back- bones (e.g., (1R,2R)-1,2-diaminocyclohexane, (1R,2R)-1,2- diphenylethylenediamine, (2S,2'S)-2,2'-bi-pyrrolidine, and (2S,2'S)-2,2'-bipiperidine) were synthesized through a two- step, one-pot “click” reaction (Figure 2A).^[15] These ligands can be easily synthesized in multigram scale and do not require column chromatography purification, thus making this process concise and efficient. Subsequently, the corresponding nonheme iron complexes (Figure 2B, C1~C6) were prepared by reacting equimolar amounts of the linear N4 ligands with iron(II) triflate. Single crystals suitable for X-ray inspection were obtained by slowly diffusing anhydrous diethyl ether into tetrahydrofuran/dichloromethane (V∶V=2∶1) solutions of complexes C1 and C4 (Figure 2B). It is revealed that the chiral diamine-triazole ligands dictate the ∆-cis-α configuration of the octahedral iron center (Figure 2B).^[16] The two triazole moieties coordinate in a trans manner, while the two N—Me groups adopt an anti-conformation (Figure 2B). The remaining two cis- coordination sites, which are labile and trans to the aliphatic tertiary amines, are occupied by either a hydroxide ion or a triflate ion in the solid state (Figure 2B). In addition, the average bond lengths of Fe—N_diamine and Fe—N_triazole for [Fe(R,R-L5)(OH)₂] and [Fe(R,R-L8)(OH)(OTf)] are similar, ranging between 0.214 and 0.227 nm, characteristic of high-spin iron(II) complexes.^[17]

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Figure 2 “Click” synthesis of chiral diamine-triazole ligands and the corresponding nonheme iron(II) complexes.

X-ray crystal structures of [Fe(R,R-L5)(OH)₂] and [Fe(R,R- L8)(OH)(OTf)] as an ORTEP drawing with 30% probability ellipsoids (Fe, aquamarine; N, new midnight blue; O, red; F, yellow green; S, yellow, C, black). Selected bond distances (nm) for [Fe(R,R-L5)(OH)₂]: Fe(1)—N(1)=0.2164(7), Fe(1)—N(2)=0.2259(6), Fe(1)—N(3)=0.2236(7), Fe(1)—N(4)=0.2188(7); for [Fe(R,R-L8)(OH)(OTf)]: Fe(1)—N(1)=0.2156(6), Fe(1)—N(2)=0.2278(6), Fe(1)—N(3)=0.2259(6), Fe(1)—N(4)=0.2130(6).

To demonstrate the application potential of the above nonheme iron complexes supported by chiral diamine-tria- zole ligands, we evaluated their catalytic activity in the asy- mmetric epoxidation of olefins using chalcone as a model substrate in the presence of acetic acid (Table 1). At room temperature, the complex C1 derived from (1R,2R)-1,2-di- aminocyclohexane achieved a yield of 93% and an enantiomeric excess (ee) of 75% (Table 1, Entry 1). Replacing the phenyl group at the 1-position of the triazole with 2,6-dimethylphenyl or 4-methoxyphenyl groups resulted in decreased yield and ee value of the epoxide product (Table 1, Entries 2 and 3). Therefore, further optimization focused solely on the chiral diamine backbone, without modifying the phenyl group at the 1-position of the triazole. It was found that replacing the (1R,2R)-1,2-diaminocyclohexane backbone with (1R,2R)-1,2-diphenylethylenediamine, (2S, 2'S)-2,2'-bipyrrolidine, or (2S,2'S)-2,2'-bipiperidine did not improve the yield or enantioselectivity (Table 1, Entries 4~6). After confirming that complex C1 was the optimal catalyst, the effect of reaction temperature was investigated (Table 1, Entries 7~9). Lowering the temperature significantly enhanced both the yield and enantioselectivity of the epoxide product. Lowering the temperature from room temperature to－30 ℃ afforded a yield of 99% and an ee of 84% (Table 1, Entry 9). Furthermore, the effect of carboxylic acids was examined (Table 1, Entries 10~16). It was shown that replacing acetic acid with steric bulkier carboxylic acids improved the enantioselectivity of the epoxide product. Among them, eba achieved a yield of 99% and an ee of 91% (Table 1, Entry 10). In contrast, chiral carboxylic acids were found to be detrimental to both the yield and ee value (Table 1, Entries 15 and 16). These experimental results demonstrated that, in the enantioselectivity-deter- mining step, the carboxylic acid molecule acts as an auxiliary ligand and participates in the active intermediate.^[5] That is, the carboxylic acid facilitates the heterolytic cleavage of the O—O bond in the putative iron(III)-hydro- peroxide species via hydrogen bonding, thereby generating the catalytically active iron(V)-oxo carboxylate intermediate (Figure 1B).^[5]

