Iron-catalyzed asymmetric Csp³–H/Csp³–H coupling: improving the chirality induction by mechanochemical liquid-assisted grinding

Abstract

The iron-catalyzed asymmetric oxidative coupling is a challenging transformation that is typically restricted to naphthol substrates (Csp²–H) with carefully designed chiral ligands. Herein, we established a mechanochemical protocol for iron-catalyzed asymmetric Csp³–H/Csp³–H coupling between glycines and β-ketoesters. By using size-tunable liquid additives via non-covalent bond interactions with simply designed chiral salen ligands and substrates under mechanochemical treatment, it is possible to improve the asymmetric induction and offer a variety of structurally diverse α-amino acid derivatives in high enantiopurity. Mechanistic studies revealed that the iminium ion derived from acid-assisted aerobic oxidation of glycine ester was the key intermediate of the reaction, and the liquid additive t-BuOH acted both as a stabilizer for the iminium ion via N–H⋯O interaction and as an assistant for enantio-control. Moreover, a safer, cleaner, and more energy-conserving route via mechanochemically accelerated aging was first disclosed for this asymmetric Csp³–H/Csp³–H coupling reaction.

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Introduction

The development of the transition-metal catalyzed asymmetric cross-dehydrogenative coupling (CDC) reaction¹ is highly important because it offers a sustainable alternative to traditional cross-coupling reactions, which heavily rely on prefunctionalization of the coupling partners (Fig. 1A). Although significant contributions on metal-catalyzed CDC reactions² have been made by the Li group and others, their catalytic asymmetric variants³ are much less operational. Even more frustrating is the lack of Csp³–H/Csp³–H coupling reactions and only a few metal-catalyzed studies have been reported using Cu,⁴ Ni⁵ and cooperative bimetallic⁶ catalyst systems. In recent years, iron catalysis has aroused much attention due to its advantages of earth abundance, eco-friendliness, and low toxicity.⁷ However, sporadic examples of iron catalyzed CDCs have been reported, which are limited to the oxidative cross couplings between naphthols⁸ or with azonaphthalenes⁹ which are induced by chiral redox iron complexes (Fig. 1B). The main issues resulting in the absence of enantioselective versions potentially arise from two aspects: (1) the wide array of formal oxidation states and thus the multifarious chemical nature of the iron metal, particularly under strong oxidative conditions, made the stereo-control of iron-catalyzed CDC reactions highly challenging;¹⁰ (2) reversible single electron transfer (SET) and delocalization of the Fe–substrate complex often led to depreciation of the enantiopurity (Fig. 1B).^8c,d Therefore, the development of a reliable chiral iron catalytic system to access the asymmetric CDC reaction with alternative hybrid carbon under facile oxidative conditions is a highly important objective.

Fig. 1 Background studies and this work.

Mechanochemistry¹¹ provides exciting synthetic opportunities with no dissolution concerns to generate new chemical reactivity¹² and selectivity.¹³ However, the utilization of ball milling in asymmetric organic synthesis has not been adequately investigated which concentrated on the condensation, addition and substitution reactions.¹⁴ Recently, our group focused on asymmetric oxidative coupling reactions using the liquid-assisted grinding (LAG)¹⁵ strategy, a useful technique derived from mechanochemistry, by which tiny liquid additives could participate in the catalytic cycle to endow high reactivity and enantioselectivity.^15b Besides, LAG plays an important role in accelerating some metal-catalyzed/based reactions via coordination interactions (Fig. 1C). For example, Ito and co-workers’ recent elegant studies showed that the coordinative 1,5-cyclooctadiene (1,5-cod) acts as both a dispersant and stabilizer for a palladium catalyst to facilitate solid-state cross-coupling.¹⁶ Meanwhile methanol (MeOH) was proved by our group to accelerate the palladium-catalyzed oxidative addition of carbon–chloride bonds via ligand exchange.¹⁷ Besides, tetrahydrofuran (THF) has been used as an alternative ligand to suppress the side reaction of lithium-based Birch reduction and to improve the reactivity of magnesium-based carbon nucleophiles, respectively.¹⁸ Inspired by our previous studies on mechano-synthesis and enantioselective reactions,¹⁹ we envisioned whether the non-covalent bond interactions between size-tunable liquid additives and chiral ligands/substrates promoted by mechanochemical LAG could be employed to create a suitable spatial environment that facilitates asymmetric induction for iron-catalyzed oxidative cross-coupling. This strategy, if successful, would provide an alternative expedient to metal catalytic chirality induction.

