Enantioselective synthesis of C–C and C–N axially chiral pyrazole-based heterobiaryls

Abstract

Axially chiral five-membered heteroaryls are prevalent in bioactive molecules. Their catalytic asymmetric synthesis remains challenging due to their relatively low rotational energy barriers. We developed a chiral nickel(II) complex-catalyzed asymmetric cycloaddition/oxidation sequential reaction of hydrazonoyl chlorides with α,β-unsaturated enones, which involves asymmetric [3 + 2] 1,3-dipolar cycloaddition of hydrazonoyl chlorides with α,β-unsaturated enones followed by oxidation to realize central-to-axial chirality transfer. A class of pyrazole-based heterobiaryls were prepared efficiently with high yields and good enantioselectivities. Based on the mechanistic study and control experiments, a possible mechanism was proposed to elucidate the reaction process and enantioinduction.

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Introduction

Atropisomers are widely spread in natural products,¹ drug molecules,² materials science,³ and asymmetric catalysis.⁴ Consequently, the catalytic enantioselective synthesis of atropisomers has emerged as a prominent research hotspot within the domain of asymmetric synthesis.⁵ Among the diverse classes of atropisomers, six-membered axially chiral (hetero)biaryls, linked via C–C axes, represent the most prevalent and well-established structural scaffolds.⁶ In contrast, the catalytic asymmetric construction of axially chiral five-membered (hetero)biaryls is relatively less developed (Scheme 1a).⁷ This research gap primarily stems from the inherent characteristics of five-membered systems, their lower rotational barriers and diminished configurational stability, which collectively hinder effective stereocontrol during synthesis.⁸ In recent years, significant progress has been made in addressing this challenge, with the successful catalytic asymmetric synthesis of axially chiral five–six-membered heterocyclic frameworks, such as aryltriazoles,⁹ arylimidazoles,¹⁰ arylisothiazoles,¹¹ arylfurans,¹² and arylpyrroles.¹³ Despite this advancement, the catalytic asymmetric construction of five–five-membered heteroaromatic skeletons remains comparatively underreported; existing studies also tend to focus narrowly on systems with C–C or N–N axes.¹⁴ To the best of our knowledge, only a limited number of reports have thus far described the catalytic asymmetric synthesis of C–N axially chiral five–five-membered heteroaromatic scaffolds.^9e,12f,15

Scheme 1 Background of synthesis of axially chiral pyrazoles.

Arylpyrazole derivatives, representing a class of five-membered heteroaryl atropisomers, are frequently encountered in natural products, biologically active compounds and chiral ligands (Scheme 1b).¹⁶ For the synthesis of axially chiral arylpyrazoles, the Li group,^17a the Tang group^17b and others,^17c–h developed an organocatalytic and Pd-catalyzed C–H arylation strategy. Recently, Huang and coworkers have successfully constructed pyrazole-indole scaffolds featuring both C–C axial chirality and central chirality, utilizing a dynamic kinetic resolution (DKR) strategy.¹⁷ⁱ In 2023, the Wang group synthesized axially chiral arylpyrazole atropisomers containing a phosphorus unit through a De novo pyrazole synthesis via the Huisgen-cycloaddition/aromatization cascade reaction (Scheme 1c).^17j Despite these notable advances, the development of five–five-membered pyrazole-based heterobiaryls with a C–N chiral axis remains unreported.

Arylhydrazonoyl chlorides are well-documented as 1,3-dipole species and serve as effective precursors for dihydropyrazole synthesis.¹⁸ We hypothesized that reacting sterically hindered aryl-substituted unsaturated ketones with arylhydrazonoyl chlorides in the presence of a chiral Lewis acid would trigger an asymmetric 1,3-dipolar cycloaddition. This reaction would yield centrally chiral dihydropyrazoles, which could then undergo oxidation to form axially chiral arylpyrazoles via a central-to-axial chirality transfer process.¹⁹ This strategy would thereby provide a novel approach for the synthesis of axially chiral pyrazole derivatives.

Herein, we report a chiral N,N′-dioxide/Ni(II) complex-catalyzed asymmetric [3 + 2] cycloaddition/oxidation sequential reaction,²⁰ which enables the versatile and efficient construction of two distinct classes of axially chiral arylpyrazole atropisomers: C–C-linked five–six-membered systems and C–N-linked five–five-membered systems (Scheme 1d).

