General and Modular Access to Enantioenriched α-Trifluoromethyl Ketones via Nickel-Catalyzed Reductive Trifluoroalkylation

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES4 Jul 2022General and Modular Access to Enantioenriched α-Trifluoromethyl Ketones via Nickel-Catalyzed Reductive Trifluoroalkylation Dengkai Lin, Yongzhi Chen, Zhan Dong, Pan Pei, Haiting Ji, Lanzhu Tai and Liang-An Chen Dengkai Lin Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author , Yongzhi Chen Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author , Zhan Dong Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author , Pan Pei Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author , Haiting Ji Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author , Lanzhu Tai Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author and Liang-An Chen *Corresponding author: E-mail Address: [email protected] Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202076 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The development of new catalytic enantioselective access to stereogenic CF3-containing molecules is of great interest for expediting the discovery of lead compounds that remain challenging. Specifically, enantioselective synthesis of valuable ketones featuring stereogenic α-CF3 has rarely been reported. We devise a general and modular approach to facilely access enantioenriched α-CF3 ketones via nickel-catalyzed reductive cross-coupling of readily available acid chlorides and racemic α-CF3 alkyl bromides in an enantioconvergent fashion under mild conditions. This protocol features neighboring directing group-free, high chemoselectivity, excellent functional group tolerance, facile scale-up, and notable amenability to straightforward downstream elaboration toward pharmaceutically useful enantioenriched β-trifluoromethylated secondary and tertiary alcohols, thus constituting a reliable, direct, practical, and efficient synthetic alternative to furnish enantiopure α-CF3 carbonyls. Interestingly, an appropriate choice of the phosphine ligand as co-ligand plays an important role in high efficiency and asymmetric induction. Mechanistic studies suggest a radical chain pathway. Download figure Download PowerPoint Introduction Fluorine-containing compounds play an important role in pharmaceuticals, agrochemicals, and advanced functional materials due to their unique biological, chemical, and physical properties.1–6 In particular, the trifluoromethyl group is broadly employed as a valuable and privileged structural motif in medicinal chemistry because it can substantially impact solubility, lipophilicity, metabolic stability, bioavailability, and binding affinity of lead drug candidates.7–9 Thus, significant endeavors have been devoted to incorporating the CF3 groups into organic molecules over recent decades.10–17 However, compared to the booming synthesis of trifluoromethylated aromatic compounds, the methods for installing molecules bearing Csp3–CF3, particularly the enantioenriched variants, remain limited.18–22 Although not abundant compared with other versions, likely due to a dearth of effective asymmetric assembly methods, CF3-containing stereogenic centers are still present in many lead compounds and marketed drugs, and, not surprisingly, are ever-growing (Figure 1a).21,22 Therefore, the quest to develop general and efficient strategies for asymmetrically setting the trifluoromethylated stereocenters into molecules, especially with synthetically versatile functionalized molecular architectures, is of great importance and highly sought after. In this context, the enantiopure α-CF3 carbonyl compounds have gained considerable attention because they bear both a valuable chiral trifluoromethylated stereocenter for pursuing the clinical success of drug candidates and an easily derivatized carbonyl group for further rapid elaboration of molecular complexity and diversity, thereby potentially offering numerous application opportunities to furnish diverse molecules of biological interest (Figure 1a).23 