New CF2H-Synthon Enables Asymmetric Radical Difluoroalkylation for Synthesis of Chiral Difluoromethylated Amines

doi:10.21203/rs.3.rs-5290118/v1

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New CF₂H-Synthon Enables Asymmetric Radical Difluoroalkylation for Synthesis of Chiral Difluoromethylated Amines

https://doi.org/10.21203/rs.3.rs-5290118/v1

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The difluoromethyl group (CF₂H) is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design and screening. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by reaction scope, lower reactivity, and reduced enantioselectivity. Leveraging the unique fluorine effect, we designed and synthesized a novel radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions, broad substrate scope, and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules for pharmaceutical research and development.

Physical sciences/Chemistry/Organic chemistry/Stereochemistry

Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology

Organofluorine chemistry has emerged as a highly significant field over the past few decades, enabling the on-demand synthesis of a wide range of unnatural fluorinated molecules which has garnered considerable research interests, particularly in pharmaceuticals, agrochemicals, and specialized materials.^1–12 Standing out as one of the most significant fluorinated moieties due to its unique biological properties, difluoromethyl group (CF₂H) has been recognized as an excellent bioisostere for hydroxyl, thiol, or amide groups, and as a lipophilic hydrogen-bond donor which could significantly enhance binding affinity, membrane permeability, and bioavailability while incorporated into parent molecules,^13–14 thus attracts increasing interest in drug design and screening. Indeed, several CF₂H-containing drugs and bioactive molecules have been developed,^15–17 including FDA-approved drugs and others in clinical trials (Scheme 1a). Given the inherent chiral nature of biological systems, drug chirality is widely recognized as a crucial aspect of medicinal research. Under these contexts, the synthesis of optically active CF₂H-containing drug-like molecules has proven to be a powerful strategy for lead optimization in drug development.

Besides few notable examples exist for the asymmetric construction of difluoromethylated stereocenters via fluorination¹⁸ or hydrogenation^19–22, the most common approaches for obtaining enantioenriched difluoromethyl compounds have focused on direct asymmetric difluoromethylation and the functionalization of CF₂H-containing starting materials. Interestingly, nucleophilic addition with Me₃SiCF₂H, relying on chiral auxiliaries covalently linked to imines, has typically resulted in only moderate diastereoselectivities, even at low temperatures (-78 ºC).²³ In contrast, similar additions of carbanion nucleophiles to CF₂H-imines have shown significantly higher diastereoselectivity.^24–27 Consequently, various CF₂H synthons have been designed and applied in the enantioselective synthesis of chiral difluoromethylated compounds, employing both chiral auxiliary and asymmetric catalytic strategies. The most widely used electrophilic CF₂H synthons include difluoromethylated imines,^24–27 aldehydes/ketones,^28–32 and olefins,^33–37 where different nucleophiles attack C = X double bonds enantioselectively to form chiral stereogenic centers featuring a difluoromethyl group. Additionally, the only nucleophilic CF₂H synthon designed so far is a heterocyclic α-imino ketone, utilized as a bidentate directing group for asymmetric 1,4-additions.³⁸ However, these CF₂H synthons generally exhibit limited reactivity and enantioselectivity, especially compared to their trifluoromethylated analogs, and the reaction types are restricted. Therefore, a highly efficient and general strategy for the diversity-oriented synthesis of difluoromethylated compounds remains underdeveloped and is urgently needed.

Owing to their unique reactivity, structural diversity, and broad functional group tolerance, highly reactive radicals have facilitated a range of mild and efficient transformations, enabling the rapid assembly of functionalized, complex molecules, particularly through multi-step cascade reactions. Over the past few decades, catalytic enantioselective fluoroalkylation has seen remarkable progress, largely due to the relative stability of fluoroalkyl radicals conferred by the distinctive effects of fluorine. However, while asymmetric radical trifluoroalkylation has advanced rapidly,^39–46 transition-metal-catalyzed enantioselective radical difluoroalkylation has lagged behind, likely because of the weaker electron-withdrawing nature and smaller steric bulk of the difluoromethyl group. The only reported radical CF₂H synthon, described by Shen, enabled a nickel-catalyzed asymmetric arylation, yielding difluoromethylated 1,1-diarylalkanes with typically moderate enantiomeric excesses (ees), which were noticeably lower than those of their trifluoromethylated counterparts (Scheme 1b)⁴⁷. Given that achieving high stereoselectivity in radical transformations requires sufficient recognition time within the chiral pocket of a metal complex, the design of new radical CF₂H synthons should focus on incorporating functional groups that promote the in situ generation of more stabilized and persistent radicals.