Results and discussion

To construct five–six-membered C–C axially chiral arylpyrazole atropisomers, hydrazonoyl chloride A1 and α,β-unsaturated enone B1 were selected as model substrates to optimize the reaction conditions via a one-pot protocol consisting of [3 + 2] cycloaddition followed by DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidation (Table 1). Initially, various metal salts were screened by complexing with N,N′-dioxide L₃-PrPr₂. Most metal salts showed no chiral induction ability, with the exception of Mg(OTf)₂, Co(OTf)₂, and Ni(OTf)₂ though enantioselectivity remained low. The Ni(OTf)₂ complex afforded the target axially chiral pyrazole product C1 in 40% yield with 64 : 36 er (entry 3). Subsequently, the chiral backbone of the ligand was evaluated. (S)-Pipecolic acid-derived L₃-PiEt₂ proved superior to L-proline-derived L₃-PrEt₂ and L-ramipril-derived L₃-RaEt₂ in terms of enantioselectivity (entries 4–6). Further investigations into the ligand's amide moiety revealed that 2,6-diethyl-4-adamantyl benzenamine derived L₃-PiEt₂Ad gave C1 in 23% yield with 77 : 23 er (entry 8). Replacing Et₃N with ⁱPr₂NEt as the base resulted in a slight improvement in both yield and enantiomeric ratio (entry 9). When THF was used as the solvent and the temperature was increased to 40 °C, arylpyrazole product C1 was obtained in 74% yield with 91.5 : 8.5 er (entry 10). Increasing the loadings of B1 and ⁱPr₂NEt, combined with performing the oxidation in EtOAc at 10 °C, further enhanced enantioselectivity while preserving yield (entry 11). Notably, adding a trace amount of H₂O as an additive boosted the yield. C1 was finally produced in 91% yield with 95.5 : 4.5 er (entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	Metal salt	Ligand	Yield^b (%)	er^c
a Unless otherwise noted, all reactions were carried out with A1 (0.1 mmol), B1 (0.1 mmol), metal/ligand (1/1, 10 mol%), Et3N (0.1 mmol) in DCM (1.0 mL) at 30 °C for 24 h under N2 protection. Subsequently, DDQ (0.1 mmol) and CH2Cl2 (0.5 mL) were added, and the reaction mixture was stirred at 30 °C for 3 h. b Isolated yield. c Determined by HPLC analysis. d ^iPr2NEt (0.1 mmol). e THF (0.5 mL) at 40 °C. f A1 (0.14 mmol), ^iPr2NEt (0.14 mmol); EtOAc (1.0 mL) at 10 °C for oxidation. g With 3 μL H2O.
1	Mg(OTf)2	L3-PrPr2	23	53.5 : 46.5
2	Co(OTf)2	L3-PrPr2	17	57.5 : 42.5
3	Ni(OTf)2	L3-PrPr2	40	64 : 36
4	Ni(OTf)2	L3-PrEt2	42	64 : 36
5	Ni(OTf)2	L3-RaEt2	41	70.5 : 29.5
6	Ni(OTf)2	L3-PiEt2	32	73.5 : 26.5
7	Ni(OTf)2	L3-PiEt3	27	75.5 : 24.5
8	Ni(OTf)2	L3-PiEt2Ad	23	77 : 23
9^d	Ni(OTf)2	L3-PiEt2Ad	26	78 : 22
10^d^,^e	Ni(OTf)2	L3-PiEt2Ad	74	91.5 : 8.5
11^d^,^e^,^f	Ni(OTf)2	L3-PiEt2Ad	78	96 : 4
12^d^,^e^,^f^,^g	Ni(OTf)2	L3-PiEt2Ad	91	95.5 : 4.5

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With the optimized reaction conditions established, the substrate scope was investigated (Scheme 2). For hydrazonoyl chlorides, substituting the nitrogen-bonded phenyl group with a p-bromophenyl or p-methoxyphenyl group resulted in lower enantioselectivity (products C1–C3). In contrast, using a p-trifluoromethylphenyl substituent led to a sharp decline in oxidation reactivity—highlighting the critical role of the nitrogen-bonded substituent in the oxidation step (see the SI for details). Both electron-donating and electron-withdrawing substituents on the aromatic ring of hydrazonoyl chlorides were well-tolerated, affording products C4–C9 with enantioselectivities ranging from 78.5 : 21.5 er to 88 : 12 er (C4–C9). Additionally, naphthaldehyde-derived hydrazonyl chloride was compatible with the reaction, yielding the corresponding axially chiral product C10 in 85% yield with 88 : 12 er. Next, the scope of α,β-unsaturated enones B was explored. Various 2-alkoxy substituents were tolerated in the cyclization/oxidation sequence, furnishing target axially chiral products C11–C14 in high yields and good enantioselectivities. Substitution on the 3, 5, 6, or 7-position of the enone scaffold had little effect on the reaction. Notably, when a phenanthryl-substituted enone B12 was employed, enantioselectivity decreased sharply (C21, 74 : 26 er), which might be due to the increased steric hindrance. The absolute configuration of the product C1 was determined to be (R) via single-crystal X-ray diffraction analysis.²¹