However, the ability to craft these chiral functionalized building blocks with CF3-containing stereogenicity remains challenging and limited to date. Generally, the strategies for accessing optically pure α-CF3 carbonyl compounds are divided into two categories based on enolate chemistry. The first strategy involves asymmetric electrophilic α-trifluoromethylation of carbonyl-derived enolate or enolate equivalent, often utilizing specially tailored CF3-delivery reagents (Figure 1b).24–31 In addition, most successful examples that achieve good enantioselectivity typically proceed with stoichiometric chiral auxiliary-derived imides and tertiary α-alkyl β-ketoesters/amides.24–29 Remarkably, in terms of step-economy, an elegant approach to catalytic enantioselective α-trifluoromethylation of aldehyde was achieved employing enamine-based organocatalysis in combination with Lewis acid or photoredox catalysis.30,31 The second strategy relies on asymmetric α-functionalization of a prochiral CF3-containing substrate through an intermediate α-CF3 enolate under basic conditions (Figure 1c).32–34 However, the stoichiometric chiral Evans-type auxiliaries or complex amide-based directing groups with two-point coordination sites are strictly employed to dictate the enantioselectivity, thus leading to frustrated atom- and step-economy. Despite these efforts, it is important to emphasize that, to the best of our knowledge, there remains a paucity of highly enantioselective catalytic methods for constructing valuable ketones featuring an α-trifluoromethylated stereocenter without the aid of neighboring coordination groups,35,36 presumably due to the inherent difficulty in site-selective formation of the ketone enolate and controlling the stereochemistry during the bond formation from enolate intermediates. Additionally, owing to the salient electron-withdrawing nature of the CF3 substituent, it is a daunting challenge to prevent the potential racemization of the newly formed labile α-tertiary CF3-containing stereocenter of carbonyl compounds, particularly in the case of ketones and aldehydes that exhibit lower pKa for α-hydrogens because of their stronger resonance stabilization in comparison to amides and esters. In this vein, it is highly desirable to develop a new simple, mild, and general method for asymmetric catalytic preparation of this class of chiral CF3-containing ketone compounds, especially their tertiary enantiomerically enriched variants. Figure 1 | (a) Bioactive molecules with CF3-containing stereogenicity. (b–d) Strategies for asymmetric synthesis of enantiomerically pure α-CF3 carbonyl compounds. Download figure Download PowerPoint Nickel catalysis has garnered significant interest in the context of reductive cross-coupling reactions because it opens up a general and powerful paradigm for utilizing alkyl electrophiles to furnish Csp3-enriched centers through a single-electron oxidative addition pathway.37–45 Typical features include atom- and step-economical profiles, mild (less basic) reaction conditions, and broad functional group compatibility.46,47 Accordingly, the effort toward developing enantioselective catalytic forms is a preeminent goal of this great synthetic promise, yet it remains a tedious exercise partially due to a highly reactive radical species.48–52 The Reisman group has pioneered a chiral nickel-catalyzed enantioselective reductive cross-coupling reaction of acyl chlorides with commonly used racemic benzylic chlorides as stabilized radical coupling partners to afford enantiopure α-aryl-α-alkyl ketones.53 Herein, we described an enantioselective nickel-catalyzed reductive cross-coupling between acyl chlorides and electronically inactive racemic α-trifluoroalkyl bromides to facilely access enantioenriched α-CF3 ketones in an enantioconvergent fashion under mild conditions (Figure 1d). In this context, the two kinds of employed electrophiles are highly appealing, mainly due to their convenience and relative cheapness. Additionally, a majority of acid chlorides are commercially available