Copper-Catalyzed Enantioconvergent Nucleophilic Fluorination of Alkyl Electrophiles to Generate α‑Fluoroamides

Abstract

Despite the pharmaceutical significance of alkyl fluorides wherein a fluorine-bearing carbon is stereogenic, progress in the development of catalytic asymmetric methods for their synthesis has been limited; furthermore, the approaches that have been described to date predominantly employ electrophilic fluorinating agents (e.g., NFSI and Selectfluor) rather than more economical nucleophilic fluorinating agents (e.g., CsF and KF). Herein, we describe a method for the catalytic asymmetric synthesis of alkyl fluorides through copper-catalyzed enantioconvergent substitutions of racemic alkyl halides, specifically, fluorinations of α-haloamides by CsF, enabling carbon–fluorine bond formation with good enantioselectivity and in good yield under simple and mild conditions. We have applied this new process to a streamlined, catalytic asymmetric synthesis of a bioactive α-fluoroamide and to the synthesis of other classes of enantioenriched fluorinated compounds.

Introduction

In recent years, we and others have pursued the development of transition-metal catalysts that can broaden the scope of nucleophilic substitutions of alkyl electrophiles beyond classical S_N1 and S_N2 pathways, including enantioconvergent reactions. − In previous studies, we have established that transition metals can catalyze enantioconvergent substitutions of racemic alkyl electrophiles by carbon, nitrogen, boron, and oxygen nucleophiles. Naturally, we have been interested in expanding our investigations to new families of nucleophiles.

From the standpoint of bioactivity, incorporating fluorine in a molecule can lead to advantageous properties (including improved bioavailability, binding affinity, and metabolic stability). As a consequence, in 2023, 12 of the 32 (37.5%) small-molecule drugs that were approved by the FDA included at least one fluorine. The development of efficient new methods for the synthesis of organofluorine compounds has therefore been the focus of significant and increasing effort.

Because interesting bioactivity has been observed for alkyl fluorides wherein fluorine is attached to a stereogenic carbon (e.g., Figure A), − a variety of groups have pursued the discovery of effective approaches to enantioselective carbon–fluorine bond formation. , Whereas most catalytic enantioselective processes reported to date have employed electrophilic fluorinating agents (e.g., NFSI and Selectfluor; oxidizing conditions), some reports have utilized mild, simple, and relatively inexpensive nucleophilic fluorinating agents (e.g., CsF and KF). ,

1.

Overview. (A) Bioactive compounds with a stereocenter that includes fluorine. (B) Metal-catalyzed enantioconvergent nucleophilic fluorination. PPI = protein–protein interaction.

A catalytic enantioconvergent substitution of a racemic alkyl halide (or pseudohalide) by nucleophilic fluoride could provide a straightforward route to enantioenriched alkyl fluorides. Impediments to the development of such a method include side reactions (e.g., elimination of HX rather than substitution), a competing nonenantioselective background reaction, and catalyst deactivation by the nucleophilic fluoride. To our knowledge, at the time that we initiated this study in 2021, only two families of halides, allylic (transition-metal catalyst) and functionalized benzylic (organocatalyst), had been reported to engage in enantioconvergent fluorinations.

In view of the bioactivity of α-fluorocarbonyl compounds (e.g., Figure A), we chose to explore metal-catalyzed enantioconvergent nucleophilic fluorinations of α-halocarbonyl compounds. Herein, we report that a chiral copper catalyst can indeed achieve this objective, specifically, that racemic α-haloamides undergo fluorination by CsF under simple and mild conditions with good enantioselectivity and in good yield (Figure B). We note that, as this work was nearing completion, outstanding studies of enantioconvergent fluorinations of racemic α-halo-ketones (aryl ketones) have been described by Gouverneur and by Sun, exploiting organocatalysts. ,

Results and Discussion

Upon exploring a variety of reaction conditions, we determined that, in the presence of a copper­(I) precatalyst ([Cu­(MeCN)₄]­ClO₄) and a readily available ligand (L*; synthesized in one step from a commercially available precursor), enantioconvergent fluorination of electrophile 1 ^Cl proceeds in good yield and excellent ee with CsF as the source of nucleophilic fluoride (80% yield and 97% ee; entry 1 of Figure ); essentially no racemization of the product occurs under these mild conditions. Control experiments establish that alkyl fluoride 1 is not formed in the absence of the copper complex or of ligand L* (entry 2). We have found that CsF is much more effective than KF (entry 3) and that, if the catalyst loading is reduced in half, only a very small loss in yield and enantioselectivity is observed (entry 4). The presence of water or of air impacts the yield, but not the enantioselectivity, of the enantioconvergent fluorination (entries 5 and 6).