To address the aforementioned challenges, we have incorporated isoindolinone—a key structural motif widely used in various biologically active compounds^48–55 into alkyl halides to create a new CF₂H synthon for asymmetric radical transformations. Our design is based on the following considerations: (1) the nitrogen atom can stabilize the in situ-formed difluoromethylated α-radical, enhancing chiral recognition during the radical oxidation step; (2) the carbonyl oxygen serves as a coordination site for the metal center, facilitating control over the preferential geometry of the lower-energy enantiomeric transition state; and (3) the isoindolinone ring acts as a sterically hindered group to discriminate the CF₂H moiety. Moreover, this newly designed CF₂H synthon offers several advantages, including easy preparation, bench stability, low cost, and convenient removal.

Herein, we present an efficient strategy for the general and asymmetric construction of carbon stereocenters containing a difluoromethyl group via a nickel-catalyzed enantioconvergent Negishi cross-coupling with arylzinc reagents. This method features mild reaction conditions, a broad substrate scope, good catalytic efficiency, and excellent enantioselectivity. The resulting difluoromethylated isoindolinone derivatives could be further converted into chiral difluoromethylated amines, allowing for the straightforward synthesis of chiral analogs bearing CF₂H-substituted stereogenic centers found in various known bioactive molecules. Given that both optically pure difluoromethylated amines and isoindolinones are important structural motifs in numerous biologically active compounds, this strategy provides an innovative and practical approach for the highly efficient synthesis of CF₂H-containing chiral drug-like molecules, offering valuable potential for drug research and development.

Optimization of reaction conditions. Our initial study commenced with 2-(1-chloro-2,2-difluoroethyl) isoindolin-1-one (1) as the CF₂H-containing coupling partner and arylzinc reagent bearing CO₂Me at the para position (2) as the nucleophile to optimize conditions for this nickel-catalyzed stereoconvergent Negishi arylation (Table 1). Given their critical role in asymmetric reaction, several chiral bis-oxazoline were initially evaluated under catalytic condition, using NiBr₂•DME (10 mol%) and NaBr (2.0 equiv) in THF at -20 ºC (Table 1; For more details see Table S1 in the SI). To our delight, bis-oxazoline (Box) ligand L7 could deliver the desired product 3a with moderate yield (35%) and acceptable ee value (59%), whereas 2,2-bis(2-oxazoline) (Bi-ox) ligand L1 was less effective in asymmetric induction. When sterically bulkier ligands L8 and L9 were employed, the reaction proceeded smoothly to furnish the CF₂H-containing amide with higher yields and ee (46% yield, 76% ee and 48% yield, 88% ee), respectively. The use of L10, which carries a bulkier substituent, led to a significant loss in enantioselective control, resulting in a decrease in the ee value to 35%. Subsequently, different kinds of solvents have been carefully tested in this reaction (Table 1, entries 1–4;). Notably, the ee value increased to 90% while maintaining a comparable yield when 2-Me-THF was used in place of THF. Based on this outcome of solvent screening, 2-Me-THF was selected as a co-solvent with THF and a promising result was achieved. (entry 3; 64% yield, 91% ee). After the carefully evaluation of additives and nickel catalysts, 0.5 equivalent of NaI was proved to be the best choice, providing the desired arylation product in 66% yield with slightly higher enantioselectivity (93% ee, entry 8) while NiCl₂•DME or NiBr₂ decreased the reactivity of this coupling process obviously. (Table 1, entries 9 and 10). Finally, extending the reaction time to 48 h, the α-CF₂H amide could be obtained in acceptable yield without diminishing the enantioselectivity (Table 1, entries 11; 88% yield, 93% ee).

