Copper-catalyzed enantioselective fluoroalkenylation of cyclic imino esters

Abstract

A copper-catalyzed enantioselective fluoroalkenylation of cyclic imino esters was developed. Under mild conditions, fluoroalkenylated products of cyclic imino esters were delivered in good yields with a broad substrate scope. A full-substituted carbon center along with a tetrasubstituted fluoroalkene was forged with good stereoselectivity. Late-stage functionalization of pharmaceuticals was also illustrated through this protocol with high enantioselectivities.

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Introduction

Fluorine, which is of small size with high electronegativity, as expected, possesses some unique properties. More specifically, the incorporation of fluorine or fluorine-containing structural motifs into organic molecules could dramatically influence physical and chemical properties and bioactivity, in particular, solubility, lipophilicity and metabolic stability, compared to their non-fluorinated counterparts.¹ Among numerous fluorine-containing molecules, monofluoroalkenes are of particular importance: (a) they are frequently found in pharmaceuticals and bioactive molecules (Scheme 1a);² (b) they can serve as ideal amide bond mimics with enhanced peptidase stability and a stable conformation in drug discovery (Scheme 1b);³ and (c) they have been used as powerful fluorinated synthons in the field of synthetic organic chemistry in recent years. Therefore, great efforts have been devoted to developing efficient approaches for their synthesis.

Scheme 1 Examples of fluorovinyl-containing bioactive compounds and their application in drug discovery.

Among the strategies developed for the synthesis of monofluoroalkenes, transition-metal catalyzed (Cu,⁴ Ni,⁵ Pd,⁶ Rh⁷ and Co⁸) cross-coupling of gem-difluoroalkenes has been proven to be an efficient and prevalent method, where C, H, Si and B reagents (quinolones,^7bN-pyrimidinylindoles,⁸ alkyl halides,^5b arylboronic acids,^4f,5a protons,^4b,6e Et₃SiBpin,^4d (Bpin)₂,^4a,cetc.) have been established as reactive coupling nucleophiles to construct structurally diverse monofluoroalkenes (Scheme 2a). Mechanistically, according to the difference of the C–F bond cleavage, these reactions generally entail an oxidative addition of a transition metal to the C–F bond or β-F elimination after nucleophilic addition, where the cleavage of the C–F bond via β-F elimination under mild conditions was more feasible^4,7,8 than through the oxidative addition of a C–F bond (120–129 kcal mol⁻¹ for olefinic C–F bonds;⁹ a high temperature was always necessary^5a,6). On the other hand, introduction of monofluoroalkenyl groups to construct chiral C-center-fluoroalkenyl bonds has been rather rare to date. Kong¹⁰ first realized the enantioselective Ni-catalyzed monofluoroalkenylation of aryl bromides with gem-difluoroalkenes. Very recently, our group¹¹ reported the enantioselective Cu-catalyzed nucleophilic addition of fluorinated reagents with gem-difluoroalkenes. Nevertheless, employing distinctive partners and developing a novel and efficient method to acquire structurally diverse monofluoroalkenes containing a chiral center through a β-F elimination process is still challenging and highly desirable.

Scheme 2 Approaches for the synthesis of monofluoroalkenes and the reaction design.

Recently, our group¹² has achieved the copper-catalyzed enantioselective electrophilic sulfenylation of cyclic imino esters. In this context, the chiral copper/Phosferrox complex could coordinate with the cyclic imino esters, a kind of versatile synthetic intermediate for the preparation of natural and biologically active compounds, to afford an enolate intermediate that could engage in the asymmetric sulfenylation reaction. We envisaged that in an enantioselective copper catalyzed system, nucleophilic addition of a chiral Cu-coordinated enolate (from cyclic imino esters with the assistance of a base) to fluorinated electrophiles (gem-difluoroalkenes) could be accomplished, followed by β-F elimination to afford the desired products. Herein, we reported the copper-catalyzed enantioselective fluoroalkenylation of cyclic imino esters with difluoroacrylates (Scheme 2b). Following the present protocol, a quaternary carbon stereocenter along with tetrasubstituted monofluoroalkenes was forged with a good enantioselectivity and E/Z ratio.