or can be readily prepared from cheap carboxylic acid in an operationally simple reaction. A variety of widely available fluoroalkyl bromides and acyl chlorides with various functional groups are eligible for direct coupling in good to high yields and good enantioselectivity without using heteroatom-containing directing groups. Interestingly, it was found that an appropriate choice of the phosphine ligand as a co-ligand plays an important role in the high efficiency and asymmetric induction. This protocol constitutes a reliable, direct, and efficient synthetic alternative to the existing strategies for preparing enantiopure α-CF3 carbonyl compounds. Experimental Methods In a N2 filled glovebox, Ni(COD)2 (5.6 mg, 0.02 mmol, 10 mol %), Mn (33.0 mg, 0.60 mmol, 3.0 equiv), L9 (8.6 mg, 0.03 mmol, 15 mol %), and P(p-CF3C6H4)3 (4.7 mg, 0.01 mmol, 0.05 equiv) were added to a screw capped vial (13 × 100 mm). Then acyl chloride (0.20 mmol, 1.0 equiv) and α-trifluoromethylated alkyl bromides (0.24 mmol, 1.2 equiv) were dissolved in N,N-dimethylacetamide (DMA; 2.0 mL, 0.1 M) and was added via syringe. The vial was sealed with a Teflon-lined screw cap and removed from the glovebox. The mixture was stirred vigorously at −10 °C for 10 h. The reaction was then quenched upon the addition of 2.0 mL NH4Cl (sat.). The aqueous layer was extracted with EtOAc (3 × 2.0 mL), and the combined organic layers were dried over anhydrous Na2SO4, and then the solvent was removed by rotary evaporator. The residue was purified by silica gel column chromatography. Results and Discussion Optimization of reaction conditions The development of this direct reductive cross-coupling reaction to achieve an enantioselective variant was accomplished using model substrates benzoyl chloride 1 and α-CF3 alkyl bromide 2 as outlined in Table 1. To our delight, the reaction occurred at room temperature in the presence of NiCl2(DME), L1, and Mn0, allowing the formation of the coupling product 3 in 56% yield and 36% ee of the trifluoromethylated stereogenic center (entry 1). Meanwhile, substantially related hydrodebrominated and β-fluorine eliminated byproducts from substrate 2 were observed. A lower reaction temperature was helpful for both the yield and selectivity (entry 2). After many evaluations of the reaction temperature, −10 °C was identified as the optimal temperature for the formation of the chiral trifluoromethylated product (entry 3, also see the Supporting Information Table S1). Subsequently, various chiral bis-oxazoline ligands were evaluated; it was found that L5 with geminal diaryl substituents increased the selectivity (entries 4–7). Table 1 | Optimization of Reaction Conditionsa Entry [Ni] 10 mol % L P Yield (%)b erc 1d NiCl2(DME) L1 — 56 68:32 2e NiCl2(DME) L1 — 73 72:28 3 NiCl2(DME) L1 — 61 74:26 4 NiCl2(DME) L2 — 49 65:35 5 NiCl2(DME) L3 — 39 −73:27 6 NiCl2(DME) L4 — 21 −67:33 7 NiCl2(DME) L5 — 46 75:25 8 Ni(COD)2 L5 — 30 76:24 9 Ni(DPPF)Cl2 L5 — 32 86:14 10 Ni(PPh3)2Cl2 L5 — 24 88:12 11 Ni(COD)2 L5 PPh3 51 90:10 12f Ni(COD)2 L5 PPh3 64 90:10 13f Ni(COD)2 L5 P(2-furyl)3 85 89:11 14f Ni(COD)2 L5 P(p-CF3C6H4)3 81 90:10 15f Ni(COD)2 L6 P(p-CF3C6H4)3 83 89:11 16f Ni(COD)2 L7 P(p-CF3C6H4)3 82 94:6 17f Ni(COD)2 L8 P(p-CF3C6H4)3 74 94.5:5.5 18f Ni(COD)2 L9 P(p-CF3C6H4)3 80 94.5:5.5 19f,g Ni(COD)2 L9 P(p-CF3C6H4)3 88 94.5:5.5 20f,g Ni(COD)2 L9 P(p-CF3C6H4)3 96 (90)j 94.5:5.5 21f,g,h,i Ni(COD)2 L9 P(p-CF3C6H4)3 89 ( 84)j 95:5 a 1 (0.10 mmol), 2 (0.10 mmol), 10 mol % nickel catalyst, 11 mol % ligand, Mn (0.30 mmol) in 2.0 mL of DMA at −10 °C. COD, 1,5-cyclooctadiene; DME, 1,2-dimethoxyethane; DPPE, 1,1-bis(diphenyphosphino)ferrocene. bYields were determined by gas chromatography analysis with a calibrated internal standard. cEnantiomeric excess determined by high-pressure liquid chromatography on a chiral stationary phase. dPerformed at room temperature. ePerformed at 0 °C. f1.0 mL DMA was used. g1.2 equiv 2 was used. h15 mol % L9 was used. i5 mol % P(p-CF3C6H4)3 was used. jThe yields in the parentheses were isolated. Interestingly, in