Herein, we demonstrated the realization of this strategy for iron-catalyzed asymmetric oxidative Csp³–H/Csp³–H coupling of glycines and β-ketoesters using a salen-type ligand (Fig. 1D). Under mechanochemical LAG, the liquid additive t-BuOH of high steric hindrance could significantly improve the enantioselectivity and stabilize the iminium intermediate via a N–H⋯O interaction as evidenced by experimental and computational studies. This reaction provides an expedient way to access enantioenriched unnatural α-amino acid derivatives,²⁰ with salient features that include (1) the first iron catalyzed asymmetric coupling reaction, (2) green oxygen or air as the sole oxidant, (3) excellent chirality control with a simply designed salen ligand, and (4) mechanistic insights into LAG induced enantiocontrol.

Results and discussion

We commenced our study by examining the asymmetric coupling reaction between β-indanone ester 1a and N-p-methoxy phenylglycine ethyl ester 2a using Fe(OTf)₃ as the catalyst. Preliminary screening of the ligand scaffold and oxidant showed that the salen-type ligand gave superior stereoselectivity and yield, and oxygen was necessary and optimal for this transformation (for details, see Table S1†). Considering that a Brønsted acid is beneficial for driving the aerobic oxidation of glycine derivatives,²¹ several acidic additives were then tested (Table S1,† entries 10–14) and trifluoroacetic acid (TFA) gave the best result (49% yield with 23% ee and 60 : 40 dr). Further optimization of iron salts revealed Fe(OTf)₃ to be the best choice (Table S1,† entries 15–19). To improve the enantio- and diastereo-selectivity, a series of salen ligands with different steric hindrance and electronic properties were examined (Table 1, L8–L13, and Table S2†). The results indicated that the steric hindrance from the phenol ring rather than the amine sources (Table 1, L12–L13) was effective for the stereo-control of this transformation, while electronic properties proved to be futile (Table 1, L9–L11). Encouraged by these results, we replaced the phenol moiety with bulky naphthol (Table 1, L14) and incorporated tertiary butyl (Table 1, t-Bu, L15) and adamantyl (Table 1, Ad, L16) groups at both C3 and C6 positions of the naphthol ring. Pleasingly, L15 was found to be optimal to give 3aa in 65% yield with 46% ee and 68 : 32 dr, while the over-congested Ad group led to depreciation in both yield and enantioselectivity. Nevertheless, there is still plenty of room for improvement of selectivity.

Table 1 Optimization of reaction conditions^a

a Reaction conditions: Fe(OTf)₃ (10 mol%), L (12 mol%), TFA (12.5 mol%), and NaCl (3.0 g) were pre-milled at 25 Hz for 30 min, using two stainless-steel balls (d_MB = 1.0 cm) in a 25 mL stainless-steel vial, then, 1a (0.2 mmol), 2a (0.2 mmol) and O₂ were added in through a gas inlet valve and milled for another 30 min. b Yield of the isolated product. c Determined by HPLC analysis. d Determined by ¹H NMR analysis. n.d. = not detected. MM = mixer mill.

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To avoid elaborate ligand design, we then took advantage of the LAG strategy by exploring suitable liquid additives (LAGs) with good hydrogen bonding interaction with the ligand and/or substrates to further improve the stereo-control under ball-milling conditions. The results depicted in Fig. 2A and Table S3† show that the reaction enantioselectivity and diastereoselectivity are highly sensitive to the steric hindrance of these liquid additives, and among them t-BuOH (η = 1.16) of high steric hindrance gave the best performance (75% yield, 87% ee and 85 : 15 dr). Further experimental insights into the influence of mechanochemical parameters on the asymmetric oxidative reaction are also presented (Table S4†). A medium frequency (20 Hz) ball-milling for 55 min using two stainless-steel balls (14 diameter) and 2.0 g of NaCl was finally chosen to give the best yield (88%), ee (95%) and dr (90 : 10) values. In this case, the amount of t-BuOH could be reduced to 75 μL (η = 0.58) (Table S4,† entry 10). Comparisons to solution-stirred and neat-stirred approaches were then carried out, demonstrating that the solution analogue (in 4 mL t-BuOH) is slower than the ball-milling process and poorer enantio-control was imparted, as only 7% yield and 46% ee of the product were observed after 30 min (Fig. 2B), which implies the importance of reaction acceleration by mechanochemical LAG. Likewise, the dry-stirring analogue with t-BuOH (150 μL, 4 equiv.) as an additive was much inferior to the ball-milling approach, providing only 7% yield of 3aa with 16% ee after 24 h (Fig. 2C). Besides, under Wang's solution conditions^3a using a copper/L1 catalyst and DDQ oxidant, the reaction showed little activity (Fig. 2D). In so doing has highlighted the importance of the iron catalytic system and the mechanical treatment for the enantiocontrol of the current transformation.