Enantioselective Construction of Difluoromethylated Tertiary Stereocenters by Nickel-catalyzed C-C Coupling Reaction. With the optimized conditions established, we proceeded to investigate the substrate scope of this enantioselective Negishi cross-coupling. As illustrated in Scheme 2, a diverse array of arylzinc reagents was initially examined in this reaction, coupling with 1a to yield products with excellent enantioselective control (Scheme 2). Notably, both electron-withdrawing groups such as ester (3a, 3b), trifluoromethyl (3c,3d), fluoro (3e), chloride (3f) and electron-donating groups including OMe (3g,3h), OBz (3i), methyl (3k), phenyl (3m) were well tolerated under the standard conditions. Besides, fused ring derivatives such as phenyl (3n) and naphthyl (3o), were also smoothly difluoroalkylated to afford the desired products. Furthermore, Polysubstituted benzenes were successfully obtained under these optimized conditions(3p,3q,3r,3s), yielding 59–75% with 90%-95% ee. Notably, the Rivastigmine intermediate(3j) was synthesized with a yield of 61% and an ee of 95%.

Next, CF₂H-substituted alkyl chlorides 1 were investigated in this Negishi cross-coupling reaction. As shown in Scheme 2, secondary α-CF₂H chlorides with electron-withdrawing substituents were examed, such as fluorine (3t,3u), chloride (3v,3w), bpin(3x) and CF₃(3y), furnishing the coupling products with excellent ee values. Additionally, electron-donating groups such as OMe(3z), TMS (4a) and ^tBu (4b) were also tested, yielding corresponding products with good yields and enantioselectivity. Notably, this reaction is compatible with 3,4-dihydro-2H-isoquinolin-1-one (4c-4h), resulting in moderate yields (55–75%) and excellent ee values (97–98%).

Motivated by the favorable functional group compatibility demonstrated in our reactions, we set out to explore the potential application of this asymmertic difluoroalkylation in modofying biologically active molecules. Notably, the desired products were obtained with good yields and excellent enantiomeric excess (ee) values in all cases, including (L)-menthol (4i), (L)-borneol (4j), majantol (4k), (S)-ibuprofen (4l), canagliflozin (4m), leaf alcohol (4n), and gemfibrozil (4o), which demonstrates applicational potential of incorporating CF₂H-substituted stereogenic center in commercially available drugs and natural products.

Synthetic applications. To further illustrate the synthetic utility of this transformation, we conducted a large-scale experiment under the optimized condition. The corresponding product 3b was obtained with 68% yield accompanied by excellent ee value (95%) (Scheme 3a). Additionally, given the modification potential of substituting a methyl group with a difluoromethyl group in drug molecules, we achieved a 0.5 mmol-scale synthesis of α-CF₂H amide 3j via this asymmetric Negishi cross-coupling, achieving a 58% yield with 95% ee. This intermediate could be further converted into a Rivastigmine analogue in three steps, with an overall yield of 49% while maintaining enantiocontrol. (Scheme 3b)

Mechanism Investigation. To gain a deeper understanding of the mechanism underlying this reaction, series of control experiments were conducted. Firstly, the reaction was inhibited by the addition of radical scavenger 2,2,6,6-Tetramethylpiperidinooxy (TEMPO), high resolution mass spectra (HRMS) indicated the presence of 5n, suggesting a radical pathway in the catalytic cycle (Scheme 3c). As illustrated in Scheme 3d, the addition of 0.02 equivalents of TEMPO to the reaction (green line) resulted in an induction period of approximately 40 hours, continuing beyond 48 hours. This observation suggests that a radical process might be involved in the catalytic cycle. Furthermore, the addition of Ni(cod)₂ significantly reduced the induction period induced by TEMPO (red line) while Ni(cod)₂ was unable to initiate the reaction (black line) in the absence of NiBr₂•DME. These results indicated that the Ni(I) species formed through the comproportionation reaction of Ni (II) and Ni (0) might facilitate the generation of radicals.