Table 1 Optimization of reaction conditions^a

Entry	Cat.	Temp./℃	Acid	Yield^b/%	ee^c/%
1	C1	r.t.	HOAc	93	75
2	C2	r.t.	HOAc	76	57
3	C3	r.t.	HOAc	81	61
4	C4	r.t.	HOAc	84	64
5	C5	r.t.	HOAc	86	72
6	C6	r.t.	HOAc	85	70
7	C1	0	HOAc	98	80
8	C1	－20	HOAc	99	82
9	C1	－30	HOAc	99	84
10^d	C1	－30	eba	99	91
11^d	C1	－30	2-eha	99	86
12^d	C1	－30	cxa	99	73
13^d	C1	－30	dmba	78	73
14^d	C1	－30	aca	81	68
15^d	C1	－30	(S)-2-mba	25	56
16	C1	－30	(S)-Ibuprofen	54	73

^a Reaction conditions: 3.0 equiv. of H₂O₂ [diluted from 30% (w) H₂O₂ solution with acetontrile] was added dropwise via a syringe pump over a period of 0.5 h to a vigorously stirred acetonitrile solution of Fe complex (1.0 mol%), 1a (0.5 mmol), and acid (2.5 mmol).^b Isolated yield. ^c Determined by HPLC analysis on a chiral stationary. ^d eba=2-ethylbutanoic acid, 2-eha=2-ethylhexanoic acid, cxa=cyclohexanecarboxylic acid, dmba=2,2-dimethylbutanoic acid, aca=1-adamantanecarboxylic acid, (S)-2-mba=(S)-2-methylbutanoic acid.

After establishing the optimal reaction conditions, the substrate scope of this catalytic system was investigated (Table 2). Firstly, this catalytic system demonstrated excellent compatibility with chalcones, achieving the target disubstituted α,β-epoxyketones with up to 99% yield and 94% ee (Table 2, Entries 1~11). The reaction proceeded smoothly regardless of the electronic properties of substituents on either the phenyl ring adjacent to the C=C double bond (Table 2, Entries 1~5) or the phenyl ring directly connected to the carbonyl group (Table 2, Entries 6~10), consistently delivering excellent yields and ee values. However, replacing the phenyl group on the carbonyl side with a 2-naphthyl group resulted in a substantial reduction in enantioselectivity (Table 2, Entry 11). The enantioselective epoxidation of trisubstituted α,β-enones enables the construction of a chiral quaternary carbon center bearing an oxygen atom. The presented catalytic system has been demonstrated to be effective for the enantioselective epoxidation of such trisubstituted α,β-enones (Table 2, Entries 12~15). High yields and moderate to high ee values were achieved for trisubstituted exocyclic enones with different ring sizes (Table 2, Entries 12~15), although the enantioselectivity significantly decreased as the ring size increased. Additionally, trisubstituted enones containing O-heterocycles proceeded smoothly, yielding moderate ee values (Table 2, Entry 14). On the other hand, the epoxidation of acyclic β,β-disubstituted enone 16a resulted in a relatively low ee value (Table 2, Entry 16), probably due to the steric repulsion at the β-carbon atom and the resulting reduction in the electrophilicity of the C=C double bond.^[18] Therefore, the development of enantioselective epoxidation methods for acyclic β,β-disubstituted enones remains a formidable challenging in synthetic chemistry. Furthermore, this catalytic system is also applicable to the asymmetric epoxidation of trans-cinnamic esters, delivering excellent yields and high ee values (Table 2, Entries 17~22).

Table 2 Substrate scope of epoxidations^a

Entry	Substrate	Yield^b/%	ee^c/%

1	1a: R¹=R²=C₆H₅	99	91
2	2a: R¹=p-MeC₆H₄, R²=C₆H₅	99	94
3	3a: R¹=p-FC₆H₄, R²=C₆H₅	99	93
4	4a: R¹=p-ClC₆H₄, R²=C₆H₅	99	92
5	5a: R¹=p-BrC₆H₄, R²=C₆H₅	99	93
6	6a: R¹=C₆H₅, R²=p-MeOC₆H₄	96	82
7	7a: R¹=C₆H₅, R²=p-MeC₆H₄	98	85
8	8a: R¹=C₆H₅, R²=p-FC₆H₄	99	91
9	9a: R¹=C₆H₅, R²=p-ClC₆H₄	99	90
10	10a: R¹=C₆H₅, R²=p-BrC₆H₄	99	90
11	11a: R¹=C₆H₅, R²=2-naphthyl	94	83
12		89	87
13		95	89
14		82	52
15		92	66
16		75	19

17	17a: R¹=C₆H₅, R²=Me	99	87
18	18a: R¹=C₆H₅, R²=Et	99	90
19	19a: R¹=o-ClC₆H₄, R²=Et	99	92
20	20a: R¹=m-ClC₆H₄, R²=Et	99	91
21	21a: R¹=p-ClC₆H₄, R²=Et	99	93
22	22a: R¹=p-BrC₆H₄, R²=Et	99	92

^aReaction conditions: 3.0 equiv. of H₂O₂ [diluted from 30% (w) H₂O₂ solution with acetonitrile] was added dropwise via a syringe pump over a period of 0.5 h to a vigorously stirred acetonitrile solution of C1 (1.0 mol%), 1a~22a (0.5 mmol), and eba (2.5 mmol) at －30 ℃, total reaction time was 0.5 h. ^b Isolated yield. ^c Determined by HPLC analysis on a chiral stationary.