Fig. 2 Screening of LAGs^a,b (A) and comparative experiments (B–D). ^a For reaction conditions see Table 1. ^b LAGs [η = V (liquid; μL)/m (reagents; mg)] were added in the pre-milling process. ^c Two stainless-steel balls (d_MB = 1.4 cm) were used and the mixtures were milled at 20 Hz for (30 + 25) min. ^d NaCl (2.0 g) and t-BuOH (η = 0.58) were used. MM = mixer mill.

With the optimized reaction conditions in hand, we began to explore the reaction scope by varying the glycine component 2 in combination with β-indanone esters (Table 2). The reaction is amenable for a range of glycine esters that possess different ester groups (OEt, OMe, Oi-Pr, Ot-Bu and OBn), resulting in moderate to good product yields (67–90%), excellent enantioselectivities (89–99%) and satisfactory diastereoselectivities (85 : 15 to >20 : 1 dr). However, the substituents on benzene rings were limited to electron-donating groups (Me and OMe) in the para position, while a 2,6-dimethyl substituent (3ag) and an m-chloro substituent (3ah) failed to react. It was probably due to the beneficial effects of para electron-donating substituents for aerobic α-C–H oxidation. With respect to β-indanone esters, both electron-rich and electron-deficient substrates were found to efficiently react with N-PMP glycine ethyl ester 2a, as demonstrated by the good to excellent yields and ee values of the coupling products 3ba–3da. The tert-butyl ester substituent in 1f was compatible with the reaction conditions, maintaining high enantioselectivity and diastereoselectivity (3fc). However, a small-sized methyl ester 1f′ completely suppressed the reaction enantioselectivity (3f′a, no ee value), indicating the vital importance of the steric hindrance of the ester groups. As extensions of this reaction, tetralone β-keto ester and aliphatic cyclic β-keto ester derivatives were tolerated as well in the current system, generating the related products 3ea, 3ga and 3gc in good to excellent yields (78–95%) and high enantio- and diastereoselectivities (96–>99% ee and 88 : 12–>20 : 1 dr). It is worth noting that switching the carbocyclic β-keto ester to biologically active benzofuran-3(2H)-ones gave rise to enantioenriched α-alkyl α-amino acid derivatives in 70–90% isolated yields with 96–99% ee values and >20 : 1 dr values. In these cases, regardless of the electronic properties and/or positions of the substituents on the benzene rings of benzofuran-3(2H)-ones, all of the reactions ran well, constituting an efficient and unprecedented method for accessing benzofuranone derived α-amino acid derivatives. The relative configuration of minor diastereomers [(RR)-form and (SS)-form] of 3aa was confirmed by X-ray crystallography analysis²² and HPLC analysis (for details see the ESI, section 5†) and the absolute configuration of the major stereoisomer was further supported by DFT calculations (vide infra).

Table 2 The substrate scope under the mechanochemical LAG conditions^a

a Reaction conditions: Fe(OTf)₃ (10 mol%), L15 (12 mol%), TFA (12.5 mol%), t-BuOH (η = 0.58) and NaCl (2.0 g) were pre-milled at 20 Hz for 30 min, using two stainless-steel balls (d_MB = 1.4 cm) in a 25 mL stainless-steel vial, then, 1a (0.2 mmol) and 2a (0.2 mmol) were added and O₂ was supplied through a gas inlet valve and milled for another 30 min. MM = mixer mill.

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Our subsequent efforts were directed toward further increasing the greenness of the reaction through the accelerated aging (AA) technique, which possesses inherently simple, safe, low-cost, and energy-saving properties.²³ Despite being rarely studied by organic chemists, it has been practically applied to the C–H functionalization of glycines by our group very recently.²⁴ After optimization of the aging conditions (Table S5†), 3aa could be formed in 68% yield and 90% ee by 30 min of pre-grinding and 2 h of aging without any additional oxidant. Substrate adaptability under AA conditions was also tested and the results are shown in Table 3. Generally, regardless of the type of β-keto ester and glycine ester, all of the reactions ran smoothly under open air, furnishing the corresponding coupling products in 52–75% isolated yields with 85% to 95% ee values and 70 : 30 to 93 : 7 dr values, which were lower than those obtained by a continuous LAG strategy. Among them, benzofuran-3(2H)-ones (aging for 0.5 h) gave better performance than β-indanone esters in terms of enantioselectivity and diastereoselectivity. Nevertheless, pyridinofuran-3(2H)-one 1q and benzothiophen-3(2H)-one 1p could not furnish any products. Additionally, a series of green chemistry metrics including the environmental impact factor (E-factor), solvent intensity (SI) and mass intensity (MI) were quantified which showed this methodology to be sustainable and cost-effective (see Table S6 and Scheme S6†).

