Mechanically Enabled Formal Reductive Cross-Coupling Reaction of Two Inert Bonds

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Mechanically Enabled Formal Reductive Cross-Coupling Reaction of Two Inert Bonds

https://doi.org/10.21203/rs.3.rs-4565591/v1

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Reductive cross-coupling reactions involving two electrophilic reagents have become increasingly important in modern synthetic chemistry. Previous studies have investigated electrophilic reagents featuring zero or one inert bond; however, reactions involving electrophilic reagents with two inert bonds remain unexplored. This study presents the inaugural nickel-catalyzed reductive cross-coupling reaction induced by mechanical force, involving aryl ethers and aryl fluorides, both of which contain inert bonds. This reaction results in the successful assembly of a series of versatile biaryl compounds and demonstrates excellent tolerance for various functional groups. This novel coupling reaction offers innovative approaches for polymer degradation and the development of luminescent materials.

Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology

Physical sciences/Chemistry/Catalysis/Heterogeneous catalysis

Cross-coupling reactions are pivotal in organic chemistry, playing essential roles in pharmaceutical manufacturing, developing novel materials, and constructing complex and novel organic structures.^1-3 Since the 1970s, traditional C-C bond cross-coupling reactions, which rely on preformed organometallic nucleophilic reagents, have become a dominant method for synthesizing biaryl units.^4-8 With the continuous progress of synthesis methodology, an alternative approach involving the direct coupling of two readily available electrophilic reagents, offers a more straightforward pathway to form C-C bonds and eliminates the need for prepared organometallic nucleophiles.^9-12 However, this strategy faces challenges, particularly in achieving efficient cross-coupling between two distinct electrophilic reagents, as it frequently results in substantial homocoupling products. Overcoming the inherently poor chemical selectivity to realize expected cross-coupling is essential, which usually necessitates carefully optimized catalytic conditions.

In the past decades, phenol derivatives have become environmentally friendly alternatives to aromatic halides in traditional cross-coupling reactions due to their abundant sources, much lower toxicity and high flexibility in reactivity.^13-17 These derivatives, including sulfonates, phosphates, carbamates, carboxylates, and ethers, have made significant progress in reductive cross-coupling reactions (Fig. 1A).^18-27 Among them, aryl ethers are particularly notable for their widespread availability, cost-effectiveness, safety, and excellent atom economy. Nonetheless, activating the C-O bond in aryl ethers, which is inherently inert with a bond dissociation energy (BDE) of 100 kcal/mol, poses substantial challenges.^13,27 Concurrently, there is burgeoning interest in the activation of the C-F bond, which is one of the strongest bonds in organic chemistry.^28-33 The dissociation of C-F bond in fluorinated arenes (Ar-F; BDE 126 kcal/mol) tends to be more difficult compared to that in other halogenated (Cl, Br, I) arenes.³⁰ Activation of the C-F bond entails overcoming considerable thermodynamic barriers and disrupting the conjugative interactions between the aromatic π-system and the C−F bond. Consequently, employing both aryl ethers and aryl fluorides directly as electrophilic reagents in reductive cross-coupling reactions remains a formidable challenge.

Mechanochemistry has garnered significant attention for its operational simplicity and ability to unveil novel reaction pathways unattainable in liquid-phase environments. This method is distinguished by its benefits including abbreviated reaction times, the use of insoluble starting materials, minimal solvent/reagent consumption, and enhanced reaction activity and selectivity.^34-40 Recently, research teams led by Harrowfield,⁴¹ Hanusa,⁴² Ito,⁴³ Bolm,⁴⁴ Kananovich,⁴⁵ Wei,⁴⁶ and Yu^47-48 have exploited ball-milling conditions to activate C-X (X= I, Br, Cl) bonds using metallic magnesium, facilitating the synthesis of Grignard reagents that proved effective in organic synthesis. Despite these advancements in generating Grignard reagents under mechanochemical conditions with zero-valent magnesium, the mechanochemical activation of aryl fluorides remains underexplored due to the inertness of the C-F bond, which displays limited efficiency.⁴² In response to this challenge, we present the first instance of a mechanical-force-induced, nickel-catalyzed formal reductive cross-coupling reaction between two traditionally inert electrophilic agents: aryl ether and aryl fluoride (Fig. 1B). This reaction progresses under mild conditions, eliminating the requirement for prior metallic magnesium activation and extensive solvent use. This approach simplifies the operational procedure, reduces the reaction time, and introduces new strategies for polymer degradation and the construction of luminescent materials. Moreover, this mechanical reaction cannot be achieved using traditional solvent-based systems, underscoring the method's inherent value and potential applications.