3 Conclusions

In summary, a series of chiral diamine-triazole ligands through “click” chemistry has been efficiently synthesized. The corresponding nonheme iron complexes demonstrated excellent catalytic activity and enantioselectivity in the asymmetric epoxidation of di- and trisubstituted enones, as well as trans-cinnamic esters. This work highlights the potential of “click” chemistry in the design and synthesis of chiral ligands for asymmetric catalytic transformations. Future study will focus on elucidating the reaction mechanism of the epoxidation reaction through the synthesis, spectroscopic characterization, and kinetics studies of high- valent iron-oxo intermediates. Additionally, efforts will be directed toward applying nonheme metal complexes bearing chiral diamine-triazole ligands to other types of biomimetic asymmetric oxidation reactions.

4 Experimental section

4.1 General information

All reactions were performed under argon atmosphere using dried solvent and standard Schlenk techniques unless otherwise noted. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates. Flash column chromatography was performed on silica gel (particle size 200~300 mesh) and eluted with petroleum ether/ethyl acetate. H₂O₂ (w=30%) was purchased from Energy Chemical (Shanghai, China). Fe(CF₃SO₃)₂•(CH₃CN)₂ was synthesized by reacting iron powder with trifluoromethane- sulfonic acid (CF₃SO₃H) under inert atmosphere in H₂O, and then recrystallized with CH₃CN/Et₂O.^[19]

NMR spectra were recorded on a Bruker AVQ-400 (400 MHz for ¹H; 101 MHz for ¹³C) or a AVANCE III HD-600 (600 MHz for ¹H; 151 MHz for ¹³C). The chemical shifts (δ) are relative to CDCl₃ (δ 7.26 for ¹H) or TMS (δ 0 for ¹H) and CDCl₃ (δ 77.0 for ¹³C). High-resolution mass spectra (HRMS) data were obtained with Thermo LTQ-FTICR (ESI) mass spectrometers. For X-ray structural analysis, crystallographic data collections were carried out on a Bruker SMART AXS diffractometer equipped with a monochromator in the Mo Kα (λ=0.071073 nm) incident beam. Chromatographic resolution of enantiomers was performed on a High Performance Liquid Chromatography (HPLC, Agilent 1260 Infinity II) equipped with a diode array detector (G7115A). Melting points were recorded using a X-5 Micro melting point instrument (Beijing Tech Instrument Co., LTD.). Optical rotation was measured on a Rudolph-Autopol IV Polarimeter.

4.2 General procedure for ligand synthesis

(1R,2R)-N,N′-Dimethylcyclohexane-1,2-diamine (10 mmol, 1.42 g) was dissolved in 15 mL of tetrahydrofuran (THF), followed by the addition of anhydrous K₂CO₃ (30 mmol, 4.15 g). The mixture was stirred at 10 ℃ for 20 min. Propargyl bromide (22 mmol, 2.62 g) was dissolved in 6.0 mL of THF, and this solution was added dropwise to the reaction mixture over 1.0 h. The reaction was continued at 10 ℃ for 12 h. The reaction mixture was filtered, and the filtrate was collected. Under a nitrogen atmosphere, the filtrate was transferred to a 100 mL tube. Phenyl azide (30 mmol, 3.57 g), copper(I) iodide (10 mmol, 1.90 g), and 6.0 mL of triethylamine were added to the tube. The mixture was stirred in the dark for 24 h. After completion, the mixture was filtered, and the filtrate was collected. The solvent was removed under reduced pressure. Saturated brine was added to the residue, and the mixture was extracted with dichloromethane. The organic phase was collected and dried over anhydrous sodium sulfate. The dried organic phase was filtered, and the solvent was evaporated. The resulting solid was washed first with acetonitrile and then with petroleum ether, yielding (R,R)-N,Nʹ-dimethyl-N,Nʹ-bis((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)cyclohe-xane-1,2-diamine (L5) as a yellow solid (2.8 g, 6.1 mmol, 61% yield). m.p. 123.4~124.8 ℃; R_f=0.20 [V(petroleum ether)∶V(DCM)∶V(TEA)=1∶1∶0.01];