Scheme 2 The substrate scope of C–C axially chiral pyrazoles. ^aUnless otherwise noted, all reactions were carried out with A (1.4 equiv.), B (0.1 mmol), Ni(OTf)₂/L₃-PiEt₂Ad (1/1, 10 mol%), ⁱPr₂NEt (1.4 equiv.), H₂O (3 μL) in THF (0.5 mL) at 40 °C for 24 h under N₂ protection. The mixture was subsequently concentrated in vacuo. Then, DDQ (1.0 eq.) and EtOAc (1.0 mL) were added, and the reaction mixture was stirred at 10 °C. ^bH₂O (4 μL).

Next, α,β-unsaturated enone D2 was employed to access five–five-membered C–N axially chiral pyrazoles (Table 2). The one-pot protocols led to challenges in purifying product F2, as deeply colored impurities were generated. Thus, the cycloaddition product E2 was isolated prior to the oxidation step. Initially, K₂CO₃ was used as the base; while the diastereomeric ratio (dr) and enantiomeric ratio (er) of the desired product E2 were excellent (>19 : 1 dr, 99.5 : 0.5 er), the yield was only 43%. Modifying the reaction conditions—switching the solvent from THF to DCM and lowering the temperature from 40 °C to 20 °C—improved the yield of E2 to 92%, with dr and enantiomeric excess (ee) remaining excellent. Subsequently, the dehydrogenative aromatization of pyrazoline to pyrazole was evaluated. Using DDQ alone as the oxidant led to the slow formation of F2, affording the product F2 in 43% yield with 70 : 30 er (entry 1). Notably, the oxidizing capacity of DDQ is significantly enhanced upon visible light excitation;²² leveraging this property, the oxidation of E2 was efficiently achieved using DDQ under blue light irradiation at 20 °C (entry 2). Further accelerating the reaction rate by introducing basic conditions allowed isolation of F2 in 84% yield with 92 : 8 er. Finally, decreasing the temperature to −20 °C and increasing the reaction basicity further improved the enantiomeric ratio to 95 : 5 (entry 4).

Table 2 Optimization of the reaction conditions for construction of C–N axially chiral pyrazoles^a

Entry^a	hv (nm)	Base	Yield^b (%)	er^c
a Unless otherwise noted, all oxidations were performed with E2, base (1.0 equiv.), DDQ (1.5 equiv.) in toluene (0.1 M) under an air atmosphere at 20 °C and under 5 W LED irradiation. b The overall isolated yield of the two steps. c Determined by HPLC analysis on a chiral stationary phase. d At 60 °C. e At −20 °C.
1^d	—	—	43	70 : 30
2	420	—	55	70 : 30
3	420	K2CO3 (0.8 equiv.)	84	92 : 8
4^e	420	Cs2CO3 (1.0 equiv.)	80	95 : 5

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Subsequently, the scope of C–N axially chiral pyrazoles was explored (Scheme 3). For enones with an indolyl tether, modifying the ester group—from methyl to ethyl, isopropyl, or phenyl—had little impact on the reaction performance; cycloaddition products E1–E4 were obtained in 80–92% yield with > 19 : 1 dr and 96:4–97.5 : 2.5 er, while the corresponding oxidized pyrazoles F1–F4 were isolated in 67–82% yield with 95 : 5 er. In contrast, replacing the ester group with a benzenesulfonyl group led to reduced enantioselectivity (E5 and F5). When using enone D6 derived from 2-phenylindole, the cycloaddition product E6 was formed in high yield and enantioselectivity; however, the subsequent oxidation afforded axially chiral product F6 with only 80 : 20 er. A wide range of aryl-substituted hydrazonyl chlorides were also evaluated. Those bearing electron-withdrawing or electron-donating groups were well-tolerated in the sequential cycloaddition/oxidation process, with the exception of p-ethynyl-substituted derivatives. Specifically, cycloaddition products E7–E19 were obtained in 80–96% yields with 9 : 1–19 : 1 dr and 82.5 : 17.5–99.9 : 0.1 er, while the oxidized pyrazoles F7–F19 were isolated in 40–81% yields with 78.5 : 21.5–96 : 4 er. Notably, enones with substituted indole rings, regardless of the electronic properties and positions of the substituents, were compatible with the reaction, furnishing target axially chiral pyrazoles F20-F26 in 56–82% yields with 93.5 : 6.5–95 : 5 er. A limitation emerged, however, when using the enone D14 bearing a pyrrole ring, while the cycloaddition product E27 was formed in 97% yield, it decomposed during oxidation, resulting in only 35% yield of F27. Finally, the absolute configurations of E2 and F2 were determined via single-crystal X-ray diffraction analysis as (4S,5R) and (S),²³ respectively.