Reaction optimization

We began to explore the reductive cross-coupling reaction between naphthyl methyl ether (1a) and 4-fluorotoluene (2a) employing ball-milling techniques. This process was facilitated by using 10 mol% Ni(PCy₃)₂Cl₂ as catalyst, 2.0 equiv Mg as the reductant, and 5.0 equiv 2-Me-THF as a liquid assisted grinding (LAG) agent under an argon atmosphere. The reaction took place in a stainless-steel milling jar (10 mL) at 30 Hz, using two stainless-steel balls (10 mm in diameter). After milling for 2 hours, the targeted reductive cross-coupling product (3a) was obtained with a 15% yield (Table 1, entry 1). Subsequent screening of six different additives yielded I₂ as the most effective, dramatically increasing the yield to 91% (Table 1, entries 2–7). However, changing the metallic reductant from Mg to either Zn or Mn led to the failure in producing the target product 3a (Table 1, entries 8–9). Control experiments without the nickel catalyst or Mg confirmed their critical roles, as the product 3a was not observed (Table 1, entries 10–11). Further refinement was achieved by reducing the Ni catalyst to 5 mol%, Mg to 1.75 equiv., and 2-Me-THF to 2.0 equiv., coupled with shortening the reaction time to 90 minutes. These adjustments successfully maintained a high yield of 90% for the desired product 3a (Table 1, entry 12). Based on these results, the optimal condition (Table 1, entry 12) was established as the standard for subsequent experiments.

Substrate scopes

With the optimized conditions in place, we expanded our investigation to examine the versatility of the mechanical force-induced reductive cross-coupling reaction. Conducted under the standard experimental conditions, our designed reaction demonstrated broad compatibility with various aryl methyl ethers, producing the C-C cross-coupling products with generally high to excellent yields, as depicted in Fig. 2. Specifically, the reaction was compatible with more sterically hindered a-substituted methoxynaphthalene (3b) achieving an 80% yield. Substrates possessing electron-donating groups also successfully underwent the transformation, with high product yields (3c-3e). Furthermore, the phenyl ring and its derivatives, substituted at different positions on the methoxynaphthalene ring, were also well tolerated in the cross-coupling reaction, resulting in good to excellent yields ranging from 79–98% (3f-3l). The versatility of this reaction was further evidenced by its efficacy with various fused-aromatic and polycyclic hydrocarbon substrates, including anthracene, phenanthrene, pyrene, perylene, and triphenylene, which yielded products (3m-3r) ranging from 55–89%. Notably, alkyl methyl ether (3s) proved amenable to the reaction conditions. Additionally, anisole derivatives lacking an extended π-system were explored; for example, phenyl substituted anisole smoothly underwent the reaction (3t). Anisoles with electron-donating amino groups demonstrated good compatibility (3u-3w), while with the electron-withdrawing trifluoromethyl group showed reduced coupling efficiency (3x) with a 34% yield. Furthermore, methyl ether substrates containing tetrastyrene, quinoline, N-methylcarbazole, and fluorene also gave products (3y-3ab) in moderate yields.

After expanding the scope of aryl methyl ethers, the reactivity of various aryl fluorides was assessed. Aryl fluorides with electron-neutral (3ac) and electron-donating substitutes (3ad-3aj) were successfully coupled, producing the target products in good yields. It is worth noting that under this condition, the C-O bond of 4-methoxyfluorobenzene can be retained (3ag), providing an opportunity for next cross-coupling to prepare more complex molecules. Furthermore, substrates containing heterocyclic segments like pyrrole and indole were also compatible with the process (3ak and 3al), showcasing the broad applicative potential of this mechanical-force-induced reductive cross-coupling technique.