Based on the experimental results and previous literature,^56–68 we hypothesize a plausible reaction mechanism. Firstly, the alkyl radicals E may be generated by the reduction of the alkyl chloride 1 by Ni(I) species (D), and then E is captured by the aryl nickel species to form Ni (III) species C. Finally, the Ni (III) species C undergoes a reduction elimination process to produce product 3 and regenerates Ni(I) species D into the next catalytic cycle (Scheme 3e).

In conclusion, we have developed an efficient and versatile nickel-catalyzed asymmetric Negishi cross-coupling for difluoroalkylation, utilizing newly designed radical CF₂H synthons. This approach allows the synthesis of a diverse array of chiral amines with difluoromethylated stereogenic centers. The method is characterized by straightforward operations, mild reaction conditions, excellent functional group tolerance, and high catalytic activity with exceptional enantioselectivity. It facilitates the late-stage modification of complex bioactive molecules and the synthesis of chiral analogues with CF₂H-substituted stereogenic centers from known bioactive amines. This asymmetric radical transformation provides a practical and efficient solution for the synthesis of chiral difluoromethylated drug-like molecules, offering significant potential for drug discovery and development. Ongoing work in our laboratory focuses on the design, synthesis and application of various fluorine-containing synthons for asymmetric radical fluoroalkylation to enable the rapid and efficient construction of chiral fluorinated biologically active compounds.

General Procedure C for Enantioselective Construction of Difluoromethylated Tertiary Stereocenters by Nickel-catalyzed C-C Coupling Reaction

NiBr₂•DME (10 mol%, 0.02 mmol), L9 (13 mol%, 0.026 mmol) were firstly combined in a 25 mL oven-dried sealing tube. The vessel was evacuated and backfilled with Ar (repeated for 3 times), 2 mL 2-MeTHF was added via syringe and the complex was allowed to pre-stir at 25 ˚C for 30 min. Then CF₂H-substituted secondary alkyl chloride 1 (1.0 equiv, 0.20 mmol) and NaI (0.5 equiv. 0.10 mmol) was added and the tube was cooled to -20 ˚C. And arylzinc reagent 2 (1.8 equiv, 0.36 mmol) was added dropwise. The tube was sealed with a Teflon lined cap and stired at -20 ˚C for 48 h. The reaction mixture was then diluted with EtOAc (~ 10 mL) and filtered through a pad of celite. The filtrate was added brine (20 mL) and extracted with EtOAc (3×15 mL), the combined organic layer was dried over Na₂SO₄, filtrated and concentrated under vacuum. The residue was then purified by flash column chromatography to give desired products.

Data availability

All data needed to support the conclusions of this manuscript are included in the main text or supplementary information. Data supporting the findings of this manuscript are also available from the authors upon request. X-ray crystallographic data for 3k (CCDC 2383618) has been deposited at the Cambridge Crystallographic Data Center. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Competing interests

The authors declare no competing interests.

Author contributions

X.-S. W. and X.N. designed the experiments and directed the project. P. L., Y. H. performed chemical experiments and prepared the supplemental information. C.-H. J., W.-X. C. and T. Z. prepared several ligands and substrates. X.-S. W., R.-X. J. and W.-R. R. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

Acknowledgements

We gratefully acknowledge the National Key R&D Program of China (2021YFF0701700) and the National Science Foundation of China (22271264, 2197128) for financial support. Part of this research was conducted at the Instruments Center for Physical Science at the University of Science and Technology of China.

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Table 1 is available in the Supplementary Files section.

Schemes 1 to 3 are available in the Supplementary Files section

There is NO Competing Interest.

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New CF₂H-Synthon Enables Asymmetric Radical Difluoroalkylation for Synthesis of Chiral Difluoromethylated Amines

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General Procedure C for Enantioselective Construction of Difluoromethylated Tertiary Stereocenters by Nickel-catalyzed C-C Coupling Reaction

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Supplementary Files

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