2.

Effect of reaction parameters on the yield and the ee of a copper-catalyzed enantioconvergent fluorination. Each entry represents the average of two runs, one with each enantiomer of L*, on a 0.10 mmol scale. Yields were determined by analysis via ¹⁹F NMR spectroscopy, using 4-fluorobiphenyl as an internal standard.

Our standard conditions for the copper-catalyzed asymmetric nucleophilic fluorination of electrophile 1 ^Cl can be applied to a wide array of α-aryl-α-chloroamides (Figure ). Good enantioselectivity is observed regardless of whether the aromatic ring is electron-rich or electron-poor (entries 2–9). Similarly, the aryl substituent may be para-substituted (entries 2–9), meta-substituted (entries 10–13), or ortho-substituted (entries 14 and 15), and it may be an extended aromatic system (entry 16) or heteroaromatic (entry 17). A broad spectrum of functional groups, including a thioether, aryl bromide, aryl iodide, boronate ester, nitrile, ketone, and thiophene, are compatible with the enantioconvergent fluorination process (an alkyne, aniline, aryl triflate, benzofuran, benzylic chloride, epoxide, nitroarene, and trialkyl phosphate are also compatible, whereas a pyridine is not: see the Supporting Information). Carbon–fluorine bond formation proceeds with similar ee and yield on a 6.0 mmol scale (1.16 g of product; 5.0 mol % [Cu­(MeCN)₄]­ClO₄ and 6.0 mol % L*) as on a 0.60 mmol scale (entry 1).

3.

Copper-catalyzed enantioconvergent nucleophilic fluorination of α-chloroamides: scope. Reactions were conducted on a 0.60 mmol scale, unless otherwise noted. All ee values and yields are for purified products (average of two runs). DCE = 1,2-dichloroethane; Bpin = pinacolatoboron; 2,4-DMP = 2,4-dimethoxyphenyl. ^a5.0 mol % [Cu­(MeCN)₄]­ClO₄ and 6.0 mol % L*.

In the past several years, a variety of copper-catalyzed enantioselective reactions of α-halo secondary amides have been reported, nearly all of which employ N-aryl, rather than N-alkyl, amides; in this regard, our success with N-benzyl amides as electrophiles in these asymmetric fluorinations is anomalous (Figure , entries 1–17). It is noteworthy that N-benzyl amides are not uniqueenantioconvergent fluorinations of other N-alkyl amides also proceed with high ee. Thus, the alkyl substituent can vary in steric demand from linear to fully substituted (entries 18–21), and it can bear a range of functional groups (entries 22–25). In the case of an N-alkyl substituent that includes a proximal stereocenter, the stereochemistry of the catalyst, rather than of the substituent, primarily determines the stereochemistry of the product (entry 26).

Although we have focused on the use of N-alkyl amides as electrophiles, we have also explored the application of our catalytic asymmetric fluorination to N-aryl amides. We were pleased to determine that the standard conditions that we developed for N-alkyl amides (Figure ) can be applied directly to N-aryl amides. Excellent enantioselectivity is observed not only for the parent substrate bearing a phenyl substituent (Figure , entry 27), but also for electron-rich or electron-poor aromatic rings (entries 28–30) and for ortho-, meta-, or para-substituted rings (entries 28–34); indeed, enantioconvergent carbon–fluorine bond formation proceeds in good yield and high ee even in the case of very hindered aromatic groups (entries 33 and 34). The N-substituent can be an extended heterocyclic aromatic ring (indole; entry 35), and functional groups such as an ester, aldehyde, and carbamate are compatible with the fluorination reaction.

With regard to scope, we have also explored other leaving groups. For example, we have determined that the standard conditions that we developed for asymmetric nucleophilic substitution of a chloride can be applied without modification to mesylates, providing the desired alkyl fluorides with excellent ee and good yield (Figure A). Whereas numerous studies of metal-catalyzed enantioconvergent substitution reactions of α-halocarbonyl compounds have been described, we are not aware of reports that employ sulfonates as leaving groups. ,

4.

Copper-catalyzed enantioconvergent nucleophilic fluorination. (A) Variation of the leaving group: Mesylates. (B) Application to the catalytic asymmetric synthesis of a Keap1–Nrf2 PPI inhibitor. (C) Generation of additional families of enantioenriched fluorinated compounds. All ee values and yields are for purified products (average of two runs).