our efforts to investigate the influence of varieties of nickel catalysts on the enantioselectivity, we surprisingly found that nickel catalyst bearing phosphine ligands were capable of vastly improving the enantiomeric ratio, albeit with a slightly decreased yield (entries 8–10). In this regard, we deemed it possible that an additional phosphine ligand might serve as an ancillary ligand to the nickel complex and accordingly play an important role in the enantiocontrol. Gratifyingly, augmented yield and enantioselectivity were observed by adding a catalytic amount of PPh3 as a co-ligand with the combination of Ni(COD)2 (entries 8–10 vs entry 11).54–56 At this stage, we screened different phosphine ligands (see the Supporting Information Table S6) and found that P(p-CF3C6H4)3 supported the formation of 3 in 81% yield and 80% ee. We then turned our attention to sequentially fine-tuning the steric hindrance of the geminal diaryl substituents based on L5 in the presence of 20 mol % P(p-CF3C6H4)3. Delightedly, the enantioselectivity of the related product improved by increasing the steric hindrance at the ortho position of the diaryl substituents (entries 16–19). The reaction was performed with an increased amount of alkyl bromide, which facilitated the formation of the targeted product in an improved yield (entry 19). Astonishingly, comparable yields and enantioselectivity were reached even at a lower P(p-CF3C6H4)3 loading of just 5 mol % (entries 18 and 20). Finally, increasing the amount of ligand L9 loading to 15 mol % resulted in a slightly improved stereoinduction outcome (entry 21). As anticipated, control experiments further revealed that the reaction components, such as nickel catalyst, reductant, and ligand, proved to be crucial for success (see the Supporting Information Table S8). Substrates scope With the optimized conditions in hand, we subsequently evaluated the generality of the developed protocol (Table 2). With respect to acid chloride coupling partners, aroyl chlorides bearing electron-donating ( 4–6, 9, 12, 13, and 16), electron-withdrawing ( 7– 11), and sterically demanding substituents ( 4, 15, and 16) were suitable for the reductive coupling. Furthermore, various functional groups on aromatic rings such as fluoride, chloride, and bromide could be coupled with complete chemoselectivity ( 7, 8, and 10– 12), providing useful synthetic outlets for further elaboration. The catalytic coupling reactions with heteroaromatic acyl chlorides delivered the corresponding CF3-containing product in good yields and enantioselectivities ( 16– 18). It is worth emphasizing that alkyl acid chlorides could be applied to smoothly forge the enantioenriched α-CF3 substituted dialkyl ketones in good yields and enantiomeric excess ( 19– 23). To the best of our knowledge, accessing this class of α-substituted chiral dialkyl ketones through classic enolate chemistry is highly challenging because of the unpredictable site-selective enolization and mixed E/Z enolate formation.57 Table 2 | Substrate Scope of Acid Chloridesa aReaction conditions: acyl chloride (0.20 mmol), 2 (0.24 mmol), 10 mol % Ni(COD)2, 11 mol % L9, 5 mol % P(p-CF3C6H4)3, Mn (0.60 mmol) in 2.0 mL of DMA at −10 °C for 10 h under nitrogen. b15 mol % L9 was used. Next, the scope of the developed protocol was investigated against a broad range of α-trifluoromethylated alkyl bromides (Table 3). The alkyl bromides were functionalized with an array of valuable functional groups such as tosylate ( 25), ether ( 26), chloride ( 27), ester ( 28– 30), and amino acid derivative ( 33), which were ideally compatible with the catalytic enantioselective coupling protocol. Notably, the heterocycles having potentially coordinating atoms furnished the desired α-CF3 substituted ketones smoothly with a good enantiomeric excess ( 30– 32). Finally, encouraged by the broad generality of this method, we envisioned that our developed asymmetric protocol might not only greatly simplify the synthesis of simple enantiopure α-trifluoromethylated ketone building