Scheme 3 The substrate scope of C–N axially chiral pyrazoles. ^aUnless otherwise noted, all reactions were carried out with A (1.2 equiv.), D (0.1 mmol), Ni(OTf)₂/L₃-PiEt₂Ad (1/1, 10 mol%), and K₂CO₃ (1.2 equiv.) in CH₂Cl₂ (1.5 mL) at 20 °C for 12 h under N₂ protection. Then, after purification on silica gel, E, Cs₂CO₃ (1.0 eq. of E), and DDQ (1.5 eq. of E) in toluene (0.1 M) were reacted under an air atmosphere at −20 °C and under 5 W 420 nm LED irradiation. ^bThe overall isolated yield of the two steps.

Axially chiral diaryl ethers constitute a class of atropisomers characterized by a unique dual C–O axis.²⁴ Their catalytic enantioselective synthesis currently relies predominantly on desymmetrization strategies. Furthermore, axially chiral diaryl ethers incorporating a five-membered heterocyclic framework remain unreported. Building on our current system, we therefore attempted the synthesis of C–O axially chiral pyrazole derivatives (Scheme 4a). Using Ni(NTf₂)₂/L₃-TQMe₂CPh₃ as the catalyst, the asymmetric synthesis of compound E28 was achieved with a 50% NMR yield, >19 : 1 dr and 96 : 4 er.

Scheme 4 Gram-scale synthesis and further transformations.

Subsequent dehydrogenation of E28 in the presence of N-chlorosuccinimide afforded the corresponding C–O axially chiral pyrazole F28 in 30% yield and 64 : 36 er, which might be attributed to the phenoxy group's robust leaving ability coupled with the conformational flexibility imparted by the two C–O bonds throughout the rearomatization process.

To evaluate the synthetic potential of this protocol, scale-up experiments were conducted. Specifically, hydrazonoyl chloride A1 was reacted with α,β-unsaturated enone B1 (3.0 mmol) or D4 (2.0 mmol), affording the target axially chiral pyrazole C1 in 83% yield with 94.5 : 5.5 er and F4 in 64% yield with 94 : 6 er, respectively (Scheme 4b). Subsequently, derivatization studies were performed to expand the synthetic scope. Treatment of C1 with NaBH₄ yielded secondary alcohol G1 in 89% yield with 1.5 : 1 dr and 93.5 : 6.5 er/93 : 7 er. Additionally, compound F4 underwent slow chlorination to form product G2 in 65% yield with 93 : 7 er. To investigate the configurational stability of these axially chiral arylpyrazoles, racemization experiments were carried out to determine the rotational barriers (see the SI for details). For compound C1, the free energy of activation (ΔG^‡) was calculated to be 27.32 kcal mol⁻¹ by monitoring the enantiomeric excess (ee) values at different time intervals at 70 °C. Similarly, the racemization barrier of F4 was measured to be 29.66 kcal mol⁻¹ at 85 °C. The racemization half-life (t_1/2) of both compounds was also determined. At their respective test temperatures, the t_1/2 of compound C1 was calculated to be 3.6 hours, while that of F4 was calculated to be 16.6 hours.