α-Fluoroamide A (Figure A) has been reported by Otake and Harada to be a novel, orally bioavailable Keap1–Nrf2 PPI inhibitor that displayed the greatest inhibitory activity among a wide range of compounds that they examined, including the nonfluorinated compound (>30-fold less potent); on the basis of crystallography, isothermal titration calorimetry (ITC) data, and molecular dynamics (MD) simulations, they attributed the “remarkable fluorine phenomenon” to fluorine serving both as a hydrogen-bond acceptor and as a steric impediment to a serine/glutamine interaction in the binding site. We have applied our new method to a streamlined route to alkyl fluoride 37, the penultimate intermediate in the synthesis of A, and its diastereomer (38) from a common intermediate (36) via catalyst-controlled, highly stereoselective carbon–fluorine bond formation (Figure B). The properties of diastereomer 38 (which would have required a separate four-step synthesis according to the original, chiral-auxiliary-based route) were not investigated by Otake and Harada.

In addition to being valuable enantioenriched organofluorine compounds in their own right, α-fluoroamides can be transformed into an array of useful derivatives. Thus, α-fluoroesters, α-fluoroacids, and β-fluoroalcohols can be generated with essentially no racemization (<1% ee) (Figure C).

We have begun to explore the mechanism of this new copper-catalyzed enantioconvergent fluorination. By subjecting the individual enantiomers of electrophile 1 ^Cl to the reaction conditions, we have confirmed that the process is indeed enantioconvergent, with the two enantiomers undergoing fluorination with a relative rate of ∼ 2:1 (Figure A).

5.

Mechanistic observations. (A) Support for enantioconvergent fluorination. (B) Investigation of copper­(II) species present during catalysis. CW X-band EPR: 9.4 GHz, 2 mW MW power, 77 K; ORTEP: thermal ellipsoids at 50% probability, hydrogen atoms omitted for clarity. (C) Linear relationship between the ee of L* and the ee of the product. (D) Reaction in the presence of TEMPO. (E) Competence of an aziridinone as an electrophile.

Examination via EPR spectroscopy of a reaction in progress reveals an EPR-active species, which we have assigned to a copper­(II) complex that bears two deprotonated L* ligands (42; ∼ 7% of total copper), based on independent synthesis and crystallographic characterization (Figure B). Whereas copper­(II) complex 42 shows minimal activity as a fluorination catalyst (Figure B; 6% yield), the rate of fluorination greatly increases when [Cu^I(MeCN)₄]­ClO₄ is added to the reaction mixture, consistent with a copper­(I)/L* complex serving as the active catalyst under our optimized conditions. Under these standard conditions, we observe a linear relationship between the ee of L* and the ee of product 1, consistent with an active catalyst that bears a single chiral ligand (not copper complex 42) (Figure C).

The addition of TEMPO (2,2,6,6-tetramethylpiperidin-N-oxyl), a radical trap, to a copper-catalyzed fluorination inhibits, but does not entirely shut down, C–F bond formation; an adduct of TEMPO is observed that is consistent with the generation of an organic radical from the electrophile (Figure D). We have observed that an aziridinone (43) can also undergo enantioselective fluorination; the yield is modest, but higher than for the corresponding alkyl chloride (44) (Figure E). These data are consistent with the aziridinone serving as an intermediate in the fluorination of an alkyl chloride, as is our observation that a tertiary amide derived from 1 ^Cl does not undergo fluorination under our standard conditions.

Conclusions

We have developed a chiral transition-metal catalyst that achieves enantioconvergent nucleophilic fluorinations of racemic electrophiles, specifically, copper-catalyzed asymmetric substitutions of α-aryl-α-chloro (and α-mesyloxy) amides by CsF. The fluorinations proceed under simple and mild conditions, and they display excellent functional-group compatibility. We have applied the method to the streamlined catalytic asymmetric synthesis of a bioactive molecule and to the generation of other families of enantioenriched fluorinated compounds, such as α-fluoroacids and β-fluoroalcohols. Efforts to develop additional metal-catalyzed enantioconvergent substitution processes are underway.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.6c03178.

• Experimental details: general information, preparation of electrophiles, enantioconvergent fluorination of alkyl electrophiles, effect of reaction parameters, functional-group compatibility, derivatization of the fluorinated product, mechanistic studies, assignment of absolute configuration, references, and NMR spectra and stereoselectivity analysis (PDF)

The authors declare no competing financial interest.