Table 3 The reaction of glycine esters and β-ketoesters under the accelerated aging conditions^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), Fe(OTf)₃ (10 mol%), L15 (12 mol%), TFA (12.5 mol%), t-BuOH (η = 0.58) and NaCl (2.0 g) were pre-milled at 20 Hz for 30 min, using two stainless-steel balls (d_MB = 1.4 cm) in a 25 mL stainless-steel vial, and then aged in an open flask (50 mL) for 2 h. MM = mixer mill. b Aging for 0.5 h.

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To gain insights into the mechanism of the reaction, control experiments were conducted with the reaction between 1a and 2a (Fig. 3). In sharp contrast to the high efficiency exhibited by the reaction carried out under the standard LAG conditions (87% yield and 95% ee), no reaction occurred for the model substrates under inert gases (Fig. 3A), even in the presence of a stoichiometric Fe(III) catalyst (Fig. 3B). In addition, the reaction was completely inhibited in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-t-butyl-4-methylphenol (BHT), and the latter could trap an amine radical to afford 2a-BHT in 30% isolated yield (Fig. 3C and Scheme S4†). These results revealed that oxygen is essential and it is the only oxidant for this mechanochemical asymmetric Csp³–H/Csp³–H coupling reaction, which is possibly involved in the radical oxidation of the glycine esters.

Fig. 3 Control experiments. Mechanochemical reactions of 1a and 2a under nitrogen atmospheres (A and B). Mechanochemical reaction of 1a and imine 2–2′ (C). Radical trapping experiments (D). Solution reactions of 1a and 2a in THF with or without t-BuOH (4 equiv., 75 μL) as the additive (E). Iron-complex capturing experiments (F).

When replacing 2a with imine 2–2′, it can be easily captured by 1a even without the assistance of a chiral catalyst, leading to a strong racemic background reaction. In this case, 3aa was obtained in 88% yield with only <5% ee value (Fig. 3D and Scheme S3†). Besides, solution reactions in both t-BuOH and THF exhibited poor performance, and very low transformations were observed during the first 30–60 min, while prolonging the reaction to 240 min gave rise to obvious racemization²⁵ (Fig. 3E). It should be noted that an obvious enhancement of the ee value was observed by adding small drops of t-BuOH (4 eq.) to the THF solution, indicating that the coordination effect was not exclusive to mechanochemistry. However, this positive effect was weakened by thermodynamically controlled racemization, highlighting the importance of reaction acceleration by mechanochemistry to ensure the stereoselectivity.

The dramatic enhancement of enantioselectivities under LAG conditions prompted us to probe the iron-complexes in the LAG system. ESI-MS analysis^19c was employed to detect the mixtures after ball-milling of Fe(OTf)₃, L15 and t-BuOH (Fig. 3F). Two peaks attributed to Fe-complexes [L15-Fe]⁺ (m/z 700.4) and [L15-Fe-t-BuOH + MeCN]⁺ (m/z 815.5) were found. In stark contrast, neat grinding of Fe(OTf)₃ and L15 followed by physical mixing with t-BuOH offered only [L15-Fe]⁺ (m/z 700.4) and [L15 + H]⁺ (m/z 647.5) species, implying that the mechanical impact was essential for accessing the L-Fe-butanol complex, which is likely an active catalytic species, and the interference caused by ionization during the MS detection could also be excluded (for details see Scheme S5 and Fig. S1 in the ESI†). However, when 2a was added to the mixtures, no Fe-complexes containing 2a were detected after ball-milling which means that the β-keto ester might fail to coordinate with the iron center by direct ligand exchange (vide infra).