To gain insight into the mechanism of central-to-axial chirality transfer for C–N axially chiral pyrazoles, control experiments were performed (Scheme 5a). Under either nitrogen or oxygen atmospheres, oxidation of E4 resulted in significant decreases in both yield and enantioselectivity of product F4, indicating that an air atmosphere is critical for the oxidation step. Notably, adding a trace amount of water under an oxygen atmosphere afforded F4 in 69% yield with 92 : 8 er, suggesting that trace water present in air may act as a promoter. Oxidation conducted under an air atmosphere without DDQ still yielded F4 in 52% yield, implying that both DDQ and atmospheric oxygen function as oxidants. Additionally, the reaction proceeded under an air atmosphere in the absence of Cs₂CO₃, ruling out a mechanism involving deprotonation of E4 followed by reaction with oxygen to form a peroxide.^18c UV-vis absorption spectra revealed that the dearomatized cycloaddition intermediates E1 and E4 absorb blue light at 420 nm, whereas their oxidized products F1 and F4 exhibit very weak absorption at this wavelength (Scheme 5b). This observation suggests that the cycloaddition intermediates may undergo photoexcitation under light irradiation. In the singlet oxygen trap experiment (Scheme 5c), the addition of singlet oxygen scavengers DHN and DPBF increased the yield of product F25, and no products from the reaction of DHN and DPBF with singlet oxygen were detected during the reaction process. This indicates that singlet oxygen was not generated upon light irradiation; instead, triplet oxygen reacted directly with photoexcited E25. When A11 was used as the substrate, the oxidation proceeded very slowly, resulting in only trace yields of the corresponding axially chiral product (Scheme 5d). These observations suggest that the DDQ-mediated dehydrogenative rearomatization of dihydropyrazoles proceeds via a single-electron transfer (SET) mechanism rather than a direct hydrogen atom transfer (HAT) pathway.

Scheme 5 Mechanistic studies and the proposed mechanism.

Based on the experimental results and previous studies,^20g,j a plausible mechanism is proposed in Scheme 5e. The chiral N,N′-dioxide ligand coordinates to the Ni^II center in a tetradentate fashion, forming an octahedral complex. Substrate D2 then coordinates bidentately to this N,N′-dioxide-Ni^II catalyst, undergoing cycloaddition with the nitrile imine, predominantly via the Re–Re face of D2, to form (4S,5R)-E2. Under blue light irradiation, two pathways for oxidation are feasible: (1) E2 undergoes single-electron oxidation by photoexcited DDQ* to generate a radical cation intermediate and DDQ^·–; (2) photoexcited E2 participates in single-electron transfer with oxygen and DDQ*, producing the radical cation intermediate, O₂˙⁻ and DDQ˙⁻. This radical cation is subsequently converted to a cation via proton abstraction mediated by DDQ˙⁻ and superoxide O₂˙⁻ coupled with a single-electron-transfer step. In this cation intermediate, the N-indole group rotates around the C–N bond, generating two rotamers Int1 and Int2. Due to steric repulsion between the larger ester group and other substituents on the dihydropyrazole ring, less sterically hindered Int1 undergoes efficient central-to-axial chirality transfer, selectively forming (S)-F2. In contrast, for the C–C axially chiral product C1, the naphthyl group exhibits greater steric hindrance than the methoxy group. This drives the reaction to proceed preferentially via the less hindered rotamer Int4, ultimately affording the (R)-C1 product. The longer C–C bond increases the conformational flexibility in the cationic intermediate, which may account for the lower enantioselectivities compared to the C–N system.

Conclusions

In conclusion, an efficient catalytic asymmetric [3 + 2] cycloaddition/oxidation sequential reaction between hydrazonoyl chlorides and α,β-unsaturated enones was achieved, using a chiral N,N′-dioxide/Ni(II) complex as the catalyst. This protocol leverages readily accessible starting materials and provides facile access to two distinct classes of axially chiral arylpyrazoles, the C–C five–six-membered and C–N five–five-membered arylpyrazoles, in high yields and good enantioselectivities. The synthetic utility of this methodology is further supported by scale-up experiments, product derivatization studies, and initial attempts to construct the more challenging C–O axially chiral pyrazole scaffolds. Ongoing work is focused on extending this strategy to the enantioselective synthesis of other classes of atropisomers.

Author contributions

J. H. performed experiments and prepared the SI and paper. Y. Z. repeated some experiments. L. L. L. helped with modifying the paper and SI. X. M. F. conceived and directed the project.

Conflicts of interest

There are no conflicts to declare.

Data availability

Further details of the experimental procedure, ¹H, ¹³C{¹H} and ¹⁹F {¹H} NMR spectra, HPLC chromatograms, and X-ray crystallographic data for C1, E2, F2 and D5 are available in the SI. See DOI: https://doi.org/10.1039/d5sc06841j.

CCDC 2467819, 2467820 and 2467821 contain the supplementary crystallographic data for this paper.^21,23,25

Acknowledgements

The authors acknowledge financial support from the National Key R&D Program of China (2023YFA1506700) and the National Natural Science Foundation of China (No. 22171189). We are grateful to Dr Yuqiao Zhou (Sichuan University) for the X-ray single crystal diffraction analysis.

Notes and references

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