blocks but also be amenable to late-stage stereoselective modification of natural products, drug molecules, and amino acid derivatives. For example, α-CF3 substituted alkyl bromides tethered to d-alanine, Isoxepac, Indomethacin, and Probenecid containing many functional groups (ketone, ester, amide, and sulfamide) successfully produced chiral trifluoromethylated products in synthetically useful yields and good enantioselectivity ( 33– 36). This protocol exhibits excellent chemoselectivity toward trifluoroalkyl bromide, whereas substrates with CF2H and C2F5 groups failed to deliver the coupling products ( 38 and 39) under the optimized conditions. However, the corresponding racemic compounds were accessed under the title condition using 1,10-phenanthroline instead of L9 as a ligand. Table 3 | Substrate Scope of α-CF3 Alkyl Bromidesa aReaction conditions: acyl chloride (0.20 mmol), 2 (0.24 mmol), 10 mol % Ni(COD)2, 15 mol % L9, 5 mol % P(p-CF3C6H4)3, Mn (0.60 mmol) in 2.0 mL of DMA at −10 °C for 10 h under nitrogen. DMA, N,N-dimethylacetamide; COD, 1,5-cyclooctadiene. bThe reaction performed with benzoyl chloride using 20 mol % P(p-CF3C6H4)3 at 0 °C. cbrsm: based on recovery of starting material trifluoroalkyl bromide (26%). To further showcase the synthetic utility of this coupling method, two examples of preparative-scale synthesis were conducted under the developed conditions (Figure 2), resulting in the formation of products 9 (R=F) and 12 (R=OMe) with good yields and enantioselectivity (Figure 2a). Furthermore, one of the notable features of the enantioenriched α-trifluoromethyl ketones is the amenability to subsequent various practical synthetic transformations. Representatively, diastereoselective reduction by NaBH4 and nucleophilic addition reactions of ketone with CH3MgBr were separately performed in a single-step operation with ease, leading to the pharmaceutically useful enantioenriched β-trifluoromethylated secondary and tertiary alcohol ( 40 and 41) in good yields and excellent diastereoselectivity (dr > 20∶1), and more notably, without any detectable erosion of enantiopurity in both courses. Notably, this protocol displays excellent chemoselectivity of secondary alkyl bromide over primary alkyl bromide in C–C coupling under our developed conditions. A stunning example ( 42→ 43) illustrates the notable chemoselectivity of this coupling method (Figure 2b). In summary, this protocol is characterized by facile scale-up, exceptional chemoselectivity, and easy downstream chemistry towards the valuable chiral CF3-containing products with structural complexity and diversity, thus enriching the chemical space and the alternative medicinal toolbox. Figure 2 | (a) Preparative-scale synthesis and further synthetic transformations. (b) Example of chemoselectivity between 2° and 1° alkyl bromides. Download figure Download PowerPoint Mechanistic study Next, we launched control experiments to gain insights into the reaction mechanism. First, the radical inhibition experiment was performed to probe for the intermediacy of radical species through the treatment of 1 and 2 with addition of 2,2,6,6-tetramethyl-1-piperinedinyloxy (TEMPO; 2.0 equiv) under the same conditions as entry 20. We found that the reaction completely shut down the delivery of the desired product 3, yet only gave rise to the TEMPO trapping adduct benzoyl-TEMPO 44 in 46% isolated yield (Figure 3a),58 suggesting an alkyl radical might be highly involved in the catalytic cycle. Furthermore, the radical clock experiment was conducted upon the addition of α-cyclopropyl styrene (2.0 equiv) to the reaction of 1 and 2, leading to the ring-opening expansion product 45 in 21% yield and 43% yield of coupling product 3 (Figure 3b). To summarize, these findings demonstrate that the catalytic cycle likely involves a radical pathway, and the oxidative addition of acid chlorides to the nickel(0) complex exists.59–64 Additionally, the control coupling reaction of 1 and 2 under the same conditions as entry 20 (Ni(COD)2 as the catalyst) without using