Collectively, the overall catalytic cycle was proposed through the combination of density functional theory (DFT) calculations using PBE0 methods²⁶ (for details see the ESI, section 9†). As illustrated in Fig. 4B, the catalytic cycle started with the LFe complex INT 1 (although the dissociation of INT 1 into [LFe]⁺ had a high free energy barrier of 99.5 kcal mol⁻¹, OTf⁻ could be lost during the MS detection²⁷). Direct ligand exchange of OTf⁻ with t-BuOH or 1f-enol was energetically disfavoured (Fig. 4A), while an associative pathway involving INT 1, 1f-enolate and t-BuOH was workable to afford INT 3 bearing t-BuOH on the naphthol-O of L15 (−24.3 kcal mol⁻¹). In this context, 1f-enolate was obtained from the deprotonation of 1f by CF₃CO₂⁻ (20.5 kcal mol⁻¹) rather than by OTf⁻ (43.1 kcal mol⁻¹), while the former was derived from the TFA assisted two-step single-electron oxidation of 2c. Next, Si- or Re-face coordination of INT 3 to two faces of the iminium 2c-2 led to two potential enantiomeric intermediates INT 4^SR and INT 4^RS, respectively (here only the major diastereomers were considered), where the iminium ions were stabilized by t-BuOH via a N–H⋯O interaction. Afterwards, nucleophilic addition occurred in transition states (TS^SR and TS^RS) to yield the LFe-containing adducts (INT 5^SR and INT 5^RS) and then the catalyst and t-BuOH were released to close the catalytic cycle and afford the product 3fc in two enantiomeric forms. As showcased in Fig. 4C, the favourable transition state TS^SR leading to the desired (SR)-form final product P^SR was computed to be lower in free energy than TS^RS forming the (RS)-form product P^RS by about 4.1 kcal mol⁻¹ in the vacuum phase, indicating the (SR)-form to be the major enantiomer. Notably, a comparison of free energy barriers of INT 4^SR and INT 4^SR-1 suggests that t-BuOH plays a major role in stabilizing the iminium ion (Fig. S3†). The enantioselectivity seems to be provided by the steric interaction between the salen ligand, ketoester and t-BuOH. As seen from the bottom view of the enantioselectivity models (Fig. S3†), the tert-butyl group of ketoester in TS^SR is bent significantly to be away from the bulky naphthol of the ligand (Fe–O^A as 97.3°), which might contribute to the lower free energy of TS^SR and is consistent with the experimental results (3aavs.3f′a) that a smaller-sized ester group of 1 was detrimental for the enantiocontrol. In addition, the H–H repulsion in TS^RS between the butyl group of t-BuOH and the cyclohexyl group on the ligand also contributes to the enantiocontrol which results in higher free energy (Fig. 4C). Above all, given the X-ray crystallography analysis and DFT calculations, the absolute configuration of the product was speculated as the (SR)-form.

Fig. 4 DFT studies and the proposed mechanism. (A) Formation pathway of the catalytic iron species. (B) The proposed mechanism. (C) The enantio-determining transition states. The DFT-calculated free energies, in kcal mol⁻¹, are shown in parentheses. All of the Fe-complexes are in the sextet spin state.

Conclusions

In summary, a chiral Fe/salen (L15)/O₂ system was used to drive the mechanochemical asymmetric oxidative coupling of glycines and β-ketoesters in a highly stereoselective manner with the assistance of t-BuOH as a liquid additive. This method provides a new mode of chiral control which is barely effective in solution chemistry. Notably, various amino acid derivatives bearing β-indanone esters, aliphatic cyclic β-ketoesters, tetralone β-ketoesters and benzofuran-3(2H)-ones were produced in good yields with high enantiopurity, demonstrating the capability of this mechanochemical asymmetric protocol. The mechanistic study elucidated that the mechanical impact was essential for accessing the active catalytic species (L-Fe-butanol complex), and t-BuOH played a crucial role in stabilizing the iminium intermediate and boosting enantiocontrol via non-covalent interactions in the enantio-determining step. In addition, a mechanochemical accelerated aging (AA) strategy with short-lasting low-energy impetus was applied to this asymmetric Csp³–H/Csp³–H coupling, which will open a new avenue for iron catalyzed asymmetric reactions.

Author contributions

P. and J. B. suggested the idea; P., T. and H. performed the experiments. K. Y. conducted catalyst recovery experiments. W. K. and J. B. supervised the project. Writing – review and editing were conducted by P. and J. B. All authors have read and approved the final manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (21978270), the Zhejiang Provincial Natural Science Foundation of China (LY23B060005), and the National Key R&D Program of China (2021YFC2101000) for financial support.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC: 2271241. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01467c

‡ These authors contributed equally to this work.

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