Results and discussion

We initiated our study with cyclic imino ester 1a and difluoroacrylate 2a as model substrates to evaluate the feasibility of this transformation. Under the reaction conditions (Cu(MeCN)₄PF₆ (10 mol%) as the copper source and Cs₂CO₃ (1.5 equiv.) as the base), chiral ligands were first investigated (Table 1, for details, see the ESI†). Most of the chiral ligands applied here could exhibit good reactivity (78–99%) with an (E)-isomer as the major product for the fluoro-olefin, but the enantiocontrol varied (8–98% ee). Specifically, for the SOPs from our group,¹³P-dialkyl-SOP (L1) with an electron-rich phosphine moiety (ⁱPr) provided better results than P-diaryl-SOP (L2) (Table 1, entries 1 and 2, 31% vs. 8%), which indicated that a more electron-rich ligand is beneficial for enantioselectivity. Subsequently, a variety of commercially available ligands were carefully screened. Biaryl-type ligands, such as (R)-BINAP (L3), (R)-SEGPHOS (L4) and (R)-BIPHEP (L5), were all tolerated in the reaction, resulting in good yields but poor enantioselectivities (Table 1, entries 3–5). Fortunately, chiral ligands with a ferrocene skeleton, which usually showed excellent enantiocontrol in copper catalysis,¹⁴ were found beneficial for the stereo-outcome, and the enantioselectivities were greatly improved (Table 1, entries 6–10). We next evaluated various Phosferrox ligands with different moieties and modulated the substituents on the oxazole ring. L9 with an electron-rich and steric resistant moiety (ⁱPr) on the oxazole ring provided the best results (Table 1, entry 9, 95% yield, E/Z = 12.6 : 1, 98% ee). Thus, after the systematic evaluation of other reaction parameters (for details, see the ESI†), 3aa could be obtained in 78% isolated yield with a satisfactory E-selectivity (E/Z = 12.9/1) and excellent enantioselectivity (98%), using a combination of cyclic imino esters 1a (1.0 equiv.), difluoroacrylate 2a (1.5 equiv.), Cu(MeCN)₄PF₆ (10 mol%), L9 (12 mol%) and Cs₂CO₃ (1.5 equiv.) in tetrahydrofuran (THF) at 20 °C for 15 h (Table 1, entry 11). The absolute configuration of the product was assigned as (R)-configuration by X-ray crystallography of 3ka.

Table 1 Optimization of the reaction conditions^a

Entry	Ligand	Yield^b (E/Z)	ee (%)^c (E)
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Cs2CO3 (0.15 mmol), Cu(MeCN)4PF6 (10 mol%) and ligand (12 mol%) in 1.0 mL of THF at 20 °C for 15 h. b Yields and the E/Z ratio were determined by ^1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. c The ee values were determined by chiral HPLC analysis. d Isolated yield (E isomer). e 2a (0.15 mmol) was used.
1	L1	88% (6.3/1)	31
2	L2	88% (7.8/1)	8
3	L3	99% (2.4/1)	42
4	L4	92% (4.4/1)	36
5	L5	91% (5.1/1)	12
6	L6	88% (6.3/1)	83
7	L7	91% (3.8/1)	98
8	L8	99% (13.1/1)	95
9	L9	95% (66%)^d (12.6/1)	98
10	L10	95% (7.6/1)	98
11^e	L9	78%^d (12.9/1)	98

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With the optimal conditions in hand, we next explored the substrate scope of cyclic imino esters 1 (Table 2). A variety of functional groups, such as alkyl (Me), halogen (F and Br), ether (OMe and OCF₃) and aryl groups (Ph), could be installed at the para- and meta-positions of the aryl ring with little effect on the enantiocontrol, and the corresponding products could be obtained in good yields (59–89%) with excellent enantioselectivities (97–98% ee) and high E/Z-selectivities (11 : 1 → 15 : 1 for E-isomers) (3aa–3ja). The effect of the ester groups (3ka and 3la) was also investigated, and E-selectivity was found to decrease with the increase of bulkiness of the ester group; when a tert-butyl ester was employed, the E/Z-ratio was reduced to 4 : 1 (3la). When 7-membered cyclic imino ester 1l was introduced, no positive results were achieved.