Control experiments & synthetic applications

Our research then explored the influence of different forms of unactivated magnesium (0) sources on the reaction, utilizing magnesium chips, foil, and rods as alternatives to previously used powdered magnesium in the experiments. The experiments results indicated that the morphology of magnesium had little impact on the reaction results, as evidenced by the consistently good yields in all cases (Fig. 3A). This outcome also demonstrates the excellent compatibility of the reaction system. In subsequent control experiments, reaction vessels made of different materials were tested in the reaction. Replacing the conventional stainless-steel jar and balls with a ZrO₂ jar and balls resulted in an 87% yield of product 3a, similar to the outcomes using stainless-steel (Fig. 3B). This suggests that the composition of the stainless-steel grinding jar is not critical to success of the reaction.⁴⁹ Conversely, employing a polytetrafluoroethylene (PTFE) jar and balls resulted in a significantly reduced yield to 10%, likely due to the insufficient hardness of PTEF and therefore unable to generate adequate mechanical force for activating Mg (0) under ball-milling conditions. Additional control experiments were carried out in 2-Me-THF within a glass setup where all the reactants were added without employing any activation technique or reagent for Mg (0). Simply stirring the mixture for 2 hours produced only a negligible 0.7% yield of the target compound 3a, and under reflux conditions, yield was slightly higher at 1.7%, further confirming that magnesium activation in our system is driven mechanically rather than thermally. To demonstrate the applicability of this method, we scaled up the cross-coupling reaction on a 10 mmol scale in a 50 mL stainless-steel milling jar with ten milling balls, leading to the generation of 3a in an 84% yield (1.82 g) (Fig. 3C). Interestingly, this mechanically assisted technique enabled the degradation of polymers containing thioether motifs. Specifically, we managed to degrade polyphenylene sulfide (PPS) under mild conditions, achieving 37% yield of degradation product (5) as the main product (Fig. 3D). This showcased a meaningful and potential strategy for degradation. Additionally, our method facilitated the modification of 9,10-bis(20-naphthyl)anthracene (BNA) derivative, an OLED material known for its exceptional electroluminescence,^50–51 under standard conditions. From starting materials ether 6 and aryl fluoride 2h, compound 8 was successfully synthesized with a 65% yield and exhibited strong photoluminescence properties in dichloromethane, displaying a bright green emission at a maximum wavelength (λ_em, max) of 510 nm when excited at 355 nm (Fig. 3E). These findings underscore the versatility of our novel cross-coupling protocol, advancing the discovery and development of novel luminescent materials.

In summary, we have developed a nickel-catalyzed formal reductive cross-coupling reaction between aryl methyl ethers and aryl fluorides under ball milling conditions. This method unlocks a challenging cross-coupling reaction between two electrophilic reagents, each featuring an inert bond. Demonstrations of the method’s efficacy in gram-scale synthesis, polymer degradation, and modification of luminescent materials highlights its synthetic practicality. Given its efficiency and mildness, we anticipate widespread adoption of this technique across various domains.

General procedure for the reductive cross-coupling reaction: In an argon fulfilled glovebox, aryl ethers (0.2 mmol, 1.0 equiv), Ni(PCy₃)Cl₂ (5 mol%), I₂ (15 mol%), Mg (0.35 mmol, 1.75 equiv), aryl fluorides (0.3 mmol, 1.5 equiv),and 2-Me-THF (2.0 equiv) were added successively into stainless-steel milling jar (10.0 mL) with two stainless-steel balls (10 mm diameter). The jar was then closed and was placed in Beijing Grinder vibration ball mill (90–180 min, 30 min break 5 min for three or six times) at 30 Hz. After grinding, the reaction mixture was washed with ethyl acetate. Subsequently, the solvents were evaporated and the residual was purified through column chromatography on silica gel to give the corresponding products.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information file. Any further relevant data are available from the authors on request.

Acknowledgements

This work is supported by National Natural Science Foundation of China (22301192), Sichuan Science and Technology Program (2024NSFSC1124), West China Hospital 135 project (ZYYC23017) and Postdoctor Research Fund of West China Hospital, Sichuan University (2024HXBH027).

Author contributions

Z. L. conceived the idea and led the project. T. L. and X. Z. designed, conducted, and analyzed the experiments. T. L. and X. Z. wrote the paper. All authors participated in result discussions and provided feedback on the manuscript.

^†T. L. and X. Z. contributed equally.

Competing interests

The authors declare no competing interests.

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Table 1 is available in the Supplementary Files section

There is NO Competing Interest.

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Mechanically Enabled Formal Reductive Cross-Coupling Reaction of Two Inert Bonds

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Abstract

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Introduction

Results

Reaction optimization

Substrate scopes

Control experiments & synthetic applications

Summary

Methods

Declarations

References

Table

Additional Declarations

Supplementary Files

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