Mn reductant was carried out, yet failed to deliver the desired product 3. Whereas the stoichiometric reaction of 1 and 2 with Ni(COD)2 (1.0 equiv), L8 (1.0 equiv), and P(p-CF3C6H4)3 (0.5 equiv) in the absence of smoothly the desired product 3 in 81% yield and ee (Figure these that the species are likely the catalyst and in the addition to acid chloride by the in Figure the reductant Mn is not for reduction of alkyl bromides to alkyl Mn was for the of nickel species from the related high nickel the of alkyl likely by alkyl bromides with Although further studies are for the at this stage, our findings the of this coupling reaction through a radical chain the addition of alkyl radical to complex a reduction Figure 3 | Mechanistic Download figure Download PowerPoint on our and the of the species from the racemic alkyl in nickel a radical chain catalytic cycle for this asymmetric reaction is as in Figure The catalytic cycle with oxidative addition of acid chloride to chiral bis-oxazoline complex the resulting complex Subsequently, the of complex by the secondary alkyl radical and a complex through a radical addition without the for Mn Meanwhile, to for stereogenicity we the stereoinduction model for the two complex (Figure The nickel catalyst complex was by compared with the alkyl group from the on the chiral bis-oxazoline L9 due to the steric In due to steric hindrance between the and group the of the CF3 group be to the the and courses. Subsequently, this complex reductive to furnish the observed in a as as to a corresponding complex that can the reduction of alkyl bromides to rise to the secondary alkyl radical via or single-electron the resulting complex be to nickel(0) intermediate by the Mn reductant, the catalytic The of the enantiomerically enriched product was via analysis (Figure which to be with the stereoinduction model under the chiral ligand L9, and the of other examples were Figure 4 | radical chain mechanism. Download figure Download PowerPoint Figure 5 | model and for the compounds and Download figure Download PowerPoint the important from phosphine co-ligand for efficiency and in this we conducted control experiments to the First, a of chiral bis-oxazoline ligands ( were evaluated in the coupling reaction of 1 and 2 with and without phosphine ligand or (see the Supporting Information as in the the reactions with a phosphine co-ligand to CF3-containing products 3 with increased yields and improved enantiomeric compared with that without phosphine ligands under conditions. To further the of phosphine we conducted a of reactions in the presence and absence of P(p-CF3C6H4)3 (Figure Astonishingly, the of P(p-CF3C6H4)3 not only the reaction for of desired product 3 but also vastly augmented the yield and the catalytic cycle in a vs yield in 4 In this regard, we it possible that the suitable phosphine ligand be as an ancillary ligand to the nickel complex and the oxidative addition of acid chloride to the complex to complex for the subsequent of the radical (Figure 4, to This is to be highly for the radical chain in nickel To probe the of phosphine co-ligand on the stereochemistry for the asymmetric the chiral phosphine ligands were evaluated in the reaction (Figure For example, the reactions were to the two of chiral in the presence of chiral both delivered product 3 with the (Figure thus the phosphine ligands might not influence the stereochemistry of the product during the catalytic Furthermore, upon treatment of the reaction with 1,10-phenanthroline in combination with optically pure completely racemic product 3 was (Figure these demonstrate that the stereochemistry over the coupling reaction was by the chiral bis-oxazoline ligand and not the of the phosphine at this the role of the phosphine ligands in improving the yields and enantioselectivity still further the appropriate combination of the simple chiral ligand and readily available ligand is of synthetically interest and accordingly an alternative for challenging in improving catalytic and asymmetric induction. Figure 6 | (a) (b)