Table 2 Substrate scope of cyclic imino esters (1)^a

a Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Cs₂CO₃ (0.15 mmol), Cu(MeCN)₄PF₆ (10 mol%) and L9 (12 mol%) in 1.0 mL of THF at 20 °C for 15 h. The E/Z ratio was determined by crude ¹H NMR. The ee values were determined by chiral HPLC analysis. Isolated yields of E-isomers.

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Next, we turned our attention to study the scope of difluoroacrylates 2 (Table 3). When different functional groups (Me, OMe and halogen) were installed at the para-position, the reaction could proceed smoothly to deliver the corresponding products in good yields with excellent enantioselectivities and no remarkable electronic effect was observed on the enantiocontrol (3ab–3af), while a lower reactivity and decreased E/Z-selectivity (3ag, 56%, E/Z = 6 : 1) were observed for a meta-substituted difluoroacrylate, which was probably caused by a steric effect (3aevs.3ag). 2-Naphthyl difluoroacrylate was capable of providing the corresponding product in good yield with excellent enantioselectivity (3ah). The ester group played an important role in reactivity (3ahvs.3ah′), but had no detrimental effect on stereocontrol (3ah′ and 3ai). When benzyl difluoroacrylate was applied, the E/Z ratio could be improved to an excellent level (3aj).

Table 3 Substrate scope of difluoroacrylates (2)^a

a Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Cs₂CO₃ (0.15 mmol), Cu(MeCN)₄PF₆ (10 mol%) and L9 (12 mol%) in 1.0 mL of THF at 20 °C for 15 h. The E/Z ratio was determined by crude ¹H NMR. The ee values were determined by chiral HPLC analysis. Isolated yields of E-isomers.

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Finally, to further demonstrate the utility of the developed protocol, a scale-up experiment and late-stage functionalization of pharmaceuticals were carried out (Scheme 3). First, this protocol can be readily scaled up to 1 mmol of 1a with no loss in reactivity and stereocontrol (Scheme 3a). gem-Difluoroalkenes derived from felbinac (NSAIDs) and gemfibrozil (cholesterol-lowering agents) were applied to the transformation under the standard conditions. Pleasingly, the corresponding products could be obtained in satisfactory yields with excellent enantioselectivities (Scheme 3b).

Scheme 3 Synthetic utility. ^aStandard conditions: 1a (0.1 mmol), 2 (0.15 mmol), Cs₂CO₃ (0.15 mmol), Cu(MeCN)₄PF₆ (10 mol%) and L9 (12 mol%) in 1.0 mL of THF at 20 °C for 15 h. The E/Z ratio was determined by crude ¹H NMR. The ee values were determined by chiral HPLC analysis. Isolated yields of (E)-3 are shown.

Based on the previous work^4c,12,14b and the X-ray structure of (E)-3ka, a possible mechanism was proposed to illustrate the current stereo-outcome (Scheme 4). After the deprotonation of cyclic imino ester with the assistance of Cs₂CO₃, the Phosferrox ligand and imino ester could coordinate with the central Cu(I) atom to generate the chiral Cu-coordinated enolate Int-A. Due to the steric hindrance between the Ph group (from cyclic imino esters 1) and the isopropyl group (from the oxazoline ring of the chiral ligand) (TS-A), the Re-face of cyclic imino esters was shielded, thus the Si-face predominantly underwent a nucleophilic addition, and then β-F elimination occurred in accordance with the steric repulsion between the cyclic imino ester moiety and the phenyl group (from 2) to give more thermodynamically stable products ((R, E)-3ka).

Scheme 4 Proposed mechanism and transition states.

Conclusions

In summary, a highly enantioselective copper-catalyzed fluoroalkenylation of cyclic imino esters using ⁱPr-Phosferrox as the chiral ligand under mild conditions was developed. Using this protocol, nucleophilic addition and β-F elimination occurred smoothly and tetrasubstituted monofluoroalkenes bearing a chiral cyclic imino ester were afforded in good yields with high E/Z-selectivities and excellent enantioselectivities. In addition, the application was demonstrated by the late-stage functionalization of pharmaceuticals.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported financially by the Youth Innovation Promotion Association CAS (2022375), the National Natural Science Foundation of China (No. 21871251 and 22171258) and the Biological Resources Programme, Chinese Academy of Sciences (KFJ-BRP-008).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2151837. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2qo01141g

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